Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial.

BACKGROUND: Patients with advanced biliary tract carcinoma face a particularly dismal prognosis, and no standard palliative chemotherapy has yet been defined. Among several different single agents, mitomycin C and, more recently, the oral fluoropyrimidine capecitabine and the nucleoside analogue gemcitabine, have been reported to exert antitumour activity. In view of a potential drug synergy, the present randomised phase II trial was initiated. The aim was to investigate the therapeutic efficacy and tolerance of mitomycin C (MMC) in combination with gemcitabine (GEM) or capecitabine (CAPE) in previously untreated patients with advanced biliary tract cancer. PATIENTS AND METHODS: A total of 51 patients were entered in this study and randomly allocated to treatment with MMC 8 mg/m2 on day 1 in combination with GEM 2000 mg/m2 on days 1 and 15 every 4 weeks, or MMC 8 mg/m2 on day 1 plus CAPE 2000 mg/m2/day on days 1-14, every 4 weeks. In both arms, chemotherapy was administered for a total of 6 months unless progressive disease occurred earlier. RESULTS: Pretreatment characteristics were well balanced between the two treatment arms. The overall independent review committee-confirmed response rate among those treated with MMC + GEM was 20% (five of 25) compared with 31% (eight of 26) among those treated with MMC + CAPE. Similarly, median progression-free survival (PFS; 4.2 versus 5.3 months) and median overall survival (OS; 6.7 versus 9.25 months) tended to be superior in the latter combination arm. Chemotherapy was fairly well tolerated in both arms, with a comparably low rate of only grade 1 and 2 non-haematological adverse reactions. Also, only four (17%) patients in both treatment arms experienced grade 3 leukocytopenia, and three (13%) and four (17%) had grade 3 thrombocytopenia in the MMC + GEM and MMC + CAPE arm, respectively. CONCLUSIONS: The results of this study indicate that both combination regimens are feasible, tolerable and clinically active. The MMC + CAPE arm, however, seems to be superior in terms of response rate, PFS and OS, and should therefore be selected for further clinical investigation in advanced biliary tract cancer.     

Comparison of gemcitabine plus cisplatin versus capecitabine plus cisplatin as first‐line chemotherapy for advanced biliary tract cancer

Aim : It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine and cisplatin in advanced biliary tract cancer (BTC). Methods : Patients with advanced BTC who were treated with first‐line chemotherapy at Asan Medical Center were retrospectively analyzed. All patients received either cisplatin followed by gemcitabine on days 1 and 8 every 3 weeks (GP group), or capecitabine on days 1–14 with cisplatin on day 1 every 3 weeks (XP group). Results : Of the 134 patients who met the inclusion criteria, 78 received XP and 56 were treated with GP. After a median follow‐up of 26.2 months, the progression‐free survival was 5.7 months for XP versus 4.1 months for GP (hazard ratio [HR] = 0.81, P = 0.31). The overall survival (OS) was 11.0 months for XP versus 9.8 months for GP (HR = 0.84, P = 0.36). In the multivariate analysis, there were no significant differences in PFS and OS between the two groups. Conclusion : XP seems to be as effective as GP in patients with advanced BTC. The XP regimen is feasible and might offer increased convenience regarding the schedule of drug administration.     

Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study

A total of 50 patients with advanced pancreatic cancer were enrolled in a phase II study of bevacizumab 15 mg kg⁻¹, capecitabine 1300 mg m⁻² daily for 2 weeks and gemcitabine 1000 mg m⁻² weekly 2 times; cycles were repeated every 21 days. Radiological response rate was 22%; progression-free survival and over survival were 5.8 and 9.8 months respectively. Grade 3 or 4 toxicities included neutropaenia (22%), thrombocytopaenia (14%), thromboembolic events (12%), hypertension (8%) and haemorrhage (6%).     

吉西他滨治疗晚期胆管癌临床疗效评价

目的:观察吉西他滨治疗晚期胆管癌的临床疗效及不良反应。方法:回顾分析近10年收治的晚期胆管癌患者42例,分为吉西他滨化疗组（G）和非吉西他滨化疗组（NG）,比较两组临床疗效。结果:G组与NG组客观有效率分别为33.3%、5.6%,疾病控制率分别为75.0%、44.4%,中位生存时间分别为10.6个月、7.4个月,两组生活质量改善分别为79.2%、50%,差异均有显著性。不良反应可耐受,除血小板下降外余无明显差异。结论:晚期胆管癌接受含吉西他滨方案化疗可提高近期疗效,改善生活质量,延长生存时间。     

Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer

Background:

An increasing proportion of patients are exposed to anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting. Re-exposure in the metastatic stage is limited by drug resistance, thus evaluation of non-cross-resistant regimens is mandatory.

Methods:

Anthracycline-pretreated patients were randomly assigned to three gemcitabine-based regimens. Chemotherapy consisted of gemcitabine 1.000 mg m⁻² plus vinorelbin 25 mg m⁻² on days 1+8 (GemVin), or plus cisplatin 30 mg m⁻² on days 1+8 (GemCis), or plus capecitabine 650 mg m⁻² b.i.d. orally days 1–14 (GemCap), q3w. The primary end point was response rate.

Results:

A total of 141 patients were recruited on the trial. The overall response rates were 39.0% (GemVin), 47.7% (GemCis) and 34.7% (GemCap). Median progression-free survival was estimated with 5.7, 6.9 and 8.3 months, respectively. Corresponding median survival times were 17.5 (GemVin), 13.0 (GemCis) and 19.4 months (GemCap). Neutropenia ⩾grade 3 occurred in 16.7% (Gem/Vin), 4.4% (GemCis) and 0% (Gem/Cap), whereas non-haematological toxicities were rarely severe except grade 3 hand–foot syndrome in 2.0% of the GemCap patients (per patient analysis).

Conclusions:

This randomised phase II trial has revealed comparable results for three gemcitabine-based regimens regarding treatment efficacy and toxicity. Gemcitabine-based chemotherapy appears to be a worthwhile treatment option for pretreated patients with metastatic breast cancer.     

Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter, phase II study.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (GEM) combined with capecitabine (CAP) in untreated patients with inoperable or metastatic pancreatic cancer. PATIENTS AND METHODS: Fifty-three patients with pancreatic cancer (85% stage IV) were enrolled. Patients were treated with GEM 1000 mg/m2 on days 1 and 8 and CAP 1300 mg/m2 per day PO (per os), divided into two equal doses on days 1-14, in 21-day cycles. RESULTS: In an-intention-to-treat analysis, 10 (18.9%) objective partial responses were achieved (95% confidence interval 8.33% to 29.4%). Twenty-two (42%) patients had stable disease and 15 (28%) had progressive disease. The median response time was 3 months (range 1.5-7.0) and the median time to tumor progression was 6.5 months (range 3.5-15.5). Median overall survival time was 8 months (range 1.0-15.5) and 1-year survival was 34.8%. Pain improvement during treatment was observed in 23 of 43 (53%) patients, and eight of 18 (44%) patients who had been receiving opioids discontinued their use. Weight gain was observed in 12 of 33 (36%) patients. Grade 3 anemia occurred in five (9%) patients and grade 3-4 thrombocytopenia occurred in three (6%). Grade 3-4 neutropenia occurred in 13 (25%) and five (9%) patients, respectively, and two (4%) developed febrile neutropenia. Non-hematological toxicity was mild. CONCLUSION: In patients with pancreatic cancer, the combination of GEM with CAP is an active and well tolerated regimen that merits further evaluation in prospective randomized studies.     

Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study

OBJECTIVE: Patients with advanced biliary tract cancers have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of gemcitabine as a single agent in the treatment of patients with unresectable biliary tract cancers. METHODS: From May 2002 to April 2004, 23 chemotherapy-na?ve patients with locally advanced or metastatic biliary tract adenocarcinomas were enrolled. The median age was 59 years (range 37-76). Fifteen patients (65.2%) had cholangiocarcinomas and eight (34.8%) had gallbladder adenocarcinomas. Patients received gemcitabine 1000 mg/m(2) over 60 min once a week for 2 weeks followed by a week off therapy. Treatment was discontinued when unacceptable toxicities occurred or there was evidence of disease progression. RESULTS: A total of 110 cycles of chemotherapy were performed with a median of four cycles (range 1-10). The median follow-up was 13.4 months. Among the 23 patients, six (26.1%) had a partial response, eight (34.8%) had stable disease and nine (39.1%) had disease progression despite treatment. The overall response rate was 26.1% [95% confidence interval (CI) 22.08-30.12]. The median time to disease progression was 8.1 months (95% CI 3.33-12.87) and the median overall survival was 13.1 months (95% CI 1.64-24.56). Toxicities were generally mild and treatment was well tolerated. Of the 23 patients, one patient experienced a grade 3-4 neutropenia and one a grade 3-4 thrombocytopenia; however, no cases of febrile neutropenia or treatment-related deaths were noted. CONCLUSION: In this phase II trial, therapy with gemcitabine was well tolerated and clinically active in patients with locally advanced or metastatic biliary tract cancers.     

A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer

Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients with histologically confirmed unresectable or metastatic AGC were treated with capecitabine 825 mg m(-2) p.o. twice daily on days 1-14 and paclitaxel 175 mg m(-2) i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Between June 2002 and May 2004, 45 patients, of median age 57 years (range=38-73 years), were treated with the combination of capecitabine and paclitaxel. After a median 6 cycles (range=1-9 cycles) of chemotherapy, 43 were evaluable for toxicity and response. A total of 2 patients showed complete response and 20 showed partial response making the overall response rate 48.9% (95% CI=30.3-63.5%). After a median follow-up of 42.2 months (range=31.2-54.3 months), median time to progression was 5.6 months (95% CI=3.9-7.2 months) and median overall survival was 11.3 months (95% CI=8.1-14.4 months). Grade 3 or 4 adverse events include neutropaenia (46.5% of patients), hand-foot syndrome (9.3%), arthralgia (9.3%), and asthenia (4.7%). There was no neutropaenic fever or treatment-related deaths. Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC.     

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.     

Phase II trial of cisplatin and gemcitabine in patients with advanced gastric cancer.

BACKGROUND: This phase II study was performed to determine the efficacy and toxicity of cisplatin and gemcitabine in patients with advanced gastric cancer. PATIENTS AND METHODS: Forty chemo-na?ve patients with measurable locoregionally advanced or metastatic gastric cancer were included; the median patient age was 53 years (range 35-71). Cisplatin was administered at a dose of 50 mg/m2, given in 1 h intravenously (i.v.) on days 1 and 8, followed after 24 h by gemcitabine at a dose of 800 mg/m2 given in 30 min i.v. on days 2, 9 and 16, every 28 days. RESULTS: A median number of four therapy cycles were given (range 2-8). Myelosuppresion was the most important toxicity. Grade 3-4 thrombopenia was observed in 19 patients (48%) and grade 3-4 leukopenia was observed in 23 (58%). Myelotoxicity was cumulative and caused omission of gemcitabine on day 16 in 55% of cycles. Non-haematological toxicity consisted mainly of grade 1-2 nausea and vomiting. Objective responses were observed in 30% of patients including two complete remissions and 10 partial remissions. Median survival was 11 months (range 3-27+). CONCLUSIONS: This cisplatin-gemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity. Further studies with this combination may be warranted.     

A phase II study of capecitabine and docetaxel combination chemotherapy in patients with advanced gastric cancer

Capecitabine and docetaxel have considerable single-agent activity in gastric cancer with distinct mechanisms of action and no overlap of key toxicities. A synergistic interaction between these two drugs is mediated by taxane-induced upregulation of thymidine phosphorylase. We investigated the activity and the feasibility of capecitabine and docetaxel combination chemotherapy in patients with previously untreated advanced gastric cancer (AGC). From September 2001 to March 2003, 42 patients with AGC received 21-day cycles of oral capecitabine (1250 mg x m(-2) twice daily on days 1-14) and docetaxel (75 mg x m(-2) i.v. on day 1). The patients received a total of 164 cycles of chemotherapy. The median age was 53.5 years (range 33-73 years). The overall response rate in the 38 efficacy-evaluable patients was 60% (95% confidence interval, 45-74%). The median progression-free survival was 5.2 months (range, 1.0-15.5+ months) and the median overall survival was 10.5 months (range, 2.9-23.7+ months). The most common grade 3/4 adverse events were hand-foot syndrome (HFS: G3 50%), neutropenia (15%) and leucopenia (12%). Further studies of this combination are clearly warranted, albeit with lower doses of both agents (1000 mg x m(-2) twice daily and 60 mg x m(-2)) to reduce the rate of HFS and onycholysis.     

Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial.

BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. RESULTS: The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.     

吉西他滨联合卡培他滨治疗耐药性乳腺癌近期疗效观察

目的：对蒽环类和（或）紫杉类耐药性乳腺癌尚无标准解救方案.本研究探讨既往接受过蒽环类和或紫杉类药物治疗失败的晚期乳腺癌患者,使用吉西他滨联合卡培他滨方案治疗的疗效和不良反应.方法：23例患者入选,均给予吉西他滨1000mg/m2,静脉滴注,第1、8天;卡培他滨2000mg/m2,分2次口服,第1-14天;每3周为1周期,至少应用2周期,评价临床疗效和不良反应,并进行随访.结果：23例患者中完全缓解1例,部分缓解11例,总有效率52.2%.主要不良反应为骨髓毒性及手足综合症,均较轻.结论：吉西他滨联合卡培他滨方案治疗蒽环类和（或）紫杉类耐药晚期乳腺癌有较好的近期疗效,不良反应小,值得临床选择应用.     

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer

Purpose: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer.

Methods: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000?mg/m² on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety.

Results: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3–4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months.

Conclusions: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.     

A phase II study of capecitabine plus 3-weekly oxaliplatin as first-line therapy for patients with advanced gastric cancer

Capecitabine plus oxaliplatin every 3 weeks (XELOX regimen) has proven efficacy in patients with colorectal carcinoma. We investigated this combination in patients with previously untreated advanced gastric carcinoma. The study population comprised patients with histologically confirmed nonresectable advanced gastric adenocarcinoma. Patients received intravenous oxaliplatin 130 mg m(-2) over 2 h on day 1 plus oral capecitabine 1000 mg m(-2) twice daily on days 1-14, every 3 weeks. Patients received a maximum of eight cycles. Twenty evaluable patients (17 men, 3 women) with a median age of 64 years (range 38-75) were enrolled. The overall response rate was 65% (95% confidence interval (CI), 44-86%), with complete responses in two patients and partial responses in 11 patients. Median progression-free survival was 7.5 months (95% CI, 3.2-11.7 months); median overall survival was not reached during the study period. There was no grade 4 and little grade 3 toxicity. The most common haematological adverse event was anaemia (65% of patients) and the most common nonhaematological toxicities were vomiting (65%), neuropathy (60%), diarrhoea (30%), and hand-foot syndrome (20%). In conclusion, XELOX is apparently as effective as triplet combinations and is well tolerated as first-line therapy for advanced gastric carcinoma. We are starting a large multi-institutional phase II study of XELOX in this setting.     

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas

Background:

This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy.

Methods:

Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m⁻² and cisplatin 25 mg m⁻² on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m⁻², cisplatin 20 mg m⁻² and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome.

Results:

A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes.

Conclusion:

The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.     

Phase II clinical trial of capecitabine and gemcitabine chemotherapy in patients with metastatic renal carcinoma

We report a single institution phase II study of gemcitabine 1200 mg m(-2) i.v. on days 1 and 8 and capecitabine 1300 mg m(-2) twice daily on days 1-14 of each 3-week cycle in patients with metastatic renal carcinoma. Patients had a WHO performance status of 0, 1 or 2. Of the 21 enrolled patients, 19 had received prior immunotherapy or chemoimmunotherapy. All had progressive disease at study entry. In all,19 patients had multiple sites of disease. The median duration of metastatic disease was 12.3 months (range 1.2-78.1 months). Three of the 19 evaluable patients achieved a partial response to treatment, with no complete responses, producing an objective overall response rate of 15.8% (95% CI, 3.4-39.6%). The median time to disease progression was 7.6 months, and median overall survival was 14.2 months. Treatment was reasonably well-tolerated, neutropenia being the most frequently observed grade 3 or 4 toxicity, occurring in 57% of patients. Other side effects were consistent with the established toxicity profile of the two drugs, including diarrhoea, palmar-plantar erythema, fatigue, nausea, vomiting and infection. This combination of gemcitabine and capecitabine has modest activity in immunotherapy-refractory metastatic renal carcinoma with manageable toxicity.