Medical Practice

Practice recommendations for respiratory syncytial virus prophylaxis among children in Hong Kong

Hong Kong Med J 2025 Feb;31(1):48–57 | Epub 17 Feb 2025

MEDICAL PRACTICE

Practice recommendations for respiratory syncytial virus prophylaxis among children in Hong Kong

KL Hon, MB, BS, MD¹; Eddie WY Cheung, MB, BS, MMedSc²; Albert Martin Li, MB, BCh, MD³; Genevieve PG Fung, FHKAM (Paediatrics), FRCPCH³; David SY Lam, FHKAM (Paediatrics), FRCPCH⁴; Maria SH Lee, FHKAM (Paediatrics), FRCPCH⁵; Robert SY Lee, FHKCP, FHKAM⁶; Maurice Ping Leung, MB, BS, MD⁷; Daniel KK Ng, MB, BS, MD⁸

¹ Department of Paediatrics, CUHK Medical Centre, The Chinese University of Hong Kong, Hong Kong SAR, China

² Department of Paediatrics, Hong Kong Adventist Hospital, Hong Kong SAR, China

³ Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China

⁴ Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong SAR, China

⁵ Department of Paediatrics and Adolescent Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China

⁶ Department of Paediatrics and Adolescent Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

⁷ Division of Paediatrics, Premier Medical Centre, Hong Kong SAR, China

⁸ Department of Paediatrics, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China

Corresponding author: Prof KL Hon (ehon@hotmail.com)

Full paper in PDF

Abstract

Hong Kong has a high burden of hospitalisations associated with respiratory syncytial virus (RSV) infection in young children. Most international guidelines concerning RSV prophylaxis are based on studies conducted in temperate climates and may not fully apply to subtropical locations such as Hong Kong. In July 2022, a group of nine experts in neonatology, paediatric intensive care, paediatric respiratory medicine, and paediatric cardiology in Hong Kong convened to formulate recommendations for RSV prophylaxis. The recommendations were based on literature review and expert discussion. Each expert reviewed evidence specific to a particular area and formulated consensus statements. The expert panel reached a consensus on 11 statements, which addressed the epidemiology of RSV infection in Hong Kong, the goals and outcomes of RSV prophylaxis in preterm infants and infants with congenital heart disease or bronchopulmonary dysplasia, safety, and cost. Because there is no clear seasonality pattern for RSV infection in Hong Kong, panel members emphasised using gestational age, rather than season, to guide prophylaxis recommendations. The experts agreed that RSV prophylaxis should be considered for 5 to 6 months after hospital discharge among preterm infants born at <29 weeks gestational age; it should also be considered for children aged <1 year with haemodynamically significant congenital heart disease or bronchopulmonary dysplasia.

[Abstract in Chinese]

Introduction

Acute lower respiratory tract infections associated with respiratory syncytial virus (RSV) are a common cause of hospitalisation among young children.1 2 In Hong Kong, RSV infection is the leading reason for hospitalisation among children aged <5 years with respiratory viral infections, causing 50% of deaths in this age-group.3 A study conducted at a paediatric intensive care unit (ICU) in Hong Kong revealed that paramyxovirus infections, predominantly RSV, caused 5% of all paediatric ICU admissions and were associated with significant morbidity.4 Among the RSV-infected patients, 39.4% needed mechanical ventilation and 21.1% needed inotropic support.4 Treatment for viral bronchiolitis is mainly supportive because no pharmacological treatment or novel therapy has been shown to improve outcomes compared with supportive care.5

Although numerous vaccines, therapeutic antibodies, and antiviral drugs for the prevention and treatment of RSV infection are in development,6 the only available prophylactic agent is palivizumab,7 a humanised immunoglobulin G1 monoclonal antibody that targets the fusion protein of RSV.8 Palivizumab is effective in reducing the rate of RSV hospitalisation (RSVH) among high-risk children.9 International guidelines recommend palivizumab prophylaxis in groups such as preterm infants, former preterm infants with chronic lung disease/bronchopulmonary dysplasia (BPD), and children aged <2 years with haemodynamically significant congenital heart disease (hsCHD).7 10

In Hong Kong, local healthcare practices regarding palivizumab prophylaxis are informed by data from international studies and guidance statements.10 11 12 However, these international publications do not reflect the local treatment landscape. Palivizumab is reimbursed by the government for preterm infants born at <34 weeks gestational age (wGA) who have chronic lung disease requiring home oxygen therapy or medication at discharge, up to a chronological age of 6 to 9 months (maximum of five doses). The perception among clinicians is that palivizumab use varies across hospitals. Furthermore, international guidance is predominantly derived from studies in regions with temperate climates and may not fully apply to subtropical locations such as Hong Kong, particularly with respect to the seasonality of RSV infection.13 14 In this article, we summarise RSV prophylaxis recommendations developed by a group of experts in Hong Kong, with the aim of assisting physicians engaged in treating children at risk of RSV infection, both locally and internationally.

Methods

A meeting was convened in July 2022 to formulate evidence-based recommendations for RSV prophylaxis among children in Hong Kong. The panel comprised experts in neonatology, paediatric intensive care, paediatric respiratory medicine, and paediatric cardiology, representing both private and public healthcare sectors. A set of clinical questions was established, and selected panel members screened the results of a series of focused literature reviews. These reviews were centred around the following topics: the epidemiology of RSV infection (including seasonality), the burden of RSV infection in vulnerable paediatric populations, international guidance concerning RSV prophylaxis, and the efficacy and safety of prophylaxis. Literature searches were performed using PubMed to identify relevant English-language publications, with an emphasis on studies published in the past 10 years (up to April 2022). Proposed statements were drafted and evaluated during the meeting using a modified Delphi method. Panel members rated the statements using a Likert scale (1–Agree completely; 2–Agree with reservation; 3–Disagree with reservation; 4–Disagree completely). Consensus was defined as ≥75% of panel members responding ‘1–Agree completely’ or ‘2–Agree with reservation’. In the absence of consensus, the relevant statements were revised and re-evaluated until consensus was reached. Where applicable, the quality of evidence supporting each statement was evaluated according to the Oxford Centre for Evidence-Based Medicine’s 2011 Levels of Evidence.15 Treatment recommendations were assigned a subjective strength (strong, moderate, or weak) based on the level of evidence and degree of consensus.

This manuscript was prepared in accordance with the AGREE (Appraisal of Guidelines for Research and Evaluation) Reporting Checklist.16

Consensus statements

Eleven statements were formulated and met the consensus criteria during the meeting. These statements, including their level of evidence, strength of recommendation and agreement, are summarised in the Table.15

Table. Summary of consensus statements concerning respiratory syncytial virus prophylaxis

Statement 1: The disease burden of respiratory syncytial virus is high in Hong Kong; infants are most affected.

Data concerning RSV epidemiology in Hong Kong are scarce, but two studies provided important insights. A single-centre study conducted from 1998 to 2012 revealed that the annual rate of RSVH among children aged <5 years was 157.7 per 10 000; most hospitalisations involved infants aged <1 year.3 This RSVH rate was higher than the rates reported in a 2015 systematic review and modelling study, which estimated that RSVH rates in high-income countries were 26.3, 11.3, and 1.4 per 1000 in children aged ≤5 months, 6 to 11 months, and 12 to 59 months, respectively2; corresponding mortality rates were 0.2%, 0.9%, and 0.7%.2 Almost half of the hospitalisations and hospital deaths attributed to RSV-associated acute lower respiratory tract infection occurred in children aged <6 months.2 More recent local epidemiological data were provided by a multicentre case-control study conducted in four hospitals from 2013 to 2015, which included 3538 admissions for paediatric RSV infection.17 The mortality rate was 0.14%, and 44.6% of hospitalisations involved infants aged ≤12 months17; this rate is lower than comparable data from Western countries (ie, 75%-90% in infants aged ≤12 months).18 Meta-analysis data from China indicate that RSV is the leading cause of viral acute respiratory tract infections, present in 18.7% of cases overall and 26.5% of cases among infants aged ≤1 year.19 The actual burden of RSV infection in China may be higher, due to the limited sensitivity of diagnostic methods used during studies included in the meta-analysis.19 Although differences in study designs may explain the discrepancies between international and local data, there is no doubt that RSV is associated with a substantial disease burden among infants in Hong Kong.

Statement 2: Respiratory syncytial virus infection does not demonstrate a clear seasonal pattern in Hong Kong, but its incidence tends to peak from March to April and again during the summer (July to August).

In Western European countries, laboratory-confirmed RSV infections generally exhibit a well-defined seasonal pattern, with peaks in winter and spring; few cases occur in summer and autumn.20 In Hong Kong, an analysis of RSVH across all age-groups at a single centre over 15 years showed annual peaks of approximately 12 cases per week occurring around March and September; moderate levels of cases (5-10 cases per week) were observed from May to August, and the lowest rate of hospitalisation (<5 cases per week) occurred from October to February.3 A multicentre study of paediatric RSV admissions across four Hong Kong hospitals from 2013 to 2015 revealed a similar pattern of peaks in hospitalisation from March to April and July to August, separated by moderate inter-peak levels during the summer; the lowest levels of hospitalisation were observed from October to February.17 Similar seasonality patterns were observed both overall and among a subset of patients with heart disease.17 Most infections (87.7% in the entire cohort and 91.1% in the heart disease group) occurred between January and September.17 The same study showed that RSV incidence was positively correlated with relative humidity, whereas it was negatively correlated with wind speed and atmospheric pressure.17 Despite differences in populations, the pattern of RSVH seasonality was consistent between these two studies; both demonstrated that RSVH in Hong Kong mainly occurs in warmer months.3 17

Statement 3: Although respiratory syncytial virus incidence decreased during coronavirus disease 2019 lockdown periods, some countries experienced a resurgence after social restrictions had been lifted, with altered epidemiological patterns. The exact impact on respiratory syncytial virus prevalence in Hong Kong remains unknown.

Data from Australia,21 France22 and Japan23 show that strict infection control measures implemented during the coronavirus disease 2019 (COVID-19) pandemic led to a substantial reduction—up to 98%—in RSV cases during 2019 and 2020. In Australia, after the relaxation of physical distancing measures in late 2020, the usual incidence peak in autumn was replaced by a peak in summer21; RSV incidence was higher in the 2020 summer peak than it had been in winter peaks from 2012 to 2019.21 Furthermore, the median patient age after COVID-19 restrictions were lifted in 2019 to 2020 was 18.4 months, significantly older compared with previous years (7.3-12.5 months from 2012 to 2019; P<0.001)21; this shift likely resulted from decreased prior exposure and declining collective immunity. Data from Hong Kong suggest that measures adopted during the COVID-19 pandemic (eg, social distancing, face masks, and enhanced personal hygiene) reduced the incidence of RSV infection; the surge in RSV cases during late 2021 coincided with the relaxation of these measures.24 However, the overall impacts of measures adopted during the COVID-19 pandemic on RSVH rates, affected populations, and seasonality in Hong Kong are unclear.

Statement 4: The goals of respiratory syncytial virus prophylaxis are to reduce adverse effects on the lungs and circulation, while decreasing hospitalisations and intensive care unit stays, in vulnerable infants.

Various international studies have demonstrated that the risk of severe illness from RSV infection increased among at-risk children, namely preterm infants and those with CHD or BPD. A retrospective cohort study in the US (1989-1993; 248 652 child-years) showed that children with BPD had a higher rate of RSVH in the first year of life compared with children who lacked underlying medical conditions (388 vs 30 per 1000, respectively).25 The same study also revealed that preterm infants with CHD had a RSVH rate of 120.8 per 1000 from 0 to 6 months after birth (vs 44.1 in low-risk infants); this rate declined in the second year of life to 18.2 per 1000 (vs 3.7 for low-risk infants).25 A multicentre study in Korea (n=1140) demonstrated that BPD increased the risk of re-admission to neonatal ICUs among preterm infants born at <34 wGA compared with similar preterm infants who did not exhibit BPD (odds ratio [OR]=2.95, 95% confidence interval [CI]=1.44-6.04; P=0.003).26 The results of a retrospective database study in Australia (2001-2010; n=870 314) indicated that BPD had the largest effect on RSVH risk among various risk factors.27 Furthermore, a meta-analysis of 29 studies by Chaw et al28 assessed RSVH risk and other measures of severe illness from RSV infection among young children with BPD. In addition to an increased risk of hospitalisation (OR=2.6, 95% CI=1.7-4.2; P<0.001), children with BPD had an increased risk of ICU admission (OR=2.9, 95% CI=2.3-3.5; P<0.001), increased need for oxygen supplementation (OR=4.2, 95% CI=0.5-33.7) and mechanical ventilation (OR=8.2, 95% CI=7.6-8.9; P<0.001), and longer median length of stay (7.2 days vs 2.5 days) compared with children who did not exhibit BPD.28 Overall, these studies have shown that children with BPD experience higher risks of hospitalisation and severe illness from RSV infection relative to children without BPD.

Illustrative data concerning the impact of prematurity on RSV infection burden were provided by SENTINEL1, an observational cohort study conducted in the US involving preterm infants (29-35 wGA, <12 months old) who did not receive prophylaxis and were hospitalised for RSV during peak season (2014-2015).29 Infants aged <6 months experienced 78% of hospitalisations and 87% of ICU admissions; they comprised 92% of cases requiring invasive mechanical ventilation.29 Among infants aged <3 months who had been born at 29 to 32 wGA, the ICU admission rate was 68%; 44% of these infants required invasive mechanical ventilation.29 Regression analysis demonstrated that earlier gestational age at birth and younger chronological age at the time of RSV infection were factors associated with ICU admission and the need for invasive mechanical ventilation.29 A pooled analysis of seven prospective observational studies conducted in the Northern Hemisphere (2000-2014) assessed the burden of RSV infection in preterm infants who had been born at 33 to 35 wGA, lacked co-morbidities, and were not receiving immunoprophylaxis (n=7820).30 The pooled incidence rate of RSVH was 3.41%; among the infants, 22.2% required neonatal ICU admission and 70.4% required supplemental oxygen.30 Although these two studies are not directly comparable due to differences in design and population—notably the infants’ gestational age at birth—they consistently demonstrate a high burden of severe illness in preterm infants with RSV infection.29 30

Similar to preterm infants, infants with CHD have an increased risk of severe disease.12 The local burden of RSV infection among children with CHD is unclear, but the multicentre study by Lee et al17 assessing paediatric RSVHs included a subset of children with heart disease (not limited to CHD). Relative to children without heart disease, children with heart disease had a longer median hospital stay (4 days vs 2 days; P<0.001), higher complication rate (28.6% vs 9.8%; P<0.001), and higher rates of intensive care (11.6% vs 1.4%; P<0.001) and mechanical ventilation (3.6% vs 0.4%; P=0.003).17 Based on the local and international data summarised above, and in alignment with guidelines from the American Academy of Pediatrics (AAP),11 we recommend that RSV prophylaxis should focus on reducing the disease burden in preterm infants and young children with BPD or heart disease.

Statement 5: Respiratory syncytial virus prophylaxis should be considered for 5 to 6 months after hospital discharge among preterm infants born at <29 weeks gestational age.

The AAP published guidance in 2009 recommending palivizumab prophylaxis at the start of RSV season among infants born at <31 wGA, as well as among infants born at 32 to 35 wGA who have risk factors for increased exposure (eg, attending a day-care facility or living with young siblings).7 The AAP made a substantial change to the guidance in 2014 by narrowing the intended population to infants aged <12 months who had been born at <29 wGA.11 An observational study in Italy compared the RSVH rates among infants aged <2 years before (up to 2016) and after changes in palivizumab reimbursement criteria that aligned with the changes in AAP recommendations.31 The study identified a reduction in RSVH rates from 6.3 per 1000 (95% CI=6.0-6.7) to 5.5 per 1000 (95% CI=5.0-5.9) after the change.31 These data suggest that 29 wGA is an appropriate age cut-off for palivizumab prophylaxis; our recommendation for this age threshold concerning prophylaxis in preterm infants aligns with the AAP’s 2014 guideline.11

As noted above, the seasonality of RSV incidence is less distinct in Hong Kong than in Europe,3 17 20 but local data indicate that gestational age is a key determinant of RSVH risk. One study showed that the cost-effectiveness of palivizumab prophylaxis was higher among infants born at <27 wGA than among infants born at <29 wGA, regardless of the season.32 Therefore, gestational age, rather than season, should be a primary factor guiding prophylaxis recommendations in Hong Kong.

Statement 6: Children aged <1 year with bronchopulmonary dysplasia are vulnerable to serious lower respiratory tract illness and have a higher risk of hospitalisation compared with healthy children after respiratory syncytial virus infection; respiratory syncytial virus prophylaxis should be considered for these children.

In the IMpact-RSV study, preterm children aged ≤6 months who had been born at ≤35 wGA or children aged ≤24 months with BPD were randomly assigned to receive five monthly doses of palivizumab or placebo.9 Overall, RSVH rates were reduced by 55% in the palivizumab group compared with the placebo group (P<0.001); palivizumab treatment also led to a 39% reduction in RSVH (vs placebo) among children with BPD.9 These results were subsequently reinforced by a meta-analysis of three randomised studies (n=2831) showing favourable efficacy of palivizumab, with a 51% reduction in RSVH (vs placebo) among preterm children and children born with BPD.33 In the US, a registry study of infants receiving palivizumab (n=2116, predominantly born at ≤35 wGA) demonstrated an RSHV rate of 2.9%,34 which compares favourably to the 4.8% hospitalisation rate observed in the pivotal trial.9 Based on these data, we recommend palivizumab prophylaxis for 5 to 6 months after hospital discharge among children aged <12 months who are receiving medication for BPD, irrespective of prematurity.

Statement 7: Respiratory syncytial virus prophylaxis reduces the number and duration of respiratory syncytial virus–related hospitalisations among children aged <2 years with haemodynamically significant congenital heart disease.

Statement 8: A 6-month prophylaxis regimen (six doses) in the first year of life is suggested for children with haemodynamically significant congenital heart disease.

We define hsCHD based on the population included in the study by the Cardiac Synagis Study Group.35 This included cyanotic patients (oxygen saturation <85%, either unoperated or partially corrected by surgery or interventional catheterisations), patients with hypercyanotic episodes (paroxysmal hypoxic events characterised by severe reductions in pulmonary blood flow lasting from minutes to several hours), patients receiving cardiac medications, patients with congestive heart failure (requiring treatment with two medications), patients with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg for >3-4 months of life) and patients with increased pulmonary blood flow.35

Prophylaxis for children aged ≤12 months with hsCHD is widely supported by international guidelines, but recommendations for prophylaxis among children aged 12 to 24 months vary.12 In Hong Kong, an individualised approach should be taken; prophylaxis should be considered for children aged ≤12 months with hsCHD, congestive heart failure, or pulmonary hypertension, especially at the start of the local RSV season. Prophylaxis for children aged 12 to 24 months may be considered after corrective surgery if residual defects are present, but prophylaxis beyond 6 months post-surgery should be carefully considered on a case-by-case basis. Currently, there are insufficient data to recommend prophylaxis for children aged >24 months with hsCHD.

The evidence supporting these statements was collected from randomised clinical trials and real-world studies. A placebo-controlled randomised clinical trial of palivizumab prophylaxis, delivered as five monthly injections, among young children (aged ≤24 months; n=1287) with hsCHD demonstrated a 45% relative reduction in RSVH (P=0.003) and a 56% reduction in total days of RSVH per 100 children (P=0.003), compared with placebo.35 The same study revealed a 73% reduction in total RSVH days requiring increased supplemental oxygen per 100 children (P=0.014).35 The efficacy of six doses of palivizumab prophylaxis among children aged ≤12 months with hsCHD is also supported by findings from an observational study in Taiwan (n=1556), which showed a 49% reduction in RSVH and a 57% reduction in admission days compared with propensity-matched controls.36 A database study from the US that included 2518 children with hsCHD demonstrated a decline of 36% in RSVH among children with hsCHD between pre- and post-palivizumab guideline eras, compared with an 8% decline among children without hsCHD (P<0.001).37 Additional data confirming the efficacy of palivizumab prophylaxis against RSVH among children with hsCHD have been acquired through real-world studies in Spain38 and Australia.39 In Spain, a prospective, multicentre study of children aged ≤24 months with hsCHD (n=2613) showed that those with adequate palivizumab prophylaxis (n=2366) had a lower rate of RSVH than those with inadequate prophylaxis (n=247; 3.3% vs 7.9%, respectively).38 An observational cohort study in Australia compared RSHV rates among infants aged ≤12 months with haemodynamically significant cardiac disease between 2008-2009, when palivizumab prophylaxis was administered in a coordinated manner, to the rates during 2005-2007, when prophylaxis was given on an ad hoc basis.39 Admission rates for RSV bronchiolitis in 2008-2009 (2% per year) were significantly reduced compared with the rates in 2005-2007 (5%-9% per year; P<0.03).39 These findings support our recommendation for prophylaxis among children aged ≤24 months with hsCHD; our suggested duration of dosing is based on the above studies and the limited seasonality of RSV observed in Hong Kong.

Clinical experience regarding palivizumab prophylaxis for other special populations in Hong Kong (eg, immunocompromised children and children with Down syndrome, cystic fibrosis, or neuromuscular disorder) is extremely limited. For cases involving these children, clinicians should refer to international recommendations.11

Statement 9: Current evidence indicates that the use of palivizumab as respiratory syncytial virus prophylaxis is safe and well-tolerated, with minimal risk of adverse reactions.

Statement 10: The only contraindication to the use of palivizumab is a previous history of confirmed hypersensitivity reaction to palivizumab.

The favourable safety profile of palivizumab has been demonstrated in clinical trials and observational studies. In the pivotal IMpact-RSV trial, which involved premature infants with BPD, adverse event rates were similar in the palivizumab and placebo groups (10%-11%).9 Discontinuations due to palivizumab-related adverse events were rare (0.3%), as were reports of injection site reactions (1.8% [placebo] vs 2.7% [palivizumab]) and fever (3.0% vs 2.8%).9 Observational data from several studies suggest that palivizumab is well-tolerated in at-risk children. The prospective observational CARESS study from Canada included 13 025 infants treated with palivizumab (63.1% born at ≤35 wGA, 11.1% aged <2 years with hsCHD, and 7.5% exhibiting BPD) and monitored serious adverse events from 2008 to 2013.40 Hospitalisations for respiratory illness unrelated to palivizumab were reported in 915 patients.40 Other than these hospitalisations, 62 serious adverse events were reported in 52 patients.40 Of these 62 adverse events, 14 hypersensitivity episodes in six patients (2.8 per 10 000 patient-months) were deemed possibly or probably related to palivizumab.40 The events experienced by these six patients included erythema or urticaria, difficulty swallowing, vomiting, nasal congestion, bronchospasm, and acute respiratory distress; two patients required hospitalisation.40 All six patients discontinued palivizumab, and their symptoms resolved after 30 days of monitoring with no immediate life-threatening consequences.40 In a prospective study involving 100 high-risk children in Russia, 94 children completed their palivizumab dosing schedule; there were no reported RSV-related hospitalisations or deaths.41 Three non-serious adverse events were considered palivizumab-related: rhinitis and acute intermittent rhinitis (both occurring in one patient) and atopic dermatitis.41 Data concerning palivizumab use in immunocompromised children (n=167) and children with Down syndrome (n=138) were obtained during a post-marketing surveillance study in Japan.42 Adverse drug reactions occurred in 25 patients (8.22%), including 11 patients (3.62%) who experienced palivizumab-related serious adverse drug reactions.42 Further support for palivizumab safety in immunocompromised children was presented in a Japanese study of children aged ≤2 years; of the 30 included participants, 26 (92.9%) completed the study.43 Most adverse events were mild to moderate; only two patients experienced serious adverse events, none of which were considered palivizumab-related.43 Overall, these data indicate that in routine clinical practice, palivizumab-related adverse effects and hypersensitivity reactions are rare; palivizumab is well-tolerated in various patient populations.

Statement 11: The cost-effectiveness of palivizumab prophylaxis in Hong Kong is unclear.

International studies regarding the costeffectiveness of palivizumab prophylaxis yielded mixed results. For example, a systematic review of 28 studies suggested that the incremental costeffectiveness ratio for preterm infants (born at 29-35 wGA) ranged from US$5188 to US$791 265 per quality-adjusted life-year, with 90% of estimates below US$50 000 per quality-adjusted life-year.44 The authors concluded that prophylaxis was cost-effective for preterm infants and infants born with lung complications.44 However, another systematic review (also comprising 28 studies) by Hussman et al45 concluded that the overall cost-effectiveness of palivizumab prophylaxis was inconsistent: some studies showed favourable outcomes, whereas others showed unfavourable outcomes or inconclusive results. A cost-effectiveness study conducted in Hong Kong concluded that palivizumab was more cost-effective among preterm infants born at <27 wGA than among those born at <29 wGA, but the authors advised careful interpretation of the results because patient selection was biased towards individuals with more severe lung disease.32 Another Hong Kong study, a retrospective analysis by Chen et al,46 assessed the cost-effectiveness of palivizumab prophylaxis using data from 236 patients aged <12 months with hsCHD, 26 of whom had RSVH. The study, which assumed no local seasonality of RSV, concluded that palivizumab prophylaxis was not cost-effective for this population in Hong Kong46; this result contrasts with our suggested regimen in Statement 8. This study, identified after our main literature review and consensus meetings, provides an alternative local opinion. For this reason, Statement 8 is presented as a suggestion with moderate strength, rather than a recommendation. As noted above, the study by Chen et al46 assumed no local RSV seasonality, despite the existence of peaks in March to April and July to August; its applicability is limited by its reliance on relative risk reductions in RSVH from studies conducted in temperate regions.46 Our opinion is that further cost-effectiveness studies of palivizumab in Hong Kong and other tropical locations are required. Furthermore, because reimbursement policies and healthcare costs considerably vary among locations, and because we aim to provide consensus statements that are useful to healthcare professionals elsewhere in Asia, decisions regarding the cost-effectiveness of prophylaxis must be guided by local data.

Conclusion

The burden of RSVH in Hong Kong is high, and children aged <1 year experienced more than half of all hospitalisations.3 Respiratory syncytial virus infections generally peak in the summer months in Hong Kong, although the seasonality pattern is less distinct compared with temperate regions.3 17 20 Therefore, our recommendations place greater emphasis on patient populations, rather than seasonality.

Our criteria for prophylaxis would lead to a substantial increase in the number of infants eligible for palivizumab prophylaxis in Hong Kong, relative to current practice. Consistent with guidance from the AAP, we recommend prophylaxis for preterm infants born at <29 wGA.11 Although the <29 wGA cut-off may appear to be more restrictive than the current Hospital Authority limit (<34 wGA), most premature infants are discharged without oxygen or medication and therefore do not meet the existing criteria for palivizumab prophylaxis.

Our guidance statements aim to identify the populations for which RSV prophylaxis is appropriate and to summarise the efficacy and safety data supporting palivizumab prophylaxis. Although a high level of consensus was reached for these statements, all recommendations should be tailored to the needs of individual patients, ideally using a multidisciplinary clinical approach.

As of early 2025, three RSV vaccines have been approved for medical use in the US.47 In June 2024, the US Centers for Disease Control and Prevention recommended that people aged ≥75 years and people aged 60 to 74 years who are at increased risk of severe RSV receive the RSV vaccine.48 One of the RSV vaccines, Abrysvo, is indicated for active immunisation for the prevention of lower respiratory infection caused by RSV in people ≥60 years of age, high-risk individuals aged 18 years through 59 years, and pregnant individuals at 32 through 36 weeks gestational age to prevent severe disease in their infants from birth through 6 months of age.49 However, currently in Hong Kong, the Scientific Committee on Vaccine Preventable Diseases under the Centre for Health Protection does not recommend universal RSV vaccination for elderly persons or pregnant women.50 Recommendations about childhood RSV immunisation by local expert panel should be called for in the not-so-remote future.

Author contributions

Concept or design: GPG Fung, KL Hon, AM Li, MSH Lee, DKK Ng.
Acquisition of data: EWY Cheung, KL Hon, DSY Lam, MSH Lee.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: EWY Cheung, KL Hon, RSY Lee, AM Li, MSH Lee, DKK Ng.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

MP Leung, AM Li and DKK Ng have received an honorarium for this consensus meeting from AstraZeneca Hong Kong. EWY Cheung has received an honorarium for lectures from AstraZeneca Hong Kong. As an editor of the journal, KL Hon was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Acknowledgement

The authors thank Mr Mika Mok, Ms Magdalene Chu and Dr Alister Smith of MIMS Hong Kong for their assistance in the planning and coordination of the consensus meeting, as well as the medical writing of this manuscript, with funding from AstraZeneca Hong Kong.

Funding/support

The development of this manuscript and the meeting it documents were funded by an unrestricted grant from AstraZeneca Hong Kong to the Hong Kong Society of Paediatric Respirology and Allergy. The funder had no role in the formulation of clinical questions or consensus statements, data collection/analysis/interpretation, or manuscript preparation.

References

1. Ruangnapa K, Kaeotawee P, Surasombatpattana P, et al. Viral and atypical bacterial infection in young children hospitalized due to acute lower respiratory tract infection in Southern Thailand. Pediatr Respirol Crit Care Med 2019;3:67-71. Crossref

2. Shi T, McAllister DA, O’Brien KL, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017;390:946-58. Crossref

3. Chan PK, Tam WW, Lee TC, et al. Hospitalization incidence, mortality, and seasonality of common respiratory viruses over a period of 15 years in a developed subtropical city. Medicine (Baltimore) 2015;94:e2024. Crossref

4. Tong AS, Hon KL, Tsang YC, et al. Paramyxovirus infection: mortality and morbidity in a pediatric intensive care unit. J Trop Pediatr 2016;62:352-60. Crossref

5. Hon KL, Leung AK, Wong AH, Dudi A, Leung KK. Respiratory syncytial virus is the most common causative agent of viral bronchiolitis in young children: an updated review. Curr Pediatr Rev 2023;19:139-49. Crossref

6. Mazur NI, Martinón-Torres F, Baraldi E, et al. Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics. Lancet Respir Med 2015;3:888-900. Crossref

7. Luna MS, Manzoni P, Paes B, et al. Expert consensus on palivizumab use for respiratory syncytial virus in developed countries. Paediatr Respir Rev 2020;33:35-44. Crossref

8. Johnson S, Oliver C, Prince GA, et al. Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 1997;176:1215-24. Crossref

9. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group [editorial]. Pediatrics 1998;102:531-7. Crossref

10. Zhang XL, Zhang X, Hua W, et al. Expert consensus on the diagnosis, treatment, and prevention of respiratory syncytial virus infections in children. World J Pediatr 2024; 20:11-25. Crossref

11. American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014;134:415-20. Crossref

12. Tulloh RM, Medrano-Lopez C, Checchia PA, et al. CHD and respiratory syncytial virus: global expert exchange recommendations. Cardiol Young 2017;27:1504-21. Crossref

13. Suryadevara M, Domachowske JB. Epidemiology and seasonality of childhood respiratory syncytial virus infections in the tropics. Viruses 2021;13:696. Crossref

14. Hon KL, Leung TF, Cheng WY, et al. Respiratory syncytial virus morbidity, premorbid factors, seasonality, and implications for prophylaxis. J Crit Care 2012;27:464-8. Crossref

15. Oxford Centre for Evidence-Based Medicine. Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Available from: https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf. Accessed 3 May 2022.

16. Brouwers MC, Kerkvliet K, Spithoff K; AGREE Next Steps Consortium. The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines. BMJ 2016;352:i1152. Crossref

17. Lee SH, Hon KL, Chiu WK, Ting YW, Lam SY. Epidemiology of respiratory syncytial virus infection and its effect on children with heart disease in Hong Kong: a multicentre review. Hong Kong Med J 2019;25:363-71. Crossref

18. Bont L, Checchia PA, Fauroux B, et al. Defining the epidemiology and burden of severe respiratory syncytial virus infection among infants and children in western countries. Infect Dis Ther 2016;5:271-98. Crossref

19. Zhang Y, Yuan L, Zhang Y, Zhang X, Zheng M, Kyaw MH. Burden of respiratory syncytial virus infections in China: systematic review and meta-analysis. J Glob Health 2015;5:020417. Crossref

20. Broberg EK, Waris M, Johansen K, Snacken R, Penttinen P; European Influenza Surveillance Network. Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016. Euro Surveill 2018;23:17-00284. Crossref

21. Foley DA, Yeoh DK, Minney-Smith CA, et al. The interseasonal resurgence of respiratory syncytial virus in Australian children following the reduction of coronavirus disease 2019–related public health measures. Clin Infect Dis 2021;73:e2829-30. Crossref

22. Casalegno J, Javouhey E, Ploin D, et al. Delayed start of the respiratory syncytial virus epidemic at the end of the 20/21 Northern Hemisphere winter season, Lyon, France. medRxiv 2021 Mar 12. Available from: https://www.medrxiv.org/content/10.1101/2021.03.12.21253446v1. Accessed 3 May 2022.

23. Ujiie M, Tsuzuki S, Nakamoto T, Iwamoto N. Resurgence of respiratory syncytial virus infections during COVID-19 pandemic, Tokyo, Japan. Emerg Infect Dis 2021;27:2969-70. Crossref

24. Centre for Health Protection, Department of Health, Hong Kong SAR Government. Detection of other respiratory viruses in respiratory specimens in 2021. 2022. Available from: https://www.chp.gov.hk/en/statistics/data/10/641/642/6933.html. Accessed 3 May 2022.

25. Boyce TG, Mellen BG, Mitchel EF Jr, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr 2000;137:865-70. Crossref

26. Lee JH, Kim CS, Chang YS, Choi JH; Committee on Data Collection and Statistical Analysis of the Korean Society of Neonatology. Respiratory syncytial virus–related readmission in preterm infants less than 34 weeks’ gestation following discharge from a neonatal intensive care unit in Korea. J Korean Med Sci 2015;30 Suppl 1(Suppl 1):S104-10. Crossref

27. Homaira N, Oei JL, Mallitt KA, et al. High burden of RSV hospitalization in very young children: a data linkage study. Epidemiol Infect 2016;144:1612-21. Crossref

28. Chaw PS, Hua L, Cunningham S, et al. Respiratory syncytial virus–associated acute lower respiratory infections in children with bronchopulmonary dysplasia: systematic review and meta-analysis. J Infect Dis 2020;222 (Suppl 7):S620-7. Crossref

29. Anderson EJ, Krilov LR, DeVincenzo JP, et al. SENTINEL1: an observational study of respiratory syncytial virus hospitalizations among U.S. infants born at 29 to 35 weeks’ gestational age not receiving immunoprophylaxis. Am J Perinatol 2017;34:51-61. Crossref

30. Anderson EJ, Carbonell-Estrany X, Blanken M, et al. Burden of severe respiratory syncytial virus disease among 33-35 weeks’ gestational age infants born during multiple respiratory syncytial virus seasons. Pediatr Infect Dis J 2017;36:160-7. Crossref

31. Belleudi V, Trotta F, Pinnarelli L, Davoli M, Addis A. Neonatal outcomes following new reimbursement limitations on palivizumab in Italy. Arch Dis Child 2018;103:1163-7. Crossref

32. Lee SR, Kwok KL, Ng DK, Hon KL. Palivizumab for infants <29 weeks in Hong Kong without a clear-cut season for respiratory syncytial virus infection—a cost-effectiveness analysis. J Trop Pediatr 2018;64:418-25. Crossref

33. Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev 2013:CD006602. Crossref

34. Parnes C, Guillermin J, Habersang R, et al. Palivizumab prophylaxis of respiratory syncytial virus disease in 2000-2001: results from The Palivizumab Outcomes Registry. Pediatr Pulmonol 2003;35:484-9. Crossref

35. Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003;143:532-40. Crossref

36. Chiu SN, Wang JN, Fu YC, et al. Efficacy of a novel palivizumab prophylaxis protocol for respiratory syncytial virus infection in congenital heart disease: a multicenter study. J Pediatr 2018;195:108-14.e1. Crossref

37. Chu PY, Hornik CP, Li JS, Campbell MJ, Hill KD. Respiratory syncytial virus hospitalisation trends in children with haemodynamically significant heart disease, 1997-2012. Cardiol Young 2017;27:16-25. Crossref

38. Medrano López C, García-Guereta L; CIVIC Study Gorup. Community-acquired respiratory infections in young children with congenital heart diseases in the palivizumab era: the Spanish 4-season civic epidemiologic study. Pediatr Infect Dis J 2010;29:1077-82. Crossref

39. Alexander PM, Eastaugh L, Royle J, Daley AJ, Shekerdemian LS, Penny DJ. Respiratory syncytial virus immunoprophylaxis in high-risk infants with heart disease. J Paediatr Child Health 2012;48:395-401. Crossref

40. Chen JJ, Chan P, Paes B, et al. Serious adverse events in the Canadian registry of children receiving palivizumab (CARESS) for respiratory syncytial virus prevention. PLoS One 2015;10e0134711. Crossref

41. Turti TV, Baibarina EN, Degtiareva EA, et al. A prospective, open-label, non-comparative study of palivizumab prophylaxis in children at high risk of serious respiratory syncytial virus disease in the Russian Federation. BMC Res Notes 2012;5:484. Crossref

42. Kashiwagi T, Okada Y, Nomoto K. Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan. Paediatr Drugs 2018;20:97-104. Crossref

43. Mori M, Onodera M, Morimoto A, et al. Palivizumab use in Japanese infants and children with immunocompromised conditions. Pediatr Infect Dis J 2014;33:1183-5. Crossref

44. Mac S, Sumner A, Duchesne-Belanger S, Stirling R, Tunis M, Sander B. Cost-effectiveness of palivizumab for respiratory syncytial virus: a systematic review. Pediatrics 2019;143:e20184064. Crossref

45. Hussman JM, Li A, Paes B, Lanctôt KL. A review of costeffectiveness of palivizumab for respiratory syncytial virus. Expert Rev Pharmacoecon Outcomes Res 2012;12:553-67. Crossref

46. Chen RH, Chiu SS, Lee SL, Yung TC. Population-based respiratory syncytial virus hospitalization disease burden and cost effectiveness of palivizumab prophylaxis in infants with hemodynamically significant congenital heart diseases. J Pediat Infants 2021;4:48-55. Crossref

47. United States Centers for Disease Control and Prevention. FDA has approved vaccines and monoclonal antibodies to protect against RSV. Available from: https://www.fda.gov/consumers/covid-19-flu-and-rsv/respiratory-syncytial-virus-rsv. Accessed 12 Feb 2025.

48. United States Centers for Disease Control and Prevention. RSV vaccines. 2024 Aug 30. Available from: https://www.cdc.gov/rsv/vaccines/index.html. Accessed 12 Feb 2025.

49. Fleming-Dutra KE, Jones JM, Roper LE, et al. Use of the Pfizer respiratory syncytial virus vaccine during pregnancy for the prevention of respiratory syncytial virus–associated lower respiratory tract disease in infants: recommendations of the Advisory Committee on Immunization Practices—United States, 2023. MMWR Morb Mortal Wkly Rep 2023;72:1115-22.Crossref

50. Centre for Health Protection, Department of Health, Hong Kong SAR Government. Scientific Committee on Vaccine Preventable Diseases issues interim consensus on respiratory syncytial virus vaccines [press release]. 2025 Jan 17. Available from: https://www.info.gov.hk/gia/general/202501/17/P2025011700541.htm. Accessed 12 Feb 2025.

2024 Hong Kong College of Obstetricians and Gynaecologists Guidelines for cervical cancer prevention and screening

Hong Kong Med J 2024 Dec;30(6):488–97 | Epub 3 Dec 2024

https://doi.org/10.12809/hkmj2411547

MEDICAL PRACTICE CME

2024 Hong Kong College of Obstetricians and Gynaecologists Guidelines for cervical cancer prevention and screening

Siew-fei Ngu, FHKCOG, FHKAM (Obstetrics and Gynaecology)¹; Annie NY Cheung, FRCPath, FHKAM (Pathology)²; Kwok-kwan Jong, FHKCPath, FHKAM (Pathology)³; Jessica YP Law, FHKCOG, FHKAM (Obstetrics and Gynaecology)⁴; Andrea Ying Lee, FHKCOG, FHKAM (Obstetrics and Gynaecology)³; Jacqueline HS Lee, FHKCOG, FHKAM (Obstetrics and Gynaecology)⁵; Wai-hon Li, FHKCOG, FHKAM (Obstetrics and Gynaecology)⁶; Vinci Ma, FHKCPaed, FHKAM (Paediatrics)³; Grace CY Wong, FHKCOG, FHKAM (Obstetrics and Gynaecology)⁷; Richard WC Wong, FRCPA, FHKAM (Pathology)⁸; Karen KL Chan, FHKCOG, FHKAM (Obstetrics and Gynaecology)¹

¹ Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China

² Department of Pathology, The University of Hong Kong, Hong Kong SAR, China

³ Department of Health, Hong Kong SAR Government, Hong Kong SAR, China

⁴ Department of Obstetrics and Gynaecology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

⁵ Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Hong Kong SAR, China

⁶ Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR, China

⁷ The Family Planning Association of Hong Kong, Hong Kong SAR, China

⁸ Department of Pathology, United Christian Hospital, Hong Kong SAR, China

Corresponding author: Dr Siew-fei Ngu (ngusiewf@hku.hk)

Full paper in PDF

Abstract

Primary prevention of cervical cancer is best achieved by vaccinating girls with a prophylactic human papillomavirus (HPV) vaccine. Despite the high efficacy of such vaccines, cervical cancer screening remains necessary because current vaccines do not offer full protection. Secondary prevention via cervical screening should target all women from age 25 years or at the onset of sexual activity, whichever occurs later, until age 64 years. Screening is recommended at 3-year intervals after two consecutive normal annual cytology results, or at 5-year intervals using HPV-based testing (either HPV co-test with cytology or HPV stand-alone). Women who have undergone hysterectomy with cervix removal for benign disease and have no prior history of cervical dysplasia can discontinue screening. Women with HPV-positive, cytology-negative co-test results should either undergo repeat co-testing in 12 months or immediate HPV16/18 genotyping. Immediate referral of women with positive stand-alone HPV test results for colposcopy without further triage is not recommended. A second triage test using cytology, genotyping for HPV16/18, or p16/Ki-67 dual-stain should be conducted to accurately identify women at high risk for high-grade lesions who thus require colposcopy referral. Women with HPV-positive, cytology-positive co-test results, or high-grade abnormal cytology results should be referred for colposcopy. Treatment with a loop electrosurgical excision procedure is recommended for women with high-grade squamous intraepithelial lesions (HSILs). After HSIL treatment, long-term follow-up with HPV-based testing over 25 years is preferred. When cytology results show atypical glandular cells, colposcopy and sampling of the endocervix and endometrium are recommended.

[Abstract in Chinese]

Introduction

To achieve the goal of the World Health Organization (WHO) of eliminating cervical cancer by 2030,1 strategies should include human papillomavirus (HPV) vaccination for girls, high-performance screening of eligible women, and treatment of pre-invasive disease. The Guidelines for cervical cancer prevention and screening was last updated in 2016.2 Since then, there have been several important new developments. Thus, the authors were invited to form a working group to revise the Guidelines. This article summarises the guidelines (January 2024 revised version) available on the Hong Kong College of Obstetricians and Gynaecologists website.3

Primary prevention: prophylactic vaccine

Primary prevention of cervical cancer is best achieved by vaccinating girls with a prophylactic HPV vaccine before they become sexually active. All HPV vaccines contain virus-like particles (VLPs) for protection against high-risk HPV (hrHPV) types 16 and 18, which cause approximately 70% of cervical cancer worldwide.4 The nonavalent vaccine contains additional VLPs for protection against hrHPV types 31, 33, 45, 52, and 58. These seven HPV types cause approximately 90% of squamous cell carcinomas.5 The quadrivalent and nonavalent vaccines also contain VLPs to protect against HPV types 6 and 11, which are associated with anogenital warts. Human papillomavirus vaccines are highly immunogenic, generating stronger antibody responses than those produced via natural infection. Real-world data have demonstrated the vaccines’ effectiveness in reducing HPV infections, anogenital warts, and cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) among hrHPV-naive women.6 7 Despite the high efficacy of HPV vaccines, cervical cancer screening remains necessary because current vaccines do not offer full protection.

All HPV vaccines are indicated for use in girls and women aged ≥9 years; they demonstrate high efficacy and excellent safety profiles. Human papillomavirus vaccines were initially licensed with a three-dose vaccination schedule. The WHO recommends primarily targeting girls aged 9 to 14 years with two-dose schedule administered at least 6 months apart, ideally within a 12-month period, through national immunisation programmes.8 The nonavalent HPV vaccine has been incorporated into the Hong Kong Childhood Immunisation Programme, with a two-dose schedule and a coverage rate exceeding 80%.9 Current HPV vaccines do not influence viral clearance in women with preexisting infection.10 Meta-analyses have suggested that adjuvant HPV vaccination might reduce the risk of subsequent disease after an excisional procedure for CIN, irrespective of causal HPV type.11 12 However, higher-quality studies are needed to confirm this suggestion.

Secondary prevention: screening

Target population

The target population encompasses all women aged ≥25 years, or those beginning sexual activity (whichever is later), and continues until age 64 years (Table). Considering the low incidence of cervical carcinoma among women aged <25 years in Hong Kong,13 along with the relatively high rates of spontaneous regression for HPV infection and cytological abnormalities in this age-group, screening before age 25 years is less cost-effective and could result in unnecessary interventions. Nevertheless, women aged <25 years with a high-risk profile may be screened after assessment by doctor. The Table shows the recommended intervals for routine screening.

Screening methods

Cervical cytology

Cervical cytology may be used as a screening test (either alone or as part of a co-test) or triage test (for hrHPV-positive cases in stand-alone HPV screening).14

Human papillomavirus testing

Human papillomavirus testing can be used as a screening test (either as part of a co-test or stand-alone in primary HPV screening) [Figs 1 and 2, respectively], a triage test (in cytology-based screening for cases reported as atypical squamous cells of undetermined significance [ASCUS]) [Fig 3], or a test of cure (after treatment for HPV-associated lesions) [online supplementary Fig 1].

The main advantage of HPV testing is its high sensitivity in detecting HPV-associated malignancies and precursor lesions. Various studies have shown that HPV-based screening exhibits greater sensitivity than cytology in detecting high-grade squamous intraepithelial lesions (HSILs) and more severe lesions.14 15 Considering the lower specificity of a positive HPV test result, a triage test is generally necessary. Similar to other laboratory tests, HPV testing has limitations and may yield false negative results due to various biological and technical factors.16 Importantly, a negative HPV test result does not definitively exclude cervical pathology because multiple HPV-independent cervical neoplasms exist and false negatives are possible.

Human papillomavirus testing should exclusively target hrHPV types.17 There is a wide range of commercially available HPV testing devices with diverse technologies and detection targets.18 19 Although no local regulatory body governs which HPV testing devices are suitable for screening or non-screening purposes, regulatory approval statuses in other countries can be considered when selecting an HPV test.

The use of self-collected specimens for HPV testing (also known as self-sampling) is emerging as an alternative strategy to increase cervical screening coverage and compliance. The WHO has suggested using self-collected vaginal samples for screening20; some countries (such as Australia21 and Malaysia22) now offer this option. Specific considerations for self-collected samples include the validation of sampling devices for self-collected vaginal specimens as well as the performance and regulatory approval of HPV tests for these specimens.23 Other self-collected specimens (eg, urine and menstrual blood) have been explored for HPV testing. Currently, the use of these additional specimens is not recognised or recommended as a standard primary screening method, although this perspective may change when data from more definitive studies become available.

Biomarkers

Several cellular and molecular biomarkers have been evaluated for potential applications in cervical screening; some have been shown to improve the identification and triage of women with positive screening tests.24 Currently, most biomarkers have not been specifically approved for clinical use in primary screening. The p16/Ki-67 dual-stain is an immunocytochemistry-based technique that detects cells co-expressing p16 and Ki-67 on a cytology slide. The presence of both markers is relatively specific to HPV-associated dysplastic lesions. The p16/Ki-67 dual-stain was recently approved by the United States Food and Drug Administration for the triage of patients with hrHPV positivity.25

Use of human papillomavirus testing in screening

Testing for the triage of atypical squamous cells of undetermined significance smears

Reflex HPV testing as a triage option for patients with ASCUS constitutes an alternative to repeat cytology at 6 months when making decisions regarding colposcopy referral,26 except among women aged <20 years (Fig 3).

Testing as primary screening

The implementation of HPV testing as a screening strategy may enhance disease detection and extend the screening interval. However, this increased sensitivity must be balanced with the potential risks of unnecessary testing and treatment. Considering the high prevalence of HPV in young women and the median age of cervical cancer patients in Hong Kong, primary HPV screening is not recommended for women aged <30 years. Among women who previously underwent HPV vaccination, primary HPV screening can be considered before the age of 30 years. In a population with high vaccine uptake among women aged 25 to 33 years, primary HPV screening was associated with significantly increased detection of CIN2+ relative to cytology; there was no significant difference in the colposcopy referral rate.27

Testing as a co-test with cytology

In many studies, the addition of HPV testing to cytology resulted in greater CIN3 detection sensitivity during the first round of screening, along with a decrease in CIN3 or cancer detection during subsequent rounds of screening.14 28 29 Women with negative co-test results have low risks of concurrent CIN3+30 and cervical cancer.31 Immediate colposcopy is not recommended for women with HPV positivity and negative cytology results. Instead, either repeat co-testing in 12 months or immediate HPV16/18 genotyping is acceptable (Fig 1).

Testing as a stand-alone test

Although HPV and cytology co-testing improves detection sensitivity for high-grade lesions, this approach requires each woman to undergo two tests; thus, it carries substantial resource and cost implications. Stand-alone HPV testing can be considered for cervical screening (Fig 2). In several studies in a systemic review,32 primary HPV screening significantly increased CIN3+ detection during the initial round of screening compared with cytology. A negative HPV test result has high negative predictive value. However, immediate colposcopy referral is not recommended for HPV-positive women without further triage tests. A second triage test should be conducted to accurately identify women at high risk for CIN2+ lesions who thus require colposcopy referral. Various triage strategies can be considered. Reflex cytology is recommended for all women with positive stand-alone HPV test results to guide colposcopy referral and subsequent management. Alternatively, HPV16/18-positive women should be referred for colposcopy, regardless of cytology results. Another triage method for HPV-positive women (particularly those with non–16/18 hrHPV types) involves the p16/Ki-67 dualstain. Dual-stain cytology has significantly higher detection sensitivity for CIN3+ relative to cytology, with comparable specificity. After referring all HPV16/18-positive women for colposcopy, the use of dual-stain cytology as a triage test for women with other hrHPV positivity resulted in higher CIN3+ sensitivity relative to cytology-based triage, with a similar number of colposcopies.33

Management of normal and abnormal smears

Figures 1, 3 and 4 summarise the management of normal and low-grade abnormal cytology. Patients with high-grade abnormal cytology should be referred for colposcopy. Suggested actions for other cervical cytology results of normal and squamous lesions, glandular lesions, and others are shown in online supplementary Tables 1, 2, and 3, respectively.

Colposcopy and treatment for cervical intraepithelial neoplasia

The colposcopist examines the transformation zone, defines the extent of the lesion, and biopsies the most abnormal area for tissue diagnosis. Histological confirmation of the colposcopic diagnosis is recommended before treatment. In patients with a colposcopic diagnosis of high-grade lesion, a ‘see and treat’ approach (ie, loop excision without biopsy) is adopted by some colposcopists. Immediate treatment is an option for women aged ≥25 years with HSIL cytology who have rarely or never undergone screening, especially if they exhibit HPV16 positivity.34 Although this approach decreases the need for additional visits, it risks over-treatment of patients with low-grade lesions.

Most low-grade lesions spontaneously regress within 2 years; thus, immediate treatment may be unnecessary.35 36 Approximately 15% of patients show progression to high-grade lesions and eventually require treatment. If a low-grade lesion is confirmed by colposcopy and biopsy, follow-up with HPV testing or co-testing at 12 months is recommended, irrespective of the patient’s age (Fig 5). Because a negative cytology result is not associated with lower subsequent risk of CIN3 relative to a negative HPV test result,37 HPV testing is preferred for follow-up after colposcopy. Cytology remains acceptable if HPV testing is unavailable.

For non-pregnant women with CIN3, treatment is recommended. For non-pregnant women with CIN2, treatment is also recommended; however, if the squamocolumnar junction is fully visualised, observation can be considered for women with concerns regarding the effect of treatment on future pregnancies. Treatment should be performed if CIN2 persists for >24 months. The preferred treatment method is loop electrosurgical excision procedure (LEEP). Hysterectomy is not recommended unless there are concomitant gynaecological issues that justify the procedure; it should not be performed solely for cytological abnormalities without proper colposcopy examination and biopsy.

For women with high-grade abnormal cytology but only low-grade lesions on colposcopy-directed biopsy, a review of materials is recommended. If the low-grade lesions are confirmed, HPV testing or co-testing should be conducted at 12 and 24 months. For women with HSIL cytology whose biopsy results indicate histological low-grade squamous intraepithelial lesion (LSIL) or not worse than LSIL, an immediate diagnostic excisional procedure is acceptable. An alternative option is observation with HPV testing or co-testing and colposcopy at 1 year. This approach requires the squamocolumnar junction and upper limit of any lesion to be fully visualised at the initial colposcopic examination; if collected, endocervical samples must show less than CIN2. A diagnostic excisional procedure is recommended for women with cytologic HSIL at either the 1- or 2-year visit, as well as women with persistent ASC cannot rule out high-grade squamous lesion at the 2-year visit.

For patients with LSIL involving >2 quadrants of the cervix and patients with LSIL who are unable or unwilling to attend follow-up visits, treatment should be considered. Treatment is also acceptable if the lesion persists for >2 years. If the final histology analysis after treatment confirms low-grade lesions, the patient should be monitored in a manner similar to other patients with low-grade lesions on cervical biopsies. Positive treatment margins for CIN2/3 are associated with a higher recurrence rate, but this association is insufficient to justify routine repeat excision.38

Human papillomavirus testing or co-testing is preferred over cytology for follow-up after histological HSIL treatment because it provides the most accurate prediction of treatment outcomes.15 Human papillomavirus testing or co-testing should be performed at 6 months, then annually until two consecutive normal results are obtained. Cytology only is less preferred for surveillance after histological HSIL treatment but remains acceptable if HPV testing is unavailable (online supplementary Fig 1).

Among patients who underwent hysterectomy for CIN with clear margins, HPV testing or co-testing with a vaginal smear should be performed annually for two consecutive years. If both results are normal, further vaginal smears are unnecessary. If HPV testing is unavailable, vaginal smear cytology should be performed at 6, 12, and 24 months. No further vaginal smears are needed after three consecutive normal cytology results. If excision was incomplete, margin clearance is uncertain on hysterectomy, or the patient exhibited vaginal intraepithelial neoplasia, HPV testing or co-testing with a vaginal smear should be performed at 12 and 24 months. If both results are negative, HPV testing or co-testing with a vaginal smear should be continued every 3 years for 25 years or until age 65 years, whichever is later. If HPV testing is unavailable, vaginal smear cytology should be performed at 6 and 12 months, then annually for 10 years, then every 3 years for 15 years or until age 65 years, whichever is later.

Management of glandular lesions

For cytology results indicating adenocarcinoma in situ (AIS) and all subcategories of atypical glandular cells—except those specified as ‘atypical endometrial cells’—colposcopy, endometrial sampling, and endocervical sampling are recommended, regardless of HPV test results (online supplementary Table 2 and online supplementary Fig 2). Reflex HPV testing is not recommended. For atypical glandular cells (favour neoplasia) and AIS, if no significant pathology can explain the source of abnormal cells, a diagnostic excisional procedure (preferably cold-knife conisation) is recommended.

Management of adenocarcinoma in situ

A diagnostic excisional procedure is recommended for all patients with a diagnosis of AIS on cervical biopsy or cytology to rule out invasive adenocarcinoma, even if a definitive hysterectomy is planned. Excisional procedures should aim to provide an intact specimen to facilitate accurate interpretation of margin status. The excision specimen length should be at least 10 mm, where feasible. Endocervical sampling above the excision site to assess residual disease is recommended. A ‘top hat’ endocervical excision to increase specimen length is not recommended.

In cases of concomitant AIS and CIN, management should follow recommendations for AIS. Hysterectomy is the preferred option for all patients with histologically confirmed AIS. For women with confirmed AIS and negative margins on the excision specimen, simple hysterectomy is preferred. For women with confirmed AIS and a positive margin on the excision specimen, re-excision to achieve a negative margin is preferred to rule out malignancy, even if a hysterectomy is planned. If a positive margin is present on the re-excision specimen, or further excisional procedures are not feasible, a simple or modified radical hysterectomy is acceptable. Fertility-sparing management is not recommended for these patients. However, fertility-sparing treatment with an excisional procedure alone may be considered for women with negative margins on the excisional specimen who are willing to adhere to surveillance recommendations.

Management for special categories

Young women, including adolescents

Considering the low prevalence of high-grade cytological abnormalities and rarity of cervical cancer in adolescents aged <21 years,39 cervical screening is not recommended in this age-group. Unnecessary screening could lead to avoidable procedures and over-treatment.40 Most cytological abnormalities in adolescents are minor and exhibit spontaneous clearance within 2 years; thus, immediate colposcopy is discouraged. For ASCUS or LSIL, cervical cytology should be repeated annually; routine screening can be resumed after two consecutive negative cytology results. Colposcopy should be performed if high-grade abnormal cytology is evident or abnormal cytology persists for 2 years.

If CIN3 is confirmed on biopsy, LEEP is indicated. If CIN2 is confirmed on biopsy, observation via cytology and colposcopy every 6 months is suggested due to the high regression rate in this age-group.41 However, treatment is recommended if CIN2 persists for 2 years. If no high-grade lesion is detected on satisfactory colposcopic examination, cytology should be repeated every 6 months. If HSIL persists at 1 year, colposcopy should be repeated; if HSIL persists at 2 years, LEEP should be considered.29 If colposcopy for HSIL yields unsatisfactory results, cytology and colposcopy should be repeated at 6 months. If HSIL persists and colposcopy results remain unsatisfactory at 1 year, LEEP should be offered.

Pregnant women

The goal of colposcopy in pregnant women is exclusion of invasive cancer. Cancer risk is relatively low among pregnant women with ASCUS or LSIL; thus, deferred colposcopy is acceptable (until at least 6 weeks after delivery). Pregnant women with high-grade abnormal cytology or HPV16/18 positivity should undergo colposcopic examination. Endocervical curettage is contraindicated, but repeat colposcopy early in the third trimester may be considered. Pregnancy does not appear to alter the risk or rate of progression from cervical precancer to cancer. The only indication for immediate treatment is invasive cancer; otherwise, treatment for high-grade disease can be postponed until the postpartum period. A colposcopy-guided biopsy or diagnostic excisional procedure is indicated only if malignancy is suspected.

Chronically immunocompromised women

Women with chronic immunosuppression have a higher risk of persistent HPV infection, increasing the likelihood of progression to CIN and cervical cancer. They should be informed of the increased risk associated with HPV infection and encouraged to undergo regular screening. Given the limited literature regarding cervical screening for immunocompromised women without human immunodeficiency virus (HIV), screening and management guidelines generally follow recommendations for women with HIV.42 Cervical cancer rates among women with HIV are elevated across all age-groups from 25 to 54 years; zero cases were reported among women aged <25 years.43 Although there is limited and inconsistent evidence concerning the benefit of cervical screening for younger age-groups, it may be helpful to screen women aged 21 to 24 years; this would provide an early detection window prior to age 25 years, when the cervical cancer risk in women with HIV exceeds that of the general population.43 Recent data suggest that screening intervals may be extended for these women.44 A 3-year interval can be considered after two consecutive normal annual cytology results45 or a negative HPV-based screening test result. Subsequent management for any abnormal screening results and treatment of high-grade cytological abnormalities should follow guidelines for non-immunocompromised individuals. Low-grade lesions should be regularly monitored for progression because they respond poorly to treatment.

Author contributions

Concept or design: All authors.
Acquisition of data: SF Ngu, ANY Cheung, JYP Law, AY Lee, JHS Lee, W Li, GCY Wong, RWC Wong.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: SF Ngu, ANY Cheung, JYP Law, AY Lee, JHS Lee, W Li, GCY Wong, RWC Wong.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Acknowledgement

This guideline was produced by the Hong Kong College of Obstetricians and Gynaecologists as an educational aid and reference for obstetricians and gynaecologists practising in Hong Kong. The guideline does not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognised clinical methods and techniques for consideration by practitioners for incorporation into their practice. It is acknowledged that clinical management may vary and must always be responsive to the needs of individual patients, resources, and limitations unique to the institution or type of practice. Particular attention is drawn to areas of clinical uncertainty in which further research may be indicated.

Declaration

The content of this guideline has been published in the Hong Kong College of Obstetricians and Gynaecologists Guidelines Number 4, revised January 2024,3 which is a revised version of the 2016 Hong Kong College of Obstetricians and Gynaecologists Guidelines for Cervical Cancer Prevention and Screening.2

Funding/support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Supplementary material

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine and the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

References

1. World Health Organization. Global strategy to accelerate the elimination of cervical cancer as a public health problem. 2020. Available from: https://iris.who.int/bitstream/handle/10665/336583/9789240014107-eng.pdf?sequence=1. Accessed 26 Nov 2024.

2. Hong Kong College of Obstetricians and Gynaecologists. HKCOG Guidelines Number 4: Guidelines for Cervical Cancer Prevention and Screening. Revised November 2016. Available from: https://www.hkcog.org.hk/hkcog/Download/Cervical_Cancer_Prevention_and_Screening_revised_November_2016.pdf. Accessed 11 Nov 2024.

3. Hong Kong College of Obstetricians and Gynaecologists. HKCOG Guidelines Number 4: Guidelines for Cervical Cancer Prevention and Screening. Revised January 2024. Available from: https://www.hkcog.org.hk/hkcog/Download/Guidelines_for_Cervical_Cancer_Prevention_and_Screening.pdf. Accessed 11 Nov 2024.

4. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-56. Crossref

5. Serrano B, de Sanjosé S, Tous S, et al. Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer 2015;51:1732-41. Crossref

6. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev 2018;5:CD009069. Crossref

7. Drolet M, Bénard É, Pérez N, Brisson M; HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet 2019;394:497-509. Crossref

8. World Health Organization. Weekly Epidemiological Record No 50. Human papillomavirus vaccines: WHO position paper, December 2022. 2022 Dec 16. Available from: https://www.who.int/publications/i/item/who-wer9750-645-672. Accessed 11 Nov 2024.

9. Scientific Committee on Vaccine Preventable Diseases, Centre for Health Protection, Department of Health, Hong Kong SAR Government.. Updated recommendations on the use of 9-valent human papillomavirus vaccine in Hong Kong (as of 30 November 2022). November 2022. Available from: https://www.chp.gov.hk/files/pdf/updated_recommendations_on_the_use_of_human_papillomavirus_vaccine_in_hong_kong_30nov.pdf. Accessed 11 Nov 2024.

10. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007;298:743-53. Crossref

11. Di Donato V, Caruso G, Petrillo M, et al. Adjuvant HPV vaccination to prevent recurrent cervical dysplasia after surgical treatment: a meta-analysis. Vaccines (Basel) 2021;9:410. Crossref

12. Kechagias KS, Kalliala I, Bowden SJ, et al. Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis. BMJ 2022;378:e070135. Crossref

13. Hong Kong Cancer Registry, Hospital Authority, Hong Kong. Hong Kong Cancer Statistics. Cervical cancer in 2021. October 2023. Available from: https://www3.ha.org.hk/cancereg/pdf/factsheet/2021/cx_2021.pdf. Accessed 11 Nov 2024.

14. Chan KK, Liu SS, Wei N, et al. Primary HPV testing with cytology versus cytology alone in cervical screening—a prospective randomized controlled trial with two rounds of screening in a Chinese population. Int J Cancer 2020;147:1152-62. Crossref

15. Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012;30 Suppl 5:F88-99. Crossref

16. Petry KU, Cox JT, Johnson K, et al. Evaluating HPV-negative CIN2+ in the ATHENA trial. Int J Cancer 2016;138:2932-9. Crossref

17. World Health Organization. WHO technical guidance and specifications of medical devices for screening and treatment of precancerous lesions in the prevention of cervical cancer. Geneva: World Health Organization; 2020.

18. Salazar KL, Duhon DJ, Olsen R, Thrall M. A review of the FDA-approved molecular testing platforms for human papillomavirus. J Am Soc Cytopathol 2019;8:284-92. Crossref

19. Arbyn M, Simon M, Peeters E, et al. 2020 list of human papillomavirus assays suitable for primary cervical cancer screening. Clin Microbiol Infect 2021;27:1083-95. Crossref

20. World Health Organization. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition. Geneva: World Health Organization; 2021.

21. Department of Health and Aged Care, Australian Government. Self-collection for the cervical screening test. Available from: https://www.health.gov.au/self-collection-for-the-cervical-screening-test. Accessed 26 Nov 2024.

22. Family Health Development Division, Ministry of Health Malaysia. Guidelines for cervical cancer screening in Malaysia (Second Edition 2023). 2023. Available from: https://www2.moh.gov.my/moh/modules_resources/bookshelf/Guidelines_For_Cervical_Cancer_Screening_in_Malaysia_2023/Guidelines_For_Cervical_Cancer_Screening_in_Malaysia_2023.pdf. Accessed 26 Nov 2024.

23. National Pathology Accreditation Advisory Council. Requirements for validation of self-collected vaginal swabs for use in the national cervical screening program (First Edition 2019). Canberra: National Pathology Accreditation Advisory Council; 2019.

24. Molina MA, Carosi Diatricch L, Castany Quintana M, Melchers WJ, Andralojc KM. Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection. Expert Rev Mol Diagn 2020;20:1099-120. Crossref

25. United States Food and Drug Administration, United States Government. Summary of safety and effectiveness data (SSED): CINtec PLUS Cytology. 2020 Mar 10. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190024B.pdf. Accessed 11 Nov 2024.

26. Solomon D, Schiffman M, Tarone R; ALTS Study Group. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-9. Crossref

27. Lew JB, Simms KT, Smith MA, et al. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. Lancet Public Health 2017;2:e96-107. Crossref

28. Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014;383:524-32. Crossref

29. Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2020;24:102-31. Crossref

30. Egemen D, Cheung LC, Chen X, et al. Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020;24:132-43. Crossref

31. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a populationbased study in routine clinical practice. Lancet Oncol 2011;12:663-72. Crossref

32. Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Weyrich MS. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2018;320:687-705. Crossref

33. Wright TC Jr, Behrens CM, Ranger-Moore J, et al. Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: results from a sub-study nested into the ATHENA trial. Gynecol Oncol 2017;144:51-6. Crossref

34. Demarco M, Egemen D, Raine-Bennett TR, et al. A study of partial human papillomavirus genotyping in support of the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020;24:144-7. Crossref

35. Lee SS, Collins RJ, Pun TC, Cheng DK, Ngan HY. Conservative treatment of low grade squamous intraepithelial lesions (LSIL) of the cervix. Int J Gynaecol Obstet 1998;60:35-40. Crossref

36. Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993;12:186-92. Crossref

37. Katki HA, Gage JC, Schiffman M, et al. Follow-up testing after colposcopy: five-year risk of CIN 2+ after a colposcopic diagnosis of CIN 1 or less. J Low Genit Tract Dis 2013;17(5 Suppl 1):S69-77. Crossref

38. Kwok ST, Chan KK, Tse KY, et al. Outcome after loop electrosurgical excision procedure for cervical high-grade squamous intraepithelial lesion. Taiwan J Obstet Gynecol 2023;62:45-9. Crossref

39. Hosier H, Sheth SS, Oliveira CR, Perley LE, Vash-Margita A. Unindicated cervical cancer screening in adolescent females within a large healthcare system in the United States. Am J Obstet Gynecol 2021;225:649.e1-9. Crossref

40. Moscicki AB, Cox JT. Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis 2010;14:73-80. Crossref

41. Loopik DL, Bekkers RL, Massuger LF, Melchers WJ, Siebers AG, Bentley J. Justifying conservative management of CIN2 in women younger than 25 years—a population-based study. Gynecol Oncol 2019;152:82-6. Crossref

42. Moscicki AB, Flowers L, Huchko MJ, et al. Guidelines for cervical cancer screening in immunosuppressed women without HIV infection. J Low Genit Tract Dis 2019;23:87-101. Crossref

43. Stier EA, Engels E, Horner MJ, et al. Cervical cancer incidence stratified by age in women with HIV compared with the general population in the United States, 2002-2016. AIDS 2021;35:1851-6. Crossref

44. Massad LS, D’Souza G, Tian F, et al. Negative predictive value of pap testing: implications for screening intervals for women with human immunodeficiency virus. Obstet Gynecol 2012;120:791-7. Crossref

45. Cancer Expert Working Group on Cancer Prevention and Screening, Centre for Health Protection, Department of Health, Hong Kong SAR Government. Recommendations on prevention and screening for cervical cancer for health professionals. June 2021. Available from: https://www.chp.gov.hk/files/pdf/cervical_cancer_professional_hp.pdf. Accessed 18 Dec 2023.

Management of chronic kidney disease: a Hong Kong consensus recommendation

Hong Kong Med J 2024 Dec;30(6):478–87 | Epub 27 Aug 2024

https://doi.org/10.12809/hkmj2311309

MEDICAL PRACTICE CME

Management of chronic kidney disease: a Hong Kong consensus recommendation

Sydney CW Tang, MD, PhD¹; Kelvin KL Ho, FRCP (Edinburgh), FHKAM (Medicine)²; Welchie WK Ko, FHKAM (Family Medicine)³; Albert Lee, MD, FHKAM (Family Medicine)⁴; CB Leung, FRCP, FHKAM (Medicine)⁵; WK Lo, MD, FHKCP⁶; Ronald CW Ma, FRCP, FHKCP⁷; SL Pang, MB, BS, FHKAM (Family Medicine)⁶; Kathryn CB Tan, MBBCh, MD⁸; MW Tsang, FRCP⁹; Martin CS Wong, MD, FHKAM (Family Medicine)⁴; William CW Wong, MPH, MD¹⁰; Francis KM Wong, FRCP⁶; CC Szeto, MD, FRCP¹¹

¹ Division of Nephrology, Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China

² Department of Nephrology, Virtus Medical Group, Hong Kong SAR, China

³ Department of Family Medicine and Primary Healthcare, Queen Mary Hospital, Hong Kong SAR, China

⁴ The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

⁵ Central Administration Office, Hong Kong Baptist Hospital, Hong Kong SAR, China

⁶ Private Practice, Hong Kong SAR, China

⁷ Division of Endocrinology and Diabetes, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China

⁸ Division of Endocrinology and Metabolism, Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China

⁹ United Medical Practice, Hong Kong SAR, China

¹⁰ Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

¹¹ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China

Corresponding author: Prof Sydney CW Tang (scwtang@hku.hk)

Full paper in PDF

Abstract

Chronic kidney disease (CKD) imposes a significant burden on healthcare systems worldwide, and diabetes is a major risk factor for CKD. There is currently no consensus in Hong Kong regarding the prioritisation of early identification and intervention for CKD. A comprehensive and Hong Kong–specific diabetes and CKD treatment guideline is also lacking. A multidisciplinary group of experts discussed issues surrounding the current management of CKD and reviewed evidence in the context of local experience to support recommendations. The experts used a modified Delphi approach to finalise recommendations. Consensus was regarded as ≥75% acceptability among all expert panel members. The panel members finalised 14 CKD-focused consensus statements addressing disease definition, screening, disease monitoring, lifestyle management, and treatment strategies. The recommendations provided are relevant to the Hong Kong healthcare setting and can be used as a guide by physicians across various specialties to facilitate the appropriate management of CKD.

[Abstract in Chinese]

Introduction

Chronic kidney disease (CKD) is a leading cause of mortality that affects >800 million people worldwide, and its burden is the greatest among individuals with a lower socio-economic status.1 In Hong Kong, survey data from 2020 to 2022 showed that 0.7% of the general population aged ≥15 years had a confirmed diagnosis of renal impairment.2

Chronic kidney disease is classified into five stages; stages 4 and 5 have a considerably increased risk of death or risk of cardiovascular events.3 Early detection of CKD in adults can prevent progression to kidney failure, while early identification by screening provides an opportunity to stratify patients according to risk, thereby enabling treatment that can modify the disease course.3 Diabetes is a leading risk factor for CKD; >40% of people with diabetes will develop CKD, and many of these people will require dialysis and transplantation.4 Considering the increasing prevalence of diabetes,4 it is important to develop comprehensive guidelines for the treatment of diabetes and CKD.

In Hong Kong, there has been no consensus on prioritising early identification and intervention for CKD. Guidelines for early CKD evaluation and management have not been universally adopted, due to a lack of incentives.5 This article documents the findings of an expert panel established to formulate the first consensus recommendations for CKD screening and management in Hong Kong, with the intention of providing practical guidance to local healthcare practitioners based on evidence and expert opinion.

Methods

Literature search

A search of PubMed was conducted to identify peer-reviewed articles regarding CKD screening and treatment. Local (ie, Hong Kong or Chinese study populations) English-language publications from January 2017 to September 2022 were retrieved. Publication types were limited to clinical trials (ie, randomised controlled or controlled clinical trials), practice guidelines, and meta-analyses or systematic reviews.

Consensus method

In accordance with published international guidelines4 6 7 8 and literature search results, consensus development leaders (first author and last author) drafted a set of preliminary statements concerning the definition, screening, and management of CKD. Twelve Hong Kong experts (nephrologists, endocrinologists, and family medicine specialists from public hospitals and private clinics) were invited to join the development leaders to form a 14-member consensus expert panel. All panel members were tasked with reviewing the draft statements in the context of current local practice and available evidence, and then discussed those statements during two expert meetings held in October and November 2022.

The consensus statements were developed through a modified Delphi process. Panellists evaluated each draft statement using a 5-point Likert scale (A: accept completely; B: accept with some reservations; C: accept with major reservations; D: reject with reservations; E: reject completely). When necessary, statements were modified, and a second vote was conducted. A consensus was recorded if ≥75% of the group accepted a statement completely or with reservations. When applicable, the level of evidence was evaluated using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.9 10

Consensus statements

In total, 14 statements met the threshold for consensus; these are summarised in Table 1.

Table 1. Summary of Hong Kong consensus recommendations on the management of chronic kidney disease

Disease definition

Statement 1: Chronic kidney disease is defined as abnormalities of kidney structure or function with health implications, which are present for ≥3 months.

Chronic kidney disease stages 1 and 2 are characterised by structural abnormalities and persistent proteinuria, albuminuria, or haematuria. Patients present with a normal to mildly decreased estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m², as well as other markers of kidney disease. Stage 3 is characterised by impaired kidney function, defined as an eGFR between 30 and 59 mL/min/1.73 m² on at least two occasions ≥3 months apart, irrespective of other markers of kidney disease. Stage 4 is defined as a severely reduced eGFR (15-29 mL/min/1.73 m²), and stage 5 is considered kidney failure (eGFR <15 mL/min/1.73 m²).3

Most patients with early CKD are asymptomatic and unaware of their disease. Diagnosis is often based on incidental findings during routine medical examinations. The detection of CKD in its early stages could lead to timely interventions, avoid inappropriate exposure to nephrotoxic agents, and delay CKD progression.3

Screening

Statement 2: People with hypertension, diabetes or cardiovascular disease should be screened for chronic kidney disease.

The screening of patients with higher CKD risk provides an opportunity to modify the disease course. Hypertension, diabetes, and cardiovascular diseases each has a single intermingled cause-and-effect relationship with CKD.1 Hypertension is a common cause of CKD, particularly in older adults, as well as a risk factor for faster progression of kidney disease.3 The Hong Kong Renal Registry lists hypertension as the third most common cause of renal replacement therapy in Hong Kong.11

In Hong Kong, diabetes is the most common primary aetiology leading to renal replacement therapy (49.6%).11 It has also been identified as a risk factor for CKD; most patients with stages 1 and 2 CKD are asymptomatic (36.0% and 47.1%, respectively).12 This recommendation is consistent with the 2019 Hong Kong College of Physicians Clinical Practice Guidelines for the Provision of Renal Services in Hong Kong.13

Statement 3: Chronic kidney disease screening and risk stratification must consist of a combined assessment of estimated glomerular filtration rate and albuminuria (ie, urine albumin-creatinine ratio). If urine albumin-creatinine ratio assessments are not feasible or available, screening with spot urine albumin concentration, urine protein-creatinine ratio, or urine protein dipstick test may be regarded as alternatives.

Measurements of renal function are complex, and no single method provides an accurate overall assessment of renal function. Combined evaluation of GFR and albuminuria is the gold standard for CKD screening.14 Glomerular filtration rate screening detects existing kidney damage, whereas albuminuria screening detects kidney damage occurring before substantial loss of nephron mass.14 A change in albuminuria level also serves as a surrogate endpoint for CKD progression.15

In clinical practice, eGFR is used.14 The Kidney Disease: Improving Global Outcomes (KDIGO) guideline defines CKD as an eGFR of <60 mL/min/1.73 m² or the detection of markers associated with kidney damage, or both, that persists for ≥3 months, regardless of the underlying cause.14 Estimated glomerular filtration rate–based CKD detection can accurately assess kidney function.16 In clinical practice, the eGFR is often derived from the serum creatinine concentration using the Chronic Kidney Disease Epidemiology Collaboration equation or the Modification of Diet in Renal Disease Study equation. Recent studies suggest that the Chronic Kidney Disease Epidemiology Collaboration equation predicts prognosis more accurately than the Modification of Diet in Renal Disease Study equation.3 17 18

Although urinary albumin excretion is an important prognostic biomarker for CKD, various methodologies are currently used to measure urinary albumin concentrations; these methodologies are not standardised in clinical practice.14 The gold standard for urinary albumin measurement is the urine albumin-creatinine ratio (uACR). The normal range of uACR is <30 mg/g (<3 mg/mmol); values above this range indicate kidney damage. The KDIGO 2012 guideline provided the reference ranges for eGFR and uACR categories (Table 2; see Disclaimer at the end of this article).3

Table 2. Prognosis of chronic kidney disease according to glomerular filtration rates and albuminuria categories: Kidney Disease: Improving Global Outcomes (KDIGO) 20123

The expert panel recognised that uACR testing is not available to all clinicians. Therefore, spot screening for urinary albumin concentration, urine protein-creatinine ratio (uPCR), or a urine protein dipstick test may be regarded as alternatives. A cohort study of Indo-Asian patients showed that spot screening for urinary albumin concentration and the uACR could be considered comparable to screening for albuminuria.19 Another study has also shown that the uPCR is positively correlated with the uACR.20 A uPCR of >200 mg/g (>20 mg/mmol) indicates a high risk of kidney damage21; a dipstick protein reading of ≥1+ also indicates kidney damage. The expert panel noted that a diagnosis should be confirmed by repeated testing.

Disease monitoring

Statement 4: Estimated glomerular filtration rate and albuminuria/proteinuria level should be monitored at least annually in patients with early stages of chronic kidney disease and more often in patients with later stages of chronic kidney disease or with a higher risk of progression.

Patients with CKD are often asymptomatic, especially in the early stages of disease.22 Risk factors contributing to CKD progression include the underlying cause of CKD, reduced eGFR, albuminuria level, age, sex, race/ethnicity, elevated blood pressure, hyperglycaemia, dyslipidaemia, smoking, obesity, and history of cardiovascular disease.3 The panel agreed that frequent (at least annual) monitoring of eGFR and albuminuria or proteinuria levels is important to ensure early detection of disease progression and prevent worsening. Nonetheless, uACR/proteinuria measurements may not be meaningful for patients with advanced CKD, kidney failure, or nephrotic syndrome.

Statement 5: Early recognition and treatment of chronic kidney disease require awareness and involvement of clinicians, including (but not restricted to) nephrologists, endocrinologists, cardiologists, and primary care physicians.

A CKD management programme should integrate CKD screening, patient risk stratification, and treatment within existing health services and processes.23 Many international guidelines recommend a multidisciplinary approach for CKD screening and management.4 6 7 8

Patient risk stratification enabling appropriate referral to speciality care and increased follow-up frequency (when needed) can improve treatment efficiency.24 A survey of primary care physicians in the United States showed that a robust multidisciplinary care team composed of dietitians, case managers, pharmacists, and health educators is desirable for enhancing patient education and facilitating self-management of risk factors for CKD progression.25 Primary care physicians with access to multidisciplinary care teams agreed that this approach was extremely helpful.25 Strategies to improve patient awareness of CKD, adherence to treatment, and achievement of CKD care goals should include greater access to effective self-management support within primary care.25

Lifestyle management

Statement 6: Patients with chronic kidney disease should not smoke, should maintain a normal body mass index, and should avoid processed foods with high salt and phosphate contents.

Smoking has been identified as a risk factor for CKD in Chinese and other populations,26 27 and a cohort study from Taiwan revealed that obesity was associated with an increased risk of kidney failure, consistent with international data.28 This recommendation is aligned with the Asian Pacific Society of Nephrology recommendation that people with diabetic kidney disease undergo smoking cessation interventions, maintain a healthy body mass index, and consume a diet rich in plant-based proteins and free of processed meats with high salt and phosphate contents.8

Statement 7: Patients with diabetes and chronic kidney disease are advised to engage in moderate-intensity physical activity for a cumulative duration of ≥150 minutes per week or at a level compatible with their cardiovascular and physical tolerance.

Improvements in physical activity levels offer cardiometabolic, kidney, and musculoskeletal benefits to the general population, including patients with diabetes.29 A systematic review identified exercise training as a potential strategy to improve eGFR and body mass index while reducing conventional blood pressure (as measured by auscultation or oscillometric methods) in patients with CKD.30 The expert panel agreed that clinicians should encourage patients with CKD to engage in moderate-intensity activities such as brisk walking, water aerobics, cycling, tennis, ballroom dancing, or general gardening.29

Treatment strategies

Statement 8: In patients with type 2 diabetes mellitus, chronic kidney disease, and an estimated glomerular filtration rate of ≥30 mL/min/1.73 m², metformin can be used as first-line pharmacological treatment for glycaemic control.

An evaluation of the effectiveness of common medications used to treat type 2 diabetes mellitus (T2DM) showed that metformin is superior to dipeptidyl peptidase-4 inhibitors and comparable to thiazolidinediones and sulfonylureas in terms of reducing glycated haemoglobin levels (with pooled mean differences in glycated haemoglobin levels of -0.37%, -0.07%, and 0.07%, respectively).31 A meta-analysis concluded that metformin is superior to sulfonylureas in reducing the risk of hypoglycaemia among patients with normal kidney function (odds ratio [OR]=0.11; 95% confidence interval [CI]=0.06-0.20) and among patients with impaired kidney function (OR=0.17; 95% CI=0.11-0.26).4 This recommendation is aligned with KDIGO guidance for patients with mild to moderate loss of kidney function and an eGFR of ≥30 mL/min/1.73 m².4

Statement 9: In patients with diabetes and hypertension or albuminuria, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers should be initiated as first-line pharmacological treatment for renal protection and blood pressure control, and the maximum tolerated dose should be titrated.

A review by Strippoli et al32 demonstrated the impacts of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) in terms of preventing kidney disease progression; both classes of medications significantly reduced the risk of progression to end-stage kidney disease compared with placebo or no treatment (relative risk [RR]=0.60; 95% CI=0.39-0.93 and RR=0.78; 95% CI=0.67-0.91, respectively). Angiotensin-converting enzyme inhibitors and ARBs also significantly reduced the risk of progression from microalbuminuria to macroalbuminuria (RR=0.45; 95% CI=0.29-0.69 and RR=0.49; 95% CI=0.32-0.75, respectively) and reduced the risk of serum creatinine doubling (RR=0.68; 95% CI=0.47-1.00 and RR=0.79; 95% CI=0.67-0.93, respectively).32 Evaluation of ACEi or ARB efficacy in a Chinese population revealed that patients taking ACEis or ARBs had a lower mortality risk compared with untreated patients (OR=0.77; 95% CI=0.58-0.90).33

Although combination therapy with an ACEi and an ARB is superior to either medication as monotherapy in terms of reducing proteinuria and blood pressure,34 such combination therapy can lead to higher incidences of hyperkalaemia and hypotension, especially in patients with advanced CKD.35 Individualised patient management involving potassium binders may expand the applications of combined therapy34; however, the panel noted that some hypotensive patients may not tolerate ACEis or ARBs, and this approach is less popular because of emerging treatment options for CKD. Combined therapy should only be considered by experienced clinicians after careful assessment and discussion with the patient.

Statement 10: In patients with type 2 diabetes mellitus and chronic kidney disease who have an estimated glomerular filtration rate of ≥20 mL/min/1.73 m², a sodium-glucose cotransporter-2 inhibitor can be initiated as first-line pharmacological treatment for glycaemic control, renal protection, and cardiovascular protection.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) deliver glycaemic control while conferring cardiovascular36 37 38 39 and renal40 41 42 43 44 45 benefits to patients with T2DM and CKD who have an eGFR between 25 and 90 mL/min/1.73 m². In patients with T2DM and various levels of cardiovascular and renal risk, SGLT2i lowered all-cause mortality (OR=0.85; 95% CI=0.79-0.92), cardiovascular mortality (OR=0.84; 95% CI=0.76-0.92), non-fatal myocardial infarction (OR=0.87; 95% CI=0.79-0.97), and kidney failure (OR=0.71; 95% CI=0.57-0.89) compared with placebo.46 The inhibitors are expected to reduce the incidence of kidney failure per 1000 patients over 5 years for patients with very low (1 case), low (3 cases), moderate (6 cases), high (25 cases), and very high (38 cases) baseline risk.46 The effectiveness of SGLT2is in terms of glycaemic control is attenuated among patients with an eGFR of <45 mL/min/1.73 m².47 Thus, additional therapy for glycaemic control may be needed in this population.

Statement 11: Patients with type 2 diabetes mellitus who have an estimated glomerular filtration rate of ≥25 mL/min/1.73 m², normal serum potassium concentration, and urine albumin-creatinine ratio of ≥30 mg/g (≥3 mg/mmol) despite receiving the maximum tolerated dose of a renin-angiotensin system inhibitor can be treated with a nonsteroidal mineralocorticoid receptor antagonist for renal and cardiovascular protection, depending on accessibility.

Multiple studies have demonstrated the renal and cardiovascular protective effects of mineralocorticoid receptor antagonists in patients with diabetes and CKD.48 49 50 In the FIDELIO-DKD study (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease), a lower incidence (18% vs 21%; P=0.001) compared with placebo was observed for the primary composite outcome of kidney failure, a sustained 40% decline in eGFR, or death from renal causes among T2DM patients with an eGFR of ≥25 mL/min/1.73 m² who received finerenone.48 The trial showed that finerenone reduced the risk of the primary cardiovascular composite outcome of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure in T2DM patients with an eGFR of ≥25 mL/min/1.73 m² (12.4% vs 14.2% in the placebo group; P=0.03).49

A meta-analysis of the efficacy and safety of finerenone in patients with CKD concluded that, compared with placebo, finerenone significantly reduced the uACR (mean difference: -0.30; P<0.05) while decreasing the risk of cardiovascular disorders and increasing the risk of hyperkalaemia (RR=0.92; 95% CI=0.85-0.99; P<0.05 and RR=2.04; 95% CI=1.77-2.34; P<0.00001, respectively).50

Statement 12: Patients with type 2 diabetes mellitus and chronic kidney disease who have not achieved individualised glycaemic targets despite metformin and sodium-glucose cotransporter-2 inhibitor treatment or who cannot use those medications can be treated with glucagon-like peptide-1 receptor agonists.

A 2022 trial compared the effectiveness of four commonly used glucose-lowering medications in patients with T2DM, namely, insulin glargine U-100, glimepiride (sulfonylurea), liraglutide (glucagon-like peptide-1 receptor agonist [GLP-1 RA]), and sitagliptin (dipeptidyl peptidase-4 inhibitor).51 All four medications reduced glycated haemoglobin levels in combination with metformin, although glargine and liraglutide were modestly more effective in terms of achieving and maintaining glycaemic targets.51 Severe hypoglycaemia was rare in all treatment groups: glimepiride (2.2% of participants), glargine (1.3%), liraglutide (1.0%), and sitagliptin (0.7%).51 There were no differences in the rates of major adverse cardiac events, hospitalisation for heart failure, cardiovascular mortality, and all-cause mortality.51

A meta-analysis of randomised trials concluded that GLP-1 RAs are effective for cardiovascular and renal protection.52 Similarly, Sattar et al52 reported that GLP-1 RAs significantly reduced major adverse cardiac events by 14% (P<0.0001), all-cause mortality by 12% (P=0.0001), hospital admission for heart failure by 11% (P=0.013), and composite renal outcomes by 21% (P<0.0001), without increasing the risks of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. The cardiovascular and renal protective effects of GLP-1 RAs in patients with T2DM were confirmed by a second meta-analysis.46

The expert panel noted that all available evidence regarding the renal protective effects of GLP-1 RAs was derived from secondary analyses of cardiovascular outcome trials. However, there is an ongoing renal outcome–specific trial involving semaglutide to further investigate its effects on renal outcomes.

Statement 13: Non-diabetic chronic kidney disease patients with hypertension and a urine albumin-creatinine ratio of ≥200 mg/g (≥20 mg/mmol) should be treated with the maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker for blood pressure control and renal protection.

Angiotensin-converting enzyme inhibitors produce antihypertensive and renal protective effects while reducing proteinuria in non-diabetic nephropathy patients.53 The strong and consistent effects of ACEis in terms of slowing non-diabetic renal disease progression and decreasing blood pressure were confirmed in a meta-analysis of 11 randomised controlled trials.53

Coronel et al54 showed that irbesartan usage in non-diabetic patients with advanced CKD had effects on disease progression and blood pressure control similar to those of ACEis. Irbesartan also showed a stronger antiproteinuric effect compared with ACEis.54

Statement 14: Non-diabetic chronic kidney disease patients with an estimated glomerular filtration rate of ≥20 mL/min/1.73 m² and a urine albumin-creatinine ratio of ≥200 mg/g (≥20 mg/mmol) can be treated with a sodium-glucose cotransporter-2 inhibitor for renal and cardiovascular protection.

There is increasing evidence of the renal and cardiovascular protective effects of SGLT2is in non-diabetic patients with CKD. The renal protective effects of SGLT2is in patients with CKD were demonstrated in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease)41 and EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) trials.55 In the DAPA-CKD trial, dapagliflozin conferred a composite renal benefit (sustained eGFR decline of ≥50%, end-stage kidney disease, or death from renal causes; hazard ratio [HR]=0.56; 95% CI=0.45-0.68) in CKD patients with or without T2DM, an eGFR of 25 to 75 mL/min/1.73 m², and an uACR of 200 to 5000 mg/g (20-500 mg/mmol).41 Dapagliflozin also reduced all-cause mortality (HR=0.69; 95% CI=0.53-0.88).41 In the EMPA-KIDNEY trial, empagliflozin lowered the risk of kidney disease progression (defined as end-stage kidney disease, sustained eGFR decline to <10 mL/min/1.73 m², sustained eGFR decline of ≥40% from baseline, or death from renal causes; HR=0.71; 95% CI=0.62-0.81).55

Cardiovascular outcome trials showed that SGLT2is lowered the risks of heart failure hospitalisation and cardiovascular death by 30% to 35%.56 The results of the DAPA-CKD36 and EMPA-KIDNEY trials55 confirmed that SGLT2is can benefit patients with CKD, regardless of T2DM status. Dapagliflozin is the only SGLT2i with evidence of reducing all-cause mortality in a clinical trial (ie, DAPA-CKD) specifically focused on patients with CKD, with or without T2DM. In the DAPA-CKD trial,41 dapagliflozin lowered the composite risk of death from cardiovascular causes or hospitalisation for heart failure (HR=0.71; 95% CI=0.55-0.92).

Conclusion

Chronic kidney disease is a major health problem worldwide and in Hong Kong. Our consensus group developed this initial set of recommendations to familiarise Hong Kong clinicians with strategies for early CKD management. In this article, we discussed the current status of CKD management in Hong Kong; based on the limited local evidence and international evidence, we also highlighted the need for early diagnosis and treatment of CKD. Finally, we recommended appropriate treatment strategies for patients with CKD who present with co-morbid diabetes or hypertension.

Author contributions

All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

RCW Ma has received research funding from AstraZeneca, Bayer, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Roche Diagnostics, and Tricida Inc for carrying out clinical trials or studies, and from AstraZeneca, Bayer, Boehringer Ingelheim, and Merck for speaker honoraria or consultancy on advisory boards. All proceeds have been donated to The Chinese University of Hong Kong to support diabetes research. CC Szeto receives research support from AstraZeneca, Boehringer Ingelheim, and Otsuka Pharmaceutical. KCB Tan has participated in advisory boards and speakers bureaus for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Sanofi. MCS Wong is an advisory committee member for Pfizer; an external expert for GlaxoSmithKline Limited, a member of the advisory board of AstraZeneca, and an honorary advisor of GenieBiome Limited. He was paid consultancy fees for providing research advice and delivering talks. Also, as an editor of the journal, he was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Acknowledgement

English language editing and writing support, funded by an unrestricted educational grant from AstraZeneca Hong Kong Limited, was provided by Mr Poh Sien Ooi of MIMS Medica Sdn Bhd and Dr Mita Pabari of MIMS (Hong Kong) Limited. The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.

Disclaimer

This article references the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Please note that the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease57 has been published during the development of this work. As such, readers are advised to consult the most recent KDIGO guideline for the latest recommendations and information on chronic kidney disease.

References

1. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Supp (2011) 2022;12:7-11. Crossref

2. Non-communicable Disease Branch, Centre for Health Protection, Department of Health, Hong Kong SAR Government. Report of Population Health Survey 2020-22 (Part I). 2022. Available from: https://www.chp.gov.hk/files/pdf/dh_phs_2020-22_part_1_report_eng_rectified.pdf. Accessed 14 May 2023.

3. Kidney Disease: Improving Global Outcomes. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:1-150.

4. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int 2022;102(5S):S1-127. Crossref

5. Shlipak MG, Tummalapalli SL, Boulware LE, et al. The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2021;99:34-47. Crossref

6. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int 2021;100(4S):S1-276. Crossref

7. Banerjee D, Winocour P, Chowdhury TA, et al. Management of hypertension in patients with diabetic kidney disease: summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021. Kidney Int Rep 2022;7:681-7. Crossref

8. Liew A, Bavanandan S, Prasad N, et al. Asian Pacific Society of Nephrology clinical practice guideline on diabetic kidney disease—executive summary. Nephrology (Carlton) 2020;25 Suppl 2:3-11. Crossref

9. Howick J, Chalmers I, Glasziou P, et al. The 2011 Oxford CEBM Evidence Levels of Evidence (Introductory Document). 2011. Available from: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence. Accessed 27 May 2024.

10. OCEBM Levels of Evidence Working Group. Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Available from: https://www.cebm.ox.ac.uk/files/levels-of-evidence/cebm-levels-of-evidence-2-1.pdf. Accessed 27 Aug 2024.

11. Leung CB, Cheung WL, Li PK. Renal registry in Hong Kong—the first 20 years. Kidney Int Suppl (2011) 2015;5:33-8. Crossref

12. Mok KY, Chan PF, Lai LK, Chow KL, Chao DV. Prevalence of diabetic nephropathy among Chinese patients with type 2 diabetes mellitus and different categories of their estimated glomerular filtration rate based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in primary care in Hong Kong: a cross-sectional study. J Diabetes Metab Disord 2019;18:281-8. Crossref

13. Tang SC, Wong AK, Mak SK. Clinical practice guidelines for the provision of renal service in Hong Kong: general nephrology. Nephrology (Carlton) 2019;24 Suppl 1:9-26. Crossref

14. Seidu S, Barrat J, Khunti K. Clinical update: the important role of dual kidney function testing (ACR and eGFR) in primary care: identification of risk and management in type 2 diabetes. Prim Care Diabetes 2020;14:370-5. Crossref

15. Heerspink HJ, Greene T, Tighiouart H, et al. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol 2019;7:128-39. Crossref

16. Vassalotti JA, Centor R, Turner BJ, et al. Practical approach to detection and management of chronic kidney disease for the primary care clinician. Am J Med 2016;129:153-62.e7. Crossref

17. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12. Crossref

18. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med 2012;156:785-95. Crossref

19. Jafar TH, Chaturvedi N, Hatcher J, Levey AS. Use of albumin-creatinine ratio and urine albumin concentration as a screening test for albuminuria in an Indo-Asian population. Nephrol Dial Transplant 2007;22:2194-200. Crossref

20. Kulasooriya PN, Bandara SN, Priyadarshani C, et al. Prediction of microalbuminuria by analysing total urine protein-to-creatinine ratio in diabetic nephropathy patients in rural Sri Lanka. Ceylon Med J 2018;63:72-7. Crossref

21. Kamińska J, Dymicka-Piekarska V, Tomaszewska J, Matowicka-Karna J, Koper-Lenkiewicz OM. Diagnostic utility of protein-to-creatinine ratio (P/C ratio) in spot urine sample within routine clinical practice. Crit Rev Clin Lab Sci 2020;57:345-64. Crossref

22. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet 2017;389:1238-52. Crossref

23. Tsang JY, Blakeman T, Hegarty J, Humphreys J, Harvey G. Understanding the implementation of interventions to improve the management of chronic kidney disease in primary care: a rapid realist review. Implement Sci 2016;11:47. Crossref

24. Smekal MD, Tam-Tham H, Finlay J, et al. Patient and provider experience and perspectives of a risk-based approach to multidisciplinary chronic kidney disease care: a mixed methods study. BMC Nephrol 2019;20:110. Crossref

25. Sperati CJ, Soman S, Agrawal V, et al. Primary care physicians’ perceptions of barriers and facilitators to management of chronic kidney disease: a mixed methods study. PLoS One 2019;14:e0221325. Crossref

26. Elihimas Júnior UF, Elihimas HC, Lemos VM, et al. Smoking as risk factor for chronic kidney disease: systematic review [in English, Portuguese]. J Bras Nefrol 2014;36:519-28. Crossref

27. Xue L, Lou Y, Feng X, Wang C, Ran Z, Zhang X. Prevalence of chronic kidney disease and associated factors among the Chinese population in Taian, China. BMC Nephrol 2014;15:205. Crossref

28. Lin YC, Lai YJ, Lin YC, et al. Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR-TMU study. J Cachexia Sarcopenia Muscle 2019;10:756-66. Crossref

29. Milam RH. Exercise guidelines for chronic kidney disease patients. J Ren Nutr 2016;26:e23-5. Crossref

30. Mallamaci F, Pisano A, Tripepi G. Physical activity in chronic kidney disease and the EXerCise Introduction To Enhance trial. Nephrol Dial Transplant 2020;35 (Suppl 2):ii18-22. Crossref

31. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602-13. Crossref

32. Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev 2006;2006:CD006257. Crossref

33. Song YH, Cai GY, Xiao YF, Liu JQ, Chen XM. The clinical characteristics and antihypertensive medications for mortality of elderly hospitalized hemodialysis patients: a multicenter retrospective study in China. Saudi J Kidney Dis Transpl 2021;32:637-44. Crossref

34. Zhao M, Qu H, Wang R, et al. Efficacy and safety of dual vs single renin-angiotensin-aldosterone system blockade in chronic kidney disease: an updated meta-analysis of randomized controlled trials. Medicine (Baltimore) 2021;100:e26544. Crossref

35. Palevsky PM, Zhang JH, Seliger SL, Emanuele N, Fried LF; VA NEPHRON-D Study. Incidence, severity, and outcomes of AKI associated with dual renin-angiotensin system blockade. Clin J Am Soc Nephrol 2016;11:1944-53. Crossref

36. McMurray JJ, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. Crossref

37. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24. Crossref

38. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57. Crossref

39. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57. Crossref

40. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306. Crossref

41. Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46. Crossref

42. Bakris G, Oshima M, Mahaffey KW, et al. Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m²: subgroup analysis of the randomized CREDENCE trial. Clin J Am Soc Nephrol 2020;15:1705-14. Crossref

43. Chertow GM, Vart P, Jongs N, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol 2021;32:2351-61. Crossref

44. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129-39. Crossref

45. Li N, Zhou G, Zheng Y, et al. Effects of SGLT2 inhibitors on cardiovascular outcomes in patients with stage 3/4 CKD: a meta-analysis. PLoS One 2022;17:e0261986. Crossref

46. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021;372:m4573. Crossref

47. Cherney DZ, Cooper ME, Tikkanen I, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 2018;93:231-44. Crossref

48. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020;383:2219-29. Crossref

49. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021;385:2252-63. Crossref

50. Fu Z, Geng X, Chi K, et al. Efficacy and safety of finerenone in patients with chronic kidney disease: a systematic review with meta-analysis and trial sequential analysis. Ann Palliat Med 2021;10:7428-39. Crossref

51. GRADE Study Research Group; Nathan DM, Lachin JM, et al. Glycemia reduction in type 2 diabetes—glycemic outcomes. N Engl J Med 2022;387:1063-74. Crossref

52. Sattar N, Lee MM, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653-62. Crossref

53. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 2001;135:73-87. Crossref

54. Coronel F, Cigarrán S, García-Mena M, Herrero J, Calvo N, Pérez-Flores I. Irbesartan in hypertensive non-diabetic advanced chronic kidney disease. Comparative study with ACEi [in Spanish]. Nefrologia 2008;28:56-60.

55. The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023;388:117-27. Crossref

56. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 2021;107:1032-8. Crossref

57. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2024;105(4S):S117-314. Crossref

2024 Hong Kong College of Obstetricians and Gynaecologists guideline on antenatal screening and management of hepatitis B for prevention of mother-to-child transmission

Hong Kong Med J 2024 Oct;30(5):400–8 | Epub 30 Apr 2024

https://doi.org/10.12809/hkmj2311218

MEDICAL PRACTICE CME

2024 Hong Kong College of Obstetricians and Gynaecologists guideline on antenatal screening and management of hepatitis B for prevention of mother-to-child transmission

KW Cheung, MD¹; PL So, MB, BS²; Loey LY Mak, MD³; Florrie NY Yu, MB, ChB⁴; WL Cheung, MB, BS⁵; SL Mok, MB, BS⁵; TY Leung, MD⁷; Mimi TY Seto, MB, BS¹

¹ Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China

² Department of Obstetrics and Gynaecology, Tuen Mun Hospital, Hong Kong SAR, China

³ Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China

⁴ Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR, China

⁵ Department of Obstetrics and Gynaecology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

⁶ Department of Obstetrics and Gynaecology, Princess Margaret Hospital, Hong Kong SAR, China

⁷ Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China

Corresponding author: Dr KW Cheung (kawang@hku.hk)

Full paper in PDF

Abstract

Hepatitis B virus (HBV) infection remains a global threat and causes a substantial disease burden. The World Health Organization has set a goal to eliminate viral hepatitis as a public health threat by 2030. Mother-to-child transmission (MTCT) is the main route of HBV transmission. Most MTCT cases can be prevented by timely active and passive immunisation at birth, but failed immunoprophylaxis in infants continues to occur among women with a high viral load during pregnancy. Hepatitis B virus disease activity in infected mothers should be assessed during early pregnancy, and multidisciplinary management with antiviral medication should be offered to women with a high viral load. In these guidelines, we present management strategies for HBV-infected pregnant women that are intended to reduce the risk of MTCT in Hong Kong.

[Abstract in Chinese]

Introduction

Hepatitis B virus (HBV) infection is a key cause of liver diseases associated with high rates of morbidity and mortality. The World Health Organization (WHO) estimated that in 2019, 296 million people had chronic HBV infections and there were approximately 820 000 HBV-related deaths, mostly due to cirrhosis and hepatocellular carcinoma.1 2 The estimated global prevalence of HBV infection in 2019 was 3.8%.1 2 To eliminate viral hepatitis as a public health threat by 2030, the WHO has outlined a set of global impact and service coverage targets, including a prevalence of ≤0.1% for hepatitis B surface antigen (HBsAg) among children 5 years of age; this target will help eliminate mother-to-child transmission (MTCT) of HBV.3 4

Prevention is the main strategy for HBV elimination because there is currently no complete cure for HBV. In high endemic regions, MTCT, also referred to as vertical transmission, remains the primary route of HBV transmission; the risk of chronicity after HBV infection is 90% in the perinatal period, compared with 5% in adulthood.5 Hepatitis B virus can also be spread through horizontal transmission, especially during early childhood. Pregnancy offers an ideal occasion to eliminate HBV through proper screening and timely treatment for asymptomatic HBV-infected mothers and their infants. Universal timely neonatal hepatitis B vaccination is the most important intervention for reducing MTCT of HBV. The administration of hepatitis B immunoglobulin (HBIG) for infants born to HBV-infected mothers, as well as maternal peripartum prophylaxis with antivirals, would provide additional protection against MTCT of HBV.

In these guidelines, we focus on the management of HBV-infected pregnant women for reduction of MTCT risk, which is a core strategy in the Hong Kong Viral Hepatitis Action Plan 2020-2024.6

Prevention of mother-to-child transmission by active and passive immunisation

Evidence to support active and passive immunisation

Neonatal hepatitis B vaccination remains the most effective measure for prevention of MTCT; it can reduce the rate of MTCT from 90% to 21% in hepatitis B e antigen (HBeAg)–positive women and from 30% to 2.6% in HBeAg-negative women.7 The addition of a birth dose of HBIG can further reduce the risk to 6% in HBeAg-positive women and 1% in HBeAg-negative women.7 A delayed birth dose of hepatitis B vaccination and failed administration of HBIG at birth have been associated with immunoprophylaxis failure (IF) [see below].8

In Hong Kong, infants born to HBV-infected mothers have received hepatitis B vaccination and HBIG since 1984. Neonatal vaccination was extended to all infants, regardless of their mothers’ HBV infection status, in 1988. The implementation of a universal childhood hepatitis B vaccination programme has led to a continuous reduction in HBV prevalence in Hong Kong, achieving coverage rates of >99% for the birth dose, as well as the second and third doses of vaccine.9 Thus, HBsAg prevalence among the antenatal population in Hong Kong gradually decreased from 10.8% in 1992 to 2.5% in 2022.10

Recommendations of the World Health Organization

The WHO recommends the followings11 12 13:

All pregnant women should undergo HBsAg testing at least once, as early in their pregnancy as possible.

All infants should receive their first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 hours after delivery.

The birth dose should be followed by two or three doses to complete the primary vaccination series.

Recommendations of the Hong Kong College of Obstetricians and Gynaecologists

The Hong Kong College of Obstetricians and Gynaecologists (HKCOG) recommends the followings:

All pregnant women should undergo HBsAg screening in early pregnancy.

All infants should receive the birth dose of hepatitis B vaccine as soon as possible (within 24 hours after delivery), followed by the second and third doses at 1 month and 6 months of age, respectively.

Infants born to HBV-infected mothers should receive the birth dose of HBIG when they receive the birth dose of hepatitis B vaccine.

Immunoprophylaxis failure

Definition and prevalence

Among infants who undergo active and passive immunisation for hepatitis B, some do not develop adequate antibodies. Immunoprophylaxis failure is defined as persistent HBsAg seropositivity in infants when tested at the ages of 9 to 12 months, or 1 to 2 months after completion of the vaccination series.14 The reported rates of IF range from 1% to 9% in the literature.15 In Hong Kong, a single-centre study revealed an IF rate of 2.5% (3/121) in 2001.16 Another prospective study involving five maternity units in Hong Kong showed that the IF rate was 1.1% (7/641) between 2014 and 2016.17

Possible mechanisms

The possible mechanisms of IF are outlined in Figure 1.18 Germline infection is a possibility because HBV DNA has been detected in sperm and ova of people with HBV infection, as well as embryos from male HBsAg-positive/female HBsAg-negative couples or male HBsAg-negative/female HBsAg-positive couples.19 20 21 Transplacental infection is another possible mechanism of IF. The gradual decreases in the detection rates of HBV markers and layers of affected placental cells from the maternal side to the fetal side support the hypothesis that progressive HBV placental infection could lead to in utero infection.22 23 Additionally, invasive prenatal tests can cause HBV inoculation from maternal blood, especially in HBsAg-positive pregnant women with a high viral load. A retrospective cohort study showed that the risk of IF after amniocentesis was higher in women with an HBV DNA level of ≥7 log₁₀IU/mL than in women with an HBV DNA level of <7 log₁₀IU/mL (10.8% vs 0%; P=0.004).24 During vaginal delivery, contact with vaginal secretions harbouring HBV may also increase the risk of vertical transmission. Thus, a delay in vaccination to infants at birth increases the risk of IF.

Figure 1. Mechanisms of immunoprophylaxis failure18

Risk factors

The risk of IF mainly depends on the degree of viral replication, any invasive prenatal procedures, and the availability and timing of the birth dose vaccine and HBIG. Immunoprophylaxis failure is strongly correlated with the viral load (ie, DNA level) in maternal blood during the antenatal and perinatal periods.21 25 Although non-infectious HBeAg is produced during viral replication, it is associated with high HBV DNA levels. Thus, both maternal HBeAg-positive status and a high maternal HBV DNA level are risk factors for IF.17 26 27 In a multicentre study involving 641 women and 654 infants in Hong Kong, all seven cases of IF were born to HBeAg-positive mothers with an HBV DNA level of >7.2 log₁₀IU/mL.17 To reduce the maternal viral load and the risk of IF, maternal use of antivirals as peripartum prophylaxis should be considered.

Antenatal antiviral prophylaxis to prevent immunoprophylaxis failure

Evidence of the effectiveness of antenatal antiviral treatment

Immunoprophylaxis failure occurs in infants of highly viraemic mothers despite timely birth doses of hepatitis B vaccine and HBIG. Similar to human immunodeficiency virus and herpes simplex virus, antenatal antiviral treatment can suppress the viral load and reduce the risk of MTCT.28 29

A randomised controlled trial involving 200 HBsAg-positive pregnant women showed that daily oral intake of 300-mg tenofovir disoproxil fumarate (TDF) from 30 to 32 weeks of gestation could significantly lower maternal HBV DNA at delivery and thus reduce the rates of IF (intention-to-treat analysis: 5% vs 18%, P=0.007; per-protocol analysis: 0% vs 7%, P=0.01).30 Although a subsequent multicentre, double-blinded, randomised controlled trial involving 331 women did not show any significant difference in the rate of IF between women receiving TDF and placebo beginning at 28 weeks of gestation (0 vs 2%; P=0.12), the zero MTCT rate in the TDF group confirmed the efficacy of TDF intake.31 The inclusion of women with lower viral loads and the timely administration of hepatitis B vaccine and HBIG (median time: approximately 1.3 hours after birth) might explain the comparable IF rates between the TDF and placebo groups.32

In a meta-analysis, the pooled odds ratios derived from randomised controlled trials of the efficacy of peripartum antiviral prophylaxis for reducing MTCT risk were 0.10 for TDF (95% confidence interval [CI]=0.03-0.35), 0.16 for lamivudine (95% CI=0.10-0.29), and 0.14 for telbivudine (95% CI=0.09-0.21).33 Although these three antivirals are highly effective in preventing MTCT and can be safely used during pregnancy without maternal or infant safety concerns, TDF is recommended because it has a high threshold for drug resistance.11 33 34

World Health Organization and international recommendations

According to the WHO, pregnant women who test positive for HBV infection (ie, HBsAg-positive) and have an HBV DNA level of ≥5.3 log₁₀U/mL (≥200 000 IU/mL) should receive TDF prophylaxis from the 28th week of pregnancy until birth or later to prevent MTCT of HBV. This prophylaxis should be provided along with the three-dose hepatitis B vaccination for infants, including a timely birth dose.11 This recommendation is consistent with clinical guidelines from other international bodies including the American Association for the Study of Liver Diseases (AASLD),35 the European Association for the Study of the Liver,36 and the Asian Pacific Association for the Study of the Liver (Table).37 Some experts have also suggested initiation of TDF early in the second trimester for individuals with a high risk of preterm birth or an HBV DNA level of ≥8 log₁₀IU/mL (≥100 000 000 IU/mL).15

Use of antenatal antiviral treatment to prevent immunoprophylaxis failure in Hong Kong

To further reduce the risk of MTCT of HBV, since August 2020, all birthing hospitals under the Hospital Authority have been referring HBV-infected pregnant women with a high HBV viral load (ie, an HBV DNA level of >200 000 IU/mL) to hepatology clinics and hepatitis nurse clinics for assessment and consideration of initiating antiviral prophylaxis by the third trimester. Other HBV-infected pregnant women are also referred to the appropriate level of care for routine HBV management.

Recommendations of the Hong Kong College of Obstetricians and Gynaecologists

The HKCOG recommends the followings (Fig 2):

Hepatitis B virus–infected pregnant women should undergo assessments of HBV DNA level, HBeAg status, and baseline liver function in early pregnancy to determine the need for antiviral prophylaxis to prevent MTCT of HBV and the need for antiviral treatment to manage maternal indications.38 39 40

There is no need for repeat HBV DNA quantification in later stages of pregnancy. Hepatitis B virus DNA levels typically remain stable during pregnancy and similar cut-offs could be used to predict the risk of IF.40

For women with an HBV DNA level of >5.3 log₁₀IU/mL (>200 000 IU/mL), multidisciplinary care involving hepatologists is advised to discuss the indications and safety of antenatal TDF to reduce the risk of IF.11

For women with an HBV DNA level of ≤5.3 log₁₀IU/mL (≤200 000 IU/mL), reminders should be established for long-term regular monitoring and follow-up after delivery, in accordance with established protocols for patients with chronic HBV infection.34 41

Figure 2. The Hong Kong College of Obstetricians and Gynaecologists recommended pathway for managing hepatitis B virus–infected women during pregnancy and after delivery

Antenatal management and the mode of delivery

There is conflicting evidence regarding the associations of HBV infection with adverse pregnancy outcomes. The results of some studies have suggested an increased risk of gestational diabetes and preterm birth,42 43 44 45 46 47 whereas the results of other studies have not supported this association.48 49 50 More data are needed to evaluate the impacts of viral load on pregnancy complications, but the available evidence does not warrant additional antenatal surveillance. Although there is a theoretical risk of intrauterine HBV exposure after chorionic villus sampling, fetal scalp blood sampling, and the use of fetal scalp electrodes, data concerning the risk of vertical transmission after these procedures are scarce. The effects of viral load on these procedures are also unknown, but the risk of vertical transmission is likely to be smaller in women with a lower viral load. Women should be counselled about this limited evidence, and these procedures generally should be avoided. For amniocentesis, the risk of IF is low when the viral load is <7 log₁₀IU/mL. In one study, transplacental amniocentesis did not increase the rate of IF, but this finding was based on a small number of cases.51 A reasonable approach comprises implementing transamniotic amniocentesis while avoiding transplacental puncture. Caesarean delivery should not be offered solely to prevent MTCT of HBV, and the mode of delivery should be based on obstetric indications.

Breastfeeding, maternal follow-up, and neonatal follow-up after delivery

Breastfeeding is not contraindicated for mothers who continue to receive TDF. Although a low level of TDF can be detected in breast milk, there is no evidence that this low level leads to adverse outcomes.35 Infants should receive a routine three-dose course of hepatitis B vaccination at birth, 1 month of age, and 6 months of age.

The WHO emphasises the need for postvaccination serological testing (PVST) of infants born to HBsAg-positive mothers.12 This testing includes testing of antibodies to HBsAg, as well as HBsAg itself, at 9 to 12 months of age (or 1 to 2 months after the final dose of the vaccine series, if the series is delayed).14 It allows vaccine non-responders to receive a booster dose of vaccine to reduce the risk of horizontal transmission. Additionally, infants with IF should be monitored by healthcare professionals to identify liver conditions and potential complications (eg, cirrhosis and hepatocellular carcinoma).52 Finally, it can provide valuable information concerning the effectiveness of MTCT prevention strategies.

The Department of Health and the Hospital Authority established a collaboration to provide a PVST service, initiated in January 2022, for infants born to HBV-infected mothers in April 2021 or later; covered infants must attend the Maternal and Child Health Centres of the Department of Health. Beginning in June 2022, mop-up PVST was arranged for infants born in or after October 2020; testing completion was required before the age of 24 months. Blood collection for PVST is conducted in Hong Kong Children’s Hospital at 9 to 12 months of age, and up to the age of 24 months (or 1 to 2 months after the final dose of hepatitis B vaccine), to identify HBV-infected infants and infants with an inadequate immune response to the primary series of hepatitis B vaccine; these infants are eligible for re-vaccination. Hepatitis B virus–infected infants are referred to paediatric units within the Hospital Authority for management. Infants who have an inadequate or absent immune response after the second course of hepatitis B vaccine are referred to the Hong Kong Children’s Hospital for further assessment.

Lack of continuity of care has been common in Hong Kong; for example, 52.6% of HBV-infected individuals did not receive any medical care within 1 year after delivery.53 Mothers with chronic HBV infection should undergo regular monitoring of disease activity and surveillance of HBV complications, in accordance with established protocols for patients with chronic HBV infection.34 41

Indications for and duration of continued antiviral treatment after delivery

Limited evidence to support postnatal antiviral treatment

Among antiviral-treated pregnant women with HBV infection, alanine aminotransferase (ALT) flares can occur during pregnancy (10.9%), although most occur in the postpartum period (45.7%), as demonstrated by a prospective study of 303 Chinese pregnant women.54 After cessation of prophylactic antivirals, the HBV DNA level rebounded in nearly all of the women, but only 73% of the women developed ALT flares and 21% of the women required retreatment.55

In a study of 91 highly viraemic HBV-infected mothers, the incidences of postpartum flares were similar regardless of whether antivirals were stopped at 2 weeks (50%, n=22/44) or 12 weeks (40%, n=17/43) after delivery. Additionally, there were no significant differences between the two groups in terms of the timing of flare onset (8.2 vs 10.2 weeks), peak ALT level (229 U/L vs 209 U/L), proportion of severe flares (ie, ALT rise ≥20 times the upper limit of normal of 19 U/L) [14% vs 12%], and rate of spontaneous resolution of ALT flares (75% vs 53%).56 Another multicentre study showed that the rates of postpartum ALT flares were similar between women who stopped treatment at delivery (33%, n=3/9) and those who continued treatment for a longer duration (22%, n=4/18).57

Overall, there is no evidence that prolonging the duration of prophylactic antiviral treatment after delivery would reduce the rate or severity of postpartum ALT flares.

Other international recommendations concerning postnatal antiviral treatment

For HBV-infected pregnant women receiving antiviral prophylaxis during pregnancy solely to prevent MTCT (ie, without maternal indications), the recommended duration of antiviral therapy is not well-defined and varies among guidelines. The European Association for the Study of the Liver guidelines recommend continuing prophylactic antiviral treatment until 12 weeks after delivery.36 In contrast, the AASLD guidelines recommend stopping prophylactic antiviral treatment at delivery or continuing until 12 weeks postpartum. Notably, the AASLD guidelines are the only international guidelines that emphasise close monitoring of serum ALT every 3 months for up to 6 months after delivery.35 The Asian Pacific Association for the Study of the Liver guidelines also recommend stopping prophylactic antiviral treatment at delivery or continuing until 12 weeks after delivery (Table).37

Table. Recommendations from various guidelines for initiating antiviral treatment (tenofovir disoproxil fumarate) to prevent immunoprophylaxis failure

Recommendations of the Hong Kong College of Obstetricians and Gynaecologists

The HKCOG recommends the followings:

Multidisciplinary care is essential to ensure that women are counselled about the existing evidence and allowed to engage in thorough discussion with the treating physician regarding the risks and benefits of the timing for cessation of prophylactic treatment.

Importantly, although most flares are mild and spontaneously resolve, liver function tests should be performed every 3 months for 6 months after cessation of prophylactic antiviral treatment.35

Hepatitis B virus–infected pregnant women receiving antiviral treatment for maternal indications should continue therapy, even after delivery, and be managed in accordance with standard protocols.35 36 37 41

Author contributions

Conflicts of interest

LLY Mak has served as an advisor for Gilead Sciences. Other authors have disclosed no conflicts of interest.

Acknowledgement

The guidelines were produced by the Hong Kong College of Obstetricians and Gynaecologists as an educational aid and reference for obstetricians and gynaecologists practising in Hong Kong. These guidelines do not define a standard of care, nor are they intended to dictate an exclusive course of management. They present recognised clinical methods and techniques for practitioners to consider incorporating into their practices. It is understood that clinical management may vary and must always be responsive to the needs of individual patients, as well as the resources and limitations unique to each institution or type of practice. These guidelines also highlight areas of clinical uncertainty in which further research may be warranted.

The authors thank members of the Department of Health and the Hospital Authority for providing expert comments on the guidelines.

Funding/support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

1. World Health Organization. Hepatitis B. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b. Accessed 1 Oct 2023.

2. World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016–2021: actions for impact. Web Annex 1: Key data at a glance. 2021. Available from: https://iris.who.int/bitstream/handle/10665/342808/9789240030985-eng.pdf. Accessed 1 Oct 2023.

3. World Health Organization. Global Health Sector Strategy on viral hepatitis 2016-2021: towards ending viral hepatitis. 2016. Available from: http://apps.who.int/iris/bitstream/handle/10665/246177/WHO-HIV-2016.06-eng.pdf?sequence=1. Accessed 1 Oct 2023.

4. World Health Organization. Global Hepatitis Report 2017. 2017. Available from: http://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-eng;jsessionid=B32461CA5A37D9C9D7A90BCE32C43F92?sequence=1. Accessed 1 Oct 2023.

5. Edmunds WJ, Medley GF, Nokes DJ, Hall AJ, Whittle HC. The influence of age on the development of the hepatitis B carrier state. Proc Biol Sci 1993;253:197-201. Crossref

6. Department of Health, Hong Kong SAR Government. Hong Kong Viral Hepatitis Action Plan 2020-2024. 2020. Available from: https://www.hepatitis.gov.hk/doc/action_plan/Action%20Plan_Full%20Version_PDF_en.pdf. Accessed 1 Oct 2023.

7. Isaacs D, Kilham HA, Alexander S, Wood N, Buckmaster A, Royle J. Ethical issues in preventing mother-to-child transmission of hepatitis B by immunisation. Vaccine 2011;29:6159-62. Crossref

8. Kang W, Ding Z, Shen L, et al. Risk factors associated with immunoprophylaxis failure against mother to child transmission of hepatitis B virus and hepatitis B vaccination status in Yunnan province, China. Vaccine 2014;32:3362-6. Crossref

9. Department of Health, Hong Kong SAR Government Surveillance of Viral Hepatitis in Hong Kong: 2021 Report. 2022. Available from: https://www.hepatitis.gov.hk/english/health_professionals/files/hepsurv21.pdf. Accessed 1 Oct 2023.

10. Viral Hepatitis Control Office, Department of Health, Hong Kong SAR Government. Mother-to-child transmission of hepatitis B. 2023. Available from: https://www.hepatitis.gov.hk/english/mtct/maternal_transmission_of_hepatitis_b.html. Accessed 1 Oct 2023.

11. World Health Organization. Prevention of mother-to-child transmission of hepatitis B virus: guidelines on antiviral prophylaxis in pregnancy. 2020. Available from: https://www.who.int/publications/i/item/978-92-4-000270-8. Accessed 1 Oct 2023.

12. World Health Organization. Hepatitis B vaccines: WHO position paper–July 2017. 2017. Available from: https://www.who.int/publications/i/item/WER9227 . Accessed 1 Oct 2023.

13. World Health Organization. Guidelines on hepatitis B and C testing. 2017. Available from: https://www.who.int/publications/i/item/9789241549981. Accessed 1 Oct 2023.

14. Schillie S, Murphy TV, Fenlon N, Ko S, Ward JW. Update: shortened interval for postvaccination serologic testing of infants born to hepatitis B–infected mothers. MMWR Morb Mortal Wkly Rep 2015;64:1118-20. Crossref

15. Terrault NA, Levy MT, Cheung KW, Jourdain G. Viral hepatitis and pregnancy. Nat Rev Gastroenterol Hepatol 2021;18:117-30. Crossref

16. Tse K, Siu SL, Yip KT, et al. Immuno-prophylaxis of babies borne to hepatitis B carrier mothers. Hong Kong Med J 2006;12:368-74.

17. Cheung KW, Seto MT, Kan AS, et al. Immunoprophylaxis failure of infants born to hepatitis B carrier mothers following routine vaccination. Clin Gastroenterol Hepatol 2018;16:144-5. Crossref

18. Cheung KW, Seto MT, Wong SF. Towards complete eradication of hepatitis B infection from perinatal transmission: review of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2013;169:17-23. Crossref

19. Huang JM, Huang TH, Qiu HY, et al. Effects of hepatitis B virus infection on human sperm chromosomes. World J Gastroenterol 2003;9:736-40. Crossref

20. Ye F, Yue Y, Li S, et al. Presence of HBsAg, HBcAg, and HBVDNA in ovary and ovum of the patients with chronic hepatitis B virus infection. Am J Obstet Gynecol 2006;194:387-92. Crossref

21. Nie R, Jin L, Zhang H, Xu B, Chen W, Zhu G. Presence of hepatitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization. Fertil Steril 2011;95:1667-71. Crossref

22. Xu DZ, Yan YP, Zou S, et al. Role of placental tissues in the intrauterine transmission of hepatitis B virus. Am J Obstet Gynecol 2001;185:981-7. Crossref

23. Zhang SL, Yue YF, Bai GQ, Shi L, Jiang H. Mechanism of intrauterine infection of hepatitis B virus. World J Gastroenterol 2004;10:437-8. Crossref

24. Han Z, Zhang Y, Bai X, Yin Y, Xu C, Hou H. Mother-to-child transmission of hepatitis B virus after amniocentesis: a retrospective matched cohort study. Prenat Diagn 2019;39:431-40. Crossref

25. Hu XL, Zhou XP, Qian YL, Wu GY, Ye YH, Zhu YM. The presence and expression of the hepatitis B virus in human oocytes and embryos. Hum Reprod 2011;26:1860-7. Crossref

26. Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat 2012;19:e18-25. Crossref

27. Song YM, Sung J, Yang S, Choe YH, Chang YS, Park WS. Factors associated with immunoprophylaxis failure against vertical transmission of hepatitis B virus. Eur J Pediatr 2007;166:813-8. Crossref

28. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001;285:2083-93. Crossref

29. Foley E, Clarke E, Beckett VA, et al. Management of genital herpes in pregnancy. 2014. Available from: https:// www.rcog.org.uk/guidance/browse-all-guidance/other-guidelines-and-reports/management-of-genital-herpes-in-pregnancy/. Accessed 1 Oct 2023.

30. Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 2016;374:2324-34. Crossref

31. Jourdain G, Ngo-Giang-Huong N, Harrison L, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med 2018;378:911-23. Crossref

32. Cheung KW, Seto MT, Ng EH. Tenofovir to prevent perinatal transmission of hepatitis B. N Engl J Med 2018;378:2349-50. Crossref

33. Funk AL, Lu Y, Yoshida K, et al. Efficacy and safety of antiviral prophylaxis during pregnancy to prevent mother-to- child transmission of hepatitis B virus: a systematic review and meta-analysis. Lancet Infect Dis 2021;21:70-84. Crossref

34. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015. Available from: https://www.who.int/publications/i/item/9789241549059. Accessed 1 Oct 2023.

35. Terrault NA, Lok AS, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99. Crossref

36. European Association for the Study of the Liver; Williamson C, Nana M, et al. EASL Clinical Practice Guidelines on the management of liver diseases in pregnancy. J Hepatol 2023;79:768-828. Crossref

37. Kumar M, Abbas Z, Azami M, et al. Asian Pacific Association for the Study of Liver (APASL) guidelines: hepatitis B virus in pregnancy. Hepatol Int 2022;16:211-53. Crossref

38. Society for Maternal-Fetal Medicine (SMFM); Dionne-Odom J, Tita AT, Silverman NS. #38: Hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission. Am J Obstet Gynecol 2016;214:6-14. Crossref

39. Hui PW, Ng C, Cheung KW, Lai CL. Acceptance of antiviral treatment and enhanced service model for pregnant patients carrying hepatitis B. Hong Kong Med J 2020;26:318-22. Crossref

40. Cheung KW, Seto MT, So PL, et al. Optimal timing of hepatitis B virus DNA quantification and clinical predictors for higher viral load during pregnancy. Acta Obstet Gynecol Scand 2019;98:1301-6. Crossref

41. Hospital Authority and Department of Health, Hong Kong SAR Government. Management of adult patients with chronic hepatitis B in primary care. 2023. Available from: https://www.hepatitis.gov.hk/english/health_professionals/files/Management_of_Adult_Patients_with_CHB_in_Primary_Care_full_guidance.pdf. Accessed 1 Oct 2023.

42. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y. Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: a population-based cohort study. Lancet Glob Health 2017;5:e624-32. Crossref

43. Zheng S, Zhang H, Chen R, Yan J, Han Q. Pregnancy complicated with hepatitis B virus infection and preterm birth: a retrospective cohort study. BMC Pregnancy Childbirth 2021;21:513. Crossref

44. Zhao Y, Chen YL, Song HQ, et al. Effects of maternal hepatitis B surface antigen positive status on the pregnancy outcomes: a retrospective study in Xiamen, China, 2011-2018. PLoS One 2020;15:e0229732. Crossref

45. Ma X, Sun D, Li C, Ying J, Yan Y. Chronic hepatitis B virus infection and preterm labor (birth) in pregnant women—an updated systematic review and meta-analysis. J Med Virol 2018;90:93-100. Crossref

46. Lao TT, Chan BC, Leung WC, Ho LF, Tse KY. Maternal hepatitis B infection and gestational diabetes mellitus. J Hepatol 2007;47:46-50. Crossref

47. Giles ML, Davey MA, Wallace EM. Chronic hepatitis B infection and the risk of gestational diabetes: a cross-sectional study. BJOG 2020;127:1147-52. Crossref

48. Cheung KW, Wang W, So PL, et al. Relationship between viral load and pregnancy outcomes among hepatitis B carriers. Taiwan J Obstet Gynecol 2022;61:630-3. Crossref

49. Keramat A, Younesian M, Gholami Fesharaki M, et al. Inactive hepatitis B carrier and pregnancy outcomes: a systematic review and meta-analysis. Iran J Public Health 2017;46:468-74.

50. Lao TT, Sahota DS, Cheng YK, Law LW, Leung TY. Maternal hepatitis B surface antigen status and incidence of pre-eclampsia. J Viral Hepat 2013;20:343-9. Crossref

51. Han Z, Zhang Y, Bai X, Yin Y, Xu C, Hou H. Mother-to-child transmission of hepatitis B virus after amniocentesis: a retrospective matched cohort study. Prenat Diagn 2019;39:431-40. Crossref

52. Indolfi G, Easterbrook P, Dusheiko G, et al. Hepatitis B virus infection in children and adolescents. Lancet Gastroenterol Hepatol 2019;4:466-76. Crossref

53. Cheung KW, Seto MT, Wong D, et al. Pattern and predictors of medical care received by hepatitis B carriers during pregnancy and after delivery. Public Health 2019;168:36-42. Crossref

54. Wang X, Song A, Lin X, et al. Clinical characteristics of hepatitis flares during pregnancy and postpartum in Chinese chronic hepatitis B virus carriers—a prospective cohort study of 417 cases. Front Immunol 2022;13:1031291. Crossref

55. Samadi Kochaksaraei G, Castillo E, Sadler MD, et al. Real-world clinical and virological outcomes in a retrospective multiethnic cohort study of 341 untreated and tenofovir disoproxil fumarate–treated chronic hepatitis B pregnant patients in North America. Aliment Pharmacol Ther 2020;52:1707-16. Crossref

56. Nguyen V, Tan PK, Greenup AJ, et al. Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare. Aliment Pharmacol Ther 2014;39:1225-34. Crossref

57. Chang CY, Aziz N, Poongkunran M, et al. Serum aminotransferase flares in pregnant and postpartum women with current or prior treatment for chronic hepatitis B. J Clin Gastroenterol 2018;52:255-61. Crossref

Management of overactive bladder: consensus statements from the Hong Kong Urological Association and the Hong Kong Geriatrics Society

Hong Kong Med J 2024 Aug;30(4):310–9 | Epub 14 Aug 2024

https://doi.org/10.12809/hkmj2310921

MEDICAL PRACTICE CME

Management of overactive bladder: consensus statements from the Hong Kong Urological Association and the Hong Kong Geriatrics Society

William KK Wong, MB, BS, FHKCP¹; Raymond WM Kan, MB, BS, FHKAM (Surgery)²; PS Lam, MB, BS, FHKCP³; Phoebe MH Cheung, MB, ChB, FHKAM (Surgery)⁴; Elaine YL Cheng, LMCHK, FHKCP⁵; Terrilyn CT Pun, MB, BS, FHKAM (Surgery)⁶; Maria WS Tang, MB, ChB, FHKCP⁷; Clarence LH Leung, MB, ChB, FHKAM (Surgery)⁶; Sandy WS Woo, MB, BS, FHKCP⁸; TK Lo, MB, BS, FHKAM (Surgery)⁹; Peggy SK Chu, MB, BS, FCSHK⁹; Tony NH Chan, MB, BS, FHKCP¹⁰; Peter KF Chiu, MB, ChB, FHKAM (Surgery)¹¹

¹ Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China

² Division of Urology, Department of Surgery, Queen Elizabeth Hospital, Hong Kong SAR, China

³ Department of Rehabilitation and Extended Care, Wong Tai Sin Hospital, Hong Kong SAR, China

⁴ Division of Urology, Department of Surgery, Tseung Kwan O Hospital, Hong Kong SAR, China

⁵ Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong SAR, China

⁶ Division of Urology, Department of Surgery, Kwong Wah Hospital, Hong Kong SAR, China

⁷ Department of Medicine and Geriatrics, Shatin Hospital, Hong Kong SAR, China

⁸ Department of Medicine and Geriatrics, Ruttonjee Hospital, Hong Kong SAR, China

⁹ Division of Urology, Department of Surgery, Tuen Mun Hospital, Hong Kong SAR, China

¹⁰ Department of Medicine and Geriatrics, Pok Oi Hospital, Hong Kong SAR, China

¹¹ SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China

Corresponding author: Dr Peter KF Chiu (peterchiu@surgery.cuhk.edu.hk)

Full paper in PDF

Abstract

Overactive bladder (OAB) is a common urological disease with a high prevalence in older adult populations. Antimuscarinic drugs have been the most common treatment for OAB for more than a decade, but their anticholinergic side-effects and potential impact on cognitive function among older patients are usually underestimated. This consensus aimed to provide practical recommendations concerning OAB management, with a particular emphasis on older patients. A joint consensus panel was formed by representatives of the Hong Kong Urological Association and the Hong Kong Geriatrics Society. Literature searches regarding OAB and its management were performed in PubMed and Ovid. Several working meetings were held to present and discuss available evidence, develop consensus statements, and vote for the statements. A modified Delphi method was used in this consensus process. To address questions regarding various aspects of OAB, 29 consensus statements were proposed covering the following areas: diagnosis, initial assessment, non-pharmacological treatments, considerations before administration of pharmacological treatments, various pharmacological treatments, combination therapy, and surgical treatment. Twenty-five consensus statements were accepted.

[Abstract in Chinese]

Introduction

Overactive bladder (OAB) is defined by the International Continence Society as urinary urgency in the absence of urinary tract infection or other detectable diseases, usually accompanied by increased daytime frequency and/or nocturia, with or without urinary incontinence.1 Its reported prevalence ranges from 9.6% to 35.6%.2 A survey in Hong Kong showed that the age-adjusted OAB prevalence was 15.1%, and age was a significant risk factor.3

Although many patients can benefit from lifestyle modifications, medical therapy may be warranted for patients with persistent and bothersome OAB symptoms.4 Antimuscarinic agents have been the most commonly prescribed class of medications for OAB over the past two decades.4 However, their anticholinergic effects on cognitive function have long been both concerning and underestimated. This is particularly significant among older individuals because any cognitive decline they experience could easily be attributed to normal ageing or dementia.5 Such cognitive decline might be more pronounced when multiple drugs with anticholinergic side-effects are used concurrently.5 The concept of anticholinergic burden has been introduced to help clinicians estimate the combined anticholinergic effects (and potential impact on cognitive function) of all medications prescribed to a single patient.5

Beta-3 agonists represent a new class of drugs approved for the treatment of OAB.6 They do not have any anticholinergic side-effects and have therefore become alternatives to antimuscarinics for the treatment of OAB, particularly among patients with advanced age, dementia, or polypharmacy.6

To provide recommendations for the treatment of OAB in Hong Kong, a joint consensus panel was formed by representatives from the Hong Kong Geriatrics Society (HKGS) and the Hong Kong Urological Association (HKUA). Consensus statements were produced based on the latest evidence and international guidelines, supplemented by expert opinions from panel members.

Methods

The joint consensus panel consisted of 13 experts from Hong Kong: six geriatricians representing the HKGS and seven urologists representing the HKUA. Among these experts, seven were female clinicians and six were male clinicians. In total, seven meetings were held to discuss the scope of the consensus, present key evidence, formulate consensus statements, vote, and have a final discussion regarding manuscript preparation.

Literature reviews were performed in PubMed and Ovid to retrieve relevant articles related to this topic. The key words used included ‘overactive bladder’, ‘anticholinergic’, ‘antimuscarinic’, ‘beta3-adrenoceptor agonist’, ‘β3-adrenoceptor agonist’, ‘β3 agonist’, ‘guidelines’, ‘behavioural therapy’, ‘behavioural treatment’, ‘combination therapy’, and ‘surgery’. In total, 34 articles were selected for presentation and in-depth discussion, including four major guidelines, 15 meta-analyses/systematic reviews, and 15 randomised controlled trials. When discussing areas with inadequate evidence, the modified Delphi method was used. Panel discussions were carried out in a structured manner using appropriate content; each panel member contributed to the discussion in a fair and equal manner. The discussion was divided into seven parts, namely, introduction and overview of OAB, assessment and diagnostic approaches, non-pharmacological treatment, antimuscarinic agents, beta-3 agonists, combination therapy, and surgical treatment for OAB.

Panel members were divided into small working subgroups to review the existing literature, present their findings to other panel members, draft consensus statements, and finalise the consensus statements during panel meetings. In the last meeting, panellists voted anonymously on the practicability of recommendation in Hong Kong for each statement, based on predefined judgement criteria (online supplementary Table 1). If ≥75% of panellists chose ‘accept completely’ (option A) or ‘accept with some reservations’ (option B), a consensus statement was regarded as accepted. A total of 29 consensus statements were proposed, and 25 of them were accepted. The complete voting record and all consensus statements are listed in online supplementary Table 2.

The AGREE (Appraisal of Guidelines, Research and Evaluation) reporting guideline was used to ensure the methodological quality, comprehensiveness, completeness, and transparency of this consensus document.

History and physical examination

The initial assessment is intended to diagnose OAB, rule out other pathologies, assess symptom severity, and formulate an individualised management plan.

Statement 1: The clinician should begin the diagnostic process with careful history taking and physical examination.

Statement 2: Storage lower urinary tract symptoms may be a sign of more serious underlying conditions, and their management can be complicated by co-morbidities and polypharmacy. The clinician should seek a specialist’s opinion if red flag features are detected.

History taking and focused physical examination are important in the assessment of storage lower urinary tract symptoms7 8 (Tables 1 and 2). Patients with alarming symptoms should be referred to relevant specialists (Table 3). Past health also provides clues to the aetiology of the problem. In particular, medical diseases including diabetes mellitus, fluid status, obstructive sleep apnoea, as well as their treatments, can contribute to such symptoms.

Table 1. Essential information to collect during history taking7 8

Table 2. Essential components of physical examination7 8

Table 3. Findings that require referral

Symptom severity can be assessed by the number of pads used per day, degree of restriction in daily activities, and presence or absence of psychological stress.7 8 Assessments of frailty, cognitive function, and anticholinergic burden are especially relevant in older individuals, considering their implications for subsequent management.

The treatment algorithm for OAB is illustrated in the Figure.

Figure. Treatment algorithm of overactive bladder

Investigations

Statement 3: Urinalysis should be considered during the initial assessment of overactive bladder syndrome.

Urinalysis is recommended as an initial assessment for patients with OAB in most guidelines, including the European Association of Urology 2023 guidelines on lower urinary tract symptoms7 8; the results can rule out urinary tract infection, diabetes mellitus, and proteinuria.7 8

Statement 4: A bladder diary should be considered during the assessment of overactive bladder syndrome.

A bladder diary serves as documentation of the patient’s drinking habits, voiding patterns, and incontinence episodes. It is useful for OAB diagnosis, baseline symptom quantification, treatment response monitoring, and bladder training programme planning.

Statement 5: Urine culture, post-void residual urine, plain X-rays of the kidney, ureter, and bladder, and patient questionnaires may be performed during the initial assessment of overactive bladder syndrome at the clinician’s discretion.

Statement 6: If questionnaires are used for assessment of overactive bladder syndrome, appropriate questionnaires validated in the patient’s language should be used.

Statement 7: Cystoscopy, urodynamics, ultrasonography of the urinary system, and pad tests should not be routinely included in the initial assessment of overactive bladder syndrome.

Urine culture, post-void residual urine, plain X-rays of the kidney, ureter, and bladder, and symptom/quality of life questionnaires are not considered routine tests in the initial assessment. Questionnaires including the OAB Symptom Score, Urogenital Distress Inventory-6, and Incontinence Impact Questionnaire, Short Form have been validated in Cantonese within Hong Kong. The OAB Symptom Score is a screening tool used to measure symptom severity in both male and female patients, whereas Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire, Short Form are used to measure symptom distress and health-related quality of life in female patients. Cystoscopy, urodynamics, ultrasonography of the urinary system, and pad tests are not recommended for the initial assessment of OAB in most guidelines.

Treatment

Non-pharmacological treatments

Statement 8: Non-pharmacological treatments, including fluid management, bladder training, and pelvic floor exercises, should be offered to patients with overactive bladder, regardless of drug treatment initiation.

Statement 9: Clinicians should identify medications and substances that may contribute to overactive bladder and consider modifications or alternatives.

Fluid management comprising a 25% decrease in fluid intake can reduce urination frequency and urgency.9 Reduced liquid consumption after dinner or within several hours before bedtime is a reasonable management approach for nocturia. Caffeine irritates the bladder and can induce urinary urgency; therefore, caffeine intake should be avoided.

Some drugs (eg, diuretics and acetylcholinesterase inhibitors) may worsen OAB symptoms; the use of these drugs should be identified, and the patient should be switched to a suitable alternative. Additionally, angiotensin-converting enzyme inhibitors can induce coughing, thereby exacerbating urinary incontinence. Sodium-glucose cotransporter-2 (SGLT2) inhibitors cause increased urine output and higher urinary frequency; thus, they should be avoided.

Statement 10: Weight reduction should be advised for obese individuals with overactive bladder.

Among obese women, weight loss of 8.0% reduces the overall amounts of weekly incontinence episodes by 47% (vs 28% in the control group) and urgency urinary incontinence episodes by 42% (vs 26% in the control group) within 6 months.10

Statement 11: For patients who have difficulty performing pelvic floor exercises and bladder training, early pharmacological therapy should be considered.

Behavioural therapy and bladder training are recommended as conventional approaches before considering drug treatment; the success of these approaches requires active participation by patients and their caregivers. Upfront pharmacological therapy may be considered for patients (especially frail older individuals) who have difficulty complying with these approaches.

Statement 12: Before initiating treatment, clinicians should educate patients and caregivers about the symptoms and natural course of overactive bladder, and the benefits and risks of currently available treatments.

Before drug treatment is initiated, the natural course of the disease and the safety profiles of various treatment options should be explained to increase patient compliance. Clinicians should establish feasible treatment goals with patients and their caregivers.

Statement 13: Antimuscarinics should be used cautiously in patients with cognitive impairment or a high anticholinergic burden.

Statement 14: Because polypharmacy is very common, a detailed review of drug history is recommended to avoid creating a clinically significant anticholinergic burden in patients.

Cognitive impairment (eg, delirium and dementia) has been linked to the use of antimuscarinic agents, particularly in older patients.11 It is important to review drug history before prescribing antimuscarinics to this group of patients. The concurrent use of medications with anticholinergic effects, such as antihistamines and anti-Parkinson’s drugs, may potentiate the side-effects of antimuscarinic agents and should be modified accordingly.

Pharmacological treatment

Antimuscarinic agents

Randomised controlled trials have revealed improvements in symptom control and differences in the cure rates of urgency incontinence when using antimuscarinic agents. However, no single agent has demonstrated superiority over the others in terms of efficacy.12 13

Statement 15: Antimuscarinics should be offered to patients who have been unsuccessful with non-pharmacological approaches.

Statement 16: Extended-release antimuscarinics are preferred over immediate-release antimuscarinics because of better tolerability, particularly regarding dry mouth.

Statement 17: Antimuscarinics should not be used in patients with narrow-angle glaucoma unless approved by an ophthalmologist.

The overall withdrawal rates of antimuscarinic agents due to side-effects range from 3% to 10%.14 Adverse events include dry mouth, pruritus, blurred vision, and dizziness (29.6%, 15.4%, 3.8%, and 3.5%, respectively).14 The results of a meta-analysis suggested that extended-release formulations have lower rates of adverse events, particularly dry mouth.14 However, the rates of constipation and withdrawal due to side-effects are not significantly different between immediate-release and extended-release formulations. Notably, antimuscarinics can cause pupil dilation and precipitate closed-angle glaucoma, particularly among patients with narrow-angle glaucoma.15

Statement 18: Antimuscarinics are effective in treating overactive bladder but regular monitoring of voiding symptoms is recommended, especially among older individuals.

The use of antimuscarinic agents is associated with a minimal increase in post-void residual urine volume among male patients. In a study of men with proven bladder outlet obstruction, this increase in post-void residual urine volume did not lead to acute urinary retention.16 Nevertheless, changes in voiding symptoms after the initiation of antimuscarinic agents, particularly among older patients, should be monitored.

As a quaternary amine compound with hydrophilic properties, trospium has a theoretical advantage in that it does not cross the blood-brain barrier and therefore may result in less cognitive impairment. There is evidence to support the claim that trospium does not worsen cognitive function in patients with Alzheimer’s disease.17 A pooled analysis indicated that trospium has a lower treatment withdrawal rate due to side-effects compared with other anticholinergics.18 However, there remains a lack of strong evidence concerning the degree of cognitive decline from various anticholinergic agents.

Antimuscarinic agents registered for the treatment of OAB in Hong Kong are listed in Table 4.

Table 4. Comparison of antimuscarinic agents currently available in Hong Kong

Beta-3 agonists

Statement 19: Beta-3 agonists provide overall efficacy similar to that of commonly used antimuscarinic monotherapies.

Beta-3 adrenoceptor agonists (ie, mirabegron and vibegron) relax detrusor muscles in the urinary bladder wall, allowing the bladder to remain distended during the storage phase. Mirabegron significantly improved incontinence episodes and micturition frequency compared with placebo in a phase 3 trial.19 The efficacy of mirabegron 50 mg is similar to that of most antimuscarinic monotherapies regarding micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence episodes.20 Mirabegron is efficacious in improving OAB symptoms and quality of life.21 22

Statement 20: Beta-3 agonists appear to be better tolerated than antimuscarinics (eg, in terms of dry mouth, constipation, and urinary retention).

Compared with antimuscarinic monotherapy, mirabegron is better tolerated and has significantly lower risks of dry mouth, constipation, and urinary retention. This safety profile remains consistent for up to 1 year of treatment.22 Mirabegron also has better treatment persistence and adherence rates at 12 months.22 Therefore, mirabegron can serve as an alternative pharmacological treatment for older patients with OAB.23 24

Statement 21: Mirabegron should not be used in patients with severely uncontrolled hypertension.

According to recommendations from the United Kingdom25 and European26 health authorities, mirabegron is contraindicated in patients with severely uncontrolled hypertension (ie, systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg) due to the lack of studies concerning mirabegron effects in this group of patients. However, in a phase 3 randomised controlled trial comparing mirabegron 25 mg, mirabegron 50 mg, and placebo, the incidence of hypertension was similar across all subgroups (12%, 11%, and 8.5%, respectively).19 Additionally, the adjusted mean changes in systolic and diastolic blood pressures from baseline to the final visit were comparable between the mirabegron 25 mg and placebo groups. Patients in the mirabegron 50 mg group experienced a clinically insignificant increase in blood pressure (ie, 1.0-1.5 mm Hg) compared with the placebo group.19

Combination therapy

Statement 22: Combination drug treatment (a beta-3 agonist and an antimuscarinic agent) may be considered for overactive bladder that is unresponsive to monotherapy with either antimuscarinics or beta-3 agonists.

Several trials have investigated the use of combination drug therapy comprising an antimuscarinic agent and a beta-3 agonist, especially solifenacin and mirabegron, in patients with OAB.20 21 In the SYMPHONY study, three combination groups (solifenacin 10 mg/mirabegron 25 mg, solifenacin 5 mg/mirabegron 50 mg, and solifenacin 10 mg/mirabegron 50 mg) displayed significant improvements in mean volume voided per micturition, micturition frequency, and urgency episodes compared with solifenacin 5 mg monotherapy.27 Despite a slight increase in the incidence of constipation among combination groups using solifenacin 10 mg, combination drug treatments were well tolerated compared with monotherapy or placebo.

In the SYNERGY study, the combination of solifenacin 5 mg/mirabegron 50 mg was superior to solifenacin or mirabegron monotherapy in terms of reducing incontinence episodes, urgency episodes, and nocturia.28 In two other studies (BESIDE29 and MILAI30), mirabegron was used as an add-on therapy for patients with OAB who remained symptomatic on solifenacin alone. Both studies showed that the combination of solifenacin 5 mg/mirabegron 50 mg produced greater improvements in incontinence episodes and micturition frequency.29 30 The incidence and frequency of treatment-emergent adverse events were similar in the combination and monotherapy groups. The withdrawal rate related to treatment-emergent adverse events was low (ie, 1.1% to 1.5%).29 30

The long-term safety and efficacy of solifenacin and mirabegron combination treatment over 12 months were demonstrated in the SYNERGY II31 and MILAI II studies,32 and the use of antimuscarinics other than solifenacin in combination therapy was assessed in the MILAI II study.32 Similar efficacy and adverse events were observed with various combinations of antimuscarinics (eg, imidafenacin, propiverine, and tolterodine) and mirabegron.

Statement 23: Combination treatment using a beta-3 agonist and an antimuscarinic is preferred over the use of two antimuscarinics due to fewer side-effects and a lower anticholinergic burden.

There is a lack of large-scale randomised controlled trials evaluating combination therapy with two antimuscarinic agents. In a retrospective study, the long-term persistence rate for combination therapy with two antimuscarinics was poor due to adverse events.20 In contrast, the combination of an antimuscarinic agent and a beta-3 agonist exhibited a better persistence rate compared with monotherapy among patients with OAB who had moderate to severe symptoms.20 21 Considering the high anticholinergic burden in older individuals, the use of two antimuscarinics is not preferable, even if the response to monotherapy is inadequate. Instead, combination therapy with an antimuscarinic agent and a beta-3-agonist is recommended.

Surgical treatment

Statement 24: Posterior tibial nerve stimulation should be considered for patients who have been unsuccessful with pharmacological treatment.

Percutaneous tibial nerve stimulation (PTNS) is a less invasive procedure among the available surgical interventions for OAB. A meta-analysis involving 2461 patients showed that PTNS could reduce voiding frequency, nocturia frequency, urgency episodes, and incontinence episodes while increasing the maximum cystometric capacity.33 The main complication was pain at the puncture site, but its incidence was low. One trial comparing the efficacies of PTNS and tolterodine showed that PTNS had superior results concerning the composite outcome of cure or symptom improvement (79.5% vs 54.8%; P=0.01).34 Trials comparing PTNS with beta-3 agonists are ongoing.

Statement 25: Intravesical botulinum toxin injection or sacral neuromodulation should be considered in carefully selected patients who have been unsuccessful with pharmacological treatment.

A phase 3, randomised, placebo-controlled trial demonstrated that intravesical injection of botulinum toxin A significantly reduced micturition frequency, increased the rate of complete continence, and improved OAB symptoms and quality of life scores compared with placebo.35 The clinical effects of botulinum toxin A usually persisted for 3 months to 1 year, and additional injections were needed when the effects diminished. Uncomplicated urinary tract infection was the most common adverse event, and urinary retention was observed in 5.4% of patients.35

Sacral neuromodulation (SNM) utilises a principle similar to PTNS but involves implantation of electrical leads at the S3 nerve root.36 A systematic review showed that 15% of patients were completely cured with SNM, whereas 50% of patients had a >90% reduction in the number of incontinence episodes.36 The most common complications associated with SNM were pain at the implant or lead site (25%), lead migration (16%), and replacement and repositioning of the implanted pulse generator (15%).36 Pain at the implant or lead site is similar to sciatica, which radiates down to the lower back to the hip, thigh, and toes. A test implant is generally required. If the pain is intolerable, permanent implantation is not performed.

Conclusion

Overactive bladder is a common condition with a substantial impact on quality of life. The number of patients with increasing OAB complexity is expected to increase due to population ageing. Representatives of the HKGS and the HKUA have agreed upon 25 consensus statements regarding the diagnostic approach, management, and referral mechanism for OAB in primary care settings. Through collaborations among primary care practitioners, geriatricians, and urologists, we hope to provide more holistic care to patients with OAB in Hong Kong.

Author contributions

Concept or design: PSK Chu, WKK Wong, TNH Chan, RWM Kan.
Acquisition of data: RWM Kan, PS Lam, PMH Cheung, TCT Pun, TK Lo.
Analysis or interpretation of data: EYL Cheng, MWS Tang, SWS Woo, CLH Leung.
Drafting of the manuscript: TCT Pun, TNH Chan, WKK Wong, PKF Chiu.
Critical revision of the manuscript for important intellectual content: PSK Chu, WKK Wong, PKF Chiu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Supplementary material

References

1. D’Ancoa C, Haylen B, Oelke M, et al. The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. Neurourol Urodyn 2019;38:433-77. Crossref

2. Eapen RS, Radomski SB. Review of the epidemiology of overactive bladder. Res Rep Urol 2016;8:71-6. Crossref

3. Yee CH, Chan CK, Teoh JY, et al. Survey on prevalence of lower urinary tract symptoms in an Asian population. Hong Kong Med J 2019;25:13-20. Crossref

4. DB Ng, McCart M, Klein C, Campbell C, Schoenhaus R, Berner T. Evaluating outcomes in patients with overactive bladder within an integrated healthcare delivery system using a treatment patterns analyzer. Am Health Drug Benefits 2016;9:343-53.

5. Kraus SR, Bavendam T, Brake T, Griebling TL. Vulnerable elderly patients and overactive bladder syndrome. Drugs Aging 2010;27:697-713. Crossref

6. Bragg R, Hebel D, Vouri SM, Pitlick JM. Mirabegron: a beta-3 agonist for overactive bladder. Consult Pharm 2014;29:823-37. Crossref

7. European Association of Urology. Guidelines for non-neurogenic female LUTS. Available from: https://uroweb.org/guidelines/non-neurogenic-female-luts/chapter/introduction. Accessed 1 Jun 2023.

8. European Association of Urology. Guidelines for management of non-neurogenic male LUTS. Available from: https://uroweb.org/guidelines/management-of-non-neurogenic-male-luts/chapter/introduction. Accessed 1 Jun 2023.

9. Hashim H, Abrams P. How should patients with an overactive bladder manipulate their fluid intake? BJU Intl 2008;102:62-6. Crossref

10. Subak LL, Wing R, West DS, et al. Weight loss to treat urinary incontinence in overweight and obese women. N Eng J Med 2009;360:481-90. Crossref

11. Painter CE, Suskind AM. Advances in pharmacotherapy for the treatment of overactive bladder. Curr Bladder Dysfunct Rep 2019;14:377-84. Crossref

12. Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005;48:5-26. Crossref

13. Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008;54:543-62. Crossref

14. Khullar V, Chapple C, Gabriel Z, Dooley JA. The effects of antimuscarinics on health-related quality of life in overactive bladder: a systematic review and meta-analysis. Urology 2006;68(2 Suppl):38-48. Crossref

15. Khurana AK, Khurana B, Khurana AK. Drug-induced angle-closure glaucoma. J Curr Glaucoma Pract 2012;6:6-8. Crossref

16. Abrams P, Kaplan S, de Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175:999-1004. Crossref

17. Isik AT, Celik T, Bozoglu E, Doruk H. Trospium and cognition in patients with late onset Alzheimer disease. J Nutr Health Aging 2009;13:672-6. Crossref

18. Madhuvrata P, Cody JD, Ellis G, Herbison GP, Hay-Smith EJ. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev 2012;(1):CD005429. Crossref

19. Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 2013;82:313-20. Crossref

20. Wani MM, Sheikh MI, Bhat T, Bhat Z, Bhat A. Comparison of antimuscarinic drugs to beta adrenergic agonists in overactive bladder: a literary review. Curr Urol 2021;15:153- 60. Crossref

21. Kelleher C, Hakimi Z, Zur R, et al. Efficacy and tolerability of mirabegron compared with antimuscarinic monotherapy or combination therapies for overactive bladder: a systematic review and network meta-analysis. Eur Urol 2018;74:324-33. Crossref

22. Chapple CR, Siddiqui E. Mirabegron for the treatment of overactive bladder: a review of efficacy, safety and tolerability with a focus on male, elderly and antimuscarinic poor-responder populations, and patients with OAB in Asia. Expert Rev Clin Pharmacol 2017;10:131-51. Crossref

23. Nakagomi H, Mitsui T, Shimura H, et al. Mirabegron for overactive bladder in frail patients 80 years or over (HOKUTO study). BMC Urol 2022;22:40. Crossref

24. Herschorn S, Staskin D, Schermer CR, Kristy RM, Wagg A. Safety and tolerability results from the PILLAR study: a phase IV, double-blind, randomized, placebo-controlled study of mirabegron in patients ≥ 65 years with overactive bladder-wet. Drugs Aging 2020;37:665-76. Crossref

25. GOV.UK. Mirabegron (Betmiga▼): risk of severe hypertension and associated cerebrovascular and cardiac events. Available from: https://www.gov.uk/drug-safety-update/mirabegron-betmiga-risk-of-severe-hypertension-and-associated-cerebrovascular-and-cardiac-events. Accessed 1 Jun 2023.

26. European Medicines Agency. Assessment report of Betmiga (mirabegron). 2012. Available from: https://www.ema.europa.eu/en/documents/assessment-report/betmiga-epar-public-assessment-report_en.pdf. Accessed 1 Jun 2023.

27. Abrams P, Kelleher C, Staskin D, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: exploratory responder analyses of efficacy and evaluation of patient-reported outcomes from a randomized, double-blind, factorial, dose-ranging, phase II study (SYMPHONY). World J Urol 2017;35:827-38. Crossref

28. Herschorn S, Chapple CR, Abrams P, et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int 2017;120:562-75. Crossref

29. Drake MJ, Chapple C, Esen AA, et al. Efficacy and safety of mirabegron add-on therapy to solifenacin in incontinent overactive bladder patients with an inadequate response to initial 4-week solifenacin monotherapy: a randomised double-blind multicentre phase 3B study (BESIDE). Eur Urol 2016;70:136-45. Crossref

30. Yamaguchi O, Kakizaki H, Homma Y, et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a postmarketing, open-label study in Japan (MILAI study). BJU Int 2015;116:612-22. Crossref

31. Gratzke C, van Maanen R, Chapple C, et al. Long-term safety and efficacy of mirabegron and solifenacin in combination compared with monotherapy in patients with overactive bladder: a randomised, multicentre phase 3 study (SYNERGY II). Eur Urol 2018;74:501-9. Crossref

32. Yamaguchi O, Kakizaki H, Homma Y, et al. Long-term safety and efficacy of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: a multicenter, randomized study in Japan (MILAI II study). Int J Urol 2019;26:342-52. Crossref

33. Wang M, Jian Z, Ma Y, Jin X, Li H, Wang K. Percutaneous tibial nerve stimulation for overactive bladder syndrome: a systematic review and meta-analysis. Int Urogynecol J 2020;31:2457-71. Crossref

34. Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol 2009;182:1055-61. Crossref

35. Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 2017;197(2S):S216-23. Crossref

36. Brazzelli M, Murray A, Fraser C. Efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. J Urol 2006;175:835-41. Crossref

Recommendations for eligibility criteria concerning bariatric and metabolic surgical and endoscopic procedures for obese Hong Kong adults 2024: Hong Kong Society for Metabolic and Bariatric Surgery Position Statement

Hong Kong Med J 2024 Jun;30(3):233–40 | Epub 3 Jun 2024

https://doi.org/10.12809/hkmj2210656

MEDICAL PRACTICE

Recommendations for eligibility criteria concerning bariatric and metabolic surgical and endoscopic procedures for obese Hong Kong adults 2024: Hong Kong Society for Metabolic and Bariatric Surgery Position Statement

Shirley YW Liu, FRCS, FHKAM (Surgery)¹; Carol MS Lai, FRCS, FHKAM (Surgery)¹; Enders KW Ng, FRCS, FHKAM (Surgery)¹; Fion SY Chan, FRCS, FHKAM (Surgery)²; SK Leung, FRCS, FHKAM (Surgery)³; Wilfred LM Mui, FRCS, FHKAM (Surgery)⁴; Daniel KH Tong, FRACS, FHKAM (Surgery)⁵; Dennis CT Wong, FRACS, FHKAM (Surgery)⁶; Patricia PC Yam, FRCS, FHKAM (Surgery)³; Simon KH Wong, FRCS, FHKAM (Surgery)¹

¹ Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

² Department of Surgery, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

³ Department of Surgery, Tuen Mun Hospital, Hong Kong SAR, China

⁴ Hong Kong Bariatric and Metabolic Institute, Hong Kong SAR, China

⁵ Hong Kong Sanatorium & Hospital, Hong Kong SAR, China

⁶ St Teresa's Hospital, Hong Kong SAR, China

Corresponding author: Dr Simon KH Wong (wongkhmo@surgery.cuhk.edu.hk)

Full paper in PDF

Abstract

The surgical management of obesity in Hong Kong has rapidly evolved over the past 20 years. Despite increasing public awareness and demand concerning bariatric and metabolic surgery, service models generally are not standardised across bariatric practitioners. Therefore, a working group was commissioned by the Hong Kong Society for Metabolic and Bariatric Surgery to review relevant literature and provide recommendations concerning eligibility criteria for bariatric and metabolic interventions within the local population in Hong Kong. The current position statement aims to provide updated guidance regarding the indications and contraindications for bariatric surgery, metabolic surgery, and bariatric endoscopic procedures.

[Abstract in Chinese]

Obesity is a complex multifactorial disease caused by diverse combinations of genetic, behavioural, environmental, and endocrine aetiologies. In 2013, obesity was recognised by the American Medical Association as a disease state requiring treatment and prevention efforts.1 Obesity substantially increases an individual’s risks of cardiovascular diseases, metabolic illnesses, musculoskeletal problems, and cancer. For healthcare policymakers, the financial burden of treating and preventing obesity and its related conditions is exponentially growing. At the community level, reduced workforce productivity from obesity-related adverse health outcomes can lead to detrimental impacts on the broader economy.

According to the World Health Organization, adults are considered overweight when their body mass index (BMI) is ≥25 kg/m² and obese when their BMI is ≥30 kg/m².2 However, Asian populations have a higher percentage of body fat and greater metabolic risk at lower BMIs.3 A World Health Organization expert consultation identified potential public health action points for Asians as 23.0 kg/m², 27.5 kg/m², 32.5 kg/m², and 37.5 kg/m²; these values generally were 2.5 kg/m² lower than the thresholds established for Caucasians.4 Because of differences in body frame and visceral fat distribution, lower BMI thresholds were used to define overweight (≥23 kg/m²) and obesity (≥25 kg/m²) in Asians.3

Similar to other regions of the world, obesity is a substantial public health problem in Hong Kong.5 According to the latest Population Health Survey 2020/22 conducted by the Department of Health, the prevalences of obesity and overweight in people aged 15 to 84 years were 32.6% and 22.0%, respectively.6 These prevalences indicate that at least half of the local Hong Kong population faces health risks associated with overweight or obesity.

Bariatric and metabolic surgery

Bariatric surgery (ie, surgical treatment for obesity) has been continuously evolving worldwide over the past 50 years, with increasingly diverse procedural options and indications.7 In 1991, the National Institutes of Health published the first international consensus endorsing the use of gastrointestinal surgery as treatment for severe obesity.8 9 Since then, numerous studies have confirmed the effectiveness of bariatric surgery in achieving sustainable weight loss and substantial improvement in co-morbidities among obese patients.10 According to a systematic review and meta-analysis of 22 094 morbidly obese patients across 136 studies, bariatric surgery resulted in 61.2% excess weight loss.10 Resolution of diabetes, hypertension, and obstructive sleep apnoea were achieved in 76.8%, 61.7%, and 85.7% of patients, respectively.10 In a prospective randomised trial of 150 morbidly obese diabetic patients, bariatric surgery plus intensive medical therapy was associated with significantly better glycaemic and metabolic outcomes at 5 years compared with intensive medical therapy alone.11 Because bariatric surgery has demonstrated efficacy in treating type 2 diabetes mellitus (T2DM), the term ‘metabolic surgery’ was established to describe the role of bariatric interventions in treating T2DM and metabolic syndrome.7 16 In 2016, metabolic surgery was formally endorsed by 44 international diabetes organisations as a treatment option for adults with T2DM and obesity (defined as BMI >30 kg/m² for Caucasians and >27.5 kg/m² for Asians), particularly those with co-morbidities which cannot be controlled by lifestyle changes and pharmacological therapy.17

Although operative safety is a concern for morbidly obese individuals undergoing any type of major surgery, current evidence suggests that bariatric surgery has low perioperative mortality rates, ranging from 0.03% to 0.2%.12 In a systematic review and meta-analysis of 161 756 patients undergoing bariatric surgery, the 30-day mortality rates ranged from 0.08% to 0.22%, whereas the postoperative complication rates were between 9.8% and 17.0%.13 Currently, the most widely performed bariatric procedures are sleeve gastrectomy and Roux-en-Y gastric bypass. Common operative morbidities of sleeve gastrectomy include bleeding, leakage, stricture, and symptoms of gastroesophageal reflux.14 Roux-en-Y gastric bypass is associated with bleeding, leakage, stricture, stomal ulcer, small bowel obstruction, internal herniation, and dumping syndrome.15 Data from randomised controlled trials suggest that sleeve gastrectomy and Roux-en-Y gastric bypass are comparable in terms of 30-day mortality and morbidity rates.15

Primary bariatric endoscopic intervention

In recent decades, bariatric endoscopic procedures have been developed for individuals who prefer less invasive, non-surgical alternatives.18 These endoscopic therapies include intragastric space-occupying devices (intragastric balloons [IGBs]), gastric aspiration devices, endoluminal bypass barrier sleeves, the POSE (primary obesity surgery endoluminal) procedure, endoscopic sleeve gastroplasty, and duodenal mucosal resurfacing. All of these procedures can produce clinically significant short-term weight loss and improvements in obesity-related co-morbidities.19 The first bariatric endoscopic intervention in Hong Kong, IGB therapy, was introduced in 2004. An early local report confirmed its efficacy in weight reduction and co-morbidity improvement among obese patients at 6 months after treatment.20 Compared with weight-reduction medication, IGB therapy was associated with better compliance and superior weight reduction for up to 2 years after treatment.21 Because of its efficacy regarding short-term weight loss and co-morbidity improvement, IGB therapy can also serve as a bridging treatment prior to bariatric or other operative interventions; it facilitates preoperative weight loss that can reduce anaesthetic risks. Thus, IGB therapy is a justifiable non-surgical bariatric option for primary weight loss and preoperative weight loss.

Overview of bariatric and metabolic surgery in Hong Kong

Hong Kong’s first bariatric surgery programme was established in 2002 at Prince of Wales Hospital, affiliated with The Chinese University of Hong Kong.22 Encouraged by the success and safety of the early Prince of Wales Hospital obesity surgery service,23 increasing numbers of public and private hospitals have begun to provide bariatric surgical interventions to obese patients in Hong Kong (Table).

Table. Hong Kong Society for Metabolic and Bariatric Surgery survey of metabolic and bariatric procedures performed in Hong Kong during 2013 and 2020

With the goal of promoting public and professional awareness about obesity treatment, leading local bariatric practitioners formed the Metabolic and Bariatric Surgery Group under the Hong Kong Association for the Study of Obesity in 2012. In 2017, the Hong Kong Society for Metabolic and Bariatric Surgery (HKSMBS) was established as an independent society. Surveys concerning bariatric surgery types and case volumes are carried out annually by the two bodies.

Metabolic and bariatric surgery options are broadly classified as restrictive procedures and malabsorptive procedures. In Hong Kong, common restrictive procedures are gastric banding and sleeve gastrectomy. The most common malabsorptive procedure is Roux-en-Y gastric bypass. Other less common malabsorptive procedures are one anastomosis gastric bypass, sleeve gastrectomy plus duodenojejunal bypass, and biliopancreatic diversion with or without duodenal switch. Between 2013 and 2020, 1582 bariatric surgical and endoscopic procedures were performed in Hong Kong (Table). Compared with 2002 when bariatric surgery was first introduced, the number of bariatric surgeries performed each year has exponentially increased from <10 cases per year to >180 cases per year in 2020. Current data indicate that more than two-thirds of these surgeries are performed in government hospitals. Sleeve gastrectomy is the most common bariatric procedure in Hong Kong (~70%) and the second most common procedure is Roux-en-Y gastric bypass. Gastric banding, popular two decades ago, has not been favoured since 2013 (<2.5%). Biliopancreatic diversion with or without duodenal switch has not been performed in Hong Kong in the past ten years (Table).

Development of the position statement

Although extensive international guidelines for bariatric surgery have been established by various bariatric authorities,24 25 26 27 some of the existing recommendations are not applicable to the Hong Kong Chinese population because of ethnic and practical differences. Nevertheless, there is a lack of practical guidelines regarding bariatric endoscopic interventions for Asian populations.28 Among local bariatric practitioners, there has been a lack of consensus regarding the indications, contraindications, and procedural options for bariatric surgery. This heterogeneity in clinical practices surrounding bariatric surgery in Hong Kong requires a position statement to address the concerns of local bariatric practitioners.

In 1991, the National Institutes of Health published a consensus statement regarding indications for bariatric surgery; it utilised BMI thresholds of ≥40 kg/m² or ≥35 kg/m² with co-morbidities for Caucasians.9 The American Society for Metabolic and Bariatric Surgery and International Federation for the Surgery of Obesity and Metabolic Disorders recently updated the indications for metabolic and bariatric surgery.29 Their joint statement suggested a new threshold of ≥35 kg/m² to receive a recommendation for metabolic or bariatric surgery, regardless of the presence, absence, or severity of co-morbidities. Additionally, metabolic and bariatric surgery should be considered for individuals with metabolic disease and BMI ≥30 kg/m². For Asian populations, the joint statement suggested that BMI thresholds should be adjusted; specifically, individuals with BMI >27.5 kg/m² should be offered metabolic and bariatric surgery options.29 In response to these revised BMI thresholds for metabolic and bariatric surgery, published in December 2022, extensive discussions and debates have arisen in various professional bodies focusing on metabolic and bariatric surgery in Asia, including groups in Hong Kong. Due to limited experience offering metabolic and bariatric surgery to patients with BMI <30 kg/m² in Hong Kong and other parts of Asia, long-term surgical risks and benefits for such patients have not been fully elucidated. Considering that metabolic and bariatric surgery options are associated with higher risks of perioperative morbidity in patients with lower BMI, the HKSMBS has reached a consensus to refrain from adopting the newly updated BMI threshold of ≥27.5 kg/m² to receive a recommendation for metabolic and bariatric surgery in this position statement.

The following position statement is issued by the HKSMBS to define the indications and contraindications for bariatric procedures and endoscopic interventions which are suitable for the Hong Kong population. The recommendations of this position statement are based on current clinical knowledge, expert opinion, and published peer-reviewed scientific evidence.25 26 27 28

General recommendations

The HKSMBS recommends that bariatric and metabolic surgery be performed by surgeons with specialised experience and training in these procedures. Additionally, such procedures should be conducted at facilities with multidisciplinary teams of experts for appropriate perioperative assessment and follow-up care. The multidisciplinary team may include experienced surgeons, internal medicine physicians, weight management coordinators, nutritionists, exercise physiologists, and psychologists or mental health professionals.

Eligibility for bariatric surgery

We define bariatric surgery as any surgical procedure primarily intended for weight reduction to improve physical and mental health in patients with severe obesity. After careful review of available data concerning the safety and efficacy of surgery for obesity and weight-related diseases, as well as the effectiveness of such surgery as treatment for obesity and related co-morbidities, the position statement committee reached a consensus on the recommendation of bariatric surgery for the following eligible candidates in the Hong Kong adult population (aged ≥18 years) who are unable to sustain weight loss through optimal lifestyle, dietary or non-surgical interventions:30

appropriate surgical candidates who have a BMI ≥35 kg/m² with or without obesity-related co-morbidities; and
appropriate surgical candidates who have a BMI ≥30 kg/m² with clinically significant obesity-related co-morbidities.

We define obesity-related co-morbidities as conditions either directly caused by obesity or known to contribute to the presence or severity of obesity. These comorbid conditions are expected to improve or resolve with effective and sustained weight loss. The list of comorbid conditions includes, but is not limited to, metabolic syndrome,31 T2DM, non-alcoholic steatohepatitis, obstructive sleep apnoea syndrome, degenerative arthritis, and polycystic ovarian syndrome.

Eligibility for metabolic surgery

We define metabolic surgery as any surgical procedure primarily intended to improve glycaemic control in obese patients with T2DM. For adults (aged ≥18 years) with T2DM who are unable to sustain weight loss through optimal lifestyle interventions, metabolic surgery is recommended for the following eligible candidates in treating T2DM with the primary aim of glycaemic improvement:17

appropriate surgical candidates with BMI ≥37.5 kg/m², regardless of the level of glycaemic control or complexity of glucose-lowering regimens; and
appropriate surgical candidates with BMI ranging from 32.5 to 37.4 kg/m² whose hyperglycaemia is inadequately controlled by optimal medical, lifestyle, dietary, and non-surgical interventions.

In addition, metabolic surgery can be regarded as a treatment option for T2DM in appropriate surgical candidates with BMI ranging from 27.5 to 32.4 kg/m² whose hyperglycaemia is inadequately controlled despite optimal medical control by either oral or injectable medications (including insulin) and lifestyle interventions.

We consider hyperglycaemia to be inadequately controlled if the glycated haemoglobin level is >7.0% despite medical treatment involving two or more oral hypoglycaemic agents or any injectable medications (including insulin or glucagon-like peptide-1 receptor agonist) for >6 months.32 33 Fasting C-peptide levels should be checked if type 1 diabetes mellitus or latent autoimmune diabetes in adults is suspected.

Eligibility for bariatric endoscopic interventions

Intragastric balloon therapy

Intragastric balloon therapy is a minimally invasive space-occupying system intended to provide temporary weight loss by reducing gastric volume and altering gastric motility.34 35 The following recommendations regarding IGB therapy are suggested:

1. As a bridging treatment for preoperative weight loss, IGB therapy can be considered:

a. prior to metabolic or bariatric surgery for the optimisation of medical and/or anaesthetic status in severely obese individuals with very high BMI (eg, >50 kg/m²) who fail to respond to non-surgical optimisation; and
b. prior to non-bariatric surgery (eg, joint replacement surgery, ventral hernia repair, etc) for the optimisation of medical and/or anaesthetic status in obese individuals with BMI >30 kg/m².

2. As a primary interventional treatment, IGB therapy can be considered:

a. in individuals with BMI ranging from 27.5 to 32.5 kg/m² (30-35 kg/m² for Caucasians) who fail to achieve weight loss through optimal lifestyle and dietary interventions; and
b. in obese individuals who meet the eligibility criteria for bariatric or metabolic surgery but are surgically unfit or reluctant to undergo bariatric or metabolic surgery.

3. Intragastric balloon therapy should be used for a duration shorter than the maximum approved or recommended duration (usually 4 to 12 months, depending on IGB brand), or for a duration to be decided on a case-by-case basis. Patients should be informed about the intended duration of use.

Other endoscopic procedures

Currently, many restrictive and malabsorptive endoscopic procedures are available. These include, but are not limited to, the following:

space-occupying restrictive gastric devices (eg, TransPyloric Shuttle, SatiSphere, Plenity, etc);
gastric diversion devices (eg, AspireAssist aspiration therapy);
endoscopic gastric plication techniques (eg, endoscopic sleeve gastroplasty, the POSE procedure); and
malabsorptive techniques (eg, duodenojejunal bypass liner).

Some of these procedures have been approved by the United States Food and Drug Administration, whereas others remain investigational in most countries. Except for endoscopic gastric plication, AspireAssist aspiration therapy and endoscopic sleeve gastroplasty, most of these endoscopic procedures have not been explored in Hong Kong. Due to the lack of scientific evidence and universal consensus regarding their indications, efficacy, and safety, these procedures should only be conducted after careful evaluation and the acquisition of informed patient consent and/or approval from institutional review board.

Contraindications

Despite the beneficial effects of metabolic and bariatric surgery with clinically significant improvements in obesity-related co-morbidities, these procedures are not without surgical and anaesthetic risks. Moreover, most bariatric procedures involve a gastric restrictive component; an individual’s ability to maintain postoperative dietary and lifestyle changes can substantially affect surgical outcomes. Therefore, the position statement committee reached a consensus on the following suggestions.

Contraindications for bariatric and metabolic surgical and endoscopic interventions

Bariatric and metabolic surgical and endoscopic procedures should not be performed in the following situations or for the following individuals:

1. absence of multidisciplinary medical, dietary, and behavioural guidance;
2. no fully informed consent from the patient or his/ her guardian regarding the risks, benefits, and real expectations for weight loss, co-morbidity management, and durability;
3. individuals with BMI <27.5 kg/m² (<30 kg/m² for Caucasians), unless the procedures are performed under a research protocol approved by a local institutional review board and/or research ethics committee and informed patient consent has been obtained;
4. individuals with medical conditions which cannot be optimised before surgery, leading to significantly increased anaesthetic and operative risks. These conditions include, but are not limited to, the following:

a. very high anaesthetic risk (defined as grade IV under the classification system of the American Society of Anesthesiologists) with organ failure that cannot be optimised and represents a constant threat to life;
b. uncontrolled endocrine disorders (eg, hypothyroidism, Cushing’s syndrome, drug-induced obesity, etc);
c. active infection (eg, tuberculosis, human immunodeficiency virus, etc);
d. uncorrected coagulopathy;
e. end-stage liver cirrhosis with or without portal venous hypertension;
f. uncontrolled enteropathy (eg, inflammatory bowel disease, protein-losing enteropathy, etc);
g. disseminated malignancy or advanced malignancy with <5 years of remission; and
h. uncontrolled major organ dysfunction (eg, cardiac, pulmonary, or renal disorders);

5. individuals with conditions that impair their understanding of surgery and preclude them from maintaining perioperative lifestyle changes. These conditions include, but are not limited to, the following:

a. inadequately controlled psychiatric illnesses (eg, untreated schizophrenia, major depression, bipolar affective disorder, eating disorders, etc);
b. major depression with suicidal ideation and/or attempt within the past year;
c. personality disorder involving poor compliance with instructions; and
d. active substance abuse/alcoholism;

6. individuals with potential non-compliance problems regarding perioperative dietary and lifestyle changes. These conditions include, but are not limited to, the following:

a. intellectual/mental disability;
b. syndromic/genetic disease leading to obesity;
c. condition causing immobility (eg, paraplegia, stroke, etc); and
d. inability to attend regular follow-up.

Moreover, bariatric and metabolic surgical and endoscopic procedures should not be offered to pregnant women.

Contraindications specific to intragastric balloon therapy

Generally, individuals with the above contraindications for bariatric and metabolic surgical interventions are also not recommended to undergo IGB therapy. However, there are additional contraindications for IGB therapy. These contraindications include, but are not limited to, the following, where IGB therapy is not recommended for individuals:

with contraindications for endoscopies, allergies to proton-pump inhibitors, or allergies to balloon materials (eg, silicone, polyurethane, etc);
with active gastrointestinal pathology (eg, peptic ulcers, gastroesophageal varices, inflammatory bowel disease, etc), altered gastrointestinal anatomy (eg, previous gastrointestinal surgery, large hernia, suspect gastrointestinal malignancy, etc), gastrointestinal motility disorders, or a history of idiopathic acute pancreatitis; and
actively using anticoagulants or antiplatelet medications, or individuals with a bleeding tendency.

For patients who are intended to undergo swallowable IGB therapy without prior endoscopy, a preoperative endoscopic examination should be considered if gastrointestinal pathology (eg, peptic ulcer, large hiatus hernia, etc) is suspected based on clinical assessment.

Conclusion

This position statement is not intended to provide inflexible rules or requirements of practice, nor to establish a local standard of care. Clinical practitioners must use their own judgement in selecting the best evidence-based treatment for patients with informed consent. Physicians should follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of this position statement is to assist practitioners in achieving this objective. This position statement was developed under the auspices of HKSMBS position statement committee and approved by the members of executive council. These recommendations were considered valid at the time of production based on the data available. New developments in medical research and practice will be reviewed, and the position statement will be periodically updated.

Author contributions

Concept or design: All authors.
Acquisition of data: SKH Wong.
Analysis or interpretation of data: SYW Liu, SKH Wong.
Drafting of the manuscript: SYW Liu, CMS Lai, SKH Wong.
Critical revision of the manuscript for important intellectual content: SYW Liu, CMS Lai, SKH Wong.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Declaration

This position statement has been endorsed by the Hong Kong Association for the Study of Obesity. An abridged version of the position statement has been published on the website of the Hong Kong Society for Metabolic and Bariatric Surgery (http://www.hksmbs.org/).

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014;129 (25 Suppl 2):S102-38. Crossref

2. World Health Organization. Obesity and overweight. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight . Accessed 14 May 2024.

3. Ko GT, Tang J, Chan JC, et al. Lower BMI cut-off value to define obesity in Hong Kong Chinese: an analysis based on body fat assessment by bioelectrical impedance. Br J Nutr 2001;85:239-42. Crossref

4. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157-63. Crossref

5. Obesity: preventing and managing the global epidemic. Report of a WHO consultation [editorial]. World Health Organ Tech Rep Ser 2000;894:i-xii, 1-253.

6. Non-Communicable Disease Branch, Centre for Health Protection, Department of Health, Hong Kong SAR Government. Report of Population Health Survey 2020-22 (Part II). 2023. Available from: https://www.chp.gov.hk/files/pdf/dh_phs_2020-22_part_2_report_eng.pdf. Accessed 14 May 2024.

7. Buchwald H. The evolution of metabolic/bariatric surgery. Obes Surg 2014;24:1126-35. Crossref

8. Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement [editorial]. Am J Clin Nutr 1992;55(2 Suppl):615S-619S. Crossref

9. Consensus Development Conference Panel, NIH Conference. Gastrointestinal surgery for severe obesity. Consensus Development Conference Panel [editorial]. Ann Intern Med 1991;115:956-61. Crossref

10. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-37. Crossref

11. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. N Engl J Med 2017;376:641-51. Crossref

12. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA 2020;324:879-87. Crossref

13. Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg 2014;149:275-87. Crossref

14. Liu SY, Wong SK, Lam CC, Yung MY, Kong AP, Ng EK. Long-term results on weight loss and diabetes remission after laparoscopic sleeve gastrectomy for a morbidly obese Chinese population. Obes Surg 2015;25:1901-8. Crossref

15. Lee Y, Doumouras AG, Yu J, et al. Laparoscopic sleeve gastrectomy versus laparoscopic Roux-en-Y gastric bypass: a systematic review and meta-analysis of weight loss, comorbidities, and biochemical outcomes from randomized controlled trials. Ann Surg 2021;273:66-74. Crossref

16. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009;122:248-56.e5. Crossref

17. Rubino F, Nathan DM, Eckel RH, et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by International Diabetes Organizations. Diabetes Care 2016;39:861-77. Crossref

18. Sullivan S, Edmundowicz SA, Thompson CC. Endoscopic bariatric and metabolic therapies: new and emerging technologies. Gastroenterology 2017;152:1791-801. Crossref

19. Winder JS, Rodriguez JH. Emerging endoscopic interventions in bariatric surgery. Surg Clin North Am 2021;101:373-9. Crossref

20. Mui WL, So WY, Yau PY, et al. Intragastric balloon in ethnic obese Chinese: initial experience. Obes Surg 2006;16:308-13. Crossref

21. Chan DL, Cruz JR, Mui WL, Wong SK, Ng EK. Outcomes with intra-gastric balloon therapy in BMI <35 non-morbid obesity: 10-year follow-up study of an RCT. Obes Surg 2021;31:781-6. Crossref

22. Wong SK, So WY, Yau PY, et al. Laparoscopic adjustable gastric banding for the treatment of morbidly obese patients: early outcome in a Chinese cohort. Hong Kong Med J 2005;11:20-9.

23. Wu T, Wong SK, Law BT, et al. Bariatric surgery is expensive but improves co-morbidity: 5-year assessment of patients with obesity and type 2 diabetes. Br J Surg 2021;108:554-65. Crossref

24. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Obesity (Silver Spring) 2009;17 Suppl 1:S1-70, v. Crossref

25. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity (Silver Spring) 2013;21 Suppl 1(01):S1-27. Crossref

26. Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures—2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity (Silver Spring) 2020;28:O1-58.Crossref

27. Di Lorenzo N, Antoniou SA, Batterham RL, et al. Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP. Surg Endosc 2020;34:2332-58. Crossref

28. ASGE/ASMBS Task Force on Endoscopic Bariatric Therapy. A pathway to endoscopic bariatric therapies. Surg Obes Relat Dis 2011;7:672-82. Crossref

29. Eisenberg D, Shikora SA, Aarts E, et al. 2022 American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): indications for metabolic and bariatric surgery. Surg Obes Relat Dis 2022;18:1345-56. Crossref

30. Kasama K, Mui W, Lee WJ, et al. IFSO-APC consensus statements 2011. Obes Surg 2012;22:677-84. Crossref

31. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006;23:469-80. Crossref

32. NICE guideline [NG28]. Type 2 diabetes in adults: management. London: National Institute for Health and Care Excellence (NICE); 2022.

33. Qaseem A, Wilt TJ, Kansagara D, et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians. Ann Intern Med 2018;168:569-76. Crossref

34. Gómez V, Woodman G, Abu Dayyeh BK. Delayed gastric emptying as a proposed mechanism of action during intragastric balloon therapy: results of a prospective study. Obesity (Silver Spring) 2016;24:1849-53. Crossref

35. Ali MR, Moustarah F, Kim JJ; American Society for Metabolic and Bariatric Surgery Clinical Issues Committee. American Society for Metabolic and Bariatric Surgery position statement on intragastric balloon therapy endorsed by the Society of American Gastrointestinal and Endoscopic Surgeons. Surg Obes Relat Dis 2016;12:462-7. Crossref

Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma

Hong Kong Med J 2024 Apr;30(2):147–62 | Epub 9 Apr 2024

https://doi.org/10.12809/hkmj2210476

MEDICAL PRACTICE CME

Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma

Stephen L Chan, MD, FRCP^{1 #}; CL Chiang, FRCR, FHKAM (Radiology)^{2 #}; Kenneth SH Chok, MD, MS^{3 #}; AS Lee, MB, ChB, FRCR⁴; Raymond SY Tang, MD⁵; Fiona MY Lim, FRCR, FHKAM (Radiology)^6,7; KF Lee, FRCSEd, FHKAM (Surgery)⁸; Anna YP Tai, FRCR, FHKAM (Radiology)⁹; Sarah WM Lee, FRCR, FHKAM (Radiology)⁷; Regina CL Lo, MD, FRCPA⁷; Anthony WH Chan, FRCPA, FHKAM (Pathology)¹⁰; Francis PT Mok, FRCSEd, FRACS¹¹; Endorsed by the Hong Kong Society of Hepatobiliary and Pancreatic Surgery and the Hong Kong Cancer Therapy Society

¹ Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

² Department of Clinical Oncology, Queen Mary Hospital, Hong Kong SAR, China

³ Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

⁴ Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong SAR, China

⁵ Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

⁶ Department of Oncology, Princess Margaret Hospital, Hong Kong SAR, China

⁷ Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China

⁸ Department of Surgery, Prince of Wales Hospital, Hong Kong SAR, China

⁹ Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China

¹⁰ Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

¹¹ Department of Surgery and Combined Endoscopy Unit, Caritas Medical Centre, Hong Kong SAR, China

^# Equal contribution

Corresponding author: Prof SL Chan (chanlam_stephen@cuhk.edu.hk)

Full paper in PDF

Abstract

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements.

[Abstract in Chinese]

Introduction

Pancreatic ductal adenocarcinoma (PDAC), a malignant pancreatic epithelial tumour characterised by glandular and ductal differentiation, constitutes >90% of all pancreatic cancers and is usually considered synonymous with the term ‘pancreatic cancer’ itself.1 Although the exact aetiology of PDAC is unknown, many risk factors have been linked to its development, including smoking, obesity, alcohol intake, diabetes mellitus, chronic pancreatitis, and familial cancer syndromes.2 3 4 Pancreatic ductal adenocarcinoma is usually diagnosed in individuals aged >70 years, with a male-to-female ratio of 1.4:1.0. Its incidence has been increasing worldwide, particularly among individuals aged >50 years and among women.4 In 2020, PDAC had the 14th highest incidence among cancers: approximately 495 773 people were diagnosed with PDAC, constituting 2.6% of new cancer cases.5 Moreover, PDAC was the eighth most common cause of cancer death in 2020, with 466 003 deaths (4.7% of all cancer deaths worldwide).5 In China, PDAC is one of the top 10 most common cancers in men and one of the top 10 most common causes of death among men and women.6

Pancreatic ductal adenocarcinoma, a highly aggressive malignancy with a poor prognosis, has one of the lowest 5-year survivals among cancers (11%).7 Surgical resection of localised disease provides the best likelihood of a curative outcome, but approximately 80% to 85% of cases are diagnosed at an advanced, unresectable, or metastatic stage that requires palliative management.2 Although resection of localised disease with adjuvant chemotherapy can improve 5-year survival to approximately 30%, this outcome depends upon complete removal of the primary tumour and regional lymph nodes, a complex procedure with a high rate of complications.8

In Hong Kong, the incidence of PDAC has been increasing since 2010; it had become the fifth leading cause of cancer-related death by 2019.9 Considering the challenges of late diagnosis, poor clinical prognosis, and limited therapeutic options, PDAC has emerged as a key local health concern. Our group was established to develop the first set of consensus recommendations regarding the management of PDAC in Hong Kong. We initiated this project to provide practical guidance to Hong Kong healthcare practitioners based on the best available evidence and expert opinions.

Methods

Based on a literature search in MEDLINE to identify articles published in the past 10 years, consensus development leads the first, second, and third authors brainstormed and drafted preliminary statements relevant to PDAC management that addressed diagnosis, imaging, and surveillance; resectability criteria; stent management; stage-specific treatment; personalised medicine; and palliative care and supportive care. Subsequently, they invited nine Hong Kong experts to complete a 12-member consensus expert panel comprising clinical oncologists, surgeons, a gastroenterologist, and pathologists. All panel members were asked to review the draft statements in the context of current local practice and available evidence, then discuss these issues during the consensus meeting.

A virtual consensus meeting was held on 12 February 2022 to refine and vote on the statements. The consensus statements were developed through the Delphi process: after discussion, the members independently voted on each statement using a 5-point Likert scale (A: accept completely; B: accept with minor reservations; C: accept with major reservations; D: reject with reservations; E: reject completely). A consensus was reached if at least 80% of the panel members agreed with the statement (ie, selected either ‘accept completely’ or ‘accept with minor reservations’). If acceptance was <80%, the panel members identified key concerns and proposed revisions before a second vote. When applicable, the level of evidence was evaluated using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.10

Consensus statements

Diagnosis

Statement 1: Early symptoms of pancreatic cancer result from a mass effect.
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Statement 2: In addition to progressive jaundice, patients may present with nonspecific symptoms including abdominal pain, weight loss, and new-onset/recently worsening diabetes. A differential diagnosis of PDAC should be considered in the presence of the above symptoms.
A: 80%; B: 20%; C: 0%; D: 0%; E: 0%

Statement 3: The involvement of a multidisciplinary team is recommended for diagnosis and disease management.
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

The clinical presentation of PDAC varies according to whether the tumour is in the pancreatic head, neck, or tail, which would affect adjacent structures. For example, jaundice can be related to tumours in the head due to obstruction of the common bile duct, whereas pain can be related to effects on nearby vessels from tumours in the pancreas.11 12 However, many patients present with nonspecific symptoms that may be attributed to other diseases and cause further diagnostic delays (Table 1).12 13 14 15 These symptoms should alert general practitioners and other healthcare professionals to consider PDAC as a differential diagnosis. Clinicians should attempt to distinguish stone-related obstruction from malignancy-related obstruction. In our clinical experience, stone-related obstruction usually causes intermittent jaundice, whereas malignancy-related obstruction causes progressive jaundice. Notably, Chinese patients typically have clay-coloured stool. They rarely present with the steatorrhea that is common among Western patients experiencing chronic pancreatitis from alcohol consumption.

Table 1. Signs and symptoms related to pancreatic cancer

Further workup and management require a multidisciplinary team encompassing a surgeon, clinical oncologist, medical oncologist, radiologist, and pathologist.11 16 In Hong Kong, it is challenging to involve a multidisciplinary team; nevertheless, we recommend the multidisciplinary team approach to address the evolving definition of resectability, as well as the complexities of genetic profiling and planning for various treatment modalities.

Statement 4: A thin-cut contrast-enhanced computed tomography scan of the entire abdomen should be performed for initial staging of the cancer. Positron emission tomography/computed tomography may be considered in selected cases. (Level 1)
A: 40%; B: 60%; C: 0%; D: 0%; E: 0%

In many centres, a baseline ultrasound is used to initiate the investigation of gastrointestinal or biliary complaints, such as jaundice. Subsequently, a high-quality contrast-enhanced computed tomography (CT) scan of the abdomen can detect a pancreatic mass and exclude other potential causes, such as cancers of the gallbladder or bile ducts. Computed tomography scanning is a well-validated method for PDAC staging.11 16 17 18 19 A thin-cut, pancreas-specific CT scan can aid local staging by revealing adjacent vessel infiltration and lymph node involvement.17

Positron emission tomography (PET)/CT can facilitate accurate staging, particularly in cases with distant metastases. According to the National Institute for Health and Care Excellence of the United Kingdom, this approach may reduce unnecessary surgeries by 20%.16 20 However, for initial staging, PET/CT generally does not offer information beyond the results of a high-quality CT scan of the abdomen.16 20 21 Thus, a thin-cut contrast-enhanced CT scan of the entire abdomen is the imaging method of choice for initial staging. Positron emission tomography/CT can be used for preoperative staging in specific scenarios, such as lesions with borderline resectability or cases requiring lymph node staging.16 The cost of PET/CT should be discussed with patients and their families.

In Hong Kong, magnetic resonance imaging may be utilised to investigate suspected lesions not clearly defined by CT scanning, such as peritoneal lesions. Although staging laparoscopy is rarely performed, the laparoscopic approach (eg, during the Whipple procedure) is common. Staging laparoscopy can be selectively used to rule out metastases and complement other imaging tools.11 16

Statement 5: Tumour staging should follow the guidelines stipulated by the American Joint Committee on Cancer.
A: 90%; B: 10%; C: 0%; D: 0%; E: 0%

Statement 6: Pathology reports should contain all clinically significant essential parameters, including but not limited to tumour location, tumour size, histological type (according to the latest World Health Organization classification), histological grade, tumour extent, tumour response to neoadjuvant therapy (if any), lymphovascular invasion, perineural invasion, nodal status, and margin clearance status. Synoptic reports from the Royal College of Pathologists, Royal College of Pathologists of Australasia, and College of American Pathologists are recommended references.
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

Pancreatic ductal adenocarcinoma is staged according to the most recent American Joint Committee on Cancer tumour, node, and metastasis classification,22 a well-known and widely used standard in the Hong Kong oncology community. Clinicians can also categorise tumour resectability into four levels, namely, resectable, borderline resectable (BR), locally advanced (LA), and metastatic.2 3

Pathology data are necessary to fully assess the extent of PDAC. In Hong Kong, most institutions lack a standard pathology reporting protocol or minimal dataset for pancreatic specimens. Moreover, the Hong Kong College of Pathologists has not yet developed a standard report format. In the absence of such standards, we recommend that reports include all clinically significant pathology data, such as tumour location, tumour size, histological type (according to the 2019 World Health Organization classification), histological grade, tumour extent (organ-confined or local invasion to adjacent organs), tumour response to neoadjuvant therapy (if any), lymphovascular invasion, perineural invasion, nodal status, and margin clearance status (Table 2). The general structure of the report can incorporate elements from datasets provided by the Royal College of Pathologists, Royal College of Pathologists of Australasia, and College of American Pathologists.23 24 25

Table 2. Recommended items for inclusion in a pancreas pathology report

Statement 7: For patients with suspected pancreatic head cancer without a definitive pancreatic mass observed on initial cross-sectional scan, endoscopic retrograde cholangiopancreatography and endoscopic ultrasound may be considered to detect small lesions in the pancreatic head or distal common bile duct. (Level 3)
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Statement 8: For patients with intraductal papillary mucinous neoplasms and ‘worrisome features’, as defined by the 2017 international consensus Fukuoka guidelines, endoscopic ultrasound may be considered for further workup.
A: 40%; B: 60%; C: 0%; D: 0%; E: 0%

Statement 9: Endoscopic ultrasound with fine-needle tissue acquisition is recommended when (a) there is a clinical need to exclude benign pathology, (b) tissue diagnosis is needed to guide treatment for locally advanced or metastatic disease, or (c) neoadjuvant treatment is planned.
A: 90%; B: 10%; C: 0%; D: 0%; E: 0%

Pancreatic head tumours usually present with obstructive jaundice caused by bile duct strictures. In these cases, endoscopic retrograde cholangiopancreatography (ERCP) can be diagnostic (through cytology from ERCP brushings and biopsies) and therapeutic (through stent insertion for biliary drainage). Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can also retrieve tissue samples for the diagnosis of malignancy in cases of obstructive jaundice, with high sensitivity and specificity for detecting pancreatic masses and malignant strictures.26 27 28

Endoscopic ultrasound has a role in the investigation of intraductal papillary mucinous neoplasms (IPMNs). According to the Fukuoka guidelines, EUS can be used to assess ‘worrisome features’ and ‘high-risk stigmata’, with the latter indicating a need for resection in surgically fit patients.29 In Hong Kong, surgery is usually advised regardless of the EUS result because ‘worrisome features’ indicate pre-malignancy, but the Fukuoka guidelines suggest that EUS can facilitate further characterisation of ambiguous areas that cannot be resolved through cross-sectional CT scans, such as tumour nodule and main duct features, as well as cytological characteristics of the mass.29

In Hong Kong, EUS is not commonly used for routine staging. We concur with the National Comprehensive Cancer Network (NCCN) guidelines, which state that EUS with or without fine needle tissue acquisition provides information complementary to CT scans but is not recommended for routine staging.16 30 31 32 Endoscopic ultrasound accuracy is largely operator-dependent and may be affected by anatomical variations of the hepatic arteries.16 In the diagnosis of PDAC, EUS offers specificity and sensitivity comparable to CT; it may provide additional information for lesions with inconclusive results or lesions <2 cm on initial CT.18 21 Contrast-enhanced EUS, an evolving technique, can distinguish characteristic traits of malignancy (eg, hypoenhancement versus hyperenhancement) in highly vascular neuroendocrine tumours.33

Endoscopic ultrasound–FNA is an important approach for obtaining tissue to establish a cytologic diagnosis. We have listed indications that require tissue diagnosis for treatment planning; in such instances, EUS-FNA may be strongly considered, especially for cases potentially requiring chemotherapy or radiation therapy.33 34 35 36 However, the implementation of EUS-FNA may vary according to each centre’s protocols and relevant expertise.

Surveillance

Statement 10: Serum carbohydrate antigen 19-9 is recommended for diagnosis of PDAC and for treatment response monitoring, but not for routine screening of PDAC. (Level 1)
A: 80%; B: 10%; C: 10%; D: 0%; E: 0%

For the diagnosis of PDAC in symptomatic patients, serum carbohydrate antigen 19-9 (CA19-9) exhibits a sensitivity of approximately 80% and a specificity of 80% to 90%.37 38 There is also robust evidence suggesting that normal or decreased levels can predict resectability and improved survival. Carbohydrate antigen 19-9 levels <100 U/mL suggest resectability, whereas levels ≥100 U/mL suggest unresectability or metastatic disease. In the preoperative period, normal levels (<37 U/mL) may be prognostic of prolonged median survival (32-36 months) compared with elevated levels (≥37 U/mL; 12-15 months). Postoperative normalisation or decrease from baseline by 20% to 50% is associated with prolonged survival.38 However, CA19-9 is not an effective screening tool for PDAC, considering its positive predictive value of <1% in symptomatic patients.16 38

Statement 11: For patients with unresectable disease, a biopsy is recommended to obtain histological proof of PDAC.
A: 20%; B: 60%; C: 20%; D: 0%; E: 0%

As discussed in the context of EUS-FNA, a biopsy is needed to confirm a histological diagnosis of PDAC before definitive therapy. This approach is warranted when advanced or inoperable disease is suspected and neoadjuvant or palliative therapy is considered.39 Considering that some suspicious masses are not PDAC, histological proof is required to guide treatment planning. Common differential diagnoses include other malignant diseases, such as neuroendocrine tumour and teratoma, or benign conditions, such as autoimmune pancreatitis and chronic pancreatitis. Patients with tumours considered resectable based on imaging findings may be directly referred for surgical treatment without a routine biopsy.40

Statement 12: There is no consensus on screening practices for PDAC.
A: 70%; B: 20%; C: 10%; D: 0%; E: 0%

In Hong Kong, patients’ families frequently enquire about their PDAC risk and need for screening. However, local clinicians lack a standardised screening protocol for PDAC. Evidence reviewed by the United States Preventive Services Task Force suggests that screening is unnecessary for asymptomatic individuals with a low risk of PDAC.41 According to the International Cancer of the Pancreas Screening Consortium and the United States Preventive Services Task Force, screening should be conducted in a research setting with a multidisciplinary team for high-risk individuals—specifically, individuals with a history of familial pancreatic cancer, individuals with inherited genetic disorders linked to pancreatic cancer (eg, Peutz–Jeghers syndrome and hereditary pancreatitis), and individuals with germline mutations such as BRCA2 and PALB—by age 50 or 10 years earlier than the youngest relative was diagnosed with PDAC.41 42 For these individuals, pancreatic imaging with CT, magnetic resonance imaging, magnetic retrograde cholangiopancreatography, and/or EUS is suggested for annual pancreatic surveillance.41 42

The American Gastroenterological Association states that the advantages of PDAC screening for high-risk individuals include the possibility of detecting IPMNs, which may be precursor lesions to PDAC.43 There are no standard screening protocols for IPMNs. However, the Fukuoka guidelines suggest imaging for unresected, relatively indolent lesions at intervals of 3 to 6 months initially, then less frequently if the lesion size remains small. Long-term surveillance for lesions with ‘worrisome features’ or ‘high-risk stigmata’ may require more frequent monitoring, at intervals of 3 to 9 months, to detect the potential development of PDAC.29

Although these international practices can be considered, their applicability to the Hong Kong setting is uncertain.

Management of localised disease

Statement 13: Resectability depends on the involvement of the venous and arterial vasculature, mainly the superior mesenteric artery, superior mesenteric vein, celiac trunk, and hepatic artery.
A: 20%; B: 60%; C: 20%; D: 0%; E: 0%

We established resectability criteria that are consistent with the most recent NCCN guidelines.16 The assessment of resection potential involves determining the tumour’s extent into the following critical structures: superior mesenteric vein (SMV), portal vein (and its tributaries), superior mesenteric artery (SMA), celiac trunk, hepatic artery, and gastroduodenal artery.44 ‘Resectable’ PDAC lacks tumour contact with critical vessels and is characterised by the absence of metastasis. The SMV and portal vein remain patent. Borderline resectable PDAC is primarily characterised by tumour abutment with (contact with <180° of vessel wall circumference) the SMV, portal vein, SMA, and/or celiac trunk, as well as abutment with or limited enclosure of (contact with ≥180° of vessel wall circumference) the common hepatic artery. Locally advanced tumours are characterised by major occlusion of the portal vein or SMV, as well as enclosure of the SMA, celiac trunk, or proximal hepatic artery.44 45 46

Statement 14: Stent placement may be considered for cholangitis or severe jaundice, or if the waiting time for surgery exceeds 4 weeks.
A: 0%; B: 80%; C: 20%; D: 0%; E: 0%

Theoretically, preoperative biliary drainage should relieve symptoms of hyperbilirubinaemia, facilitate recovery from the metabolic derangements caused by obstructive jaundice, and improve surgical outcomes. However, as summarised by the NCCN, retrospective and prospective studies have either failed to show a decrease in postoperative mortality or have shown increases in wound complications and operating times among cases involving preoperative drainage.16 Furthermore, a randomised controlled trial (RCT) showed a higher rate of complications in the group undergoing routine preoperative biliary drainage through ERCP with a plastic stent (74% in the biliary drainage group vs 39% in the early surgery group).47 Considering the drainage preconditions in that trial and the trends we have observed in clinical practice, we recommend considering stent placement for patients with active cholangitis or severe jaundice, and in cases where the expected duration of preoperative drainage exceeds 4 weeks. In our experience, a bilirubin level of 250 μmol/L may be an acceptable threshold for stent placement, but this threshold should be evaluated in the context of the patient’s overall clinical condition. The appropriate technique for preoperative biliary stenting (ie, percutaneous biliary drainage, endoscopic biliary drainage, or ERCP) remains a subject of debate, as does the need for preoperative stenting itself.

Statement 15: The optimal procedure for resection of tumours in the pancreatic head is pancreaticoduodenectomy (Whipple procedure). The optimal procedure for resection of tumours in the pancreatic body and tail is distal pancreatectomy.
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Surgical resection of the tumour is the best option for patients with resectable PDAC. The procedure of choice depends on tumour location and its relationships with the bile duct and vessels. Patients with tumours in the head and uncinate process typically undergo pancreaticoduodenectomy (ie, the Whipple procedure). Distal pancreatectomy is usually performed as treatment for tumours of the body or tail, but a margin-negative (R0) resection should be targeted in such cases. If the tumour invades the portal vein, en bloc resection and reconstruction of the portal vein may achieve R0 resection.16

The NCCN has noted the emerging role of laparoscopic distal pancreatectomy, considering reported decreases in blood loss and length of hospital stay compared with open distal pancreatectomy.16 Another important consideration regarding the Whipple procedure is that outcomes are best when this surgical method is performed by surgeons who complete >20 such procedures annually, usually at high-volume centres.2 16 Additionally, the best outcomes are achieved when a multidisciplinary team, with members whose experience ranges from the operating room to the recovery room, has extensive experience in perioperative care and complication management.

Statement 16: Standard lymphadenectomy should involve the removal of ≥15 lymph nodes to allow adequate pathological staging of the disease.
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

This recommendation is based on the 2015 guidelines from the European Society for Medical Oncology (ESMO).11 The extent of lymphadenectomy remains a subject of debate because there is limited evidence of a benefit from extended lymphadenectomy.16 The International Study Group of Pancreatic Surgery reviewed the available evidence and identified lymph node stations that should be included in a standard lymphadenectomy, despite their acknowledgement that expert opinions varied among group members.48

Statement 17: Adjuvant therapy is recommended after surgical resection. Options include mFOLFIRINOX, gemcitabine plus capecitabine, gemcitabine monotherapy, or S-1. (Level 2)
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

Statement 18: After adjuvant treatment, patients are recommended to undergo monitoring every 3 to 6 months for 2 years and every 6 to 12 months thereafter.
A: 30%; B: 70%; C: 0%; D: 0%; E: 0%

Good outcomes from postoperative adjuvant therapy have been demonstrated in RCTs. In the CONKO-001 trial (Charité Onkologie–001) [n=368], postoperative adjuvant chemotherapy with gemcitabine alone significantly prolonged overall survival (OS) compared with observation (22.8 vs 20.2 months; hazard ratio [HR]=0.76, 95% confidence interval [CI]=0.61-0.95; P=0.010).49 The ESPAC-4 study (European Study Group for Pancreatic Cancer–4) [n=732] demonstrated that the combination of gemcitabine and capecitabine significantly prolonged postoperative OS compared with gemcitabine monotherapy (28.0 vs 25.5 months; HR=0.82, 95% CI=0.68-0.98; P=0.032).50 A mFOLFIRINOX (modified 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) regimen yielded significantly longer OS compared with gemcitabine alone (54.4 vs 35.0 months; HR=0.64, 95% CI=0.48-0.86; P=0.003) in the PRODIGE 24-ACCORD 24/CCTG PA 6 study (n=493).51 The JASPAC 01 study (Japan Adjuvant Study Group of Pancreatic Cancer) of 385 subjects in Japan showed significantly better OS with S-1, an oral 5-fluorouracil prodrug containing tegafur, gimeracil, and oteracil potassium, compared with gemcitabine alone (46.6 vs 25.5 months; HR=0.57, 95% CI=0.44-0.72; P<0.0001).52

Although we do not recommend a standard regimen, we have listed the available options for Hong Kong clinicians who may need to plan individualised therapy with limited resources. Modified FOLFIRINOX may be considered for patients with an Eastern Cooperative Oncology Group performance status (PS) score of 0 to 1. Those with a poor PS can receive gemcitabine plus capecitabine or gemcitabine monotherapy.16 S-1 may serve as an alternative to gemcitabine-based therapies.

Locally, some R2 resections (with macroscopic residual tumour) are followed by postoperative radiotherapy (RT), although the administration of RT in these cases is usually hindered by challenges regarding localisation of the tumour and administration of an adequate dose. In principle, adjuvant RT may address suspected residual disease or reduce local recurrence. However, the ESMO guidelines cite results from the EORTC (European Organisation for Research and Treatment of Cancer) and ESPAC-1 trials, which showed no benefit and suggested potential harm.11 53 54 The ESMO panel does not recommend postoperative adjuvant RT except in clinical trials.11

In our clinical experience, we have found it challenging to ensure that patients continue follow-up after curative treatment. Currently, there are no evidence-based standards for the frequency and timing of follow-up visits, use of CT scans and other imaging methods, and assessment of tumour biomarkers. Based on extensive discussion within our group, we recommend follow-up monitoring every 3 to 6 months for the first 2 years and every 6 months thereafter. This follow-up approach will enable clinicians to diagnose recurrences, detect and monitor complications, assess PS and quality of life, and provide some education and counselling.

Management of localised disease

Statement 19: Neoadjuvant therapy is recommended for borderline resectable disease. (Level 1)
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

Statement 20: There is limited evidence to support the recommendation of specific neoadjuvant regimens. Generally, combination regimens are preferred. (Level 2/3)
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Statement 21: Stereotactic body radiation therapy is not recommended outside of a clinical trial.
A: 50%; B: 50%; C: 0%; D: 0%; E: 0%

Borderline resectable PDAC is characterised by blood vessel infiltration that increases the risk of R1 resection (with microscopic residual tumour) and decreases the feasibility of upfront surgery.11 Neoadjuvant therapy may improve the likelihood of R0 resection, sterilise any potential metastasis, and assess the biological aggressiveness of the tumour to inform patient selection for surgery—if disease progression or intolerability to neoadjuvant treatment occurs, aggressive surgery may not be viable.16

The feasibility of neoadjuvant therapy in resectable and BR-PDAC was previously substantiated by a meta-analysis that evaluated various chemotherapy protocols, including gemcitabine-based and 5-fluorouracil–based combinations, with or without radiation.34 Two subsequent meta-analyses, based on the intention-to-treat approach, demonstrated that OS and R0 resection rates favoured neoadjuvant therapy (primarily gemcitabine-based, with or without radiation) over upfront surgery.55 56 Recently, several studies showed promising results for neoadjuvant therapy, specifically in BR-PDAC. First, a phase II, single-arm prospective trial (n=48) showed that neoadjuvant FOLFIRINOX followed by proton radiation (5 Gy in five fractions) with capecitabine resulted in a high degree of R0 resection among patients who underwent surgery (31/32).57 Progression-free survival (PFS) and 2-year OS among all patients were 14.7 months and 56%, respectively; among patients who underwent surgery, the respective values were 48.6 months and 72%.57 Subsequently, Korean researchers conducted the first multicentre phase II/III RCT of neoadjuvant therapy for BR-PDAC (n=58), where intention-to-treat analysis showed that among patients with BR-PDAC, gemcitabine-based neoadjuvant chemoradiation followed by surgery yielded a significantly higher 2-year survival than upfront surgery followed by chemoradiation (40.7% vs 26.1%, HR=1.495, 95% CI=0.66-3.36; P=0.028).58 The R0 resection rate also was significantly higher with neoadjuvant treatment (P=0.004).58 More recently, in the Dutch phase III PREOPANC trial (Perioperative or Adjuvant mFOLFIRINOX for Resectable Pancreatic Cancer) of patients with resectable and BR-PDAC (n=248), intention-to-treat analysis demonstrated improvements in distant metastasis-free interval (P=0.32), locoregional failure-free interval (P=0.0034), and R0 resection rate (P<0.001) among patients who received gemcitabine-based chemoradiation versus patients who underwent upfront surgery.59 The neoadjuvant group received preoperative gemcitabine with radiation; both study groups received postoperative adjuvant gemcitabine. Final OS was significantly better with neoadjuvant chemoradiation (15.7 vs 14.3 months, HR=0.73, 95% CI=0.56-0.96; P=0.025). Five-year OS also favoured neoadjuvant treatment (20.5% vs 6.5%).60

For tumours with a risk of incomplete resection, preoperative radiation may be administered after induction chemotherapy to increase the likelihood of R0 resection. Compared with fractionated RT, stereotactic body radiation therapy (SBRT) offers the potential advantage of delivering higher radiation doses while sparing adjacent tissues.16 However, the benefit of SBRT after induction chemotherapy has not been established among patients with BR-PDAC. Participants in the Alliance for Clinical Oncology trial A021501 received, prior to surgery, either eight cycles of mFOLFIRINOX or seven cycles of mFOLFIRINOX followed by hypofractionated image-guided radiation or SBRT. Patients without disease progression after neoadjuvant treatment underwent surgery and received adjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin).61 The results showed that the mFOLFIRINOX plus SBRT group had worse median OS and worse 18-month OS compared with the group that received mFOLFIRINOX alone; notably, only 19 of 56 chemoradiation patients underwent resection.61 Stereotactic body radiation therapy with chemotherapy requires further research before routine application in this setting.

Although the available literature does not provide strong support for a specific regimen, we recommend considering FOLFIRINOX or gemcitabine-based regimens. Stereotactic body radiation therapy with chemotherapy should be administered within a clinical trial; other RT techniques may be considered if neoadjuvant chemoradiation is planned.

Statement 22: Surgical candidacy should be reassessed after neoadjuvant therapy, preferably through multidisciplinary team discussions.
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

After preoperative treatment, restaging is recommended. The NCCN suggests repeating CT and performing a staging laparoscopy (if not previously conducted).16 In our experience, tumour assessment after neoadjuvant treatment is challenging and requires the involvement of a multidisciplinary team that will also contribute to discussions of future treatment with the patient and their family. Conventional imaging may not reliably assess resectability. Regardless of radiographic stability, clinical improvement and a decrease in CA19-9 level, further evaluations are needed.16 Before proceeding with resection, frozen section analyses of tumours responsive to neoadjuvant therapy should be performed to rule out metastasis and examine critical structures.

Management of locally advanced disease

Statement 23: For locally advanced disease, systemic therapy is the primary treatment. Options include FOLFIRINOX, gemcitabine plus nab-paclitaxel, gemcitabine plus capecitabine, and gemcitabine monotherapy. (Level 1/2/3)
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

The extensive infiltration of critical vessels in LA-PDAC precludes reconstruction and hinders tumour resection. The primary treatment is systemic chemotherapy. Similar to the statements regarding resectable disease, we have listed the various options for individualised management. Historically, gemcitabine has been used for LA-PDAC, providing a clinical benefit response of 23.8%, median OS of 5.65 months, and 1-year survival of 18% in one RCT focused on advanced PDAC.62 A 6-month treatment duration has been endorsed by the ESMO guidelines.11 Concerning 6-month OS, a meta-analysis showed that gemcitabine plus capecitabine reduced the mortality risk by 15% compared with gemcitabine monotherapy (relative risk=0.85, 95% CI=0.73-0.99; P=0.04).63

FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens, initially established for metastatic PDAC (mPDAC), have been applied to LA-PDAC. A meta-analysis showed that the median OS with FOLFIRINOX for LA-PDAC was 24.2 months, which was approximately twofold longer than the OS of 6 to 13 months observed with gemcitabine.64 In one case series (n=485), despite higher rates of RECIST (Response Evaluation Criteria in Solid Tumors) partial response and subsequent pancreatectomy among patients receiving FOLFIRINOX compared to those receiving gemcitabine plus nab-paclitaxel, both regimens (as first-line chemotherapy for LA-PDAC) provided similar OS (21 vs 20 months, HR=1.48, 95% CI=0.97-2.26; P=0.07).65

Statement 24: Chemoradiation or stereotactic body radiation therapy can be considered for patients with no progression after chemotherapy.
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

After tumour stabilisation via post-induction chemotherapy, concurrent chemoradiation is usually considered for LA-PDAC to optimise local control. Trials comparing chemoradiation with chemotherapy alone have shown conflicting results.66 67 68 Notably, the contemporary phase III LAP-07 study, which randomly assigned patients with non-progressing LA-PDAC after 4 months of gemcitabine plus erlotinib (n=269) to either receive RT plus capecitabine or continue chemotherapy, did not show a survival benefit from the addition of RT (median OS from date of initial chemotherapy: 16.5 vs 15.2 months; P=0.83), despite a decrease in locoregional progression (32% vs 46%; P=0.04).69 Therefore, no standard chemotherapy regimen, RT dose, or modality has been established. As previously discussed, the advantages of delivering high RT doses while sparing critical tissues make SBRT a promising option for LA-PDAC. Pooled analyses of trials involving chemotherapy with SBRT for LA-PDAC revealed a median OS of 17 months, a 1-year locoregional control rate of 72.3%, and an overall severe adverse event incidence of ≤10%.70 Another meta-analysis showed that SBRT improved 2-year OS compared with conventionally fractionated RT with concurrent chemotherapy (26.9% vs 13.7%; P=0.004), although the rates of late grade 3/4 toxicity were similar (9.0% vs 10.1%; P=0.49).71 Despite the limited evidence favouring a specific protocol, the NCCN recommends systemic therapy or induction chemotherapy for 4 to 6 months, followed by chemoradiation or SBRT.16

Management of metastatic disease

Statement 25: The primary treatment for metastatic disease is palliative systemic therapy. (Level 2)
A: 90%; B: 10%; C: 0%; D: 0%; E: 0%

Statement 26: The treatment decision depends on performance status, bilirubin level, and the preferences of the clinician and patient. Combination therapy is generally recommended for patients with good performance status, bilirubin level <1.5 times the upper limit of normal, and intention to undergo aggressive treatment.
A: 90%; B: 10%; C: 0%; D: 0%; E: 0%

Statement 27: Combination treatment options include FOLFIRINOX, gemcitabine plus nab-paclitaxel, gemcitabine plus capecitabine, and gemcitabine plus S-1. (Level 2)
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Statement 28: Monotherapy options include S-1 alone and gemcitabine alone. (Level 2)
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

The benefit of systemic chemotherapy for mPDAC has been confirmed in phase III RCTs.62 72 73 Surgery does not improve OS and should not be regarded as routine treatment.74 75 With respect to treatment planning, we noted that patients enrolled in phase III RCTs for combination chemotherapy had an Eastern Cooperative Oncology Group PS score of 0 to 1 and a normal bilirubin level. The bilirubin threshold of <1.5 times the upper limit of normal was adapted from the American Society of Clinical Oncology and ESMO guidelines.11 76 In practice, clinicians frequently accept a slightly higher level for specific chemotherapy regimens. The intended treatment strategy should be established based on the balance of benefits and harms—aggressive treatment with combination therapy may achieve good tumour control, whereas less aggressive options (eg, monotherapy) can maintain or improve quality of life for patients with clinical statuses that preclude the use of combination therapy.77

The results of the PRODIGE 4/ACCORD 11 trial (n=342) showed an improvement in median OS among patients receiving FOLFIRINOX compared with those receiving gemcitabine (11.1 vs 6.8 months, HR=0.57, 95% CI=0.45-0.73; P<0.001). Additionally, the median PFS and overall response rate were significantly better.72 However, FOLFIRINOX had an inferior safety profile compared with gemcitabine.72 The MPACT trial (n=861) demonstrated that the combination of nab-paclitaxel and gemcitabine, compared with gemcitabine alone, significantly the improved median OS (8.5 vs 6.7 months, HR=0.72, 95% CI=0.62-0.83; P<0.001), median PFS, and overall response rate.73 Compared with gemcitabine, the combination regimen had higher rates of myelosuppression and peripheral neuropathy, although these effects appeared to be reversible.73 Clinicians in Hong Kong may prefer gemcitabine plus capecitabine due to the convenience of the oral formulation. Individual trial results for this combination tended to indicate a survival benefit but did not demonstrate statistical significance; subsequent pooled analyses suggested a more robust benefit.78 79 80 81 A possible survival benefit was also detected with gemcitabine plus S-1, which we have included in the list of recommended combination therapies (Table 3).

Table 3. Options for combination chemotherapy for metastatic pancreatic ductal adenocarcinoma

As previously stated, monotherapy options are necessary for patients with poor PS or elevated bilirubin levels that do not exhibit rapid normalisation. Some clinicians and patients may also prefer single-agent treatment. Gemcitabine monotherapy for mPDAC is already established—an early phase III trial (n=126) revealed a clinical benefit response in 23.8% of gemcitabine-treated patients compared with 4.8% of 5-fluorouracil–treated patients (P=0.0022).62 Additionally, OS with gemcitabine in the MPACT and PRODIGE trials was approximately 6 months.72 73 In all trials, gemcitabine was well-tolerated.62 72 73 S-1 was evaluated in a phase III trial (n=834); its use as monotherapy led to a median OS of 9.7 months with good tolerability.81 S-1 also demonstrated non-inferiority to gemcitabine (HR=0.96, 97.5% CI=0.78-1.18; P<0.001 for non-inferiority).81 In Hong Kong, capecitabine monotherapy is used for selected patients. The efficacy and tolerability of capecitabine are currently supported by phase II evidence.82

Statement 29: The decision to undergo subsequent therapy after first-line treatment is highly individualised. Key factors to consider include the type and duration of first-line treatment, performance status, organ function, and treatment goals.
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

We recognise that some patients will undergo several lines of treatment, but there is currently no consensus regarding the approach to next-line therapy for mPDAC. According to a multivariate analysis of patient variables from a cohort study of second-line treatment, prognostic factors for OS include liver metastases, PS, pain, jaundice, ascites, duration of first-line treatment, and type of second-line regimen.83 These factors mirror our real-world experience in establishing individualised regimens for subsequent therapy. Evidence for next-line treatment is based on cohort studies, phase II trials, and phase III RCTs (Table 4).84 85 86 87 88 89 90 91 92 93 94 95 Only the regimen of nanoliposomal irinotecan plus fluorouracil and folinic acid has been evaluated in a multicentre phase III trial demonstrating significant OS improvement; thus, it is the first regimen with high-level evidence supporting usage as second-line mPDAC treatment for patients who progressed on first-line gemcitabine treatment.89

Table 4. Options for second-line treatment for metastatic pancreatic ductal adenocarcinoma

Personalised medicine

Statement 30: Germline testing of BRCA1/2 and somatic testing of microsatellite instability/mismatch repair can be considered for patients with unresectable disease, due to potential therapeutic implications.
A: 40%; B: 60%; C: 0%; D: 0%; E: 0%

Statement 31: Among patients who test positive for germline BRCA1 or BRCA2 mutations, olaparib may be considered for patients who have previously been treated with a platinum-based regimen and have not exhibited disease progression for at least 16 weeks. (Level 2)
A: 50%; B: 50%; C: 0%; D: 0%; E: 0%

Statement 32: For patients with tumours that harbour high microsatellite instability or genetic aberrations in DNA mismatch repair genes, immune checkpoint inhibitors may be considered.
A: 90%; B: 10%; C: 0%; D: 0%; E: 0%

Emerging evidence suggests that mPDAC treatment can be tailored according to underlying mutations, and we emphasise that individual tumour profiling can be considered for selecting patients who may benefit from such treatment. The notion that PDAC with germline BRCA1/2 mutations responds well to platinum-based therapy is supported by retrospective analyses.96 97 In contrast, the phase III POLO (Pancreas Cancer Olaparib Ongoing) RCT demonstrated that targeted therapy was effective for patients with a germline BRCA mutation who had prior platinum-based chemotherapy for mPDAC and whose disease had not progressed for 16 weeks; these patients experienced a clinical benefit with maintenance olaparib, a poly (adenosine diphosphate-ribose) polymerase inhibitor.98 Among those 154 study subjects, median PFS was significantly longer in patients with maintenance olaparib than placebo group (7.4 vs 3.8 months, HR=0.53, 95% CI=0.35-0.82; P=0.0038).98 The preliminary OS in both treatment groups was approximately 18 months.98 Based on the inclusion criteria and results of the POLO study, we recommend olaparib for patients with BRCA1/BRCA2-positive mPDAC that has not progressed for 16 weeks.

Approximately 2% of pancreatic cancers have mismatch repair (MMR) deficiency.99 Patients with advanced MMR-deficient cancers respond to programmed cell death protein 1 blockade. The efficacy of the anti–programmed cell death protein 1 antibody pembrolizumab was evaluated in patients with MMR-deficient tumour types. Among 86 patients, eight had pancreatic tumours. Overall, 53.5% (46/86) of the patients exhibited objective radiographic responses, whereas 76.7% (66/86) demonstrated disease control.99 These results indicate that immune checkpoint inhibition should be considered for high microsatellite instability mPDAC. The potential benefit of this approach has been acknowledged by international guidelines.16 76 100

Germline testing of BRCA1/2 and somatic testing of microsatellite instability/MMR are conducted separately. In contrast to countries with extensive reimbursement, routine testing with comprehensive gene panels is not routinely feasible for all patients due to the limited resources in Hong Kong. Hong Kong clinicians, especially in private clinics, may utilise next-generation sequencing services to obtain a comprehensive genetic mutation profile. In next-generation sequencing, a broad mutational analysis panel can identify potentially actionable alterations, including BRCA1/2 mutations. However, one study showed that only 1.3% of patients (3/225) received targeted therapy for PDAC based on next-generation sequencing results.101 This observation is similar to our clinical experience, suggesting that next-generation sequencing has limited therapeutic utility for PDAC.

Statement 33: Genetic counselling is recommended for patients who test positive for a germline mutation.
A: 50%; B: 50%; C: 0%; D: 0%; E: 0%

Germline testing for BRCA mutations in PDAC is expected to increase in Hong Kong. We recommend genetic counselling for patients who plan to undergo tests for pathogenic variants. The NCCN also recommends germline testing and subsequent referral for genetic counselling at the time of PDAC diagnosis, especially for patients with suspected familial risk based on a family history of BRCA-linked tumours.16 No detailed guidance regarding genetic counselling for PDAC is currently available. Nonetheless, guidelines regarding BRCA-associated tumours, particularly breast and ovarian tumours, recommend the provision of genetic counselling services for patients with germline pathogenic mutations.102 103 104 105

Palliative and supportive care

Statement 34: Assessments of physical and psychological symptoms should be performed for all patients with PDAC. Palliative management should be considered when clinically indicated.
A: 70%; B: 30%; C: 0%; D: 0%; E: 0%

Statement 35: Biliary drainage should be considered for patients with obstructive jaundice. Options include endoscopic or percutaneous drainage and surgical bypass.
A: 70%; B: 20%; C: 10%; D: 0%; E: 0%

Statement 36: Options for the management of gastric outlet obstruction include surgical bypass and endoscopic stenting.
A: 100%; B: 0%; C: 0%; D: 0%; E: 0%

Statement 37: Aggressive pain control is mandatory and frequently requires the involvement of a pain specialist
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

Statement 38: In addition to pharmacological interventions, a coeliac axis block can be considered to optimise pain control.
A: 60%; B: 40%; C: 0%; D: 0%; E: 0%

Statement 39: Palliative radiation can be considered to relieve severe tumour-associated pain and/or bleeding from the primary tumour site.
A: 40%; B: 60%; C: 0%; D: 0%; E: 0%

We acknowledge that palliative care and supportive care for PDAC are therapeutic aspects often overlooked by clinicians. Key guidelines have emphasised the need to coordinate palliative and supportive care with therapeutic care, thereby optimising quality of life and potentially improving survival. These guidelines have highlighted interventions to address symptoms such as pain, biliary obstruction, gastric outlet obstruction, and bleeding.11 16

Symptomatic biliary obstruction occurs in up to 75% of patients with pancreatic head tumours. Obstructive jaundice can lead to generalised wasting; untreated biliary obstruction can result in cholangitis and liver dysfunction, with the potential for early mortality.106 Primary treatments consist of endoscopic or percutaneous drainage. Surgical bypass should only be utilised as a palliative option in cases where the planned Whipple procedure revealed an unresectable tumour.

Tumour invasion into the duodenum leads to gastric outlet obstruction. The choice of treatment depends on PS and predicted length of survival16—in an otherwise young and healthy patient with an unresectable tumour, surgical bypass is the best palliative option with respect to quality of life. Endoscopic enteral stenting may be preferred for frail patients.

Pain is experienced by almost all patients with advanced PDAC and requires aggressive management. Experts in pain management, such as pain specialists or oncologists with extensive experience in pain medicine, should often be included in the care team. A coeliac axis block, which interrupts visceral pain innervation from the pancreas and nearby structures through injections of corticosteroids and anaesthetics, may be considered for severe pain refractory to analgesics or narcotics.16 107 A coeliac axis block is usually performed under fluoroscopic or CT-based guidance, but EUS-based guidance provides better visualisation of the coeliac plexus.108

Palliative RT can be used to control pain caused by the tumour or sites of metastasis. Patients with non-mPDAC and poor PS or co-morbidities that preclude definitive therapy may be offered palliative RT. Additionally, RT is an option for the management of tumour-induced gastrointestinal bleeding.11 16

Conclusion

Despite its relatively low incidence among cancers worldwide and in Hong Kong, PDAC represents a major health burden because of its aggressive nature and the complexities involved in its diagnosis and management. To familiarise Hong Kong clinicians with all aspects of PDAC care and provide practical guidance, our consensus group developed this initial set of recommendations for clinical management of PDAC. We discussed the current state of PDAC management, reviewed the best available evidence and international guidelines, and crafted statements that address real-world situations encountered by clinicians. We recognise that many aspects of PDAC treatment lack high-level evidence; moreover, clinical experiences, patient preferences, and resources availability vary across Hong Kong. Thus, several of our statements suggest options, rather than endorsing a specific technique or regimen, to facilitate individualised management based on available evidence and clinical judgement.

Author contributions

Concept or design: SL Chan, CL Chiang, KSH Chok.
Acquisition of data: SL Chan, CL Chiang, KSH Chok.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

SL Chan has served as an advisor for AstraZeneca, MSD, Eisai, and Ipsen, and has received research funding from Bayer, Eisai, Ipsen, Sirtex, and MSD. CL Chiang has served as an advisor for AstraZeneca, MSD, and Eisai, and has received research funding from Merck KGaA, AstraZeneca, and Taiho. Other authors have disclosed no conflicts of interest.

Acknowledgement

The authors thank Dr Jose Miguel (Awi) Curameng, Dr Mita Pabari, and Dr Pia Villanueva of MIMS (Hong Kong) Limited for support with meeting logistics, coordination, and medical writing.

Funding/support

The consensus meeting and manuscript development were funded by AstraZeneca. The funder had no role in study design, data collection/analysis/interpretation, or manuscript preparation.

References

1. Grant TJ, Hua K, Singh A. Molecular pathogenesis of pancreatic cancer. Prog Mol Biol Transl Sci 2016;144:241-75. Crossref

2. Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA 2021;326:851-62. Crossref

3. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet 2020;395:2008-20. Crossref

4. Huang J, Lok V, Ngai CH, et al. Worldwide burden of, risk factors for, and trends in pancreatic cancer. Gastroenterology 2021;160:744-54. Crossref

5. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49. Crossref

6. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the Global Cancer Statistics 2020. Chin Med J (Engl) 2021;134:783-91. Crossref

7. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. Crossref

8. Strobel O, Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol 2019;16:11-26. Crossref

9. Hospital Authority, Hong Kong SAR Government. Overview of Hong Kong Cancer Statistics of 2019. Available from: https://www3.ha.org.hk/cancereg/pdf/overview/Overview%20of%20HK%20Cancer%20Stat%202019.pdf. Accessed 3 May 2022.

10. Nuffield Department of Primary Care Health Sciences. Centre for Evidence-Based Medicine. OCEBM levels of evidence. Available from: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence.Accessed 30 April 2022.

11. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 Suppl 5:v56-68. Crossref

12. Schmidt-Hansen M, Berendse S, Hamilton W. Symptoms of pancreatic cancer in primary care: a systematic review. Pancreas 2016;45:814-8. Crossref

13. Walter FM, Mills K, Mendonça SC, et al. Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study. Lancet Gastroenterol Hepatol 2016;1:298-306. Crossref

14. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol 2005;7:189-97. Crossref

15. Wong HC, Lam KY, Chong CC, Chan AW, Chan SL. Impact of weight loss during chemotherapy in Chinese patients with unresectable pancreatic cancer. Nutr Cancer 2019;71:954-70. Crossref

16. National Comprehensive Cancer Network. NCCN guidelines: pancreatic adenocarcinoma. V1.2022. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455. Accessed 27 Mar 2024.

17. Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association. Radiology 2014;270:248-60. Crossref

18. Kinney T. Evidence-based imaging of pancreatic malignancies. Surg Clin North Am 2010;90:235-49. Crossref

19. Bipat S, Phoa SS, van Delden OM, et al. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr 2005;29:438-45. Crossref

20. National Institute for Health and Care Excellence. Pancreatic cancer. Quality standard [QS177] Published: 20 December 2018. Quality statement 2: staging using FDG-PET/CT. Available from: https://www.nice.org.uk/guidance/qs177/chapter/quality-statement-2-staging-using-fdg-petct. Accessed 3 May 2022.

21. Toft J, Hadden WJ, Laurence JM, et al. Imaging modalities in the diagnosis of pancreatic adenocarcinoma: a systematic review and meta-analysis of sensitivity, specificity and diagnostic accuracy. Eur J Radiol 2017;92:17-23. Crossref

22. Kakar S, Pawlik TM, Allen PJ. Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, editors. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017: 337-47.

23. The Royal College of Pathologists. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. October 2019. Available from: https://www.rcpath.org/uploads/assets/34910231-c106-4629-a2de9e9ae6f87ac1/G091-Dataset-for-histopathological-reporting-of-carcinomas-of-the-pancreas-ampulla-of-Vater-and-common-bile-duct.pdf. Accessed 8 May 2022.

24. Royal College of Pathologists of Australasia. Cancer of the exocrine pancreas, ampulla of Vater and distal common bile duct: structured reporting protocol. 2nd edition 2020. Available from: https://www.rcpa.edu.au/getattachment/0e0524b6-32cb-491c-959f-4f60355d0509/Protocol-pancreatic-cancer.aspx. Accessed 8 May 2022.

25. College of American Pathologists. Protocol for the examination of specimens from patients with carcinoma of the pancreas. November 2021. Available from: https://documents.cap.org/protocols/Panc.Exo_4.2.0.2.REL_CAPCP.pdf. Accessed 8 May 2022.

26. Chung HG, Chang JI, Lee KH, Park JK, Lee KT, Lee JK. Comparison of EUS and ERCP-guided tissue sampling in suspected biliary stricture. PLoS One 2021;16:e0258887. Crossref

27. Malak M, Masuda D, Ogura T, et al. Yield of endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography for solid pancreatic neoplasms. Scand J Gastroenterol 2016;51:360-7. Crossref

28. Rösch T, Hofrichter K, Frimberger E, et al. ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study. Gastrointest Endosc 2004;60:390-6. Crossref

29. Tanaka M, Fernández-Del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738-53. Crossref

30. Agarwal B, Abu-Hamda E, Molke KL, Correa AM, Ho L. Endoscopic ultrasound-guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer. Am J Gastroenterol 2004;99:844-50. Crossref

31. Dewitt J, Devereaux BM, Lehman GA, Sherman S, Imperiale TF. Comparison of endoscopic ultrasound and computed tomography for the preoperative evaluation of pancreatic cancer: a systematic review. Clin Gastroenterol Hepatol 2006;4:717-25; quiz 664. Crossref

32. Nawaz H, Fan CY, Kloke J, et al. Performance characteristics of endoscopic ultrasound in the staging of pancreatic cancer: a meta-analysis. JOP 2013;14:484-97. Crossref

33. Kitano M, Yoshida T, Itonaga M, Tamura T, Hatamaru K, Yamashita Y. Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer. J Gastroenterol 2019;54:19-32. Crossref

34. Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7:e1000267. Crossref

35. Chari ST, Takahashi N, Levy MJ, et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin Gastroenterol Hepatol 2009;7:1097-103. Crossref

36. ASGE Standards of Practice Committee; Eloubeidi MA, Decker GA, et al. The role of endoscopy in the evaluation and management of patients with solid pancreatic neoplasia. Gastrointest Endosc 2016;83:17-28. Crossref

37. Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33:266-70. Crossref

38. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence-based appraisal. J Gastrointest Oncol 2012;3:105-19. Crossref

39. Hartwig W, Schneider L, Diener MK, Bergmann F, Büchler MW, Werner J. Preoperative tissue diagnosis for tumours of the pancreas. Br J Surg 2009;96:5-20. Crossref

40. Függer R, Gangl O, Fröschl U. Clinical approach to the patient with a solid pancreatic mass. Wien Med Wochenschr 2014;164:73-9. Crossref

41. United States Preventive Services Task Force; Owens DK, Davidson KW, et al. Screening for pancreatic cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2019;322:438-44. Crossref

42. Goggins M, Overbeek KA, Brand R, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020;69:7-17. Crossref

43. Aslanian HR, Lee JH, Canto MI. AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review. Gastroenterology 2020;159:358-62. Crossref

44. Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009;16:1727-33. Crossref

45. Katz MH, Marsh R, Herman JM, et al. Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. Ann Surg Oncol 2013;20:2787-95. Crossref

46. Tempero MA, Arnoletti JP, Behrman SW, et al. Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012;10:703-13. Crossref

47. van der Gaag NA, Rauws EA, van Eijck CH, et al. Preoperative biliary drainage for cancer of the head of pancreas. N Engl J Med 2010;362:129-37. Crossref

48. Tol JA, Gouma DJ, Bassi C, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2014;156:591-600. Crossref

49. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013;310:1473-81. Crossref

50. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017;389:1011-24. Crossref

51. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395-406. Crossref

52. Uesaka K, Boku N, Fukutomi A, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 2016;388:248-57. Crossref

53. Smeenk HG, van Eijck CH, Hop WC, et al. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg 2007;246:734-40. Crossref

54. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-85. Crossref

55. Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 2018;105:946-58. Crossref

56. Cloyd JM, Heh V, Pawlik TM, et al. Neoadjuvant therapy for resectable and borderline resectable pancreatic cancer: a meta-analysis of randomized controlled trials. J Clin Med 2020;9:1129. Crossref

57. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol 2018;4:963-9. Crossref

58. Jang JY, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg 2018;268:215-22. Crossref

59. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol 2020;38:1763-73. Crossref

60. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch randomized PREOPANC trial. J Clin Oncol 2022;40:1220-30. Crossref

61. Katz MH, Shi Q, Meyers JP, et al. Alliance A021501: preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. J Clin Oncol 2021;39(3_Suppl):377. Crossref

62. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13. Crossref

63. Xie DR, Yang Q, Chen DL, et al. Gemcitabine-based cytotoxic doublets chemotherapy for advanced pancreatic cancer: updated subgroup meta-analyses of overall survival. Jpn J Clin Oncol 2010;40:432-41. Crossref

64. Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016;17:801-10. Crossref

65. Perri G, Prakash L, Qiao W, et al. Response and survival associated with first-line FOLFIRINOX vs gemcitabine and nab-paclitaxel chemotherapy for localized pancreatic ductal adenocarcinoma. JAMA Surg 2020;155:832-9. Crossref

66. Ambe C, Fulp W, Springett G, Hoffe S, Mahipal A. A meta-analysis of randomized clinical trials of chemoradiation therapy in locally advanced pancreatic cancer. J Gastrointest Cancer 2015;46:284-90. Crossref

67. Chang JS, Chiu YF, Yu JC, Chen LT, Ch’ang HJ. The role of consolidation chemoradiotherapy in locally advanced pancreatic cancer receiving chemotherapy: an updated systematic review and meta-analysis. Cancer Res Treat 2018;50:562-74. Crossref

68. Wang C, Liu X, Wang X, Wang Y, Cha N. Effects of chemoradiotherapy and chemotherapy on survival of patients with locally advanced pancreatic cancer: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018;97:e12260. Crossref

69. Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:1844-53. Crossref

70. Petrelli F, Comito T, Ghidini A, Torri V, Scorsetti M, Barni S. Stereotactic body radiation therapy for locally advanced pancreatic cancer: a systematic review and pooled analysis of 19 trials. Int J Radiat Oncol Biol Phys 2017;97:313-22. Crossref

71. Tchelebi LT, Lehrer EJ, Trifiletti DM, et al. Conventionally fractionated radiation therapy versus stereotactic body radiation therapy for locally advanced pancreatic cancer (CRiSP): an international systematic review and meta-analysis. Cancer 2020;126:2120-31. Crossref

72. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. Crossref

73. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. Crossref

74. Gu J, Xu Z, Ma Y, et al. Surgical resection of metastatic pancreatic cancer: is it worth it?—a 15-year experience at a single Chinese center. J Gastrointest Oncol 2020;11:319-28. Crossref

75. Lillemoe KD, Cameron JL, Yeo CJ, et al. Pancreaticoduodenectomy. Does it have a role in the palliation of pancreatic cancer? Ann Surg 1996;223:718-25. Crossref

76. Sohal DP, Kennedy EB, Khorana A, et al. Metastatic pancreatic cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:2545-56. Crossref

77. Chan SL, Chan ST, Chan EH, He ZX. Systemic treatment for inoperable pancreatic adenocarcinoma: review and update. Chin J Cancer 2014;33:267-76. Crossref

78. Scheithauer W, Schüll B, Ulrich-Pur H, et al. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 2003;14:97-104. Crossref

79. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007;25:2212-7. Crossref

80. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009;27:5513-8. Crossref

81. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013;31:1640-8. Crossref

82. Cartwright TH, Cohn A, Varkey JA, et al. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002;20:160-4. Crossref

83. Vienot A, Beinse G, Louvet C, et al. Overall survival prediction and usefulness of second-line chemotherapy in advanced pancreatic adenocarcinoma. J Natl Cancer Inst 2017;109(10). Crossref

84. Hosein PJ, de Lima Lopes G Jr, Pastorini VH, et al. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol 2013;36:151-6. Crossref

85. Boeck S, Wilkowski R, Bruns CJ, et al. Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer. Oncology 2007;73:221-7. Crossref

86. Soares HP, Bayraktar S, Blaya M, et al. A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere. Cancer Chemother Pharmacol 2014;73:839-45. Crossref

87. Pelzer U, Stieler J, Roll L, et al. Second-line therapy in refractory pancreatic cancer. Results of a phase II study. Onkologie 2009;32:99-102. Crossref

88. Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol 2016;34:3914-20. Crossref

89. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387:545-57. Crossref

90. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:2423-9. Crossref

91. Yoo C, Hwang JY, Kim JE, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 2009;101:1658-63. Crossref

92. Dahan L, Bonnetain F, Ychou M, et al. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut 2010;59:1527-34. Crossref

93. Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 2011;47:1676-81. Crossref

94. Portal A, Pernot S, Tougeron D, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after FOLFIRINOX failure: an AGEO prospective multicentre cohort. Br J Cancer 2015;113:989-95. Crossref

95. Zaanan A, Trouilloud I, Markoutsaki T, et al. FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study. BMC Cancer 2014;14:441. Crossref

96. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014;111:1132-8. Crossref

97. Pishvaian MJ, Blais EM, Brody JR, et al. Outcomes in patients with pancreatic adenocarcinoma with genetic mutations in DNA damage response pathways: results from the Know Your Tumor Program. JCO Precis Oncol 2019;3:1-10. Crossref

98. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317-27. Crossref

99. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13. Crossref

100. Sohal DP, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol 2020;38:3217-30. Crossref

101. Lowery MA, Jordan EJ, Basturk O, et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res 2017;23:6094-100. Crossref

102. Hoogerbrugge N, Jongmans MC. Finding all BRCA pathogenic mutation carriers: best practice models. Eur J Hum Genet 2016;24 Suppl 1:S19-26. Crossref

103. National Collaborating Centre for Cancer. Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2013.

104. Daly MB, Pal T, Berry MP, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:77-102. Crossref

105. Pujol P, Barberis M, Beer P, et al. Clinical practice guidelines for BRCA1 and BRCA2 genetic testing. Eur J Cancer 2021;146:30-47. Crossref

106. House MG, Choti MA. Palliative therapy for pancreatic/biliary cancer. Surg Clin North Am 2005;85:359-71. Crossref

107. Wong GY, Schroeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. JAMA 2004;291:1092-9. Crossref

108. Santosh D, Lakhtakia S, Gupta R, et al. Clinical trial: a randomized trial comparing fluoroscopy guided percutaneous technique vs. endoscopic ultrasound guided technique of coeliac plexus block for treatment of pain in chronic pancreatitis. Aliment Pharmacol Ther 2009;29:979-84. Crossref

Consensus recommendations for the screening, diagnosis, and management of Helicobacter pylori infection in Hong Kong

Hong Kong Med J 2023 Dec;29(6):532–41 | Epub 30 Jun 2023

https://doi.org/10.12809/hkmj2210321

MEDICAL PRACTICE CME

Consensus recommendations for the screening, diagnosis, and management of Helicobacter pylori infection in Hong Kong

WK Leung, MD, FHKAM (Medicine)^1,2; KS Cheung, MD, MPH¹; Philip CO Sham, MB, BS (HK), FHKAM (Paediatrics)³; Raymond SY Tang, MD⁴; CK Loo, FHKAM (Medicine), FRCP (London)⁵; Axel SJ Hsu, MB, BS (HK), FHKCP^2,6; TK Cheung, PhD, FRACP⁵; LY Lam, MB, BS (HKU)⁷; Billy CF Chiu, FHKAM (Family Medicine), MPH (HK)³; Justin CY Wu, MB, ChB, MD^2,4

¹ Department of Medicine, Queen Mary Hospital/The University of Hong Kong, Hong Kong SAR, China

² The Hong Kong Society of Gastroenterology, Hong Kong SAR, China

³ Gleneagles Hong Kong Hospital, Hong Kong SAR, China

⁴ Department of Medicine and Therapeutics, Prince of Wales Hospital/The Chinese University of Hong Kong, Hong Kong SAR, China

⁵ Private Practice, Hong Kong SAR, China

⁶ Hong Kong Sanatorium & Hospital, Hong Kong SAR, China

⁷ St Teresa’s Hospital, Hong Kong SAR, China

Corresponding author: Prof WK Leung (waikleung@hku.hk)

Full paper in PDF

Abstract

Helicobacter pylori infection causes chronic gastric inflammation that contributes to various gastroduodenal diseases, including peptic ulcer and gastric cancer. Despite broad regional variations, the prevalence of resistance to antibiotics used to manage H pylori infection is increasing worldwide; this trend could hinder the success of eradication therapy. To increase awareness of H pylori and improve the diagnosis and treatment of its infection in Hong Kong, our consensus panel proposed a set of guidance statements for disease management. We conducted a comprehensive review of literature published during 2011 and 2021, with a focus on articles from Hong Kong or other regions of China. We evaluated the evidence using the Oxford Centre for Evidence-Based Medicine’s 2011 Levels of Evidence and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and sought consensus through online voting and a subsequent face-to-face meeting, which enabled us to develop and refine the guidance statements. This report consists of 24 statements regarding the epidemiology and burden, screening and diagnosis, and treatment of H pylori. Key guidance statements include a recommendation to use the test-and-treat approach for high-risk individuals, as well as the confirmation that triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin remains a valid first-line option for adults and children in Hong Kong.

[Abstract in Chinese]

Introduction

Antibiotics are the primary treatment for Helicobacter pylori; however, resistance to common antibiotics used in eradication therapy (eg, clarithromycin, metronidazole, and quinolones) is increasing worldwide, thereby reducing the expected therapeutic benefit.1 Thus, there is an urgent need for an updated management guide that considers susceptibility patterns, disease prevalence, and patient factors in Hong Kong. Accordingly, a panel of 10 experts from Hong Kong gathered to review recently published evidence regarding the management of H pylori infection to develop this consensus report.

PubMed was searched for published peer-reviewed articles in English on the epidemiology, screening, diagnosis, and treatment of H pylori infection, with a focus on Hong Kong and China. The search included clinical trials (randomised controlled trials [RCTs] and controlled clinical trials), practice guidelines, meta-analyses, systematic reviews, and observational studies from January 2011 to August 2021.

In September 2021, the panel assigned consensus topics to specific members for literature review and statement drafting, followed by a discussion in October 2021. The Oxford Centre for Evidence-Based Medicine’s 2011 Levels of Evidence2 and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system were used to evaluate level of evidence and classify recommendations, respectively. Details of GRADE classification are shown in the online supplementary Table.

All participants were asked to indicate their level of agreement using a Likert scale (1: completely agree; 2: agree with some reservations; 3: agree with major reservations; 4: disagree with reservations; 5: completely disagree). Statements were modified as necessary, and voting was repeated online in November 2021. Consensus was achieved if at least 75% of the panel members agreed with a statement (completely or with reservations). Statements regarding consensus recommendations for the screening, diagnosis, and management of H pylori infection in Hong Kong are detailed below.

Epidemiology and burden

Statement 1: Although the prevalence of H pylori infection in many developed countries has declined in recent decades, epidemiological data for Hong Kong, except in children, are limited. (quality of evidence: 2/3; strength of recommendation: not applicable; level of consensus: 100%)

Global and regional estimates published in 2017 revealed that the prevalences of H pylori infection were 55.8% in China and 53.9% in Taiwan.3 No prevalence data for Hong Kong have been reported since 2011. Although the prevalences in many countries in Europe and Northern America have declined since 2000, the prevalences in Asia before and after 2000 were similar (53.6% vs 54.3%).3 Two retrospective studies and a population-based study explored the H pylori infection rate in Hong Kong children. In 2008, the estimated rate of H pylori infection in healthy school children (n=2480) was 13.1%.4 Among 602 children who underwent esophagogastroduodenoscopy at a tertiary centre for peptic ulcer symptoms, the H pylori infection rate decreased from 25.6% in 2005 to 12.8% in 2017.5 6

Statement 2: Although the rate of H pylori reinfection remains low (<2%) in the Chinese population, it may be higher in children than in adults. (quality of evidence: 3; grade of recommendation: not applicable; level of consensus: 80%)

In a systematic review of 132 studies, the global annual rates of H pylori recurrence, reinfection, and recrudescence were 4.3%, 3.1%, and 2.2%, respectively. The global rates of H pylori recurrence generally remained stable in the 1990s, 2000s, and 2010s, but data varied according to region.7

Data regarding the rates of H pylori recurrence, reinfection, and recrudescence in Hong Kong adults are limited. A community-based study showed that the rate of H pylori reinfection in Taiwan was 0.34 to 0.95 per 100 person-years between 2008 and 2018.8 In 2020, a prospective cohort study in China showed that the annual rate of H pylori reinfection was 1.5% per person-year.9

The rates of H pylori reinfection may be higher in children. In a study from Baoding in Hubei, China, the recurrence rate was 18.8% (41/218 children with successful follow-up).10 Moreover, the rate was higher in children aged ≤10 years than in children aged >10 years (22.8% vs 7.1%, P=0.01). Similarly, a Bolivian population-based study showed a higher annual recurrence rate in younger children than in older children: 20% for children aged <5 years, 20% for children aged 5 to 9 years, 8% among children aged 10 to 14 years, and 8% among individuals aged ≥15 years.11

Statement 3: Helicobacter pylori infection in adults has been associated with increased risks of gastric adenocarcinoma, peptic ulcer disease, non-ulcer dyspepsia, and mucosa-associated lymphoid tissue (MALT) lymphoma. Eradication of H pylori has been shown to reduce gastric cancer incidence, reduce peptic ulcer recurrence, and provide symptomatic relief in H pylori–positive patients with non-ulcer dyspepsia. (quality of evidence: 1; grade of recommendation: not applicable; level of consensus: 90%)

Helicobacter pylori infection is considered an important causal risk factor for non-cardia gastric adenocarcinoma.12 The estimated global burden of gastric cancer attributable to H pylori is 89%.13 The odds ratio of gastric cancer onset among patients with H pylori infection ranges from 5.9 to 34.5.14 15 Usually, a high incidence of gastric cancer is associated with a high prevalence of H pylori infection.12 16

A reduced risk of gastric cancer after H pylori eradication has been demonstrated in interventional trials, including RCTs.17 18 19 20 21 22 23 To prevent one case of gastric cancer in H pylori–positive patients from a region with a high risk of gastric cancer (eg, China), the minimum number needed to treat was 15 according to a meta-analysis of six RCTs.24 In 2018, a territory-wide study of 73 237 H pylori–infected patients in Hong Kong showed that eradication was associated with a reduced risk of gastric cancer, particularly among patients aged ≤60 years.25 A meta-analysis of 24 studies also showed that the benefit of H pylori eradication for gastric cancer protection was greater in patients with endoscopically resected early gastric cancer compared with asymptomatic patients; moreover, eradication was associated with a reduced incidence of metachronous recurrence.26 The available evidence suggests that, even when H pylori treatment is initiated after the development of atrophic gastritis and metaplasia, the risk of gastric cancer is reduced.

Helicobacter pylori is a causal risk factor for peptic ulcer disease; its eradication therapy is effective in treating and preventing the recurrence of both gastric and duodenal ulcers.27 28

There is a potential causal link between H pylori infection and dyspeptic symptoms. Helicobacter pylori eradication had a small but statistically significant effect on the relief of dyspeptic symptoms in H pylori–positive patients.29

Gastric MALT lymphoma was also associated with H pylori infection; remission was achieved in 77.8% of patients after successful eradication.30

Screening and diagnosis

Statement 4: Considering the declining incidence of gastric cancer in Hong Kong, screening for H pylori in the general population is not recommended. (quality of evidence: 1; grade of recommendation: conditional; level of consensus: 90%)

A screen-and-treat strategy for H pylori is most cost-effective in regions with high gastric cancer incidence (ie, 20 per 100 000 person-years).26 The 2020 age-standardised incidence of gastric cancer in Hong Kong was 8.7 and 5.3 per 100 000 person-years in male and female, respectively.31 Because of this declining incidence, a screen-and-treat strategy may not be cost-effective for gastric cancer prevention in Hong Kong.

Statement 5: Among adults without gastric symptoms, individuals at high risk of gastric cancer (eg, individuals with a family history of gastric cancer) should be tested and (if they test positive) treated for H pylori. Otherwise, routine testing of asymptomatic household members or family members of H pylori–infected adults is not recommended. (quality of evidence: 1; grade of recommendation: strong; level of consensus: 90%)

Statement 6: Adults with non-ulcer dyspepsia, peptic ulcer disease, and early gastric cancer after endoscopic treatment should be tested and (if they test positive) treated for H pylori. (quality of evidence: 1; grade of recommendation: strong; level of consensus: 100%)

Statement 7: Adults with gastric biopsy results showing atrophy, intestinal metaplasia, or dysplasia should be tested and (if they test positive) treated for H pylori. (quality of evidence: 1; grade of recommendation: strong; level of consensus: 100%)

Family history, atrophic gastritis, and intestinal metaplasia are established risk factors for gastric cancer.32 33 Therefore, it is prudent to test for and treat H pylori in patients with a family history or pre-cancerous gastric lesions.

Statement 8: Adults planning to begin long-term low-dose aspirin treatment should be tested and (if they test positive) treated for H pylori. (quality of evidence: 3; grade of recommendation: conditional; level of consensus: 90%)

Statement 9: Adult patients planning to begin other non-aspirin non-steroidal anti-inflammatory drugs, antiplatelets, and anticoagulants should be tested and (if they test positive) treated for H pylori. (quality of evidence: 3; grade of recommendation: conditional; level of consensus: 70%)

Low-dose aspirin, non-steroidal anti-inflammatory drugs, anticoagulants, and antiplatelets can increase the risk of gastrointestinal (GI) bleeding.34 35 There is limited and conflicting evidence regarding the interaction among these agents, H pylori, and GI bleeding.36 37 38 39 Therefore, the benefit of testing and treatment for all users of these agents is unclear. However, the treatment of H pylori infection along with the use of gastroprotective strategies could mitigate the risk of GI complications, particularly in patients at high risk of GI bleeding.32 40 41 Thus, despite the conflicting evidence, the consensus panel also favoured testing and treatment for H pylori infection in these patients.

Statement 10: Adults with unexplained iron deficiency anaemia, vitamin B12 deficiency, or immune thrombocytopenic purpura should be tested and (if they test positive) treated for H pylori. (quality of evidence: 1/2; grade of recommendation: conditional; level of consensus: 90%)

Iron deficiency anaemia was associated with H pylori infection in both adults and children. The effect of iron therapy for iron deficiency anaemia may be enhanced with H pylori treatment.42 43 44 45 46 In recent decades, systematic reviews have shown that H pylori eradication can also improve platelet counts in adult and paediatric patients with idiopathic thrombocytopenic purpura.47 48 49

However, this panel does not recommend testing and treatment for all children with chronic idiopathic thrombocytopenic purpura. Additionally, the identification of iron deficiency anaemia aetiology in children should be prioritised over the detection and treatment of H pylori.

Statement 11: Routine H pylori testing in asymptomatic children is not recommended. However, children with peptic ulcer disease should be tested and (if they test positive) treated for H pylori. (quality of evidence: 2/3; grade of recommendation: strong; level of consensus: 90%)

Helicobacter pylori infection in children is mainly asymptomatic and rarely causes complications; thus, routine non-invasive testing in an otherwise asymptomatic child is not usually recommended. When a child presents with GI symptoms, the clinical investigation should focus on identifying the cause of the child’s symptoms, rather than solely confirming the presence of H pylori.50 51

Statement 12: Non-invasive tests, including the urea breath test and (preferably monoclonal) stool antigen test, are highly accurate for the initial diagnosis and follow-up of H pylori. (quality of evidence: 2; grade of recommendation: not applicable; level of consensus: 90%)

The carbon-13 urea breath test and stool antigen test are non-invasive diagnostic tests with high accuracy in the detection of H pylori. The carbon-13 urea breath test has a sensitivity of 95% to 98% and a speciﬁcity of 90% to 97%.52 53 The monoclonal stool antigen test has a sensitivity of 90% to 98% and a speciﬁcity of 90% to 97%.52 54

For post-eradication therapy follow-up, reliable results can be obtained at 2 weeks after discontinuation of proton pump inhibitors (PPIs) and at least 4 weeks after discontinuation of antibiotics and bismuth.32

Statement 13: Serological testing is not recommended for initial diagnosis and post-eradication follow-up of H pylori. (quality of evidence: 2; grade of recommendation: conditional; level of consensus: 100%)

Serological testing has low accuracy and high false-negative rates for initial diagnosis32; it is not recommended for post-eradication follow-up because it can detect antibodies from past infections.55 However, it may be useful in the management of some clinical conditions characterised by decreased bacterial load (eg, GI bleeding, atrophic gastritis, gastric MALT lymphoma, and gastric cancer); other tests can lose sensitivity for these conditions.32

Statement 14: For all patients who undergo endoscopy, the initial diagnosis of H pylori can be made by the following methods: rapid urease test, histology with or without specific staining, and culture. (quality of evidence: 2; grade of recommendation: strong; level of consensus: 100%)

Gastric biopsies are ideal specimens for diagnostic rapid urease tests or histopathological assessments.32 Samples generally should be collected from both the antrum and corpus. Rapid urease tests can be used for quick assessment, but specimens with low bacterial loads can yield false-negative results.32 56 Culture-based detection of H pylori has comparatively low sensitivity and is usually reserved for instances where antimicrobial susceptibility testing is needed.

Additional information about screening for H pylori in pregnancy and diagnosis for H pylori in children are shown in the online supplementary Appendix.

Treatment

Statement 15: The choice of H pylori eradication therapy should be based on H pylori microbial resistance patterns and antibiotic stewardship in Hong Kong, as well as the efficacy of gastric acid suppression. The regimen should be simple to use and well-tolerated, with good compliance and high efficacy (>85%). (quality of evidence: 1; grade of recommendation: strong; level of consensus: 100%)

In addition to tolerability and compliance, key H pylori treatment considerations include its susceptibility and resistance to antimicrobials, both of which demonstrate temporal and geographical variability.32 40 57 58

The degree of gastric acid suppression is one of the most important factors in determining the success of H pylori eradication.2 59 The dose, frequency, and potency of PPIs, as well as host genetics (hepatic cytochrome P450 2C19 polymorphism), can influence gastric pH. The most effective acid suppression regimen should be used to increase antibiotic bioavailability.60 Analyses of potassium-competitive acid blockers have shown that greater acid suppression can improve eradication success.61 A longer eradication therapy interval could also improve the eradication rate.

Statement 16: In the first-line setting for H pylori eradication, possible therapies include (a) triple therapy with a PPI, clarithromycin, and amoxicillin for 14 days; and (b) bismuth quadruple therapy with a PPI, tetracycline, metronidazole, and a bismuth salt for 10 to 14 days. (quality of evidence: 1/2; grade of recommendation: strong/conditional; level of consensus: 100%)

Triple therapy with a PPI, clarithromycin, and amoxicillin (Table) remains the first-line option in regions with clarithromycin resistance <15% and a local eradication rate of ≥85%.32 57 Patients allergic to amoxicillin should receive metronidazole. If clarithromycin resistance exceeds 15%, bismuth quadruple therapy is recommended as another first-line option (ie, a PPI, tetracycline, metronidazole, and a bismuth salt). According to a meta-analysis published in 2018, the prevalence of resistance to clarithromycin was 10% (95% confidence interval=5%-17%) in Hong Kong; the prevalence of resistance to metronidazole was 53% (95% confidence interval=39%-66%).62 A more recent population-based study in Hong Kong showed that the overall failure rate of clarithromycin-based triple therapy was 10.1% during the period from 2003 to 2018.63 Compared with the 7-day regimen, a 14-day regimen of triple therapy is usually recommended because it produces better eradication rates.57 64

Table. Treatment options for Helicobacter pylori eradication in adults and children

Randomised trials have demonstrated eradication rates of >92% (intent-to-treat analysis) when bismuth quadruple therapy is used as empirical first-line treatment.65 66 Studies from Taiwan and Texas of the United States revealed that treatment intervals of 10 to 14 days led to eradication rates of >90%.65 67 However, the tolerability and availability of bismuth compounds could limit the widespread use of bismuth-based therapy.65

Statement 17: In the second-line setting for H pylori eradication (ie, after unsuccessful clarithromycin-based triple therapy), possible therapies include (a) bismuth quadruple therapy with a PPI, tetracycline, metronidazole, and a bismuth salt for 10 to 14 days; (b) high-dose PPI–amoxicillin dual therapy for 14 days; and (c) levofloxacin-containing triple therapy with a PPI and amoxicillin for 14 days. (quality of evidence: 1/2; grade of recommendation: conditional; level of consensus: 100%)

Second-line treatment should not repeat the previous regimen. The reuse of antibiotics that were previously unsuccessful (eg, clarithromycin and levofloxacin, both of which commonly cause post-exposure resistance) should be avoided. However, as amoxicillin and tetracycline have low rates of resistance, they can be reused. Metronidazole can also be reused if administered in combination with bismuth salt.57

If testing is feasible, the choice of therapy should be guided by antimicrobial susceptibility testing and administered with the optimal treatment interval.32 Bismuth quadruple therapy can be regarded as second-line treatment when antimicrobial susceptibility testing is unavailable.32 High-dose dual therapy (ie, high-dose PPI and amoxicillin) is emerging as a second-line treatment because of its favourable eradication rates.68 69 Levofloxacin-based triple therapy with amoxicillin and a PPI may be considered if bismuth-based therapy was used as first-line treatment.70 71 72 73 However, a recent report showed that the prevalence of levofloxacin resistance in Hong Kong was 17%.63

Quinolones and antibiotics in the tetracycline class are not currently licensed for use in young children, further limiting second-line treatment options. However, the inclusion of levofloxacin or tetracycline in triple therapy may be considered for adolescents.50

Statement 18: After unsuccessful second-line treatment, rescue therapies include (a) bismuth quadruple therapy with a PPI, tetracycline, metronidazole, and a bismuth salt for 10 to 14 days; (b) high-dose PPI–amoxicillin dual therapy for 14 days; and (c) rifabutin-containing therapy with a PPI and amoxicillin for 10 days. (quality of evidence: 2; grade of recommendation: conditional; level of consensus: 100%)

Similar to the approach involved in selection of second-line treatment, previously unused regimens may be regarded as rescue therapy. Regions with high fluoroquinolone resistance may consider a rifabutin-containing regimen (usually with a PPI and amoxicillin).32 40 57 Rifabutin use should be limited because of its potential for myelotoxicity; a 10-day regimen of rifabutin (300 mg/day) is usually recommended.74 75 76 Another concern regarding the use of rifabutin is the potential for acquired rifamycin resistance, particularly in regions where tuberculosis is endemic.

Statement 19: The use of probiotics as adjunctive therapy to reduce the side-effects associated with H pylori eradication therapy should be individualised. (quality of evidence: 1; grade of recommendation: qualified; level of consensus: 90%)

Probiotics (eg, Lactobacilli) may help to ameliorate treatment-related side-effects such as diarrhoea.32 40 57 Eradication rates may also be improved when probiotics are administered before and after H pylori treatment, for an interval of >2 weeks, or in combination with bismuth quadruple therapy.77

Statement 20: Antibiotic susceptibility testing can be considered after at least two empirical therapies with different antimicrobial agents have been unsuccessful. (quality of evidence: 1; grade of recommendation: conditional; level of consensus: 90%)

A recent meta-analysis showed that antimicrobial susceptibility–guided therapy was slightly more effective than empirical therapy.78 The available evidence suggests that an understanding of the antimicrobial susceptibility profile can guide antimicrobial selection and improve eradication, particularly in patients for whom multiple therapies have been unsuccessful.

Statement 21: There are insufficient data to provide solid recommendations concerning medical treatment for H pylori infection in children. The optimal age for eradication therapy in children also requires further investigation. (quality of evidence: 2/3; grade of recommendation: conditional; level of consensus: 100%)

The treatment of H pylori in children is not usually recommended. There are a few indications for which treatment should be carefully considered: incidental findings during endoscopy, findings of ulceration or erosion, refractory iron deficiency anaemia, and chronic idiopathic thrombocytopenic purpura.50

Statement 22: H pylori eradication may worsen gastroesophageal reflux disease in some patients. (quality of evidence: 3; grade of recommendation: not applicable; level of consensus: 90%)

In a meta-analysis, the pooled results of five cohort studies suggested that there is an increased risk of erosive gastroesophageal reflux disease in patients with peptic ulcer disease who are undergoing eradication therapy; however, this risk was not supported by the pooled results of seven RCTs in the same meta-analysis.79 In the past decade, meta-analyses also revealed that eradication therapy was not significantly associated with the development of gastroesophageal reflux disease.80 81 Generally, H pylori treatment does not have a clinically significant effect on acid production.

Statement 23: Patients may gain weight after H pylori eradication; therefore, lifestyle advice should be offered as needed. (quality of evidence: 2; grade of recommendation: qualified; level of consensus: 90%)

A meta-analysis showed that H pylori eradication increased body weight and body mass index, but it did not influence insulin resistance, fasting blood glucose, or lipid parameters.82 The mechanisms that underlie weight gain after H pylori eradication may be multifactorial, including increased appetite related to changes in ghrelin level, the resolution of dyspepsia and changes in gut microbiota.83 84 85 86 Weight monitoring is advisable after eradication therapy.

Statement 24: All patients should be tested for H pylori after eradication therapy. (quality of evidence: not applicable; grade of recommendation: strong; level of consensus: 100%)

From a practical perspective, the confirmation of eradication therapy success is strongly recommended, particularly because persistent H pylori infection can lead to complications.32 40 Considering the increasing prevalence of antibiotic resistance, there is an emerging clinical need to confirm H pylori clearance after eradication.

The urea breath test, stool antigen test, and endoscopy-based assessments (eg, rapid urease test and histology) have comparatively high sensitivity and specificity for H pylori; these approaches may be selected according to availability and patient circumstances. Non-endoscopic tests should be performed at least 4 weeks after eradication therapy and/or 2 weeks after PPI treatment.32 40

Additional information regarding treatment for H pylori in children is shown in the online supplementary Appendix.

Conclusion

After thorough review of the most recent evidence, the consensus panel highlighted the importance of appropriate diagnosis and treatment for patients with H pylori infection to prevent complications. Our current recommendations may differ from other regions; in particular, standard triple therapy remains a first-line option because clarithromycin resistance is still relatively low in Hong Kong. Moreover, our recommendations may preclude unnecessary testing (particularly in asymptomatic children), facilitate rational use of antibiotics, and improve eradication rates and clinical outcomes.

Author contributions

Development of clinical questions: WK Leung, JCY Wu.
Retrieval of evidence: All authors.
Analysis or interpretation of evidence: All authors.
Discussion and finalisation of evidence and statements: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: WK Leung, JCY Wu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

WK Leung has participated in advisory boards for Roche Diagnostics and Harbour BioMed. KS Cheung has received research grants from the Hong Kong SAR Government, consultant fees from the Xela Group, honoraria from Janssen Pharmaceuticals, meeting support from Takeda Pharmaceutical Company, and has participated in advisory boards for Janssen Pharmaceuticals and AstraZeneca. RSY Tang has received support from AstraZeneca for laboratory test kits.

Acknowledgement

The authors thank MIMS Hong Kong for meeting logistics support and medical writing support, funded by AstraZeneca. AstraZeneca had no role in study design, data collection/analysis/interpretation, or manuscript preparation.

References

1. Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology 2018;155:1372-82.e17. Crossref

2. Malfertheiner P, Link A, Selgrad M. Helicobacter pylori: perspectives and time trends. Nat Rev Gastroenterol Hepatol 2014;11:628-38. Crossref

3. Hooi JK, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology 2017;153:420-9. Crossref

4. Tam YH, Yeung CK, Lee KH, et al. A population-based study of Helicobacter pylori infection in Chinese children resident in Hong Kong: prevalence and potential risk factors. Helicobacter 2008;13:219-24. Crossref

5. Wong KK, Chung PH, Lan LC, Lin SC, Tam PK. Trends in the prevalence of Helicobacter pylori in symptomatic children in the era of eradication. J Pediatr Surg 2005;40:1844-7. Crossref

6. Tang MY, Chung PH, Chan HY, Tam PK, Wong KK. Recent trends in the prevalence of Helicobacter pylori in symptomatic children: a 12-year retrospective study in a tertiary centre. J Pediatr Surg 2019;54:255-7. Crossref

7. Hu Y, Wan JH, Li XY, Zhu Y, Graham DY, Lu NH. Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. Aliment Pharmacol Ther 2017;46:773-9.Crossref

8. Chiang TH, Chang WJ, Chen SL, et al. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut 2021;70:243-50. Crossref

9. Xie Y, Song C, Cheng H, et al. Long-term follow-up of Helicobacter pylori reinfection and its risk factors after initial eradication: a large-scale multicentre, prospective open cohort, observational study. Emerg Microbes Infect 2020;9:548-57. Crossref

10. Zhang Y, Dong Q, Tian L, et al. Risk factors for recurrence of Helicobacter pylori infection after successful eradication in Chinese children: a prospective, nested case-control study. Helicobacter 2020;25:e12749. Crossref

11. Sivapalasingam S, Rajasingham A, Macy JT, et al. Recurrence of Helicobacter pylori infection in Bolivian children and adults after a population-based “screen and treat” strategy. Helicobacter 2014;19:343-8. Crossref

12. Fock KM, Ang TL. Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol 2010;25:479-86. Crossref

13. Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer 2015;136:487-90. Crossref

14. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784-9. Crossref

15. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347-53. Crossref

16. Sipponen P, Kimura K. Intestinal metaplasia, atrophic gastritis and stomach cancer: trends over time. Eur J Gastroenterol Hepatol 1994;6 Suppl 1:S79-83.

17. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004;291:187-94. Crossref

18. Zhou L, Lin S, Ding S, et al. Relationship of Helicobacter pylori eradication with gastric cancer and gastric mucosal histological changes: a 10-year follow-up study. Chin Med J (Engl) 2014;127:1454-8.

19. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004;53:1244-9. Crossref

20. Saito D, Boku N, Fujioka T, et al. Impact of H. pylori eradication on gastric cancer prevention: endoscopic results of the Japanese Intervention Trial (JITHP-Study). A randomized multi-center trial. Gastroenterology 2005;128(Supp 2):A4.Abstract 23.

21. Li WQ, Zhang JY, Ma JL, et al. Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial. BMJ 2019;366:l5016. Crossref

22. Wong BC, Zhang L, Ma JL, et al. Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions. Gut 2012;61:812-8. Crossref

23. Choi IJ, Kim CG, Lee JY, et al. Family history of gastric cancer and Helicobacter pylori treatment. N Engl J Med 2020;382:427-36. Crossref

24. Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut 2020;69:2113-21. Crossref

25. Leung WK, Wong IO, Cheung KS, et al. Effects of Helicobacter pylori treatment on incidence of gastric cancer in older individuals. Gastroenterology 2018;155:67-75. Crossref

26. Lee YC, Chiang TH, Chou CK, et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology 2016;150:1113-24.e5. Crossref

27. Lanas A, Chan FK. Peptic ulcer disease. Lancet 2017;390:613-24. Crossref

28. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2006;(2):CD003840. Crossref

29. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006;2:CD002096. Crossref

30. Zullo A, Hassan C, Andriani A, et al. Eradication therapy for Helicobacter pylori in patients with gastric MALT lymphoma: a pooled data analysis. Am J Gastroenterol 2009;104:1932-8. Crossref

31. Hong Kong Cancer Registry, Hospital Authority, Hong Kong SAR Government. 10 most common cancers in Hong Kong in 2020. Available from: https://www3.ha.org.hk/cancereg/default.asp. Accessed 19 Jun 2023.

32. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut 2017;66:6-30. Crossref

33. Du Y, Zhu H, Liu J, et al. Consensus on eradication of Helicobacter pylori and prevention and control of gastric cancer in China (2019, Shanghai). J Gastroenterol Hepatol 2020;35:624-9. Crossref

34. Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013;145:105-12.e15. Crossref

35. Lanas Á, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-12.e2. Crossref

36. Chan FK, Ching JY, Suen BY, Tse YK, Wu JC, Sung JJ. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013;144:528-35. Crossref

37. Ng JC, Yeomans ND. Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis. Med J Aust 2018;209:306-11. Crossref

38. Venerito M, Schneider C, Costanzo R, Breja R, Röhl FW, Malfertheiner P. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018;47:1464-71.Crossref

39. Sostres C, Carrera-Lasfuentes P, Benito R, et al. Peptic ulcer bleeding risk. The role of Helicobacter pylori infection in NSAID/low-dose aspirin users. Am J Gastroenterol 2015;110:684-9. Crossref

40. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol 2017;112:212-39. Crossref

41. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015;64:1353-67. Crossref

42. Queiroz DM, Harris PR, Sanderson IR, et al. Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study. PLoS One 2013;8:e68833. Crossref

43. Yuan W, Li Y, Yang K, et al. Iron deficiency anemia in Helicobacter pylori infection: meta-analysis of randomize Crossref

44. Qu XH, Huang XL, Xiong P, et al. Does Helicobacter pylori infection play a role in iron deficiency anemia? A meta-analysis. World J Gastroenterol 2010;16:886-96. Crossref

45. Xia W, Zhang X, Wang J, Sun C, Wu L. Survey of anaemia and Helicobacter pylori infection in adolescent girls in Suihua, China and enhancement of iron intervention effects by H pylori eradication. Br J Nutr 2012;108:357-62. Crossref

46. Hudak L, Jaraisy A, Haj S, Muhsen K. An updated systematic review and meta-analysis on the association between Helicobacter pylori infection and iron deficiency anemia. Helicobacter 2017;22:e12330. Crossref

47. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009;113:1231-40. Crossref

48. Arnold DM, Bernotas A, Nazi I, et al. Platelet count response to H pylori treatment in patients with immune thrombocytopenic purpura with and without H pylori infection: a systematic review. Haematologica 2009;94:850-6. Crossref

49. Ikuse T, Toda M, Kashiwagi K, et al. Efficacy of Helicobacter pylori eradication therapy on platelet recovery in pediatric simmune thrombocytopenic purpura—case series and a systematic review. Microorganisms 2020;8:1457. Crossref

50. Jones NL, Koletzko S, Goodman K, et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr 2017;64:991-1003. Crossref

51. Kato S, Shimizu T, Toyoda S, et al. The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood. Pediatr Int 2020;62:1315-31. Crossref

52. Calvet X, Sánchez-Delgado J, Montserrat A, et al. Accuracy of diagnostic tests for Helicobacter pylori: a reappraisal. Clin Infect Dis 2009;48:1385-91. Crossref

53. Gisbert JP, Pajares JM. Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection—a critical review. Aliment Pharmacol Ther 2004;20:1001-17. Crossref

54. Makristathis A, Barousch W, Pasching E, et al. Two enzyme immunoassays and PCR for detection of Helicobacter pylori in stool specimens from pediatric patients before and after eradication therapy. J Clin Microbiol 2000;38:3710-4. Crossref

55. Feldman RA, Deeks JJ, Evans SJ. Multi-laboratory comparison of eight commercially available Helicobacter pylori serology kits. Helicobacter pylori Serology Study Group. Eur J Clin Microbiol Infect Dis 1995;14:428-33. Crossref

56. Dechant FX, Dechant R, Kandulski A, et al. Accuracy of different rapid urease tests in comparison with histopathology in patients with endoscopic signs of gastritis. Digestion 2020;101:184-90. Crossref

57. Fallone CA, Chiba N, van Zanten SV, et al. The Toronto Consensus for the Treatment of Helicobacter pylori infection in adults. Gastroenterology 2016;151:51-69.e14. Crossref

58. Graham DY, Moss SF. Antimicrobial susceptibility testing for Helicobacter pylori is now widely available: when, how, why. Am J Gastroenterol 2022;117:524-8. Crossref

59. Shah SC, Iyer PG, Moss SF. AGA Clinical Practice Update on the management of refractory Helicobacter pylori infection: expert review. Gastroenterology 2021;160:1831-41. Crossref

60. Graham DY, Tansel A. Interchangeable use of proton pump inhibitors based on relative potency. Clin Gastroenterol Hepatol 2018;16:800-8.e7. Crossref

61. Tang HL, Li Y, Hu YF, Xie HG, Zhai SD. Effects of CYP2C19 loss-of-function variants on the eradication of H pylori infection in patients treated with proton pump inhibitor–based triple therapy regimens: a meta-analysis of randomized clinical trials. PLoS One 2013;8:e62162. Crossref

62. Kuo YT, Liou JM, El-Omar EM, et al. Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017;2:707-15. Crossref

63. Guo CG, Jiang F, Cheung KS, Li B, Ooi PH, Leung WK. Timing of prior exposure to antibiotics and failure of Helicobacter pylori eradication: a population-based study. J Antimicrob Chemother 2022;77:517-23. Crossref

64. Yuan Y, Ford AC, Khan KJ, et al. Optimum duration of regimens for Helicobacter pylori eradication. Cochrane Database Syst Rev 2013;(12):CD008337. Crossref

65. Liu KS, Hung IF, Seto WK, et al. Ten day sequential versus 10 day modified bismuth quadruple therapy as empirical firstline and secondline treatment for Helicobacter pylori in Chinese patients: an open label, randomised, crossover trial. Gut 2014;63:1410-5. Crossref

66. Hung IF, Chan P, Leung S, et al. Clarithromycin-amoxycillin-containing triple therapy: a valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong? Helicobacter 2009;14:505-11. Crossref

67. Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY. Greater than 95% success with 14-day bismuth quadruple anti–Helicobacter pylori therapy: a pilot study in US Hispanics. Helicobacter 2012;17:382-90. Crossref

68. Yang JC, Lin CJ, Wang HL, et al. High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. Clin Gastroenterol Hepatol 2015;13:895-905.e5. Crossref

69. Gao CP, Zhang D, Zhang T, et al. PPI-amoxicillin dual therapy for Helicobacter pylori infection: an update based on a systematic review and meta-analysis. Helicobacter 2020;25:e12692. Crossref

70. Xin Y, Manson J, Govan L, et al. Pharmacological regimens for eradication of Helicobacter pylori: an overview of systematic reviews and network meta-analysis. BMC Gastroenterol 2016;16:80. Crossref

71. Marin AC, McNicholl AG, Gisbert JP. A review of rescue regimens after clarithromycin-containing triple therapy failure (for Helicobacter pylori eradication). Expert Opin Pharmacother 2013;14:843-61. Crossref

72. Gisbert JP, Morena F. Systematic review and meta-analysis: levoﬂoxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther 2006;23:35-44. Crossref

73. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levoﬂoxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a metaanalysis. Am J Gastroenterol 2006;101:488-96. Crossref

74. Gisbert JP, Calvet X. Review article: rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 2012;35:209-21. Crossref

75. Gisbert JP, Castro-Fernandez M, Perez-Aisa A, et al. Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures. Aliment Pharmacol Ther 2012;35:941-7. Crossref

76. Van der Poorten D, Katelaris PH. The effectiveness of rifabutin triple therapy for patients with difficult-to-eradicate Helicobacter pylori in clinical practice. Aliment Pharmacol Ther 2007;26:1537-42. Crossref

77. Shi X, Zhang J, Mo L, Shi J, Qin M, Huang X. Efficacy and safety of probiotics in eradicating Helicobacter pylori: a network meta-analysis. Medicine (Baltimore) 2019;98:e15180. Crossref

78. Gingold-Belfer R, Niv Y, Schmilovitz-Weiss H, Levi Z, Boltin D. Susceptibility-guided versus empirical treatment for Helicobacter pylori infection: a systematic review and meta-analysis. J Gastroenterol Hepatol 2021;36:2649-58. Crossref

79. Yaghoobi M, Farrokhyar F, Yuan Y, Hunt RH. Is there an increased risk of GERD after Helicobacter pylori eradication? A meta-analysis. Am J Gastroenterol 2010;105:1006-14. Crossref

80. Saad AM, Choudhary A, Bechtold ML. Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials. Scand J Gastroenterol 2012;47:129-35. Crossref

81. Tan J, Wang Y, Sun X, Cui W, Ge J, Lin L. The effect of Helicobacter pylori eradication therapy on the development of gastroesophageal reflux disease. Am J Med Sci 2015;349:364-71. Crossref

82. Upala S, Sanguankeo A, Saleem SA, Jaruvongvanich V. Effects of Helicobacter pylori eradication on insulin resistance and metabolic parameters: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017;29:153-9. Crossref

83. Nwokolo CU, Freshwater DA, O’Hare P, Randeva HS. Plasma ghrelin following cure of Helicobacter pylori. Gut 2003;52:637-40. Crossref

84. Furuta T, Shirai N, Xiao F, Takashima M, Hanai H. Effect of s infection and its eradication on nutrition. Aliment Pharmacol Ther 2002;16:799-806. Crossref

85. Liou JM, Chen CC, Chang CM, et al. Long-term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial. Lancet Infect Dis 2019;19:1109-20. Crossref

86. Lane JA, Murray LJ, Harvey IM, Donovan JL, Nair P, Harvey RF. Randomised clinical trial: Helicobacter pylori eradication is associated with a significantly increased body mass index in a placebo-controlled study. Aliment Pharmacol Ther 2011;33:922-9. Crossref

Best practices in epidermal growth factor receptor T790M testing for advanced non–small-cell lung cancer in Hong Kong

Hong Kong Med J 2023 Jun;29(3):240–6

https://doi.org/10.12809/hkmj219632

MEDICAL PRACTICE CME

Best practices in epidermal growth factor receptor T790M testing for advanced non–small-cell lung cancer in Hong Kong

Jonathan SF Nyaw, MB, ChB, FRCR¹; KM Cheung, MB, ChB, MSc²; F Hioe, FRCPA, FKCPath³; Michael TY Kam, MB, ChB, FRCR⁴; Johnny KS Lau, FHKCR, FRCR⁵; YM Lau, MRCP, FHKCP⁶; Dennis KC Leung, FHKCR, FHKAM (Radiology)⁵; Fiona MY Lim, MB, BS, FRCR⁷

¹ Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong SAR, China

² Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China

³ Department of Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

⁴ Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

⁵ Department of Clinical Oncology, Queen Mary Hospital, Hong Kong SAR, China

⁶ Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong SAR, China

⁷ Department of Oncology, Princess Margaret Hospital, Hong Kong SAR, China

Corresponding author: Dr Jonathan SF Nyaw (sfnyaw@ha.org.hk)

Full paper in PDF

Abstract

The T790M mutation in the epidermal growth factor receptor gene causes most acquired resistance to firstor second-line epidermal growth factor receptor–tyrosine kinase inhibitors in advanced non–small-cell lung cancer. The results of T790M testing can guide subsequent treatment. Despite the availability of guidelines from international organisations, T790M testing practices in Hong Kong must be streamlined and adapted to the Hospital Authority setting. To address this issue, a panel of experts in oncology and pathology met for discussion of key topics regarding T790M testing practices in Hong Kong, including the appropriate timing of testing and re-testing, as well as optimal testing methods. All panel members voted on the results of the discussion to achieve consensus. Items supported by a majority vote were adopted as consensus statements regarding current best practices for T790M testing in Hong Kong. Among the topics discussed, the panel agreed that T790M testing should be initiated upon radiological progression, including symptomatic disease progression or central nervous system–only progression. The experts also preferred initial testing with liquid biopsy, using the widely available digital polymerase chain reaction platform. This document provides the final consensus statements, as well as a testing and treatment workflow, for clinicians in Hong Kong to use as guidance in T790M testing.

[Abstract in Chinese]

Introduction

Epidermal growth factor receptor (EGFR)–directed tyrosine kinase inhibitors (TKIs) are recommended as first-line therapy for non–small-cell lung cancer (NSCLC) carrying a sensitising mutation in the EGFR gene. Compared with platinum-based chemotherapy, first- and second-generation EGFR-TKIs have shown superior efficacy; they are regarded as the standard of care for advanced NSCLC.1 2 However, acquired resistance to EGFR-TKIs eventually occurs, leading to disease progression.3 The T790M substitution mutation in exon 20, present in 50% to 60% of cases, is the most frequent cause of resistance to first- and second-generation EGFR-TKIs.4 5 6 According to a laboratory report in Hong Kong (Sanomics, unpublished data presented in a meeting on 27 June 2019), the proportion of T790M-positive NSCLC cases across seven hospitals under the Hospital Authority from 2017 to 2020 (n=3398) ranged from 19.0% to 32.8%.

In cases of resistance to first- and second-generation TKIs, next-line therapeutic options were limited prior to the introduction of osimertinib, a TKI selective for EGFR-sensitising mutations and the T790M resistance mutation. Osimertinib received accelerated Food and Drug Administration approval in the United States in November 2015, along with a companion diagnostic test for the T790M mutation; it received full approval in March 2017 based on the results of the AURA3 study.7 The AURA trials were included in a clinical investigation of osimertinib as second-line therapy in T790M-positive NSCLC.7 AURA3 was a randomised, open-label phase 3 trial that enrolled patients with T790M-positive advanced NSCLC refractory to first-generation TKIs (n=419). The study showed that progression-free survival was signiﬁcantly longer and the response rate was significantly higher in patients receiving osimertinib than in patients receiving platinum-pemetrexed chemotherapy.8 Osimertinib is now regarded as the standard of care for patients with T790M-positive tumours and acquired TKI resistance.1 2 9

Molecular analysis of T790M mutation status should be performed upon progression of EGFR-mutated NSCLC to identify patients for whom osimertinib would be an appropriate next-line option. The DNA used for testing can be obtained via repeated biopsy of tissue, or by analysis of circulating tumour DNA (ctDNA) circulating in blood or other body fluids (ie, liquid biopsy).10 Technologies available for T790M detection in tissue and body fluids include real-time polymerase chain reaction (PCR)–based methods such as the Cobas and Therascreen tests, and digital PCR (dPCR) platforms such as droplet digital PCR (ddPCR) and BEAMing (beads, emulsions, amplification, magnetics).11 Next-generation sequencing (NGS) is a high-throughput sequencing method that can simultaneously analyse variable regions of the genome and detect somatic mutations (eg, single-nucleotide variations, copy number variations, and insertion/deletions or gene fusions); the method can also be used to detect the T790M mutation as well as other genomic alterations that cause EGFR-TKI resistance.9

Guidelines published in the past several years have outlined recommendations for T790M testing within the context of a region’s reimbursement policy, hospital system, and laboratory infrastructure.12 13 To provide guidance to local hospitals under the Hong Kong Hospital Authority, a panel of Hong Kong experts was convened to discuss current practices in T790M testing and adaptations to promote optimal patient outcomes. This report summarises the resulting consensus statements, while proposing an algorithm for T790M testing and subsequent NSCLC treatment, which is intended to serve as a guidance for clinicians regarding best practices in EGFR T790M testing.

Methods

A panel of seven oncologists and a pathologist was convened to participate in the development of a consensus document regarding best practices in T790M testing in Hong Kong. During the initial face-to-face meeting, the panel members reviewed current EGFR T790M testing practices in Hong Kong Hospital Authority hospitals, then discussed relevant evidence and practical considerations. After the identification of knowledge gaps and differences in T790M testing practices within Hong Kong, the panel proposed key questions regarding the timing and procedures of testing, along with relevant clinical scenarios.

A second meeting was convened to discuss the best practices for T790M testing, in response to the key questions previously drafted. After each member’s queries and comments had been considered by the panel, the members indicated their agreement with, or selection among, the responses presented (online supplementary Appendix). If the majority of the panel agreed with a response, it was regarded as a current best practice and adopted as a consensus statement. Individual members’ comments based on practical experience in the field were integrated with the chosen responses to formulate the final consensus statements.

Recommendations

When to test for the EGFR T790M mutation

The panel members unanimously agreed that patients with EGFR-mutated NSCLC treated with first- or second-generation TKIs should undergo T790M testing upon radiological disease progression (eg, asymptomatic progression, symptomatic disease progression, or central nervous system [CNS]–only progression) [Table 1 and Fig]. Testing is warranted because these events indicate progression that may require modified treatment. Although the underlying premise of T790M testing involves assessing eligibility for third-line TKI inhibition, clinicians should concurrently investigate the feasibility of local therapy for oligoprogressive disease.

Table 1. When to test for the T790M mutation

Figure. Proposed algorithm for T790M testing in Hong Kong

Biochemical progression (eg, an increasing carcinoembryonic antigen [CEA] level) may prompt clinicians to perform additional investigation of tumour status; however, biochemical progression alone is insufficient to indicate a need for T790M testing. Radiological progression is usually defined by the Response Evaluation Criteria in Solid Tumours, which are typically used for objective assessment of tumour burden in clinical trials.3 Testing is indicated upon radiological progression, but panel members acknowledged that the definition of radiological progression may differ among clinicians.

Patients with symptomatic disease progression can experience rapid deterioration; thus, immediate assessment of T790M mutation status is needed to plan subsequent treatments that are likely to confer benefit, such as osimertinib.14 15 Similarly, regardless of the patient’s clinical state (symptomatic or asymptomatic), immediate testing is indicated for CNS-only progression because the condition carries a poor prognosis. Patients with T790M-positive CNS progression may also benefit from osimertinib, which has compelling efficacy data with respect to CNS metastases, including asymptomatic cases.16 17 18 In the AURA3 trial, osimertinib showed superior CNS efficacy compared with platinum- or pemetrexed-based chemotherapy; it also demonstrated activity against leptomeningeal metastasis.16 18 In the phase 3 FLAURA study, osimertinib had superior CNS efficacy compared with gefitinib or erlotinib.17

Oligoprogression (new lesions or regrowth in a few areas)19 alone does not warrant T790M testing and can be managed by local ablative therapy. Local therapy may prolong disease control. For example, two studies of patients with oligometastatic NSCLC while on standard TKI therapy revealed a median time to progression of 6.2 to 10.0 months from the initiation of local therapy and continuation of previous TKI.20 21

The panel members agreed that CEA level is not a reliable marker of disease progression1 2; CEA analysis alone should not be used to determine the need for T790M testing. However, an elevated CEA level suggests that disease progression should be closely monitored by other investigation methods. The level may be elevated in conjunction with radiological progression; consideration of CEA level and any evidence of radiological progression can help clinicians to determine subsequent management.

How to test for the EGFR T790M mutation

Initial testing

All panel members supported the use of liquid biopsy for initial T790M testing (Table 2). Liquid biopsy was the preferred method because it allows non-invasive assessment of tumour biology, is readily available, and has a short turnaround time.9 10 22 Conditions that may support the use of liquid biopsy as the first choice for T790M testing include limited tumour tissue availability, low tissue sample quality, poor patient health that precludes tissue biopsy, and patient refusal of tissue biopsy.1 2 9 10 Published guidelines from Australia, the United States National Comprehensive Cancer Network, and the European Society for Medical Oncology also recommend liquid biopsy for initial T790M testing.1 9 13

Table 2. How to test for the epidermal growth factor receptor T790M mutation

A liquid biopsy is generally conducted by collecting plasma ctDNA. The detection of EGFR mutations in plasma ctDNA has high concordance with tissue-based detection (up to 74%).11 Analyses of plasma ctDNA have high specificity but moderate sensitivity; thus, negative plasma results should be confirmed by tissue biopsy.9 10 13 23

Other biological fluids (eg, pleural fluids and cerebrospinal fluid [CSF]) can be used to provide ctDNA for liquid biopsy. The majority (88%) of panel members would send pleural fluid (when available) for liquid biopsy. The EGFR mutations can be detected via ctDNA from pleural effusion fluid; however, if a sufficient number of cells is collected, cell block analysis may be an alternative diagnostic method.24 25

The majority (80%) of panel members would also request CSF-based liquid biopsy in the event of CNS metastasis. Cerebrospinal fluid is suitable for ctDNA analysis of tumour mutations in patients with CNS metastasis or leptomeningeal metastasis.26 27 28 Although CSF sampling for T790M testing requires the invasive lumbar puncture procedure, CSF is considered an accessible representation of EGFR mutation status in the brain and leptomeningeal metastases, which are typically inaccessible; therefore, CSF analysis is regarded as a useful adjunct to plasma analysis.26 27

If a tissue sample is available, tissue sample–based T790M testing can be performed in parallel with liquid biopsy–based testing. This approach is supported by the Canadian guideline panel, the International Association for the Study of Lung Cancer, and a Pan-Asian group that adopted the European Society for Medical Oncology guidelines.2 10 12

The panel members agreed that all tissue samples for T790M testing should be collected from accessible and untreated sites of progression. Any type of tissue is acceptable, except necrotic tissue. Furthermore, if a bone lesion sample is used for biopsy, it should have minimal decalcification to ensure that DNA quality is sufficient for molecular analysis.

Tissue biopsy–based analyses have some limitations. For example, lung biopsy is an invasive procedure with potential complications, such as intrapulmonary haemorrhage and pneumothorax.29 30 Additionally, intratumour and intermetastatic heterogeneity in biopsied tissue may lead to false-negative results.31

Re-testing

The panel members agreed that re-testing should be performed if the initial liquid biopsy is T790M-negative. Considering that plasma liquid biopsy has a false-negative rate of 30%, tissue biopsy is warranted to confirm T790M mutation status if the result of the initial plasma liquid biopsy is T790M-negative (Table 2).23 Failure to detect the original sensitising mutation via liquid biopsy may be related to various factors, including suboptimal sample preservation or a non-secretory tumour, and further testing is highly recommended. If the initial liquid biopsy was performed with a less sensitive assay (eg, real-time PCR), a more sensitive assay such as dPCR or NGS should be considered. If tissue biopsy is indicated, it should be collected from a site of progressive disease.

Confirmatory re-testing is intended to guide clinicians in the selection of appropriate therapy; although tissue biopsy is the preferred re-test approach, factors such as site accessibility, patient symptoms, and performance status should be considered when determining re-test timing. The following treatment options may be suitable alternatives to early tissue repeated biopsy: continue EGFR-TKI therapy and perform repeated liquid biopsy later, or switch to chemotherapy and perform repeated liquid biopsy upon progression.

The optimal timing for repeated liquid biopsy is unknown. Most panel members (86%) would perform repeated liquid biopsy if there was evidence of further progression, including worsening symptoms. In contrast, for asymptomatic patients or patients with slowly progressing disease who continued to receive EGFR-TKI therapy, panel members suggested a minimum of 8 weeks between repeated liquid biopsies. In real-world setting, 8 weeks is the typical interval for further progression from the time that a patient continues TKI therapy after the first progression event; further progression at that time would suggest a need for systemic treatment, rather than TKIs. Additionally, in phase 2 studies, tumour assessments are typically performed at around 8-week intervals to coincide with the end of a treatment cycle.32 For example, in the phase 2 ASPIRATION study that included a cohort of patients with advanced NSCLC who continued TKI therapy after progression, plasma analysis was generally conducted every 8 weeks. The study showed that the median time between the first and the second progression events was approximately 3 months.33

Most panel members (88%) agreed that, when tissue biopsy is used as the initial test, a T790M-negative result should be confirmed by liquid biopsy. Although the standard of care constitutes tissue biopsy using an adequate sample from a site of progression, tumour heterogeneity may lead to a false-negative result. Subsequent liquid biopsy using ctDNA may complement the T790M-negative findings of initial tissue biopsy.

The most effective method for EGFR T790M testing

In Hong Kong, plasma samples are generally tested by validated targeted assays, such as real-time PCR, ddPCR, or NGS. The assay used for liquid biopsy depends on the hospital’s laboratory infrastructure, but all assays should be able to detect T790M in ≤5% of viable cells.9 10

All panel members expressed a preference for dPCR to detect T790M via liquid biopsy (Table 3). An important consideration is that dPCR platforms have higher sensitivity than real-time PCR—ddPCR has a sensitivity of approximately 80% or higher for T790M.11 34 In patients who showed progression while receiving EGFR-TKIs, ddPCR had a positivity rate of 66% for T790M, whereas Cobas real-time PCR had a positivity rate of 24%.35 Next-generation sequencing has also shown high sensitivity for T790M.11 22 34 Furthermore, NGS can be used to analyse other genes implicated in the EGFR-TKI resistance (eg, MET, BRAF, ERBB2 [HER2], and KRAS), in conjunction with T790M testing.

Table 3. The most effective method for T790M testing

Tissue samples can also be tested by real-time PCR or NGS. In Hong Kong, real-time PCR is commonly used for T790M testing. As mentioned above, NGS has a high sensitivity for T790M34 and can provide additional genetic information regarding the mechanism of EGFR-TKI resistance. For repeated liquid biopsy, ddPCR is the preferred assay, but liquid-based NGS can also be considered.

Conclusion

Molecular profiling of T790M mutation status in NSCLC with acquired resistance provides important guidance for clinicians with respect to next-line treatment. It can identify patients who are candidates for second- or third-line treatment with osimertinib, which has demonstrated superior efficacy, compared with chemotherapy, in the management of advanced NSCLC refractory to first- or second-generation TKIs.10

In Hong Kong, liquid biopsy assessment by a sensitive ctDNA platform is recommended as the first-line option for T790M testing to facilitate clinical decision making. Because of its accuracy and availability, dPCR is the preferred platform for this assessment. This expert panel developed consensus statements (Tables 1, 2 and 3) and a corresponding workflow for T790M testing (Fig). Clinicians in Hong Kong can use the proposed workflow to guide the T790M testing process from the initial step of liquid biopsy to the determination of clinically appropriate situations for re-testing, followed by selection of treatment approaches.

In the future, T790M testing guidelines can be refined by adding the experience of multidisciplinary experts and new knowledge gained from research in Hong Kong and other countries.

Author contributions

Concept or design: JSF Nyaw, F Hioe, MTY Kam, JKS Lau, FMY Lim.
Acquisition of data: JSF Nyaw, F Hioe, MTY Kam, YM Lau, FMY Lim.
Analysis or interpretation of data: JSF Nyaw, F Hioe, MTY Kam.
Drafting of the manuscript: JSF Nyaw, KM Cheung, F Hioe, MTY Kam.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Acknowledgement

We thank Dr Ben Searle and Dr Pia Villanueva of MIMS (Hong Kong) Limited for editorial support, which was funded by AstraZeneca Hong Kong Limited (Hong Kong).

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

1. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv192-237. Crossref

2. Wu YL, Planchard D, Lu S, et al. Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS. Ann Oncol 2019;30:171-210. Crossref

3. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357-60. Crossref

4. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. Crossref

5. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7. Crossref

6. Campo M, Gerber D, Gainor JF, et al. Acquired resistance to first-line afatinib and the challenges of prearranged progression biopsies. J Thorac Oncol 2016;11:2022-6. Crossref

7. United States Food and Drug Administration. Osimertinib (Tagrisso). Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso. Accessed 2 Sep 2020.

8. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-40. Crossref

9. National Comprehensive Cancer Network. Non-small cell lung cancer. Version 4.2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 14 May 2021.

10. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol 2018;13:323-58. Crossref

11. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015;90:509-15. Crossref

12. Stockley T, Souza CA, Cheema PK, et al. Evidence-based best practices for EGFR T790M testing in lung cancer in Canada. Curr Oncol 2018;25:163-9. Crossref

13. John T, Bowden JJ, Clarke S, et al. Australian recommendations for EGFR T790M testing in advanced non-small cell lung cancer. Asia Pac J Clin Oncol 2017;13:296-303. Crossref

14. Yoshida T, Yoh K, Niho S, et al. RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation. Lung Cancer 2015;90:477-83.Crossref

15. Yang JJ, Chen HJ, Yan HH, et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer 2013;79:33-9. Crossref

16. Wu YL, Ahn MJ, Garassino MC, et al. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol 2018;36:2702-9. Crossref

17. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol 2018;36:3290-7. Crossref

18. Ahn MJ, Chiu CH, Cheng Y, et al. Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: the AURA leptomeningeal metastases analysis. J Thorac Oncol 2020;15:637-48. Crossref

19. Gandara DR, Li T, Lara PN, et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clin Lung Cancer 2014;15:1-6. Crossref

20. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:346-51. Crossref

21. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14. Crossref

22. Liang Z, Cheng Y, Chen Y, et al. EGFR T790M ctDNA testing platforms and their role as companion diagnostics: correlation with clinical outcomes to EGFR-TKIs. Cancer Lett 2017;403:186-94. Crossref

23. Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016;34:3375-82. Crossref

24. Yang J, Lee OJ, Son SM, et al. EGFR mutation status in lung adenocarcinoma-associated malignant pleural effusion and efficacy of EGFR tyrosine kinase inhibitors. Cancer Res Treat 2018;50:908-16. Crossref

25. Kimura H, Fujiwara Y, Sone T, et al. EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib. Br J Cancer 2006;95:1390-5. Crossref

26. Huang R, Xu X, Li D, et al. Digital PCR-based detection of EGFR mutations in paired plasma and CSF samples of lung adenocarcinoma patients with central nervous system metastases. Target Oncol 2019;14:343-50. Crossref

27. Li YS, Jiang BY, Yang JJ, et al. Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy. Ann Oncol 2018;29:945-52. Crossref

28. Pan W, Gu W, Nagpal S, Gephart MH, Quake SR. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem 2015;61:514-22. Crossref

29. Chouaid C, Dujon C, Do P, et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer 2014;86:170-3. Crossref

30. Yoon HJ, Lee HY, Lee KS, et al. Repeat biopsy for mutational analysis of non-small cell lung cancers resistant to previous chemotherapy: adequacy and complications. Radiology 2012;265:939-48. Crossref

31. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature 2013;501:355-64. Crossref

32. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-update and clarification: from the RECIST committee. Eur J Cancer 2016;62:132-7. Crossref

33. Park K, Yu CJ, Kim SW, et al. First-line erlotinib therapy until and beyond Response Evaluation Criteria in Solid Tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study. JAMA Oncol 2016;2:305-12. Crossref

34. Passiglia F, Rizzo S, Di Maio M, et al. The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis. Sci Rep 2018;8:13379. Crossref

35. Buder A, Setinek U, Hochmair MJ, et al. EGFR mutations in cell-free plasma DNA from patients with advanced lung adenocarcinoma: improved detection by droplet digital PCR. Target Oncol 2019;14:197-203. Crossref

Recommendations for the management of advanced and metastatic renal cell carcinoma: joint consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Hong Kong Med J 2022;28(6):475–81 | Epub 11 Jul 2022

https://doi.org/10.12809/hkmj219727

MEDICAL PRACTICE CME

Recommendations for the management of advanced and metastatic renal cell carcinoma: joint consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Darren MC Poon, FRCR, FHKAM (Radiology)¹; CK Chan, MB, ChB, FHKAM (Surgery)²; Kuen Chan, MB, BS, FHKAM (Radiology)¹; WH Chu, FRCSEd (Urol), FHKAM (Surgery)²; Philip WK Kwong, FRCR, FHKAM (Radiology)¹; Wayne Lam, MRCS (Eng), FRCSEd (Urol)²; KS Law, MB, BS, FHKAM (Radiology)¹; Eric KC Lee, MB, ChB, FHKAM (Radiology)¹; PL Liu, MB, BS, FHKAM (Surgery)²; Henry CK Sze, FRCR, FHKAM (Radiology)¹; Joseph HM Wong, MB, BS, FHKAM (Surgery)²; Eddie SY Chan, MD, FHKAM (Surgery)²

¹ Hong Kong Society of Uro-Oncology, Hong Kong

² Hong Kong Urological Association, Hong Kong

Corresponding author: Dr Darren MC Poon (darren.mc.poon@hksh.com)

Full paper in PDF

Abstract

Introduction: Kidney cancer, primarily renal cell carcinoma (RCC), ranks among the top 10 most common malignancies in the male population of Hong Kong. In 2019, members of two medical societies in Hong Kong formed an expert panel to establish a set of consensus statements for the management of metastatic RCC. On 22 June 2021, the same panel met to review recent evidence and reassess their positions regarding the management of advanced and metastatic RCC, with the aim of providing recommendations for physicians in Hong Kong.

Participants: The panel included 12 experts (6 clinical oncologists and 6 urologists) who had extensive experience managing patients with RCC in Hong Kong.

Evidence: The panel reviewed randomised controlled trials, observational studies, systematic reviews/meta-analyses, and international clinical guidelines to address key clinical questions that were identified before the meeting.

Consensus Process: In total, 15 key clinical questions were identified before the meeting, covering the surgical and systemic treatment of advanced or metastatic clear cell, sarcomatoid, and non-clear cell RCCs. At the meeting, the panellists voted on these questions, then discussed relevant evidence and practical considerations.

Conclusions: The treatment landscape for advanced and metastatic RCC continues to evolve. More immune checkpoint inhibitor (ICI)–based combination regimens will be indicated for the treatment of metastatic clear cell RCC. There is increasing evidence concerning the benefit of adjuvant ICI treatment for resected advanced RCC. This article summarises recent evidence and expert insights regarding a series of key clinical questions about the management of advanced and metastatic RCC.

[Abstract in Chinese]

Introduction

In 2018, kidney cancer was the ninth most common malignancy in the male population of Hong Kong, with a relative frequency of 3%.1 The predominant type of kidney cancer is renal cell carcinoma (RCC), which mainly comprises the clear cell subtype; non-clear cell RCC can be subdivided into papillary, chromophobe, and other rarer forms (eg, collecting duct).2 Many RCCs are found incidentally without symptoms suggestive of malignancy; approximately 30% of patients have metastatic disease at the time of diagnosis.2

The management of advanced and metastatic RCC has been transformed by the development of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and, more recently, immune checkpoint inhibitors (ICIs). In 2019, members of two medical societies in Hong Kong formed an expert panel to establish a set of consensus statements for the management of metastatic RCC.3 Since then, the treatment landscape has continued to change with the addition of two evidence-based ICI-TKI combination therapies: nivolumab/cabozantinib and pembrolizumab/lenvatinib.4 5 There is also increasing research concerning the role of adjuvant ICI in the treatment of advanced RCC after nephrectomy.6 Considering these advances, the same expert panel met to review recent evidence and reassess their positions regarding the management of advanced and metastatic RCC through panel votes on a series of key clinical questions, with the aim of providing treatment recommendations for physicians in Hong Kong.

Methods

The meeting was held on 22 June 2021; the expert panel included 12 clinicians (6 clinical oncologists and 6 urologists) who had extensive experience managing patients with RCC in the public or private healthcare sectors. Prior to the meeting, the panel identified 15 key clinical questions (online supplementary Appendix) regarding the surgical and systemic treatment of advanced or metastatic clear cell, sarcomatoid, and non-clear cell RCCs in various risk categories. The panel reviewed randomised controlled trials, observational studies, systematic reviews/meta-analyses, and international clinical guidelines that addressed these clinical questions. Prior to the meeting, review materials had been identified through a search of the PubMed database for publications from January 2020 to May 2021 using the key words ‘metastatic/advanced + renal cell carcinoma’; the search results were supplemented with additional articles solicited by the panellists. At the meeting, the panellists voted on the 15 questions, then discussed relevant clinical evidence and practical considerations for real-world clinical practice. The full voting record for each question is provided in the online supplementary Appendix.

Results

First-line systemic therapies for clear cell metastatic renal cell carcinoma

Current published evidence

To decide on a treatment strategy for clear cell metastatic RCC, the International Metastatic RCC Database Consortium (IMDC) risk category7 remains a key consideration. Current international guidelines largely recommend ICI-containing combination treatment as the standard of care for metastatic RCC in all IMDC risk categories (Table 1).8 9 In phase III open-label randomised trials, the recommended ICI-containing regimens significantly improved progression-free survival (PFS), overall survival (OS), and objective response rates (ORRs), when compared with sunitinib as first-line treatment for metastatic RCC in the respective primary study populations: for intermediate/poor-risk patients, ipilimumab/nivolumab10; and for intention-to-treat patients, pembrolizumab/axitinib,11 nivolumab/cabozantinib,4 and pembrolizumab/lenvatinib5 (Table 2). Post-hoc analyses showed that ipilimumab/nivolumab and nivolumab/cabozantinib were associated with better health-related quality of life compared with sunitinib12 13; there were no significant differences in health-related quality of life between sunitinib and pembrolizumab/axitinib or between sunitinib and pembrolizumab/lenvatinib.14 15

Table 1. Guideline-recommended first-line treatments for clear cell metastatic renal cell carcinoma

Table 2. Efficacy outcomes of immune checkpoint inhibitor–based regimens from phase III open-label randomised trials

Recommendations from the expert panel

Based on the available evidence and insights from the expert panel, ICI-ICI (ie, ipilimumab/nivolumab) and ICI-TKI combinations each have specific advantages and disadvantages (Table 3 4 5 10 11), which should be considered when selecting a treatment regimen.

Table 3. Expert panel opinions concerning immune checkpoint inhibitor–immune checkpoint inhibitor and immune checkpoint inhibitor–tyrosine kinase inhibitor combinations

According to the panel consensus, the IMDC risk category and burden of disease or presence of symptoms were regarded as the most important patient/disease factors when selecting the first-line treatment regimen for advanced or metastatic clear cell RCC. Efficacy (primarily OS, followed by PFS and ORR) and toxicity were regarded as the most important treatment-related factors when selecting a treatment regimen. Figure 1 illustrates the treatment algorithm recommended by the panel.

Figure 1. Expert panel recommendations of systemic first-line treatment regimens for advanced or metastatic clear cell renal cell carcinoma

For IMDC favourable-risk advanced or metastatic clear cell RCC, TKI monotherapy (pazopanib or sunitinib) was regarded as the preferred treatment regimen. In subgroup analyses of phase III open-label randomised trials, the OS benefits of ICI-TKI combinations were uncertain in favourable-risk patients, but these results should be interpreted cautiously because the numbers of participants were limited in each subgroup.4 5 16 Despite the uncertain OS benefits, ICI-TKI combinations provided significant PFS and ORR benefits compared with sunitinib; therefore, they may remain useful in favourable-risk patients, particularly patients with extensive or symptomatic disease who desire treatment with a higher ORR.

For IMDC intermediate/poor-risk advanced or metastatic clear cell RCC, ICI-based combination treatment (preferably pembrolizumab/axitinib or ipilimumab/nivolumab) is recommended. In patients with clinically significant symptoms and extensive disease, pembrolizumab/axitinib may be preferred because it appeared to offer stronger antitumour activity (ORR, 60.4%; stable disease rate, 22.9%; progressive disease rate, 11.3%) compared with ipilimumab/nivolumab, according to the KEYNOTE-426 study.11 In the CheckMate 214 study, approximately 20% of patients experienced disease progression after treatment with ipilimumab/nivolumab.10

With respect to newer ICI-TKI combinations (ie, pembrolizumab/lenvatinib and nivolumab/cabozantinib), there is a need to accumulate additional experience in Hong Kong. The optimal dose and tolerability profile of lenvatinib, particularly in Asian patients, should be further investigated; in the CLEAR study, 70% of patients required dose reductions for lenvatinib.5 For cabozantinib, there is a lack of flexibility in dose manipulation; only 60 mg, 40 mg, and 20 mg were available for use in the CheckMate 9ER study.4 In contrast, the dosage of axitinib is readily adjustable; 1-mg increments or reductions can be implemented depending on patient tolerability.

In public hospitals in Hong Kong, ICIs for the treatment of RCC remain self-financed, whereas TKI monotherapy (ie, axitinib, pazopanib, and sunitinib) is supported by the Safety Net programme.17

Adjuvant treatment after nephrectomy in patients with advanced renal cell carcinoma

Current evidence regarding adjuvant pembrolizumab treatment

Nephrectomy is the standard of care for localised RCC; however, patients with advanced RCC are at risk of disease recurrence, and thus the use of adjuvant treatment warrants investigation. In the KEYNOTE-564 phase III trial, patients with high-risk, fully resected clear cell RCC (M0 or M1 without evidence of disease) were randomised to receive adjuvant pembrolizumab or placebo.6 At the median follow-up interval of 24 months, adjuvant pembrolizumab significantly improved disease-free survival compared with placebo (77.3% vs 68.1% at 24 months; hazard ratio [HR]=0.68, 95% confidence interval [CI]=0.53-0.87; P=0.002 [two-sided]). While the OS data were immature, there was a trend in favour of adjuvant pembrolizumab (96.6% vs 93.5% at 24 months; HR=0.54; 95% CI=0.30-0.96). These results suggest that adjuvant pembrolizumab can prevent relapse after surgery in patients with advanced RCC.

Recommendations from the expert panel

The panellists noted that the use of adjuvant systemic treatment after nephrectomy depends on patient preference after a discussion of the benefits and risks. The limitations of adjuvant treatment include the lack of clear markers of efficacy, the risks of overtreatment and toxicity (particularly in older and frailer patients), and the potential for fewer available treatment regimens in patients who experience disease recurrence. Compared with adjuvant TKI, adjuvant ICI may be associated with fewer adverse effects and better quality of life, offering new treatment opportunities for high-risk patients (eg, with nodal metastases). Further studies are needed to investigate the clinical benefit of adjuvant ICI in distinct patient subgroups (eg, patients with non-clear cell RCC or bone oligometastases) and to explore a risk-adapted approach for optimising patient selection.

Treatment remains investigational for patients who develop metastatic disease after receiving adjuvant pembrolizumab. The panellists favoured TKI monotherapy (pazopanib or sunitinib), particularly for patients with a short relapse-free period (eg, <6 months) after adjuvant pembrolizumab treatment. They noted that patients with a longer relapse-free period may receive ICI-based combination treatment; for example, the antitumour activity of pembrolizumab/lenvatinib in ICI-pre-treated patients with clear cell metastatic RCC (ORR, 55.8%) was demonstrated in a phase I/IIb study.18

Treatment for advanced or metastatic renal cell carcinoma with sarcomatoid de-differentiation

The standard of care for sarcomatoid RCC has not been determined. Consistent with the previous consensus statement, the panellists favoured an ICI-containing combination for the treatment of metastatic RCC with sarcomatoid de-differentiation, which is generally within the IMDC intermediate/poor-risk category. Compared with other RCCs that lack sarcomatoid features, sarcomatoid RCCs have higher programmed death-ligand 1 expression; thus, they may be more responsive to ICI immunotherapies.19 In subgroup analyses of phase III randomised studies, ICI-containing regimens offered OS, PFS, and ORR benefits compared with sunitinib in patients who had metastatic RCC with sarcomatoid de-differentiation.20 Phase III randomised trials dedicated to the treatment of sarcomatoid RCC are expected.

Cytoreductive nephrectomy

Consistent with the previous consensus statement, the panellists favoured systemic treatment, rather than upfront cytoreductive nephrectomy (CN), for the management of de novo metastatic RCC.

The CN candidacy in IMDC favourable-risk patients remains unclear, particularly in the ICI era. Several panellists noted that CN may be irrelevant to this patient population because most will have already undergone nephrectomy or decided to avoid nephrectomy based on age and performance status, considering that the time from their diagnosis until systemic treatment is ≥1 year. However, when immediate systemic treatment is not required, upfront CN with metastasectomy may be considered for patients with asymptomatic primary tumours and limited metastases confined to the lung. There is also preliminary evidence to support the use of CN combined with ICI immunotherapy in patients with pathologically favourable tumour characteristics. An analysis of the United States National Cancer Database found that, in patients with metastatic RCC, the combination of CN (primarily in the upfront setting) and ICI immunotherapy improved median OS (not reached vs 11.6 months; HR=0.23, P<0.001) compared with ICI immunotherapy alone.21 Because ICI-based combination treatment is increasingly used, the role and sequence of CN warrant prospective validation.

The panellists recommended deciding whether to perform CN in IMDC intermediate-risk patients based on the extent of disease and symptoms. Upfront CN may be considered for patients with solitary or limited metastases (oligometastases). Otherwise, delayed CN may be considered for patients who respond well to systemic treatment. Further studies are required to explore the patient selection and optimal timing for CN in the context of ICI immunotherapy.

The panellists recommended avoiding CN in IMDC poor-risk patients, considering their low life expectancy (7-8 months) and poor prognosis, as well as the potential for surgical complications and impacts on quality of life. Retrospective data from the IMDC demonstrated that poor-risk patients did not experience survival benefits from CN.22

Treatment for advanced or metastatic non-clear cell renal cell carcinoma

The standard of care for metastatic non-clear cell RCC remains unclear, particularly considering the heterogeneity among subtypes. Based on the current evidence, the panellists favoured TKI monotherapy (cabozantinib or sunitinib). In a randomised open-label phase II trial, patients with metastatic papillary RCC were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib; only cabozantinib improved median PFS compared with sunitinib (9.0 vs 5.6 months; HR=0.60 [95% CI=0.37-0.97], one-sided P=0.019).23 The antitumour activity of sunitinib in metastatic non-clear cell RCC has been demonstrated in prospective studies.24 25

Subsequent treatment for advanced or metastatic clear cell renal cell carcinoma after progression on first-line systemic treatment

While the optimal sequence of treatment remains unclear, the principle of choosing a subsequent treatment (Fig 2) is consistent with the previous consensus statement. In patients who demonstrated progression after ICI-based combination treatment, the panellists favoured TKI monotherapy, primarily cabozantinib; its antitumour activity in patients with prior exposure to ICIs has been demonstrated in large retrospective studies.26 27 In patients who demonstrated progression after first-line TKI monotherapy, the panellists favoured nivolumab or cabozantinib based on prospective evidence,28,29 which was described in the previous consensus statement.

Figure 2. Expert panel recommendations of second-line treatment regimens for advanced or metastatic clear cell renal cell carcinoma

Conclusions

The treatment landscape for advanced and metastatic RCC is evolving. More ICI-based combination regimens have recently been shown to offer survival benefits, compared with TKI monotherapy, as first-line systemic treatment in patients with metastatic clear cell RCC. There is increasing evidence to support the feasibility of adjuvant ICI treatment after surgery in patients with advanced RCC. This article has summarised recent evidence and insights from an expert panel on a series of key clinical questions, with the goal of optimising the management of advanced and metastatic RCC in Hong Kong. These recommendations are expected to undergo regular review and updating, considering that several crucial areas (eg, the role of CN combined with ICI-based treatment, the standard of care for RCCs with sarcomatoid features or non-clear cell histology, and the optimal sequence of systemic treatments) require further investigation.

Author contributions

All authors contributed to the concept and/or design of the study, acquisition of the data, analysis and/or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors have had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Acknowledgement

The authors thank Best Solution Company Limited, Hong Kong, for providing medical writing/editorial support, which was funded by the Hong Kong Urological Association.

Funding/support

Medical writing/editorial support and the panel meeting for voting and discussions were funded by the Hong Kong Urological Association.

References

1. Hospital Authority, Hong Kong SAR Government. Hong Kong Cancer Registry. Available from: https://www3. ha.org.hk/cancereg/. Accessed 7 Jul 2021.

2. Cairns P. Renal cell carcinoma. Cancer Biomark 2010;9:461-73. Crossref

3. Poon DM, Chan CK, Chan K, et al. Consensus statements on the management of metastatic renal cell carcinoma from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology 2019. Asia Pac J Clin Oncol 2021;17(Suppl 3):27-38. Crossref

4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829-41. Crossref

5. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289-300. Crossref

6. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683-94. Crossref

7. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794-9. Crossref

8. National Comprehensive Cancer Network. NCCN guidelines kidney cancer. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440. Accessed 28 Jun 2021.

9. European Association of Urology. EAU guidelines on renal cell carcinoma. Available from: https://uroweb.org/guideline/renal-cell-carcinoma/. Accessed 18 Jun 2021.

10. Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer 2020;8:e000891. Crossref

11. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol 2021;39 (Suppl 15):4500. Crossref

12. Cella D, Grünwald V, Escudier B, et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol 2019;20:297-310. Crossref

13. Cella D, Choueiri TK, Blum SI, et al. Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate 9ER trial. J Clin Oncol 2021;39(Suppl 6):285. Crossref

14. Bedke J, Rini B, Plimack E, et al. Health-related quality-of-life (HRQoL) analysis from KEYNOTE-426: pembrolizumab (pembro) plus axitinib (axi) vs sunitinib for advanced renal cell carcinoma (RCC). Proceedings of the 35th Annual EAU Congress–Virtual; 2020 July 19; Game changing session 4.

15. Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol 2021;39(Suppl 15):4502. Crossref

16. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:1563-73. Crossref

17. Hospital Authority, Hong Kong SAR Government. Drug formulary management. Available from: https://www.ha.org.hk/hadf/en-us/. Accessed 9 Jul 2021.

18. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 2021;22:946-58. Crossref

19. Blum KA, Gupta S, Tickoo SK, et al. Sarcomatoid renal cell carcinoma: biology, natural history and management. Nat Rev Urol 2020;17:659-78. Crossref

20. Buonerba C, Dolce P, Iaccarino S, et al. Outcomes associated with first-line anti-PD-1/ PD-L1 agents vs. sunitinib in patients with sarcomatoid renal cell carcinoma: a systematic review and meta-analysis. Cancers (Basel) 2020;12:408. Crossref

21. Singla N, Hutchinson RC, Ghandour RA, et al. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: an analysis of the National Cancer Database. Urol Oncol 2020;38:604.e9-17. Crossref

22. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704-10. Crossref

23. Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet 2021;397:695-703. Crossref

24. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016;17:378-88. Crossref

25. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol 2016;69:866-74. Crossref

26. Iacovelli R, Ciccarese C, Facchini G, et al. Cabozantinib after a previous immune checkpoint inhibitor in metastatic renal cell carcinoma: a retrospective multi-institutional analysis. Target Oncol 2020;15:495-501. Crossref

27. McGregor BA, Lalani AA, Xie W, et al. Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma. Eur J Cancer 2020;135:203-10. Crossref

28. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 2020;126:4156-67. Crossref

29. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27. Crossref

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