多西他赛联合奥沙利铂和5-氟尿嘧啶方案治疗晚期胃癌41例

目的:观察多西他赛联合奥沙利铂和5-氟尿嘧啶(5-Fu)方案治疗晚期胃癌的近期疗效、毒副反应及生存状况。方法:收集2004-2010年我院41例晚期胃癌患者,多西他赛75 mg.m-2(d 1);奥沙利铂130 mg.m-2(d 2);5-Fu 400～500 mg.m-2.d-1,[d 2～d 5或持续泵入96 h(civ 96 h)],每21 d重复1次,至少2个周期。结果:总缓解率(ORR)为26.8%,疾病控制率(DCR)为78.0%。中位无进展生存期(PFS)为5.6个月(95%CI:3.52～7.6),中位总生存(OS)为12.3个月(95%CI:2.7～21.9)。1年生存率为46.3%(19/41);2年生存率为21.9%(9/41);3年生存率为7.3%(3/41)。常见的毒副反应为骨髓抑制(主要为白细胞及中性粒细胞减少)、胃肠道反应(恶心和呕吐)、腹泻和脱发等。结论:多西他赛联合奥沙利铂和5-FU方案治疗晚期胃癌疗效显著,毒副反应可耐受。化疗近期疗效是晚期胃癌PFS和OS的独立预后因素[危害比(HR):3.6;95%CI:1.8～7.3]。     

Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404

Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-na?ve patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3-43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial.     

Feasibility of gemcitabine and oxaliplatin in patients with advanced biliary tract carcinoma and a performance status of 2

The use of gemcitabine and oxaliplatin is well documented in selected patients with advanced biliary tract carcinoma (BTC), but little is known on the feasibility of systemic treatments in patients with a performance status (PS) of 2. We retrospectively examined the medical records of consecutive BTC patients with a PS of 2 receiving gemcitabine 1000 mg/m(2) plus oxaliplatin 100 mg/m(2) every 2 weeks from January 2003 to December 2011 in our institution. Body composition was analysed by computed tomography scan to detect sarcopenia. The primary evaluation criterion was safety. The secondary evaluation criteria were the response rate, progression-free survival (PFS) and overall survival (OS). Twenty-eight patients (median age: 63 years, range 41-83) received a total of 175 cycles (median per patient: 6, range 2-12). Ten patients (35.7%) had sarcopenia on the pretreatment computed tomography scan. The most frequent toxicities were thrombocytopenia (grades 2-4: n=4, 14.3%), peripheral neuropathy (grades 2-3: n=9, 32.1%) and cholangitis (n=4, 14.3%). The best response was a partial response in 10.7% of patients [95% confidence interval (CI): 0-22.2] and stable disease in 42.9% of patients. The median PFS and OS were 4.6 (95% CI: 2.5-6.3) and 7.5 (95% CI: 5.2-9.5) months, respectively. The median PFS and OS were significantly longer in patients without sarcopenia: 7.0 months (95% CI: 4.4-8.0) vs. 2.2 months (95% CI: 2.0-2.5), P less than 0.01, and 10.4 months (95% CI: 7.5-11.6) vs. 4.9 months (95% CI: 3.7-5.2), P less than 0.01, respectively. In our experience, gemcitabine-oxaliplatin was feasible and induced effective palliation in PS2 patients with advanced BTC. Further studies are warranted to confirm these findings.     

Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma

Metastatic melanoma carries a dismal prognosis and there is a need to develop new treatment strategies. Vinca alkaloids have shown consistent activity in melanoma patients, as monotherapy and as part of combination regimens. The current study evaluates the clinical activity and tolerability of vinorelbine as first-line monotherapy in patients with metastatic melanoma. Patients were eligible if they presented metastatic melanoma not amenable to curative resection, had received no prior systemic therapy for advanced disease and had an adequate performance status (ECOG 0-1). Patients received vinorelbine at a dose of 30 mg/m2 on days 1 and 8 of a 21-day cycle, on an outpatient basis. Thirteen patients were accrued into the study and received 64 cycles. All patients were assessable for response, toxicity and survival. No objective responses were documented, for an overall response rate of 0% [95% confidence interval (CI) 0-19%] and the trial was terminated in accordance to the predetermined early discontinuation rule. The median progression-free survival was 3.3 months (95% CI 2.3-4.3 months) and the estimated median overall survival was 8.1 months (95% CI 6.0-10.2 months). No life-threatening toxicities occurred. Neutropenia was the main hematologic toxicity, but none of the three episodes of grade 3-4 neutropenia were complicated by infection. The most common non-hematologic toxicities were asthenia, nausea, neuropathy and myalgia. We conclude that vinorelbine as a single agent on days 1 and 8 of a 21-day cycle has a favorable toxicity profile, but appears to have no relevant clinical activity in patients with metastatic melanoma.     

Phase II trial of biweekly pegylated liposomal doxorubicin in recurrent platinum-refractory ovarian and peritoneal cancer

Pegylated liposomal doxorubicin (PLD) is active in recurrent platinum-refractory ovarian and peritoneal cancer as demonstrated in a prospective-randomized trial. Dose-limiting toxicity in the US Food and Drug Administration-approved application schedule of PLD (50 mg/m2 every 4 weeks) was serious palmar-plantar erythrodysaesthesia (PPE). This phase II trial was aimed at reduction of the frequency of serious PPE without loss of efficacy by modifying both the application schedule and the total dose of PLD administered as palliative single-agent chemotherapy. Fifty patients were enrolled into this phase II trial. PLD was given via 30-min intravenous infusion at a dose of 20 mg/m2 every 2 weeks. Primary endpoint of the trial was the best response to chemotherapy. Secondary goals were progression-free survival, overall survival, and toxicity. Four complete responses and 16 partial responses were found resulting in an overall best response rate of 40.0%. The median progression-free survival in the intention-to-treat-population was 4.1 months [95% confidence interval (CI), 2.8-5.4 months], whereas the overall survival was 16.5 months (95% CI, 12.3-20.7 months). Although 17 (34.0%) patients developed some PPE, only one progressed to grade 3 (NCI-CTC version 2.0; 1998). No grade 4 toxicity occurred. PLD 20 mg/m2 biweekly is highly active in patients with recurrent platinum-refractory ovarian and peritoneal cancer. The frequency of grade 3 and grade 4 PPE was remarkably reduced in this trial, as compared with the frequency of serious PPE observed in patients who were administered the dose schedule of 50 mg/m2 every 4 weeks.     

Phase II study of gemcitabine plus cisplatin in metastatic breast cancer

Our objectives were to assess the efficacy and toxicity of gemcitabine plus cisplatin as first-line therapy in metastatic breast cancer (MBC). Patients with stage IV MBC and no prior chemotherapy for metastatic disease were treated with gemcitabine 1200 mg/m on days 1 and 8, and cisplatin 75 mg/m on day 1 every 21 days. Up to 6 cycles were given. A total of 46 patients with a median age of 49 years (range 24-77) and Karnofsky performance status of 80 or above were enrolled. In total, 238 cycles were administered. Of the 42 patients evaluable for response, seven (17%) achieved a complete response and 27 (64%) a partial response, for an overall response rate of 81% [95% confidence interval (CI) 69-93%]. Median time to progression was 14.9 months (95% CI 0-30.2 months). Median duration of response was 24.2 months (95% CI 11.2-37.3 months). The median survival was 27.9 months (95% CI 23.1-32.7 months), and the 1- and 2-year survival probabilities were 71.4 and 61.4%, respectively. All patients were evaluable for toxicity, and grade 3/4 WHO toxicities included neutropenia (41.3%), anemia (8.7%), thrombocytopenia (8.7%), alopecia (26.1%) and nausea/vomiting (32.6%). We conclude that gemcitabine plus cisplatin is a highly effective and safe first-line treatment for patients with MBC. The time to progression of 14.9 months compares favorably with other standard treatments (anthracyclines, taxanes). A randomized study is required to further investigate the role of this combination as first-line treatment for MBC.     

Bevacizumab and erlotinib versus bevacizumab for colorectal cancer treatment: systematic review and meta-analysis

Background Improving the survival of patients diagnosed with metastatic colorectal cancer requires the use of chemotherapy to be managed with minimum adverse effects. Randomized control trials (RCTs) have shown promising results with a combination of bevacizumab and erlotinib to block two important tumor growth pathways, namely vascular endothelial growth factor and epidermal growth factor receptor. Aim of the Review We aimed to examine the efficacy and safety of the combination of bevacizumab and erlotinib with bevacizumab alone in the maintenance treatment of metastatic colorectal cancer, by examining PFS, OS, overall response rate (ORR), and toxicity. This study performed a systematic review meta-analysis using existing randomized clinical trial. Methods Randomized controlled trials were systematically reviewed from PubMed, Cochrane library, SCOPUS, CRD, and Google scholar databases. After evaluating the quality of studies through the Cochrane checklist, data of the relevant studies were extracted. This meta-analysis included outcomes of overall survival, progression-free survival of the disease through the hazard ratio, and the upper and lower confidence intervals for the third and fourth degree side effects of relative risk. To perform the meta-analysis for both types of survival, two fixed and random effect models were used. Results A total of three trials, providing data of 682 patients who received maintenance treatment, were included in this meta-analysis. Conclusion The combination of bevacizumab and erlotinib significantly increased the overall survival compared to using bevacizumab alone [HR?=?0.78, 95% CI 0.66–0.93]. This combination, effectively increased progression-free survival [HR?=?0.81, 95% CI 0.7–0.93] too. The side effects of diarrhea and grade III rash were more frequent in the group administered bevacizumab plus erlotinib. The combination of bevacizumab and erlotinib, in the maintenance treatment of metastatic colorectal cancer, significantly improved the overall survival and progression-free survival of patients, and the resulting side effects were easily treatable.

     

Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.     

Treosulfan and gemcitabine in metastatic uveal melanoma patients: results of a multicenter feasibility study

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54-133 weeks], the progression-free survival was 28.5 weeks (95% CI 13-62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.     

Multicenter phase II study of capecitabine plus oxaliplatin as a first-line therapy in Chinese patients with advanced gastric cancer

The efficacy of chemotherapy for advanced gastric cancer with palliative intent compared with supportive care alone is now widely accepted. However, the survival advantage is small, and no internationally accepted standard regimen has emerged. This study is performed to evaluate the response rate, time to progression, and safety of the combination of capecitabine (1000 mg/m twice daily, days 1-14) plus oxaliplatin (130 mg/m as a 2-h intravenous infusion on day 1) every 3 weeks, in previously untreated Chinese patients with advanced gastric cancer. Sixty-five (95.6%) of the 68 patients were assessable for response. Three cases of complete response and 34 cases of partial response were confirmed, giving an overall response rate of 54.4% [95% confidence interval (CI), 42.6-66.2%]. The median time to progression and overall survival for all patients were 5.7 months (95% CI, 2.0-8.8 months) and 10.5 months (95% CI, 5.0-15.1 months). The most severe hematologic adverse event was neutropenia, which occurred with grade 3 intensity in three (4.6%) patients and grade 4 in one (1.5%) patient. Thrombocytopenia and leukopenia occurred with grade 3 intensity in five (7.7%) and three (4.6%) patients, respectively. However, no grade 4 thrombocytopenia and leukopenia were observed. Grade 1/2 nausea/vomiting and diarrhea were observed in 33 (50.8%), 17 (26.2%), 26 (40%), 44 (67.7%), and 13 (20%) patients, respectively, and grade 3 nausea/vomiting and diarrhea were observed in one (1.5%) and four (6.2%) patients. Yet, no grade 4 nonhematologic toxicity was observed. Capecitabine/oxaliplatin combination chemotherapy is active in Chinese patients with previously untreated advanced gastric cancer.     

Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: a retrospective,single-institution study

Background Prior to the 2008 advent of sorafenib, traditional cytotoxic agents were the therapeutic mainstay for patients with advanced hepatocellular carcinoma (HCC). We thus undertook a clinical study of sorafinib and conventional cytotoxic therapy for HCC, comparing efficacy and safety. Methods From January, 2002 to December, 2009, 173 patients with unresectable HCC were reviewed retrospectively. Among them, 44 (25.4%) had been treated with sorafenib, and the remainder had received cytotoxic therapy (CTX). We evaluated objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity profiles. Results Median OS of sorafinib was 23.0 weeks (95% CI, 8.1–37.9) vs 43.6 weeks (95% CI, 34.0–53.2) for CTX. Likewise, median PFS was 11.1 weeks (95% CI, 6.5–15.8) vs 12.4 weeks (95% CI, 8.1–16.7) for sorafenib and CTX, respectively. Neither parameter differed significantly (OS, p = 0.105; PFS, p = 0.496). ORR and disease control rate for sorafenib were 2.3% and 52.3% vs 6.2% and 43.4% for CTX. CTX-treated patients experienced more Grade 3/4 neutropenia (19.7% vs 0% for sorafenib), while sorafenib therapy was more often linked to dermatologic toxicities (all grades), such as hand-foot skin reaction, rash, and pruritus. Conclusion Although sorafenib has become the treatment of choice for advanced HCC, there are still unsettled issues regarding the optimal use of sorafenib. Our analysis indicates that conventional CTX can be another option of treatment for advanced HCC. To improve clinical outcomes, further prospective investigations which define the role of CTX are needed.     

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.     

Docetaxel plus fractionated cisplatin is a safe and active schedule as first-line treatment of patients with advanced non-small cell lung cancer: Results of a phase II study

This phase II trial evaluated the efficacy and safety of docetaxel 85 mg/m(2) (day 1) and cisplatin 80 mg/m(2) (administered as 40 mg/m(2) doses each on days 1 and 2) every 3 weeks as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Forty-two NSCLC patients were enrolled, most of them with stage IV disease (74%). A total of 195 chemotherapy cycles were administered (median 6, range 1-6). All patients were considered evaluable for efficacy and toxicity in an intention-to-treat (ITT) analysis. The overall response rate was 48% (95% CI, 33-64), including one CR (3%) and 19 PRs (45%). Stable disease was found in 6 patients (14%). The median time to disease progression was 4.9 months (95% CI, 4.0-5.7) and the median overall survival was 10.5 months (95% CI, 5.1-16.0). The survival rates at 1 and 2 years were 36.0% (95% CI, 19.9-52.0) and 18.0% (95% CI, 3.9-32.1), respectively. Overall, the combination showed an excellent safety profile. Severe hematological toxicities were uncommon: neutropenia (5% of patients, 1% of cycles) and febrile neutropenia (2% of patients, 0.5% of cycles). Asthenia (12%) was the only grade 3/4 non-hematological toxicity that affected more than 10% of patients. There were no toxic deaths. In conclusion, docetaxel plus fractionated cisplatin as first-line treatment of advanced NSCLC patients showed similar efficacy as the same combination with higher doses of docetaxel but where cisplatin was administered in a single dose. This new schedule shows promise in its excellent hematological and non-hematological toxicity profile. A randomized phase III trial is needed to confirm these results.     

Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis

BackgroundProgrammed death-ligand-1 (PD-L1) is a well-known predictive biomarker in non-small cell lung cancer (NSCLC) patients, however, its accuracy remains controversial. Here, we investigated the correlation between PD-L1 expression level and efficacy of its inhibitors, and hence assessed the predictive effect of PD-L1 expression.MethodsStudies that evaluated the efficacy of programmed death-1 (PD-1)/ PD-L1 inhibitors in advanced NSCLC patients according to tumor PD-L1 expression levels were searched for on Medline, Cochrane Library, and Embase. The pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated for the objective response rate (ORR) with overall survival (OS) and progression-free survival (PFS) were measured in terms of hazard ratio (HR) and the corresponding 95% CIs.Results1432 NSCLC patients from six randomized controlled trials (RCTs) were included and three PD-1/PD-L1 inhibitors (atezolizumab, nivolumab, and pembrolizumab) were used to treat the patients. A significantly higher ORR was observed in the high PD-L1 expression group compared to the low expression group (0.35 [95% CI, 0.30–0.40] vs 0.11 [95% CI, 0.09–0.14]). The results of the subgroup analysis, grouped by the type of drugs and antibodies which assess immune checkpoint inhibitors were identical with the pooled result. However, our study showed that PD-L1 expression was neither prognostic nor predictive of overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1/PD-L1 inhibitors compared to chemotherapy.ConclusionsPD-L1 can be a predictive biomarker for ORR. Nevertheless, PD-L1 expression is not a good predictive tool for OS and PFS.     

Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.     

Phase II study of irinotecan (CPT-11) administered every 2 weeks as treatment for patients with colorectal cancer resistant to previous treatment with 5-fluorouracil-based therapies: comparison of two different dose schedules (250 and 200 mg/m2) according to toxicity prognostic factors

Our objective was to assess the antitumoral activity and toxicity of irinotecan (CPT-11) 60-min i.v. infusion every 2 weeks as second-line monotherapy of advanced colorectal cancer. Two doses were studied (250 and 200 mg/m) according to the risk of developing toxicity. Two groups of patients were studied: high-risk group (HR, 200 mg/m, n = 45; Karnofsky score 60-80% and/or the record of prior pelvic irradiation) and low-risk-group (LR, 250 mg/m, n = 51; Karnofsky score >80% and without prior pelvic irradiation). The mean number of cycles per patient was 7: 6.6 (HR group) and 8.3 (LR group). Median RDI was 0.96. The overall response rate was 8.9% [95% confidence interval (CI) 2.5-21.2%; HR group] and 15.7% (95% CI 7.0-28.5%; LR group), respectively. The LR group showed two complete responses and a higher percentage of stable disease (56.9 versus 33.3% in HR group). The median survival was 7.1 months (95% CI 5.2-8.9 months, HR group) and 11.7 months (95% CI 8.4-15.1 months, LR group). The median time to disease progression was 3.2 months (95% CI 1.0-5.4 months, HR group) and 5.3 months (95% CI 3.8-6.7 months, LR group). Both CPT-11 treatments were well tolerated. Grade 3/4 toxicity incidence was low, e.g. granulocytopenia (7% of patients in HR group and 9% in LR group) and delayed diarrhea (18% of patients in HR group and 14% in LR group). We conclude that the treatment of patients with the adjusted dose of CPT-11 according to prognostic factors for toxicity resulted in the improved toxicity profile, but showed poorer efficacy outcome. Therefore, the dose reduction in patients with low performance and treated with radiotherapy needs further investigation to provide some new insights on the benefit:risk ratio of such treatment.     

Single-agent trastuzumab versus trastuzumab plus cytotoxic chemotherapy in metastatic breast cancer: a single-institution experience

Trastuzumab has shown significant single-agent activity in patients with Her-2/neu overexpressing metastatic breast cancer, and increased response rates, progression-free and overall survival when added to standard chemotherapy. Despite higher response rates, the combination with chemotherapy has higher toxicity and it remains unknown whether single-agent trastuzumab is equally effective as the combined treatment in terms of progression-free and overall survival. We therefore carried out a retrospective multivariate analysis of 117 patients with Her-2/neu overexpressing metastatic breast cancer who were treated with trastuzumab with or without chemotherapy at a single institution between November 1999 and December 2003. Response rates tended to be higher in patients receiving trastuzumab in combination with chemotherapy (34 versus 8%, p=0.060). However, this did not translate into a benefit in progression-free survival: median (95% confidence interval) progression-free survival was 6.2 (4.45-7.95) months in patients receiving trastuzumab plus chemotherapy versus 4.2 (1.77-6.63) months in those receiving single-agent trastuzumab (p=0.560). Likewise, no significant difference in overall survival was observed: 27.0 (19.9-34.0) versus 23.1 (16.2-30.0) months (p=0.809). We conclude that in the absence of extensive visceral involvement necessitating a higher response rate, single-agent trastuzumab may be a safe and less-toxic alternative to its combined use with other chemotherapy agents. This needs to be confirmed in prospective randomized trials.     

Efficacy and safety of doublet versus single agent as salvage treatment for metastatic breast cancer pretreated with anthracyclines and taxanes: a systematic review and meta-analysis

Aim: To perform a systematic review and meta-analysis of randomized controlled trials to compare the efficacy and safety of doublet versus single agent as salvage treatment for pretreated metastatic breast cancer.

Methods: A comprehensive literature search was performed to identify relevant randomized controlled trials (RCTs). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0).

Results: Thirteen RCTs involving 4878 pretreated metastatic breast cancer patients were ultimately identified. The pooled results demonstrated that doublet combination therapy significantly improved ORR (RR 1.13, 95% CI: 1.01–1.27, p?<?.001) and PFS (hazard ration [HR] 0.83, 95% CI: 0.73–0.96, p?=?.011), but not OS (HR 0.93, 95% CI: 0.86–1.01, p?=?.065). Similar results were observed in sub-group analysis according to treatment regimens. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities nausea and fatigue were observed in doublet combination therapy.

Conclusions: In comparison with a single agent alone, doublet combination therapy as salvage treatment for pretreated metastatic breast cancer patients significantly improves ORR and PFS, but not OS. Further studies are recommended to identify patients who will most likely benefit from the appropriate doublet combination therapy.     

Biweekly docetaxel as second-line chemotherapy of patients with advanced non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 006-00)

This phase II trial assessed the antitumoral activity and toxicity of docetaxel 50 mg/m (1-h i.v. infusion) administered every 2 weeks as second-line treatment in 45 patients with advanced non-small cell lung cancer (NSCLC). A total of 251 infusions (median 4 per patient) were administered. The actual and relative median dose intensity values were 24.2 mg/m/week and 0.97, respectively. Thirty-seven patients were evaluable for tumor response. The overall response rate was 20% [95% confidence interval (CI) 8-32%] and included one complete response (2%) and eight partial responses (18%). Stable disease was found in seven patients (16%). With a median follow-up of 4 months, the median time to disease progression was 2.8 months (95% CI 1.9-3.7), the median overall survival was 4.0 months (95% CI 3.4-4.6) and the 1-year survival rate was 23% (95% CI 9-37). The every-2-weeks docetaxel schedule was well tolerated. Grade 3/4 non-hematological toxicities showed rates of 5% or less of patients and 2% or less of cycles. The main grade 3/4 hematological toxicity was neutropenia (16% of patients and 8% of cycles). No febrile neutropenia was found. Nevertheless, one toxic death was reported. We conclude that the biweekly docetaxel schedule showed an antitumoral activity similar to that found with the every-3-weeks or weekly docetaxel schedule in a second-line setting for advanced NSCLC. This antitumoral effect was associated with a marked reduction in hematological toxicity, therefore suggesting that this new docetaxel schedule might be useful in the design of combined second-line schedules for treating NSCLC.     

Biweekly administration of docetaxel and vinorelbine as second-line chemotherapy for patients with stage IIIB and IV non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 013-02)

The current report aims to evaluate the efficacy and safety profile of a biweekly administration of docetaxel and vinorelbine to patients with advanced non-small cell lung cancer, who had previously been treated for this disease. In a prospective, multicenter, open-label, phase II trial, patients received 40 mg/m of docetaxel and 20 mg/m of vinorelbine on days 1 and 15, every 28 days. Treatment continued for up to a maximum of six cycles, unless disease progression or unacceptable toxicity occurred, or consent was withdrawn. Fifty patients were enrolled in the study and they received 174 cycles of chemotherapy, with a median of three cycles per patient. All patients were evaluated for efficacy and toxicity in an intention-to-treat analysis. The overall response rate was 10% [95% confidence interval (CI): 1-19], including one complete response (2%) and four partial responses (8%). Previous chemotherapy of 80% of the responders included paclitaxel. Median time to disease progression was 2.7 months (95% CI: 2.2-4.3) and median overall survival was 6.5 months (95% CI: 2.5-9.2). The survival rates at 1 and 2 years were 18% (95% CI: 7-29) and 4% (95% CI: 0-10), respectively. The most frequent severe toxicities were neutropenia (20% of patients) and leukopenia (8% of patients). Other toxicities appeared in 4% or fewer of the patients. Biweekly administration of docetaxel and vinorelbine is feasible as a second-line treatment for non-small cell lung cancer patients, but its level of activity and toxicity does not suggest any advantage compared with the results obtained with single-agent docetaxel in the same setting.