S-1-based combination therapy vs S-1 monotherapy in advanced gastric cancer:A meta-analysis

AIM:To assess the efficacy and safety of combination therapy based on S-1,a novel oral fluoropyrimidine,vs S-1 monotherapy in advanced gastric cancer(AGC).METHODS:We searched PubMed,EMBASE and the Cochrane Library for eligible studies published before March 2013.Our analysis identified four randomized controlled trials involving 790 participants with AGC.The outcome measures were overall survival(OS),progression-free survival(PFS),overall response rate(ORR)and grade 3-4 adverse events.RESULTS:Meta-analysis showed that S-1-based combination therapy significantly improved OS(HR=0.77,95%CI:0.66-0.91,P=0.002),PFS(HR=0.58,95%CI:0.46-0.72,P=0.000)and ORR(OR=2.23,95%CI:1.54-3.21,P=0.000).Sensitivity analysis further confirmed this association.Lower incidence of grade 3-4 leucopenia(OR=4.06,95%CI:2.11-7.81),neutropenia(OR=3.94,95%CI:2.1-7.81)and diarrhea(OR=2.41,95%CI:1.31-4.44)was observed in patients with S-1 monotherapy.CONCLUSION:S-1-based combination therapy is superior to S-1 monotherapy in terms of OS,PFS and ORR.S-1 monotherapy is associated with less toxicity.     

S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: A meta-analysis

AIM: To assess the efficacy and tolerability of S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer (AGC).METHODS: We extracted reported endpoints, including overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), objective response rate (ORR) and adverse effects, from randomized controlled trials identified in PubMed, the Cochrane library, Science Direct, EMBASE and American Society of Clinical Oncology meetings. Stata software was used to calculate the pooled values.RESULTS: Seven randomized controlled trials involving 2176 patients were included in this meta-analysis. Compared to non-S-1-based regimens, the use of S-1-based regimens were associated with an increase in ORR (RR = 1.300; 95%CI: 1.028-1.645); OS (HR = 0.89; 95%CI: 0.81-0.99; P = 0.025), TTF (HR = 0.83; 95%CI: 0.75-0.92; P = 0.000), and a lower risk of febrile neutropenia (RR = 0.225; P = 0.000) and stomatitis (RR = 0.230; P = 0.032). OS, PFS and TTF were prolonged, especially in the Asian population. In subgroup analysis, statistically significant increases in ORR (RR = 1.454; P = 0.029), OS (HR = 0.895; P = 0.041) and TTF (HR = 0.832; P = 0.000) were found when S-1-based chemotherapy was compared to 5-fluorouracil (5-FU)-based chemotherapy. The incidence of leukopenia (RR = 0.584; P = 0.002) and stomatitis (RR = 0.230; P = 0.032) was higher in the 5-FU-based arm. S-1-based regimens had no advantage in ORR, OS, PFS, TTF and grade 3 or 4 adverse events over capecitabine-based regimens.CONCLUSION: S-1-based chemotherapy may be a good choice for AGC because of longer survival times, better tolerance and more convenient use.     

Neoadjuvant chemotherapy with S-1 and CDDP in advanced gastric cancer

Purpose This retrospective study evaluated the effects of neoadjuvant chemotherapy in advanced gastric cancer.Methods Between 2002 and 2005, we treated 14 patients with advanced gastric cancer (involvement of more than five nodes or tumor invasion into pancreas) and 25 patients with Stage III gastric cancer. The group of 14 patients with advanced gastric cancer received combination chemotherapy with S-1 and cis-diamminedichloroplatinum (CDDP) as a neoadjuvant chemotherapy (NAC). This regimen was repeated every 5 weeks for a total of 2–5 cycles. The 25 patients with Stage III gastric cancer was carried surgery alone (SA). All patients underwent extensive surgery, including gastrectomy, and D2 lymphadenectomy. The rate of response and overall survival in the two groups were compared.Results All patients of NAC group completed the planned regimens of chemotherapy and surgery. Patients of the NAC group had a response rate of 78.6% (95% confidence interval 57.1–100.0%). The most common adverse effect was leukocytopenia (42.9%). However, only four patients (28.6%) had upper Grade 2 leukocytopenia, and all recovered promptly. Postoperative complications were not significant differentiated between NAC and SA group of patients (7.2 vs. 4.0%). Patients in the NAC group had a significantly better survival than those in the SA group (P = 0.03). The median survival has not been reached after 26.9 months of median follow-up for patients in the NAC group. 1-, 2-, and 3-year survival rates were 92.3, 92.3, and 61.5%, respectively. NAC was identified as an independent prognostic factor in all patients (P = 0.018).Conclusion Neoadjuvant chemotherapy with TS-1 + CDDP improves the survival in patients with advanced gastric cancer.     

Eight-year survival after advanced gastric cancer treated with S-1 followed by surgery

We report a case of advanced gastric cancer, with cervical, axillary, and abdominal paraaortic lymph node metastases, that was successfully treated with chemotherapy and surgery. The disease was initially considered unresectable, and the patient was treated with orally administered S-1. Chemotherapy was effective, and all lymph node metastases disappeared after 6 courses. After 27 mo of chemotherapy, the patient underwent curative surgery, with subtotal gastrectomy and lymph node dissection. Histopathologic...     

Apatinib for the treatment of gastric cancer

Introduction: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models.

Areas covered: Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer.

Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cancer.     

Therapeutic effects of combined oxaliplatin and S-1 in older patients with advanced gastric cardiac adenocarcinoma

AIM:To evaluate the effects and safety of combination chemotherapy with oxaliplatin (L-OHP) and S-1 (SOX regimen) in older patients with advanced gastric cardiac adenocarcinoma (GCA). METHODS: Seventy patients with advanced GCA were classified according to age into an older group (≥ 75 years) and a control group (< 75 years). The SOX regimen was administered to the two groups as follows: S-1 (40 mg/m2 po bid) on days 1 to 14 followed by a 7-d off period, plus L-OHP (65 mg/m2 iv) for 2 h on days 1 and 8 of a...     

A phase I study of combination therapy with S-1 and irinotecan (CPT-11) in patients with advanced colorectal cancer

Purpose  The aim of this study was to determine the maximum tolerated dose, recommended dose and dose-limiting toxicities of irinotecan (CPT-11) plus S-1 in advanced colorectal cancer. Methods  S-1 was administered orally at 80 mg/m² per day for 14 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 80 mg/m² per day, stepping up to 100, 120 or 150 mg/m² per day. Courses were repeated every 4 weeks, unless disease progression or severe toxicities were observed. Results  A total of 21 patients were entered in this study. The maximum tolerated dose of CPT-11 was considered to be 150 mg/m², because 2 of 3 patients developed dose-limiting toxicities such as leukopenia, neutropenia, diarrhea and anorexia. The recommend dose of CPT-11 was set at 120 mg/m². Tumor response rate was 42.8% and median progression-free survival time was 10 months (95% confidential interval, 6.0–14.0 months). Conclusion  A combination of S-1 and CPT-11 showed a good safety profile and can be recommended for further phase II studies in patients with colorectal cancer.     

Combination therapy of S-1 and CDDP for patients with colorectal cancer

Purpose We evaluate the feasibility and efficacy of S-1 in combination with cisplatin (CDDP) for patients with colorectal cancer. Methods A total of 52 patients with advanced or recurrent colorectal cancer were included. S-1 was given orally twice daily for 21 days and CDDP 30 mg/m² on day 1 and 8, followed by a 2-week period of no treatment. Results Tumor responses among patients included 18 PR, 12 SD, and 16 PD (n = 46). The overall response rate was 36.4% (18/46). The response rate of the patients with prior chemotherapy was 22.2% (4/18) and 50.0% (12/24) among the patients who had no prior therapy. The median survival periods were 555 days and the median progression free survival periods were 183 days, respectively. S-1 in combination with CDDP shows promising activity with acceptable toxicities against colorectal cancer. Conclusions A combination of S-1 and CDDP could be a standard therapy for treating colorectal carcinoma.     

S-1 in the treatment of pancreatic cancer

S-1 is an oral 5-fluorouracil (5-FU) prodrug, which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase, the key enzyme of 5-FU catabolism. Recently, two important studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study (GEST study), S-1 demonstrated non-inferiority to gemcitabine (GEM) in overall survival (OS) for metastatic or locally advanced pancreatic cancer, but combination chemotherapy with GEM and S-1 did not show superiority to GEM in OS. In the second study (JASPAC-01 study), S-1 showed superiority to adjuvant chemotherapy with GEM in OS in patients with resected pancreatic cancer. In addition to GEM, S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan. To date, many studies have investigated the effectiveness of S-1 in various settings, such as first-line chemotherapy for metastatic or locally advanced pancreatic cancer, second-line chemotherapy after GEM failure, and chemoradiotherapy for locally advanced disease. In this review, we focus on recent clinical trials of S-1-based chemotherapy for advanced pancreatic cancer.     

S-1 plus gemcitabine chemotherapy followed by concurrent radiotherapy and maintenance therapy with S-1 for unresectable pancreatic cancer

AIM: To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy (intensity modulated radiotherapy, IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer.METHODS: Subjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases, adequate organ and marrow functions, an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy, oral administration of S-1 40 mg/m² twice daily from day 1 to day 14 of a 21-d cycle, with 30-min intravenous infusions of gemcitabine 1000 mg/m² on day 1 and day 8. Two weeks after the completion of chemotherapy, S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m² per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy (1.8 Gy/d, 5 times per week, 28 fractions). One month after the completion of chemotherapy and radiotherapy, S-1 was administered orally at a dose of 80 mg/m² per day twice daily for 14 d, followed by a 14-d rest period. This cycle was repeated as maintenance therapy, until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median follow-up was 15.6 mo (range: 8.6-32.3 mo).RESULTS: Thirty-two patients completed the scheduled course of chemotherapy, while 30 patients (93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria, the objective tumor response was partial response in 17 (53.1%) patients, stable disease in 9 (28.1%), and progressive disease in 6 (18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo, respectively. The survival rates at 1 year and 2 years were 75% and 34.4%, respectively.CONCLUSION: The combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well-tolerated, promising treatment regimen.     

Three-weekly s-1 monotherapy as first-line treatment in elderly patients with recurrent or metastatic gastric cancer

Background/Aims

Elderly patients with advanced gastric cancer (AGC) have generally been excluded from clinical trials, and there are few data available on the treatment of these patients. The efficacy of palliative S-1 monotherapy as a first-line treatment regimen for elderly patients has not been well elucidated.

Methods

For this study, 25 AGC patients were enrolled between January 1, 2007 and March 31, 2009; 4 cases were recurrent AGC and 21 cases were metastatic AGC at the time of diagnosis. These patients received S-1 therapy at a dose of 40 mg/m² twice daily for 14 days every 3 weeks. All of the patients were older than 70 years.

Results

The median follow-up duration, the median progression-free survival, and the overall survival time were 8.7 months (range, 4.9 to 12.5 months), 4.9 months (range, 3.5 to 6.3 months), and 10.8 months (range, 6.6 to 15.0 months), respectively. Grade 3/4 nonhematologic toxicities were rare. Grade 3/4 neutropenia was noted in two patients. The partial response rate was 21.7% and stable disease was observed in 34.8% of the patients. Two patients (8%) died due to chemotherapy-associated toxicity during treatment (septic shock/intracranial hemorrhage).

Conclusions

Oral S-1 chemotherapy seems to be effective as a first-line treatment regimen for elderly patients with metastatic or recurrent AGC. However, elderly patients receiving S-1 treatment should undergo continuous toxicity monitoring, since they are highly susceptible to adverse effects.     

Chemotherapy beyond second-line in advanced gastric cancer

Patients with advanced gastric cancer(AGC) can be treated with multiple lines of chemotherapy. Although several randomized trials have demonstrated the benefit of second-line chemotherapy compared with best supportive care, there is no evidence that further lines of chemotherapy will result in substantial prolongation of survival. Despite this, the practice of offering chemotherapy beyond second-line agents to AGC patients is not uncommon if their performance status is well-preserved and they are willing to receive subsequent active treatments. The choice of chemotherapeutic agents depends on the patient's prior regimens. However, there are important controversial issues in the salvage setting of AGC, including a subset of patients who may benefit from chemotherapy, that still remain unanswered. This report reviews the available evidence regarding the impact of third- and subsequent lines of chemotherapy on survival and quality of life in patients with AGC.     

胃癌分子靶向治疗的现状与进展

胃癌是对人类健康危害极大的常见恶性肿瘤,大部分患者就诊时已进入进展期.我国胃癌的年死亡率在各种恶性肿瘤中占首位.随着外科手术技术的提高、传统放化疗技术的进步以及新辅助疗法的实施,早期胃癌术后5a生存率可达95%以上;而进展期胃癌疗效仍不理想,术后5a生存率仅有30%-40%.随着胃癌分子生物学研究的不断深入,针对肿瘤细胞生长、凋亡、细胞周期、侵袭浸润以及血管生成等分子生物靶点提出的分子靶向治疗成为胃癌综合治疗的重点和热点.这些策略主要包括:表皮生长因子受体靶向治疗,细胞周期抑制剂,细胞凋亡促进剂,血管生成抑制剂,基质金属蛋白酶抑制剂等.本文收集国内外近期文献就胃癌分子靶向治疗的现状与进展进行综述.     

Efficacy of S-1 vs capecitabine for the treatment of gastric cancer: A meta-analysis

AIM: To rationally evaluate the effect of S-1 vs capecitabine for the treatment of gastric cancer.METHODS: MEDLINE, EMBASE, Cochrane Controlled Trials Register, Google Scholar, and China Journal Full Text Database were accessed to collect clinical randomized controlled trials regarding the effect of S-1 vs capecitabine for the treatment of gastric cancer patients. Statistical analysis was performed by metaanalysis. Four randomized controlled trials met the inclusion criteria.RESULTS: Compared with capecitabine regimens, the 1-year survival rate in gastric cancer patients was 0.80(95%CI: 0.52-1.21, P = 0.29). The overall response rate of S-1 vs capecitabine was 0.94(95%CI: 0.59-1.51, P = 0.93). Compared with capecitabine regimens, the most frequent hematologic toxicities were neutropenia( O R = 0. 9 9, 9 5 % C I : 0. 6 5- 1. 4 9, P = 0. 9 4) a n d thrombocytopenia(OR = 0.72, 95%CI: 0.31-1.67, P = 0.44). The most frequent non-hematologic toxicities included nausea(OR = 0.85, 95%CI: 0.56-1.28, P = 0.43) and hand-foot syndrome(OR = 0.16, 95%CI: 0.10-0.27, P < 0.00001).CONCLUSION: The existing studies suggest that S-1 is not more effective than capecitabine in the treatment of gastric cancer patients, but does exhibit less toxicity with regard to hand-foot syndrome.     

老年人胃癌的外科治疗

目的探讨老年胃癌病人临床表现特点及适当的外科治疗方法。方法回顾分析我院1985～2000年收治的年龄70岁以上238例胃癌病人的临床及手术资料。结果老年胃癌发病较隐匿，主要表现为上腹隐痛不适、消瘦、食欲下降、贫血等。多数病人合并有重要器官的慢性病变。手术证实大多数为中晚期胃癌，手术切除166例，切除率为69．7％，其中根治性切除107例，64．5％；姑息性切除59例，35.5％。切除者手术后5年生存率为32．6％，根治性切除达53．7％。姑息性切除平均生存期10．8个月。手术后并发症发生率20．8％。结论老年胃癌由于发病隐匿多为晚期，应提高早期诊断率。要做充分的术前准备及积极的术后处理，大多能耐受手术。     

S-1 combined with oxaliplatin as first line chemotherapy for chinese advanced gastric cancer patients

Background/Aims: To evaluate the efficacy and safety profile of S-1 combined with oxaliplatin (SOX) against unresectable advanced or metastatic gastric cancer. Methodology: Oxaliplatin was administered intravenously at 100mg/m2 for two hours on day 1 and S-1 was administered b.i.d. at 80mg/m2/day on days 1-14 followed by a 7-day rest during the 3-week schedule. Results: All 51 patients were assessed for efficacy and adverse events. The response and disease control rates were 41% and 90%, respectively. The response rate was significantly improved in patients with ECOG performance status of no more than 1, elevated CEA levels or unresected primary cancers. The median follow-up time was 11.8 months, the median time to progression was 6.8 months, the median overall survival was 11.8 months and the 1-year survival rate was 47.4%. Patients with diffused type exhibited significantly decreased time to progression and overall survival. The grade 3/4 adverse events were hematological toxicities, including neutropenia (13.7%), thrombocytopenia (13.7%) and anemia (11.8%). The incidence of grade 3/4 non-hematological events was low (≤2%). Conclusions: The SOX regimen (oxaliplatin, 100mg/m2 d1; S-1, 80mg/m2/day, b.i.d. d1-14, q3w) provided a favorable efficacy and safety profile in Chinese patients with advanced gastric cancer.     

健脾益气法联合化疗治疗晚期胃癌的临床观察

[目的]探讨健脾益气方配合TP(紫杉醇脂质体+顺铂)方案化疗治疗晚期胃癌的疗效。[方法]将40例接受含氟尿嘧啶类方案或含紫杉类方案或含铂类方案化疗的胃癌患者,随机分为对照组和治疗组,对照组20例不服用健脾益气方,常规化疗;治疗组20例在化疗前1周开始口服自拟健脾益气方中药,至化疗结束。在化疗结束后评估恶心呕吐评分、生活质量评分及骨髓抑制评分。[结果]治疗组的恶心呕吐评分、生活质量评分及骨髓抑制评分均明显优于对照组,差异有统计学意义(P0.05)。[结论]健脾益气方配合化疗能明显减轻胃癌化疗后的不良反应,增强化疗疗效。     

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer

Background

Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. This phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1, an oral 5-FU derivative, when given with radiotherapy in elderly patients.

Methods

Patients who were age of 70 years or older with histologically confirmed esophageal cancer, and had an Eastern Cooperative Oncology Group (ECOG) score of 0–2 were eligible for this study. Radiotherapy was administered in 1.8 Gy fractions 5 times weekly to a total dose of 54 Gy. S-1 was administered on days 1–14 and 29–42 at the following dosages: 60, 70, and 80 mg/m²/day. Trial registration: {"type":"clinical-trial","attrs":{"text":"NCT01175447","term_id":"NCT01175447"}}NCT01175447 (ClinicalTrials.gov).

Results

Twelve previously untreated patients were enrolled in this study. No grade 3 or 4 toxicity was observed in six patients treated at the 60 and 70 mg/m² dose levels. DLT was observed in four of six patients treated at the 80 mg/m² dose level. Two patients developed grade 3 esophagitis, one patient developed grade 3 esophagitis and pneumonitis, and one patient developed grade 3 thrombocytopaenia. Endoscopic complete response (CR) was observed in eight patients (66.7%). The median progression free survival (PFS) was 20 months and median overall survival was 29 months.

Conclusions

The MTD of S-1 was 80 mg/m², and the recommended dose (RD) for phase II studies was 70 mg/m². This regimen was well tolerated and active in elderly patients with esophageal cancer, meriting further investigation in phase II studies.