Combination chemotherapy with irinotecan and cisplatin in pretreated patients with unresectable or recurrent gastric cancer

Background The combination of irinotecan (CPT-11) and cisplatin (CDDP) is an active regimen for metastatic gastric cancer in the first-line setting. The objective of this retrospective study was to clarify its efficacy and safety in patients with prior chemotherapy for advanced or recurrent gastric cancer. Methods Patients in the study fulfilled the following selection criteria: (1) histologically proven gastric cancer with metastatic lesions; (2) performance status of 2 or less; (3) age of 75 years or younger; (4) at least one prior chemotherapy regimen without CPT-11 or CDDP; (5) adequate bone marrow, liver, and kidney function; (6) normal cardiac function; (7) no other severe medical conditions; (8) no other active malignancy; and (9) the provision of written informed consent. The treatment consisted of CPT-11 (70 mg/m²) on day 1 and day 15 and CDDP (80 mg/m²) on day 1; repeated every 4 weeks. Results Thirty-two patients were recruited, and 28 were assessable for clinical response. There were eight partial responses, resulting in a response rate of 28%. Median time to progression was 104 days (range, 24–863 days) and median overall survival time was 283 days from the initiation of this therapy. The incidences of grade 4 neutropenia, grade 3 or higher infection, and diarrhea were 69%, 9%, and 3%, respectively. Other adverse reactions were mild. No treatment-related deaths occurred. Conclusion A combination of CPT-11 and CDDP may be active and feasible for gastric cancer patients with prior chemotherapy. Further studies with larger numbers of patients are needed to clarify this regimen's significance in the second-line setting.     

生脉注射液配合老年晚期胃癌化疗的临床观察

目的探讨生脉注射液在减轻老年晚期胃癌患者化疗中药物副反应和改善患者生存质量方面的作用。方法将符合研究标准59名患者随机分为治疗组33例和对照组26例,均接受ELF方案静脉化疗两周期,治疗组化疗期间接受生脉注射液治疗共4周。观察治疗前后两组患者近期疗效、生活质量评分、化疗期间患者胃肠道反应和骨髓功能抑制情况。结果治疗组KPS增加值≥10分者占75.8%,高于对照组(38.5%);两组均无IV度胃肠道反应,治疗组0～I度消化道反应者占87.9%,高于对照组(61.5%),治疗组II～III度消化道反应者占12.1%,低于对照组(34.6%);两组均无IV度骨髓功能抑制,治疗组0～I度骨髓功能抑制者占81.8%,高于对照组(53.8%),治疗组II～III度骨髓功能抑制者占18.2%,低于对照组(46.2%)。以上资料经统计学分析表明组间差异明显(P<0.05),有统计学意义。结论生脉注射液在减轻老年性晚期胃癌患者化疗药物副反应和改善患者生存质量方面作用显著。     

Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer

Based on single agent activities and the additive or synergistic effects of three individual drugs in gastric cancer, we performed a phase II study of a new regimen combining epirubicin, docetaxel and cisplatin (EDP) for unresectable gastric cancer. The patients with histologically confirmed metastatic or recurrent, unresectable gastric cancer and no history of palliative chemotherapy were eligible for this trial. In total, 40 mg m(-2) epirubicin (reduced to 30 mg m(-2) due to high incidence of febrile neutropaenia; 75%) intravenously (i.v.) over 30 min, followed by 60 mg m(-2) docetaxel i.v. over 1 h, then 75 mg m(-2) cisplatin i.v. over 1 h was administered every 3 weeks. Between January 2002 and February 2003, 30 patients (epirubicin 40 mg m(-2), eight; 30 mg m(-2), 22) were enrolled. The median age was 52 years (range, 33-68). The patients received a median of four cycles (range, 1-8). One patient (3%) achieved a complete response, 13 (43%) showed partial responses, 13 (43%) had stable diseases and three (10%) progressed. The overall response rate was 47% (95% CI, 28-66%), and the median duration of response was 5.0 months (95% CI, 3.0-7.0). The median time to progression was 4.1 months (95% CI, 2.4-5.9), and the median overall survival was 11.0 months (95% CI, 9.5-12.4). Grade 4 neutropaenia were observed in 41%, and febrile neutropaenia in 32%, out of the patients receiving 30 mg m(-2) of epirubicin. Grade 3 nonhaematological toxicities included nausea, vomiting, anorexia and peripheral neuropathy. In conclusion, EDP is active in gastric cancer, with a manageable and predictable toxicity profile.     

Dose intensity of mitomycin C in adjuvant cancer chemotherapy for patients with gastric cancer

Using a cohort of macroscopic curative resections of gastric cancer at stages II, III, and IV, a randomized controlled trial was performed to elucidate the dose efficacy of intensive adjuvant cancer chemotherapy with mitomycin C. Between June 1983 and December 1986, 336 patients with gastric cancer from 31 institutes were enrolled in the study. The cohort was stratified randomly by the telephone method into two arms. Group A received 20 mg and 10 mg of mitomycin C per body intravenously (IV) on postoperative days 0 and 1, respectively, and then tegafur at 600 mg/body daily perorally (PO) from postoperative week 2 for 1 year. Group B also received 0.2 mg of mitomycin C per kg IV at 3, 6, 9, and 12 months after surgery. The background factors in groups A and B were essentially identical, and the adverse effects were tolerable in both groups. The total administered doses of mitomycin C were significantly higher in group B than in group A, according to the protocol. Although no significant differences were observed in the actuarial overall survival rates between groups A and B at stages II, III, and IV, favorable survival was observed in group B, which received histologically absolute curative resection. This dose-intensive adjuvant cancer chemotherapy would be useful for gastric cancer patients treated by histologically curative surgery. © 1994 Wiley-Liss, Inc.     

晚期胃癌化疗进展

随着细胞毒药物和分子靶点药物的研发,晚期胃癌患者姑息化疗取得一定进展。患者中位生存期可接近1年。本文主要介绍新药多西紫杉醇、紫杉醇、奥沙利铂、伊立替康、卡培他滨、S1及靶向药物在晚期胃癌治疗中的作用以及局部晚期胃癌的化疗策略,尤其重点介绍Ⅲ期临床试验研究结果。提出一些新联合方案,如含多西他赛的DCF方案、含奥沙利铂的EOX和FLO方案、含卡培他滨的EOX和顺铂＋希罗达方案、含伊立替康的ILF方案、含S1的S1＋DDP方案,可以作为一线治疗晚期胃癌的新的参考方案。而靶向药物在晚期胃癌治疗中结论尚不明确,其有效性、安全性和最终收益有待进一步的研究;新辅助化疗可作为局部晚期胃癌治疗的选择。     

奥沙利铂联合卡培他滨一线治疗进展期胃癌的临床疗效观察

背景与目的：奥沙利铂联合卡培他滨（XELOX方案）是治疗进展期胃癌（advanced gastric cancer,AGC）的有效方案,但是该方案作为一线方案治疗AGC患者的疗效和安全性尚不确定。本研究旨在探讨XELOX方案作为一线方案治疗AGC的疗效及安全性。方法：33例既往未接受过化疗的AGC患者采用XELOX方案化疗．奥沙利铂130mg／m^2,静脉滴注2h,d1;卡培他滨2000mg／m^2,分2次口服．d1～14,21天为一个周期。患者最多接受8个周期化疗。结果：33例患者共接受159个周期的化疗,中位化疗周期数为5个。31例患者可评价疗效,其中完全缓解1例（3．2％）,部分缓解16例（51．6％）,稳定8例（25．8％）,进展6例（19．4％）。客观有效率54．8％（95％可信区间37．3％-72．3％）,临床获益率80．6％（95％可信区间66．7％～94．5％）。平均随访10．5个月,中位疾病进展时间5．9个月（95％可信区间4．7～7．1个月）,中位生存时间10．4个月（95％可信区间7．9～12．9个月）。常见不良反应有骨髓抑制、外周神经毒性、胃肠道反应、手足综合征等,经对症治疗后均好转．无治疗相关性死亡。结论：XELOX方案一线治疗AGC疗效显著,耐受性良好。     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.     

胃癌辅助化疗的研究进展

胃癌一直是肿瘤死亡的主要原因,手术根治性切除是治愈的唯一手段。胃癌辅助化疗是在根治性手术后减少局部和远处复发的方法。许多Ⅲ期临床研究试图证实辅助治疗的疗效,但至今仍没有确立标准的治疗方案。本文就辅助治疗在胃癌中的进展作一总结。     

Docetaxel + 5-fluorouracil + cisplatin 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer

BACKGROUND: Our objective was to verify the efficacy and safety of "docetaxel + 5-fluorouracil + cisplatin" 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer. METHODS: Between January and November 2002, we enrolled 43 patients [males 31; median age 55 years (range 24-74)] with inoperable gastric cancer who had not been seen previously in Seoul National University Hospital. The regimen used was docetaxel 70 mg/m(2) on day 1, cisplatin 40 mg/m(2) on days 2 and 3, and 5-fluorouracil 1200 mg/m(2) over 10 h on days 1-3, every 3 weeks. RESULTS: A total of 168 cycles were administered. Mean cycle number per patient was 3.9. The administered dose intensity of docetaxel was 21.23 mg/m(2)/week, 5-FU 1092.14 mg/m(2)/week and cisplatin 23.82 mg/m(2)/week, which corresponded to 91.1, 91.0 and 89.5% of planned doses. Of the 43 patients, response evaluation was possible in 40 and, of these patients, 17 (42.5%) achieved a partial response, 13 (32.5%) stable disease, and 10 patients (25%) showed progressive disease. The median time to progression was 5.6 months [95% confidence interval (CI) 4.6-6.6 months]. Median overall survival was 9.0 months. (95% CI 4.8-13.2 months). Leukopenia occurred during 21.4% of cycles (36 of 168 cycles); 14.3% grade 1, 5.3% grade 2 and 1.8% grade 3. Anemia occurred in 16.7% (28 of 168 cycles); 11.3% grade 1, 4.8% grade 2 and 0.6% grade 3. Thrombocytopenia was not observed. Diarrhea, stomatitis and hypersensitivity occurred in 4.7% (two out of 43 patients), respectively. Neutropenic fever occurred in two patients (4.7%) and myalgia in three (7.0%). CONCLUSION: "Docetaxel + 5-fluorouracil + cisplatin" 3-day combination chemotherapy is an active and tolerable regimen as a first-line treatment in patients with unresectable gastric cancer.     

Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

Background Paclitaxel scheduled every 3 weeks has shown a response rate of ∼20% for gastric cancer, with modest hematological toxicity. Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly paclitaxel for patients with metastatic or recurrent gastric cancer in clinical practice. Methods In 38 patients who had metastatic or recurrent histologically confirmed gastric cancer and a history of one prior chemotherapy regimen, other than paclitaxel or docetaxel, paclitaxel (8mg/m²) was administered weekly, three times every 4 weeks, with short-term premedication. Results All 38 patients had had prior chemotherapy that included 5-fluorouracil, the fluoropyrimidine anticancer drug S-1, or cisplatin. The median number of courses in the present regimen was 6 (range, 1–44+). Dose intensity was 5mg/m² per week, corresponding to 92% of the planned dose (6mg/m² per week). The overall response rate was 24% (6/25) in measurable lesions, and pleural effusion and ascites disappeared in 2 of 7 patients (29%) and in 3 of 21 patients (14%), respectively. Median survival time was 151 days from the commencement of this treatment, with a median follow-up period of 260 days. Grade 3 or 4 leukopenia and neutropenia were observed in 11 (29%) and 12 (32%) patients, respectively. Seven patients (18%) died within 30 days of the last administration of paclitaxel. Conclusion Weekly paclitaxel seems to be active as second-line chemotherapy against metastatic and recurrent gastric cancer. Further study is needed to confirm the efficacy and safety of weekly paclitaxel.     

The treatment of gastric cancer with combined surgical resection and chemotherapy

A series of 156 patients with gastric cancer during a 15-year period were reviewed retrospectively to determine the effectiveness of combined surgery and adjuvant chemotherapy. The patients were divided into a 9-year prechemotherapy period and a 6-year chemotherapy period. Review of the data revealed an increase in the incidence of distant disease. The utilization of surgery as the only mode of treatment declined. Combination surgery and adjuvant chemotherapy utilization increased. Comparison of survival for surgery vs. adjuvant chemotherapy, expressed as percentage of survivors for each year, revealed an increase at 1 and 2 years with no difference at 3 years for all stages. A similar comparison for patients with regional spread showed an increase at 1,2, and 3 years with no difference thereafter. The 5-year survival was 5% for both groups. The data has suggested that surgery and adjuvant chemotherapy increases 1-, 2-, and 3-year survival rates but does not affect the longterm results.     

A multicenter phase II study of biweekly paclitaxel and S-1 combination chemotherapy for unresectable or recurrent gastric cancer

Purpose  This Phase II study assessed the activity and safety of biweekly paclitaxel and oral S-1 as treatment for unresectable and recurrent gastric cancer. The maximum tolerated dose for this regimen had been established previously in a Phase I study performed in Japanese patients. Patients and methods  Chemotherapy was performed using two anticancer agents, S-1 and paclitaxel. Oral S-1 (80 mg/m²) was administered twice a day after meals for two consecutive weeks from Day 1 to 14, followed by a 2 week recovery period; paclitaxel (120 mg/m²) was administered intravenously, biweekly, on Days 1 and 15. The patient received cycles of this regimen every 4 weeks (q 28-day cycles). The primary end point was the response rate according to the Response Evaluation Criteria in Solid Tumors. Results  A total of 39 patients (median age, 65 years) were enrolled; 13 other patients were screened, but found to be ineligible. All patients had unresectable and recurrent gastric cancer. The most common treatment-related Grade 3/4 adverse events were neutropenia (37.5%), appetite loss, diarrhea, decreased sodium (each 5%), and anemia, increased alanine aminotransferase, general fatigue, and dizziness (each 2.5%). Almost all the patients experienced alopecia. Intent-to-treat analysis showed a response rate of 43.6%. With a median follow-up of 14 months (range 8–21 months), median survival was 256 days and the median time to progression was 4 months. Conclusion  A combination regimen of biweekly paclitaxel and oral S-1 was well tolerated and showed promising activity against unresectable and recurrent gastric cancer.     

Hyperthermic intraperitoneal chemotherapy in serosa-invasive gastric cancer patients

BackgroundEvaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) in reducing metachronous peritoneal metastases (MPM) risks in patients with resectable serosa-invasive gastric cancer.Materials & methodsBetween 2008 and 2016, 154 patients with gastric cancer (stage IIB-IIIC) were randomly assigned to two groups: 76 patients underwent HIPEC (cisplatin 50 mg/m² + doxorubicin 50 mg/m², 42 °C, 1 h) combined with radical surgery (HIPEC group) and 78 patients underwent only radical surgery (control group).ResultsEvaluation of HIPEC toxicity showed neither toxic complications of IV-V degree nor haematological toxicity (according to CTCAE v. 4.03). There was no significant difference in the rate of complications between the two groups (p = 0.254). There was a more frequent disease progression in the control group than in the HIPEC group: 42/55 patients (76.4%) vs. 36/68 patients (52.9%), respectively (p = 0.009). At the same time a significant decrease in the rate of MPM was observed after HIPEC administration as compared with surgery alone – 16/68 (12.8%) vs. 39/55 (27.6%) (p < 0.001). 3-year progression-free survival was 47% (95% CI 36–61)) in the HIPEC group and 27% (95% CI 17–43) in the control group – p = 0.0024.The N-stage, HIPEC procedure, type of surgery and interaction between HIPEC treatment and age were independent prognostic factors.ConclusionsHIPEC appears to be helpful in improving treatment results in radically operated gastric cancer patients.     

局部深部热疗联合化疗与单纯化疗治疗中晚期胃癌的对比研究

目的 探讨局部深部热疗联合化疗对中晚期胃癌的治疗效果及安全性.方法 回顾性分析92例中晚期胃癌患者的临床资料,根据治疗方案不同将患者分为研究组(n=50)和对照组(n=42),对照组患者接受替吉奥+奥沙利铂联合化疗,研究组患者在此基础上接受局部深部热疗.两组患者的治疗周期均为4~6个周期(具体根据患者情况而定),21 d为1个周期.比较治疗后两组患者的肿瘤大小、治疗效果、不良反应情况、生活质量改善情况及生存情况.结果 治疗后研究组患者的肿瘤直径明显小于对照组(P<0.01),治疗有效率、生活质量改善情况、累积生存率均优于对照组(P<0.05),总不良反应发生率低于对照组(P<0.05).结论 局部深部热疗联合化疗可有效提高中晚期胃癌患者的治疗效果,且安全性相对较高,值得临床推广应用.     

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.     

乌苯美司胶囊对晚期胃癌化疗患者影响的临床研究

目的评价乌苯美司胶囊对晚期胃癌化疗患者生活质量、不良反应及免疫功能的影响。方法63例晚期胃癌患者随机分为治疗组（32例）和对照组（31例）,所有患者均给予DCF方案化疗2个周期：多西他赛40mg／m2静脉滴注,d1、8;顺铂15mg／m2静脉滴注,d1～5天;替加氟600mg／m。静脉滴注,d1～5天。治疗组在化疗开始时给予乌苯美司胶囊30mg每日清晨顿服,连用8周。观察治疗前、后患者KPS评分,体重变化．血白细胞、血红蛋白、血小板变化及淋巴细胞免疫功能变化。结果治疗组化疗后KPS评分及体重与化疗前相比稳定率达65．6％和68．8％;对照组均为35．5％（P〈0．05）。治疗组化疗后血白细胞、血红蛋白、血小板降低程度小于对照组（P〈0．05）。两组T抑制、杀伤淋巴细胞（CD3＋、CD8＋）变化无统计学意义。治疗组T淋巴细胞（CD3＋）,T辅助、诱导淋巴细胞（CD3＋、CD4＋）,NK细胞（CD16＋、CD56＋）水平均较用药前有所提高,而对照组均较化疗前下降,两组相比有统计学意义（P〈0．05）。结论乌苯美司胶囊有提高肿瘤患者免疫功能的作用,同时还能减轻化疗不良反应,改善化疗患者的生活质量。     

Phase II study of capecitabine and cisplatin as first-line combination therapy in patients with gastric cancer recurrent after fluoropyrimidine-based adjuvant chemotherapy

To evaluate the efficacy and safety of capecitabine and cisplatin in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant therapy. Patients with histologically confirmed and measurable advanced gastric cancer that had relapsed after fluoropyrimidine-based adjuvant chemotherapy received oral capecitabine (1250 mg m(-2) twice daily, days 1-14) and intravenous cisplatin (60 mg m(-2) over 1 h, day 1) every 3 weeks. In total, 32 patients were enrolled, of whom 30 were evaluable for efficacy and 32 for safety. A median of 5 cycles (range 1-10) was administered. One patient achieved a complete response and eight had partial responses, giving an overall response rate of 28% (95% CI, 13-44%). The median time to progression and median overall survival were 5.8 months (95% CI, 4.1-7.5 months) and 11.2 months (95% CI, 5.5-16.9 months), respectively. Grade 3 neutropenia and thrombocytopenia were observed in 38 and 6% of patients, respectively. Grade 2/3 nonhaematological toxicities included diarrhoea (19%), stomatitis (19%) and hand-foot syndrome (31%). No grade 4 toxicity, neutropenic fever or treatment-related deaths occurred. Capecitabine in combination with cisplatin was effective and well tolerated as first-line treatment in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant chemotherapy.     

晚期胃癌二线化疗的预后因素分析

目的:探讨晚期胃癌患者二线化疗的预后因素,筛选二线化疗的最佳人群。方法:回顾性分析256例接受二线化疗的晚期胃癌患者,采用Kaplan-Meier法计算生存率,Log-rank检验比较各亚组生存率,采用Cox比例分析模型作临床病理特征对生存率影响的单因素和多因素分析。结果:二线化疗的客观有效率18.0%,中位至进展时间(TTP)3.0个月,中位生存期(OS)8.1个月,1年生存率24.4%。多因素分析发现,分化程度(RR=1.33;95%CI:1.02～1.74;P=0.04)、一线化疗的TTP(RR=2.12;95%CI:1.59～2.83;P=0.00)、二线化疗前PS评分(RR=5.42;95%CI:3.65～8.05;P=0.00)和血红蛋白(RR=3.56;95%CI:2.49～5.09;P=0.00)是晚期胃癌二线化疗的独立预后因素。根据患者含预后不良因素的个数,分为低危(0)、中危(1～2)和高危(3～4)3组,3组的中位生存期分别为10.2、6.4和3.3个月,1年生存率分别为39.2%和8.5%,0,P=0.00。结论:影响晚期胃癌二线化疗的独立预后因素包括分化程度、二线化疗前PS评分、血红蛋白和一线化疗的TTP,可作为筛选晚期胃癌二线化疗适宜人群的有效指标。