Abstract
Background/Aim: The aim of this study was to investigate the efficacy and safety of S-1 plus low-dose cisplatin for stage IIIB and stage IIIC gastric cancer patients after D2 gastrectomy. Patients and Methods: The study group comprised of 52 patients. In the first cycle, S-1 (80 mg/m2) was administered daily for 3 weeks, followed by 2 weeks of rest; low-dose cisplatin (10 mg) was administered on days 1-5 and 8-12. In the second and third cycles, S-1 was administered alone. Results: Overall survival was 47.0 months for stage IIIB patients and 24.0 months for stage IIIC (p=0.038). Disease-free survival was 17.0 and 16.0 months respectively (p=0.739). Grade 3 or 4 adverse events occurred in 20 patients (38.5%). Multivariate analysis identified stage IIIC as independent prognostic factor for survival. Conclusion: Our treatment was manageable and safe for stage IIIB or stage IIIC patients. Stage IIIC gastric cancer portends an especially poor prognosis following D2 gastrectomy.
Gastric cancer is the second leading cause of cancer death worldwide, even though patient survival improved after gastrectomy with D2 lymphadenectomy was adopted as a standard treatment (1-4). In Japan, the outcomes of patients with advanced gastric cancer remain poor. Gastric cancer is the third leading cause of cancer death, with >50% of potentially curable advanced gastric cancer patients dying because of recurrence (5). Adjuvant chemotherapy is recommended for advanced gastric cancer patients after curative resection. In 2007, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated the efficacy of adjuvant S-1 for stage II or stage III gastric cancer patients who had undergone curative resection with D2 lymphadenectomy (6). Adjuvant S-1 has since become standard treatment for stage II or stage III patients with D2 gastrectomy. However, the 5-year overall survival (OS) rates in stage III patients receiving S-1 are still limited; 67.1% for stage IIIA disease and 50.2% for stage IIIB disease (7). Subgroup analyses indicated that S-1 was less effective for stage IIIB disease [hazard ratio (HR), 0.791; 95% confidence interval (CI), 0.520-1.205]. Therefore, more effective treatment for patients with stage III is urgently needed.
Several studies have evaluated regimens designed to improve the efficacy of adjuvant chemotherapy for gastric cancer. The CLASSIC trial found that adjuvant chemotherapy with capecitabine plus oxaliplatin in patients who had undergone D2 gastrectomy for stage II, IIIA, or IIIB disease was associated with a better survival benefit than surgery alone (8, 9). The 3-year disease-free survival and estimated 5-year disease-free survival were significantly improved with capecitabine plus oxaliplatin. Takahari et al. reported the efficacy of three cycles of S-1 plus cisplatin with subsequent S-1 monotherapy for one year after surgery for stage III gastric cancer (10). We previously demonstrated the efficacy and safety of S-1 plus low-dose cisplatin as adjuvant therapy in patients with stage IIIA or stage IIIB gastric cancer (11).
In 2010, the 14th edition of the Japanese Classification of Gastric Carcinoma (12) was published; it included a revised staging of gastric cancer that differed from the classification used in almost all the previous studies of adjuvant chemotherapy for stage III gastric cancer.
The aim of this study was to evaluate the efficacy, safety and prognostic factors of S-1 plus low-dose cisplatin as adjuvant therapy in patients with stage IIIB or stage IIIC gastric cancer.
Materials and Methods
Eligibility criteria. Eligible patients had (i) histologically or cytologically confirmed stage IIIB, or stage IIIC gastric cancer (all stage III patients had R0 resection with D2 or more extensive dissection), (ii) an Eastern Cooperative Oncology Group performance status of ≤2, (iii) age ≥20 years, (iv) no previous treatment for any cancer, and (v) adequate organ function (leukocyte count >2000/μl, platelet count >50,000/μl, transaminases <2.5 times the upper limit of normal, total bilirubin <2 times the upper limit of normal, and a serum creatinine level no greater than the upper limit of normal). The criteria of the 14th edition of the Japanese Gastric Cancer Association was used to classify disease stage (12). All patients gave written informed consent before enrolling in the study.
Treatment. All patients postoperatively received S-1 plus low-dose cisplatin. Each course of treatment consisted of three 5-week cycles. In the first cycle, oral S-1 (80 mg/m2 in two divided doses) was administered daily for the first 3 weeks, followed by 2 weeks of rest. Low-dose cisplatin (10 mg) was administered on days 1-5 and 8-12 (total of 10 days). In the second and third 5-week cycles, patients received oral S-1 alone (80 mg/m2 daily in two divided doses) for 3 weeks, followed by 2 weeks of rest. This 15-week course of treatment was repeated for one year, with the exceptions of unacceptable toxicity, withdrawal of consent by the patient, or the detection of progressive disease.
Statistical analysis. The primary endpoints were OS and disease-free survival (DFS). Patients were enrolled within 2 weeks of surgery and OS was defined as the period between the date of starting the first cycle of chemotherapy and the date of death from any cause. Deaths from other diseases were considered events, and data on patients without an event were censored as of the date of the final evaluation. DFS was defined as the interval from the date of enrollment to a confirmed recurrence or death from any cause.
The secondary endpoint was safety. All patients with stage III disease were scheduled for 5 years of postoperative follow-up. Every 5 weeks, hematological tests were performed and clinical symptoms were assessed. Tumors were evaluated every 3 months by imaging studies (computed tomography, magnetic resonance imaging, chest radiography, ultrasonography) and endoscopic examination. The presence or absence of disease recurrence was determined by the same studies every 6 months. Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI–CTC) version 4.0.
Multivariate analysis was conducted using a Cox proportional hazards model to evaluate prognostic factors. A probability p-value <0.05 was considered statistically significant. All statistical analyses were performed using the JMP version 12 (SAS Institute Inc., Cary, NC, USA).
Results
Patient characteristics. From April 2010 to March 2015, 52 patients were assigned to treatment with S-1 plus low-dose cisplatin. Tables I and II show the clinical characteristics of patients. This study included 39 (75.0%) men and 13 (25.0%) women, with a mean age of 69.4±8.9 years. Ten patients (19.2%) had stage IIIB and 42 (80.8%) had stage IIIC disease. Histopathological evaluation confirmed that the majority of patients had pT4a or pT4b disease (92.3%) and N3a or N3b lymph-node involvement (80.7%).
OS and DFS. Of the 52 patients, 33 had died, six patients were alive with recurrence, and the remaining 13 were alive without recurrence at the end of follow-up. The median follow-up period was 24.0 months. The median OS was 47.0 months for stage IIIB and 21 months for stage IIIC patients, and the difference in OS was significant (p=0.038, Figure 1). The median DFS was 17.0 months for stage IIIB and 16.0 months for stage IIIC, and the difference in DFS was not significant (p=0.739, Figure 2).
Safety. Adverse events were reported by all 52 patients and events of all grades are shown in Table II. Grade-3 or grade-4 adverse events were reported by 20 of the 52 study patients (38.5%). There were no treatment-related deaths. The most frequent grade-3 or grade-4 adverse event was anorexia (21.2%), followed by anemia (15.4%), nausea (9.6%), and fatigue (7.7%).
Prognostic factors. Multivariate analysis using a Cox proportional hazards model identified stage IIIC (HR, 3.09; 95% CI, 1.02-11.26; p=0.047) and intraoperative blood loss (HR, 1.002; 95% CI, 1.000-1.003; p=0.006) as an independent prognostic factors for survival. However, postoperative complications, operation time, American Society of Anesthesiologists (ASA) physical status, body mass index (BMI), and tumor diameter were not independently related to survival (Table III).
Discussion
The results of the CLASSIC trial indicated that adjuvant capecitabine plus oxaliplatin improved the 5-year DFS of stage II, IIIA, and IIIB gastric cancer patients compared to surgery alone (8, 9). The HRs, compared with surgery, were 0.55 (95% CI: 0.38-0.80), 0.61 (95% CI: 0.44-0.84), and 0.52 (95% CI: 0.33-0.82), respectively. Takahari et al. evaluated the efficacy of three cycles of S-1 plus cisplatin followed by S-1 monotherapy for one year after D2 gastrectomy for stage IIIA or stage IIIB gastric cancer (10). The 3-year OS rates with stage IIIA and IIIB disease were 87.9% (95% CI, 70.9%-95.3%) and 80.0% (95% CI, 58.4%-91.1%), respectively. The 3-year DFS with stage IIIA and IIIB disease were 81.8% (95% CI, 63.9%-91.4%) and 64.0% (95% CI, 42.2%-79.4%). In a phase II study, Fujitani et al. reported that adjuvant therapy with four cycles of S-1 plus docetaxel followed by S-1 monotherapy for up to one year after D2 gastrectomy for stage IIIA or stage IIIB gastric cancer achieved promising OS and DFS outcomes (13). The 3-year OS rates for stage IIIA and IIIB disease were 85.7% (95% CI, 74.9%-98.1%) and 62.5% (95% CI, 42.8%-91.4%), and the 3-year DFS for stage IIIA and IIIB disease were 70.8% (95% CI, 57.1%-87.8%) and 56.2% (95% CI, 36.5%-86.7%) respectively. These results suggest that combination therapy, with a more favorable safety profile, may be associated with higher survival rates than monotherapy, such as S-1 monotherapy, in patients with stage III gastric cancer after D2 gastrectomy. Other studies have found that combined treatment with local modalities, such as chemoradiotherapy, did not decrease locoregional and distant recurrence and improve OS and DFS (14-16).
In this study, OS was 47.0 months and DFS was 17.0 months in patients with stage IIIB disease and 21.0 and 16.0 months in those with stage IIIC disease, after D2 gastrectomy.
A randomized controlled trial of S-1 plus cisplatin versus S-1 for the treatment of gastric cancer (SPIRITS) demonstrated superior survival of S-1 plus cisplatin in patients with unresectable or recurrent gastric cancer (17). However, a feasibility study of S-1 plus cisplatin as an adjuvant chemotherapy for patients with stage III gastric cancer, found that the treatment completion rate was lower than expected because of toxicity. Therefore, the S-1 plus cisplatin regimen was altered to include S-1 monotherapy in the first cycle and subsequent to S-1 plus cisplatin therapy (10).
We used a 15-week cycle consisting of S-1 plus low-dose cisplatin to reduce the incidence of adverse events and the duration of hospitalization. Most adverse events were grade 1 or 2. The most frequent grade-3 or grade-4 adverse events were anorexia (21.2%) and anemia (15.4%). The incidence of other grade-3 or grade-4 adverse events was <10%. The incidence of severe toxic effects with our regimen was lower than that in previous studies of high-dose cisplatin, and did not differ greatly from the incidence reported in the CLASSIC trial and in an oxaliplatin-based regimen (8, 17, 18).
In this patient series, stage IIIC disease (HR, 3.09; 95% CI, 1.02-11.26; p=0.047) and intraoperative blood loss (HR, 1.002; 95% CI, 1.000-1.003; p=0.006) were independent prognostic factors. However, postoperative complications, operation time, ASA, BMI, and tumor diameter were not independently associated with survival. In previous reports, intraoperative blood loss, blood transfusion, tumor diameter, total gastrectomy, and lymph node metastasis had an independent, negative impact on long-term outcomes after cancer surgery (19-23). Jin et al. reported that postoperative complications and not receiving adjuvant therapy were significantly associated with poor survival after gastrectomy for gastric cancer (24). They suggested that the effect on long-term survival depended on interaction between those variables. Postoperative complications did occur in our study, but all patients postoperatively received S-1 plus low-dose cisplatin. Therefore, experiencing a postoperative complication was not an independent prognostic factor.
Stage IIIC disease was associated with poor prognosis. The stage IIIC (T4aN3, T4bN2, or N3) gastric cancer criteria were revised by the 14th edition of the Japanese Classification of Gastric Carcinoma (12), and now includes stage IV gastric cancer as classified by the sixth edition of American Joint Committee on Cancer/Union International Contre le Cancer (25). Therefore, two-thirds of stage IIIC gastric cancer patients were excluded from several previous studies, including the CLASSIC trial. The results of this study suggest that treatment of patients with stage IIIC disease may need improvement.
We conclude that S-1 plus low-dose cisplatin as adjuvant therapy was manageable and safe for patients with stage IIIB or stage IIIC after D2 gastrectomy. However, stage IIIC gastric cancer was strongly associated with poor prognosis, even with this regimen.
Footnotes
Conflicts of Interest
Kazuhito Mita and other co-Authors have no conflict of interest.
- Received December 28, 2016.
- Revision received February 3, 2017.
- Accepted February 10, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved