Clinical experience of second-line chemotherapy with S-1/CPT-11 for highly advanced gastric cancer

We have performed chemoradiation with S-1 and low-dose CDDP as an initial treatment for 27 patients with incurable or unresectable highly advanced gastric cancer since 2002. Twelve out of 27 patients received combination chemotherapy of S-1 and CPT-11 as the second-line chemotherapy. On this regimen, S-1 was administered orally at a dose of 80 mg-120 mg daily, and CPT-11 at a dose of 60 mg/m(2) once in 2 or 3 weeks for outpatients. Clinical effects after therapy showed a response rate of 30.0%. Considering the prognostic outcome of the regimen, the one-year survival rate of the therapy was 66.7%, and the median survival time was more than 1 year, suggesting second-line chemotherapy will be one of the beneficial regimens in gastric cancer patients. Although 4 patients showed grade 3 bone marrow suppression (33.3%), they were all able to continue the therapy, after recovering from toxicity by means of G-CSF and/ or cessation of chemotherapy. The incidence and level of toxicity accompanying subjective symptoms, however, were relatively low, and the regimen was useful as an outpatient treatment maintaining good quality of life and improving their prognosis. Treatment with an appropriate regimen at an appropriate time will enable these patients to have good quality of life and survival.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer

This phase II trial studied the antitumor effect and toxicity of weekly irinotecan (CPT-11, 125 mg/m² 60 min iv infusion, weekly for 4 wk plus 2 wk rest) as second-line chemotherapy in patients with advanced colorectal cancer (CRC) resistant or refractory to prior 5-fluorouracil (5-FU) therapy. Sixty-nine patients with adenocarcinoma (57% in the colon and 43% in the rectum) were enrolled. The median number of treatment cycles received per patient was 4 (range, 1–6). Overall response rate was 18% (95% CI, 9–26), with 4 complete responses (6%) and 8 partial responses (12%), and a median duration of response of 8.1 mo (95% CI, 4.2–12.1). Stable disease was observed in 19 patients (28%). The median time to disease progression was 5.2 mo (95% CI, 4.3–6.1), and the median overall survival was 13.3 mo (95% CI, 9.8–16.8 months). The toxicity profile was favorable: grade 3/4 delayed diarrhea was observed in 10 patients (14.5%) in one cycle each, and grade 3/4 neutropenia in 6 patients (8.7%) and 6 cycles (3.3%). No febrile neutropenia or infection was documented. Grade 3/4 nausea and vomiting were reported in 1 (1.4%) and 7 patients (10.1%), respectively. In conclusion, this phase II trial showed a response rate and a toxicity profile of weekly CPT-11 in line with the results of prior phase II studies.     

Phase I study of S-1 combined with irinotecan (CPT-11) in patients with advanced gastric cancer (OGSG 0002)

OBJECTIVE: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer. METHODS: S-1 was administered orally at 80 mg/m(2)/day for 21 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 40 mg/m(2)/day, stepping up to 60, 80, 100 or 120 mg/m(2)/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study. RESULTS: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m(2), because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m(2). The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15. CONCLUSIONS: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.     

Combination chemotherapy of S-1 +CPT-11 (q 4-5 w) for metastatic gastric cancer

The effectiveness of systemic chemotherapy for metastatic gastric cancer has already been established. However, a standard chemotherapy still remains uncertain. New agents such as S-1, CPT-11 and taxanes are markedly improving the response rates for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard regimen to treat gastric cancer will be reported. In this article, we described the current state of S-1 +CPT-11 combination chemotherapy for gastric cancer. Among various CPT-11 based chemotherapy, S-1 +CPT-11 appears to be the most effective and less toxic treatment.     

替吉奥一线治疗晚期胃癌的研究进展

晚期胃癌失去手术指征,化疗可延长患者的生存时间并提高生活质量,是主要治疗选择。但针对晚期胃癌目前仍无标准化疗方案。替吉奥自上市以来,在胃癌治疗中应用广泛,一些研究采用替吉奥与顺铂、紫杉类或伊立替康等细胞毒类药物联合一线治疗晚期胃癌,有效率在40％～50％,且安全性好。     

Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.     

培美曲塞联合顺铂二线治疗进展期胃癌的疗效分析

目的 观察培美曲塞联合顺铂方案二线治疗进展期胃癌的临床疗效、不良反应及HER-2基因表达情况对其疗效的影响.方法 回顾性分析44例采用二线方案化疗的晚期胃癌患者的临床资料:培美曲塞500 mg/m2dl、顺铂75 mg/m2 dl,每21天重复1次,≥2周期.分析HER-2表达与其近期疗效、无进展生存时间(PFS)和总生存时间(OS)的关系.结果 全组共接受化疗146周期(中位4周期),其中完全缓解0例,部分缓解4例(9.1％),病情稳定22例(50.0％),病情进展18例(40.9％),总有效率(ORR)为10.0％,疾病控制率(DCR)为59.0％.中位PFS为3.6月,中位OS为7.4月.HER-2阳性与阴性表达患者的近期疗效间差异无统计学意义(P＞0.05).不良反应中最常见的为血液学毒性,Ⅲ～Ⅳ级血红蛋白减少、中性粒细胞减少、血小板减少发生率分别为11.4％、20.5％、2.3％;非血液学毒性反应较轻,Ⅰ～Ⅱ级恶心、呕吐发生率为52.3％,Ⅰ～Ⅱ级脱发、皮疹发生率为43.2％.结论 培美曲塞联合顺铂治疗晚期胃癌有明确疗效,且不良反应较小,患者可耐受.HER-2表达情况对其近期疗效无确切影响.     

CPT-11 combined chemotherapy for metastatic gastric cancer

The effectiveness of chemotherapy for metastatic gastric cancer has been already revealed. But a standard chemotherapy has not been established yet. New agents such as TS-1, CPT-11 and taxanes are improving the response rates and also the survivals for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard resume will be sent abroad. In this article, we described the current state of CPT-11 combined chemotherapy for gastric cancer. Among various CPT-11- combined chemotherapy, CPT-11 + TS-1 is the most effective and less toxic treatment.     

阿帕替尼与替吉奥二线治疗晚期胃癌患者的临床疗效比较

目的 探究阿帕替尼与替吉奥二线治疗晚期胃癌患者的临床疗效.方法 选取经化学药物治疗失败的晚期胃癌患者118例,依据治疗方案的不同将患者分为靶向组及对照组,各59例,其中,靶向组患者口服阿帕替尼进行治疗,对照组患者口服替吉奥进行治疗;观察比较两组患者治疗前及治疗过程中白细胞计数(WBC)、血小板计数(PLT)、不良反应情况及疗效.结果 治疗前两组患者的WBC及PLT比较,差异无统计学意义(P﹥0.05);治疗过程中靶向组患者腹泻、皮疹及口腔炎的发生率低于对照组,高血压及手足综合征的发生率高于对照组,差异有统计学意义(P﹤0.05);治疗后两组患者的WBC及PLT水平均降低,且对照组患者降低更为显著(P﹤0.05);靶向组患者的疗效优于对照组,差异有统计学意义(P﹤0.05).结论 靶向药物阿帕替尼相对于替吉奥对二线治疗晚期胃癌患者具有疗效显著、不良反应轻微等优势;治疗过程中靶向组出现较多的血压升高患者,经对症治疗后症状得到缓解.     

Three successful cases with CPT-11 + CDDP chemotherapy where S-1 failed to respond to recurrent gastric cancer

We report three successful cases with irinotecan (CPT-11 60 mg/m2) + cisplatin (CDDP 30mg/m2) chemotherapy (once in 2 weeks) where S-1 failed to respond to recurrent gastric cancer. Case 1: A total gastrectomy and splenectomy were performed for a cardiac gastric cancer (T3, N2, H0, P0, CY0, por 1, Stage IIIB). An abdominal CT revealed paraortic lymph node metastases 4 months after the surgery. No reductions were noted after S-1 monotherapy. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CRin after 11 courses. Case 2: A total gastrectomy, splenectomy and cholecystectomy were performed for a cardiac gastric cancer (T3, N3, H0, P0, CY1, tub1, Stage IV). After the surgery, we treated this patient with S-1 mono-therapy. However, we finished this treatment for abdominal recurrence. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CR after 24 courses. Case 3: A distal gastrectomy and cholecystectomy were performed for a pyloric gastric cancer (T2, N1, H0, P0, CY0, tub 2, Stage II). An abdominal CT revealed paraortic lymph node metastases 10 months after the surgery. We treated this patient with S-1 + paclitaxel (PTX) chemotherapy. No reductions were noted after 2 courses. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CR after 8 courses.     

Single-agent irinotecan as second-line treatment for advanced gastric cancer

AIM: To investigate the activity and toxicity of irinotecan (CPT-11) as a single agent in patients with advanced gastric cancer after failure of previous 5-fluorouracil-based combination chemotherapy. PATIENTS AND METHODS: Sixteen patients with advanced gastric received CPT-11, 350 mg/m2 every 21 days. The median age of the patients was 54.6 years; ECOG performance status was 0-1 in 14 patients and 2 in 2 patients. Dominant metastatic sites included liver, lung, lymph nodes and peritoneum. RESULTS: No complete response was observed. Two patients (12.5%) achieved a partial response to treatment. One patient (6.25%) had a minor response. Ten patients (62.5%) had progressive disease on therapy, and 3 patients (18.75%) had stable disease. The median survival of all 16 patients was 5 months. Grade 3 neutropenia was observed in 3 patients (18.75%), grade 4 thrombocytopenia in 1 patient (6.25%), and grade 3 anemia in 1 patient (6.25%). Three patients (18.75%) suffered from grade 3 diarrhea. CONCLUSIONS: CPT-11 is moderately active and a well-tolerated regimen for selected advanced gastric cancer patients who experience disease progression after receiving first-line treatment.     

Second-line chemotherapy in gastric cancer following S-1 with CPT-11 chemotherapy performed as clinical trial

We previously conducted a phase I/II study of irinotecan (CPT-11) combined with S-1 as first-line chemotherapy for metastatic advanced gastric cancer. In the present study,second-line chemotherapy was given to 32 of 44 patients whose disease became refractory to this first-line treatment. Overall survival time of the patients given second-line chemotherapy was significantly longer than that of patients not given such therapy (444 days vs. 230 days, p = 0.013). The response rate to second-line chemotherapy was 13% (4/32). Survival time of patients who responded to second-line chemotherapy was significantly longer than that of non-responders. Second-line chemotherapy may produce a better clinical response in patients who have progressive disease during first-line chemotherapy. Overall survival time and time to progression after second-line chemotherapy did not significantly differ between patients who received second-line chemotherapy regimens including S-1 and those who received regimens not including S-1.     

Long survival of advanced gastric cancer patient after total gastrectomy and postoperative treatment with S-1 despite S-1+CDDP+CPT-11 causing perforation

Here we report a rare case with perforation of gastric cancer responding to chemotherapy. The patient was a 74- year-old male who underwent abdominal ultrasonography and contrast CT because of body-weight lost and poor appetite in June, 2004 and whose lymph node(LN)swelling was seen in the level from the hepatic to the renal hilum. A gastric wall irregularity was also seen. We suspected gastric cancer with LN metastasis and carried out upper gastrointestinal endoscopy. Then it demonstrated type 2 advanced gastric cancer from the upper to the middle body. The pathological diagnosis of gastric tumor was poorly-differentiated adenocarcinoma containing por 2, tub 1, and pap. The patient was treated with S-1, CDDP and CPT-11 and remained ambulant. After completion of 1 course of chemotherapy, he complained of intense abdominal pain, so we carried out upper gastrointestinal endoscopy and found perforation in the stomach at the same location as the gastric cancer. Emergency total gastrectomy was performed at once. The histopathological finding showed disappearance of the cancer cell not only in the stomach but also accessory LN. Because the remnant LN metastasis was seen in the hepatic hilum at abdominal contrast CT after operation, S-1 was administered to the patient as 60 mg/m2/day in ambulant. Now, over 40 months after the operation, the patient has been alive with good performance status and disappearance of LN metastasis.     

A long-surviving patient with unresectable advanced gastric cancer treated with S-1 and biweekly paclitaxel combination chemotherapy as second-line treatment

A 59-year-old man with type 3 gastric cancer(signet-ring cell carcinoma)underwent simple laparotomy because of peritoneal dissemination.S -1/CDDP was started.Since the icterus of Grade 2 had appeared after 2 courses, S-1 and biweekly paclitaxel combination chemotherapy was started as second-line treatment.Throughout treatment, there was no adverse event, and this regimen was continued for 14 courses(25 months).He died 32 months after his first visit.S -1/PTX may play an important role as second-line chemotherapy for patients with unresectable advanced gastric carcinoma.