Gastric cancer is the second most common cause of cancer-related mortality worldwide, with 988 000 new cases and 736 000 deaths per year.1 Surgery is the main treatment for operable gastric cancer but recurrence rates are high and about 40% to 80% of patients develop relapsed disease after surgery. The use of adjuvant chemotherapy has been shown to improve patient outcome.2 3 4 5 After curative resection, common adjuvant chemotherapy regimens that have been recently adopted in many parts of Asia include oral administration of S-1 (tegafur, gimeracil, and oteracil potassium) based on the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) study conducted in Japan,4 as well as oxaliplatin-capecitabine combination chemotherapy based on the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer study.5 These studies have shown that adjuvant S-1 for 1 year or oxaliplatin-capecitabine combination chemotherapy for 6 months following curative gastrectomy with D2 lymph node dissection increases both overall survival (OS) and relapse-free survival in pathological stage II or III gastric cancer.4 5

S-1 is an oral anticancer agent comprising tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo) at a molar ratio of 1:0.4:1.6 Tegafur is a prodrug of 5-fluorouracil (5-FU); CDHP is a potent reversible inhibitor of 5-FU degradation; and Oxo is an inhibitor of the enzyme orotate phosphoribosyltransferase (OPRT) that catalyses the phosphorylation of 5-FU.6 Pharmacokinetic analyses have confirmed that S-1 has potent anti-tumour activity, and oral S-1 administration results in a similar serum concentration of 5-FU to intravenous 5-FU whilst sparing patients the need for continuous intravenous infusion of 5-FU and consequent toxicity.7 Nonetheless early studies have also shown that toxicity profiles may differ between Asian and non-Asian patients. In earlier studies in Japanese patients, the dose-limiting toxicity was bone marrow suppression that occurred prior to gastrointestinal adverse events. In contrast, studies in non-Asian patients revealed that diarrhoea associated with abdominal discomfort and cramping was the principal dose-limiting toxicity and bone marrow suppression was not.8 This might be due to the varied activity of OPRT between different populations. In fact, OPRT activates 5-FU in the bowel mucosa; patients with higher OPRT activity might be expected to experience a higher incidence of gastrointestinal adverse effects prior to bone marrow toxicity.9

In the ACTS-GC study, the adverse events of adjuvant S-1 were reported to be generally mild, with 65.8% of patients being able to complete the planned 1 year of therapy.4 While it has been known that patients in the West have a different toxicity profile to their Japanese counterparts,10 there are limited data on tolerability of S-1 among Chinese patients. In this multicentre retrospective study, we assessed the toxicity and tolerability profiles of Hong Kong Chinese patients with gastric cancer who had received adjuvant S-1 chemotherapy.

This was a retrospective study carrying out between June 2013 and February 2016, and involved six local centres in Hong Kong: Pamela Youde Nethersole Eastern Hospital, Princess Margaret Hospital, Prince of Wales Hospital, Tuen Mun Hospital, Queen Mary Hospital, and United Christian Hospital. This study has been approved by the institutional ethics committee of each participating centre with patient consent waived. Patients with stage II-IIIC gastric adenocarcinoma according to American Joint Committee on Cancer,11 who had completed curative surgical treatment and who had undergone S-1 adjuvant chemotherapy, were included. Patients with stage IV disease and who had had prior therapy with S-1 in the neoadjuvant setting were excluded.

Adjuvant S-1 was started at least 3 weeks after curative surgery. The intended dose of S-1 was based on that published in the ACTS-GC trial,4 and was 40 mg/m² twice daily for 4 weeks followed by 2 weeks of rest for each cycle. Specifically, during the treatment weeks, patients with body surface area (BSA) of <1.25 m² received 80 mg daily; those with BSA of 1.25 m² to <1.5 m² received 100 mg daily; and those with BSA of ≥1.5 m² received 120 mg daily. As clinically indicated, dose reductions were considered one dose level at a time; in general, one dose level reduction refers to reducing the prior daily dose by 20 mg, eg from 120 mg to 100 mg daily. As renal impairment has been associated with increased incidence of myelosuppression, dose reduction by one dose level was made in patients who had a creatinine clearance of 40-49 mL/min. A maximum of eight 6-weekly cycles were administered. The dose of S-1 was reduced in patients with significant toxicities, as assessed by the respective clinician-in-charge. Complete and differential blood count and serum chemistry were performed before each 6-week cycle. All patients had mid-cycle follow-up with complete and differential blood counts and serum chemistry in the first cycle.

Patient charts were reviewed by investigators at each centre for background information. S-1 chemotherapy records, as well as biochemical and haematological profiles, were extracted. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 3.0).12 Adverse events were documented during chemotherapy and for 28 days after the last dose of S-1. Dose interruption was defined as a need for either any dose delay and/or dose reduction.

Clinical characteristics are summarised as number of patients and percentage (%) for categorical variables, and medians with ranges for continuous variables. The frequency of adverse events was tabulated. Factors independently associated with adverse events, dose interruptions, or earlier withdrawal of S-1 were identified using the Pearson’s Chi squared (χ²) test or the Fisher’s exact test if the expected number in any cell was less than five for categorical data or any cell with an expected count of less than one for categorical data, and t test or Wilcoxon rank-sum test for continuous data. A two-sided P value of <0.05 was considered significant. All statistical analyses were performed with SAS, version 9.3 (SAS Institute Inc, Cory [NC], US).

Disease-free survival (DFS) was calculated as the period from the date of surgery to the date of recurrence or death from any cause; OS was calculated as the period from the date of surgery to the date of death from any cause. Both DFS and OS were estimated using the Kaplan-Meier method.

Thirty patients met the eligibility criteria in the six centres during the study period and were enrolled in this study. Their baseline demographic and clinical characteristics are shown in Table 1.

There were 18 males and 12 females with a median age of 65.6 years. Of the patients, 27 (90%) had ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1. Total gastrectomy was performed in 11 (36.7%) patients and partial gastrectomy in 19 (63.3%). D2 dissection was performed in 26 (86.7%) patients and two had D1 dissection; the details of two other patients were unknown. The median number of lymph nodes resected was 31. Cancer stage II disease was present in 19 (63.3%) patients and stage III in 11 (36.7%).

Of the 30 patients, two (6.7%), two (6.7%), one (3.3%), two (6.7%), one (3.3%), three (10%), and 19 (63.3%) completed one, two, three, four, five, six, and eight cycles of S-1 adjuvant chemotherapy, respectively. At the time of data cut-off on 29 February 2016, one patient was still on S-1, having completed six cycles of treatment. The reasons for treatment withdrawal included toxicities (n=5, 16.7%), patient refusal (3, 10%), recurrence (2, 6.7%), and worsening of pre-existing Parkinson’s disease (1, 3.3%).

The median follow-up period was 25.3 months (range, 16.3-29.2 months). Three patients died and two experienced recurrence (lung and peritoneum). The 3-year DFS and OS rates were 80.2% and 85.9%, respectively (Fig).

Table 2 presents the haematological and non-haematological adverse events experienced during treatment. Grade 3-4 haematological adverse events included neutropaenia (n=3, 10%), leukopaenia (1, 3.3%), and anaemia (2, 6.7%). Grade 3-4 non-haematological adverse events included non-neutropaenic septic episode (16.7%), diarrhoea (6.7%), hyperbilirubinaemia (6.7%), syncope (6.7%), reduced left ventricular ejection function (3.3%), gouty attack (3.3%), hypokalaemia (3.3%), subacute intestinal obstruction (3.3%), and urticaria (3.3%).

Of note, 10 patients developed a septic episode; apart from one patient with grade 3 neutropaenic fever, the others were non-neutropaenic. Of the latter, four had grade 3 toxicity, four had grade 2, and one had grade 1 toxicity; in one patient with grade 2 toxicity, the infection was due to pulmonary tuberculosis. This latter patient had a history of ischaemic heart disease and he also developed grade 3 reduced left ventricular ejection function whilst on S-1, as noted above.

Two out of 30 patients were found to be positive for hepatitis B surface antigen. Of these two, one was prescribed prophylactic antiviral therapy and liver function remained normal apart from one isolated episode of grade 2 hyperbilirubinaemia that resolved spontaneously without other hepatic dysfunction; the other patient did not receive prophylactic antiviral therapy but his liver function remained normal throughout S-1 therapy.

There were no treatment-related deaths.

Of the 30 patients, 17 (56.7%) were commenced on a lower-than-intended dose of S-1. The reason for reducing the first dose was: impaired renal function (n=6; with creatinine clearance ranging from 41-48 mL/min), concern of toxicity (6), aged over 70 years (4), and borderline performance status (1); four of these patients had further dose reduction in subsequent cycles. Of the other 13 patients who had the full S-1 dose in cycle 1, five had a dose reduction from cycle 2 onwards.

Dose delays occurred in 12 (40%) patients; these were due to delayed bone marrow recovery (n=3), hypokalaemia (2, including 1 who also had delayed bone marrow recovery), diarrhoea (2), sepsis (2), hypoglycaemia (1), impaired renal function (1), reduced weight (1), and abdominal pain (1).

Potential risk factors for adverse events were assessed (Table 3). Univariate analysis showed that total gastrectomy was significantly associated with haematological adverse events; 90.9% of patients who had total gastrectomy in contrast to 52.6% of the patients who had partial gastrectomy experienced grade 2-4 adverse events (P=0.034). On univariate analysis, nodal status was significantly associated with non-haematological adverse events; 76.2% of patients who experienced grade 2-4 adverse events had nodal disease, while only 33% of those who had grade 0-1 adverse events had nodal disease (P=0.031).

Potential risk factors for earlier withdrawal of S-1 and dose interruptions (dose reductions and/or dose delays) were assessed (Table 4). For earlier S-1 withdrawal, patients who had a history of regular alcohol intake were significantly more likely to have earlier treatment withdrawal than non-drinkers (80% vs 28%; P=0.044), while ever-smokers also had a tendency, though insignificant, for earlier withdrawal than never-smokers (67% vs 29%; P=0.095). For dose interruptions, univariate analysis showed lower body weight (P=0.007) and lower BSA (P=0.017) were significant associated factors, while lower body mass index (BMI) also had an increased tendency, though insignificant, for dose interruptions (P=0.055). The median body weight, BMI, and BSA of those patients who had dose interruptions were 54.5 kg, 21.4 kg/m², and 1.54 m², respectively; the corresponding data for those who did not require dose interruptions were 64.0 kg, 24.8 kg/m², and 1.67 m², respectively.

Our study results indicate that adjuvant S-1 chemotherapy is feasible for our local patients after curative resection of gastric cancer. With increased awareness of the associated toxicity, S-1 can be offered safely as standard adjuvant therapy. The toxicities experienced by the studied patients were in line with previous findings in Asian patients.4 12 13 Grade 3-4 haematological adverse events included thrombocytopaenia and anaemia. Grade 3-4 non-haematological adverse events that occurred in 5% or more of the patients included non-neutropaenic septic episode, diarrhoea, hyperbilirubinaemia, and syncope.

Previous studies have investigated factors associated with adverse events during S-1 therapy. In a Korean study of 305 patients given adjuvant S-1 therapy,13 total gastrectomy was reported to be an independent risk factor for grade 3-4 haematological toxicities and age >65 years was an independent risk factor for grade 3 non-haematological toxicities. Independent risk factors for withdrawal and dose reductions included age >65 years and male gender. Total gastrectomy has also been reported to be associated with a significantly greater risk of serious adverse events in another study of Taiwanese gastric cancer patients receiving adjuvant S-1.14

The reason for the higher incidence of serious adverse events in patients who underwent total gastrectomy whilst receiving S-1 treatment is unknown. In an earlier study, a higher incidence of adverse reactions was observed among patients who received S-1 as adjuvant treatment after gastrectomy, compared with those who had unresectable or recurrent gastric cancer. The investigators suggested the limitation in food intake soon after extensive surgery as a possible cause of exacerbation of adverse reactions such as anorexia and nausea, and proposed that a delay in the start of drug administration after gastrectomy may prevent such adverse events.15 In another study, Taiwanese patients received palliative S-1 for advanced gastric cancer at a median initial dose of 37.0 mg/m². Twelve patients had single-dosing pharmacokinetic study on day 1, and seven took part in a multiple-dosing pharmacokinetic study on day 28. The results indicated that the steady-state pharmacokinetics of 5-FU, CDHP and Oxo could be predicted from single-dose pharmacokinetic study. Six patients who underwent gastrectomy had a similar pharmacokinetic profile to another six patients who did not undergo gastrectomy.16 Nonetheless, definitive data regarding the pharmacokinetic profile of S-1 components in patients who underwent different degrees of gastrectomy are lacking.

Other factors that have been reported to be associated with treatment-related adverse events include low body mass and impaired renal function.16 These were supported by the present study in which lower body weight, BMI, and BSA were associated with an increased likelihood of dose interruptions. Earlier reports have shown that impaired renal function will reduce CDHP clearance and result in a prolonged high concentration of 5-FU in plasma, and thereby lead to more severe myelosuppression.8 17 Although impaired renal function was not identified as a risk factor for adverse events in this study, it has to be noted that all patients who had subnormal creatinine clearance were offered S-1 at lower doses at treatment initiation; this could have prevented the occurrence of severe adverse events.

The present study was limited by its retrospective nature and the limited number of patients accrued. Although there is a lack of information about patient co-morbidities, the current data suggest that patients who had a history of regular alcohol intake had an increased likelihood of earlier treatment withdrawal. The survival data are immature due to short follow-up. The findings, however, lend support to a published report on the acceptable toxicity profile and tolerability of S-1 as adjuvant therapy after curative gastric surgery for gastric cancer.4 13 14 Potential risk factors for severe adverse events are suggested. Due to the small sample size and retrospective nature of this study, a prospective study with a larger patient population is needed to confirm these findings. An awareness of treatment-related adverse events as well as potential associated factors may aid clinicians in managing patients in whom S-1 therapy is planned, and thereby improve treatment compliance and clinical outcome.

Adjuvant S-1 therapy has a tolerable toxicity profile among local patients who have undergone curative resection for gastric cancer. For gastric cancer patients in whom adjuvant S-1 therapy is planned, those with identifiable risk factors should be closely monitored for adverse events during treatment. This may enable earlier intervention with supportive therapy and optimise treatment outcome.

The authors gratefully acknowledge Mr Edward Choi for his valuable statistical advice. We thank Drs Chi-ching Law, Hoi-leung Leung, and Chung-kong Kwan of the Department of Clinical Oncology, United Christian Hospital for their support in this study.

This study has been supported by an educational grant from Taiho Pharma Singapore Pte. Ltd. W Yeo has received honorarium for advisory role for Eli Lilly, Novartis, Pfizer, and Bristol Myers Squibb and has received research grant from Novartis over the past 12 months. KO Lam has been an advisor for Amgen, Eli Lilly, Roche, Sanofi-Aventis, and has received honorarium from Amgen, Bayer, Eli Lilly, Merck, Sanofi-Aventis, Taiho and research grant from Bayer, Roche, and Taiho. Authors not named here have disclosed no conflicts of interest.

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