A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer

Purpose   The aim of this study is to investigate the efficacy and safety of gemcitabine and oxaliplatin combination chemotherapy as first-line therapy in patients with inoperable biliary tract cancer (BTC). Methods   The treatment of this non-randomized phase II study consisted of gemcitabine 1,000 mg/m² intravenously (i.v.) on day 1 and oxaliplatin 85 mg/m² i.v. on day 2 every 2 weeks until disease progression, unaccep toxicity or patients’ refusal. Results   From Sept 2006 to Oct 2007, 40 patients were enrolled. In the ITT analysis, the objective response rate was 15.0% and the disease control rate was 52.5%. The median overall survival (95% CI) was 8.5 months (6.4–10.7) and the time to progression was 4.2 months (0.5–7.9). For the 305 cycles, observed grade 3/4 toxicity was uncommon. Conclusions  Gemcitabine and dose adjusted oxaliplatin combination chemotherapy had moderate anti-tumor activity and was well tolerated as a first-line treatment for patients with inoperable BTC.     

如何优化吉西他滨在晚期胆系肿瘤中的应用

胆系肿瘤（BTC）主要包括胆囊癌、肝内胆管癌和肝外胆管癌,其中前两种近年来发病率不断攀升,仅有约10％的患者有根治性切除的机会。对于晚期胆系肿瘤,吉西他滨联合顺铂是目前一线治疗的“金标准”,但越来越多的临床实践发现以吉西他滨为主的其他联合方式或许疗效更优。如何优化吉西他滨的疗效已经成为胆系肿瘤一线治疗的热点和焦点,本文拟对该领域作一综述。     

Cetuximab,gemcitabine and capecitabine in patients with inoperable biliary tract cancer: A phase 2 study

PurposeBiliary tract cancer is rare and has dismal prognosis. Chemotherapy has its role in inoperable disease but the role of targeted agents like cetuximab remains to be defined. On the basis of high epidermal growth factor receptor expression of biliary tract cancers this study aims to investigate the efficacy of cetuximab, gemcitabine and capecitabine in an exploratory phase 2 trial.Patients and methodsInoperable biliary tract cancer patients were treated with the combination of gemcitabine (1000 mg/m² on day 1 and 8), capecitabine (1300 mg/m²/d on day 1–14) and weekly cetuximab (400 mg/m² loading and 250 mg/m² maintenance dose) in 21-d cycles until progression or the appearance of intolerable side-effects.ResultsOut of 34 patients (mean age 59.7 years) accrued in this study 16 had intrahepatic, eight extrahepatic cholangiocarcinoma and 10 gall bladder cancer. The best overall response rate was 17.6% (two complete responses and four partial responses) and the clinical benefit rate was 76.5%. After a median of 15.4 months follow-up the median progression free survival was 34.3 weeks and the median overall survival was 62.8 weeks. The performance status and chemotherapy efficacy were independent and significant markers of survival. Only moderate side-effects were registered in this study. KRAS mutation was evaluable in 24 tumours, all of these were of wild type.ConclusionThe efficacy of cetuximab, gemcitabine and capecitabine combination is encouraging and a well tolerated treatment of inoperable biliary tract cancers.     

Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer

Purpose To evaluate the efficacy and safety of gemcitabine in combination with carboplatin at standard rate or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods In this prospective study, patients with chemonaive advanced NSCLC were randomized to receive gemcitabine at a standard rate (gemcitabine 1,200 mg/m² over 30 min, the standard arm) or a fixed dose rate (gemcitabine 1,200 mg/m² over 120 min, the FDR arm) on days 1 and 8 every 3 week cycle. In both treatment arms, carboplatin at AUC of 5 was administered over 4 h following gemcitabine on day 1 of each cycle. Results From November 2003 to June 2005, a total of 42 patients, in which 7 (17%) patients had stage III_B disease and 35 (83%) had stage IV disease, were enrolled into this study. All patients were included in efficacy and toxicity assessment. No patient had a complete response. Seven (33%) patients in the standard arm and 10 (48%) in the FDR arm had a partial response. The median time to progression and median overall survival time in the standard arm was 5.4 months (95% CI, 3.8–7 months) and 11.5 months (95% CI, 8.2–14.8 months), respectively, while in the FDR arm was 6.5 (95% CI, 4.4–8.6 months) months, 12.0 months (95% CI, 11.3–12.7 months), respectively. The most frequently reported grade 3 or 4 hematological toxicities were thrombocytopenia (38% patients in the standard arm and 43% in the FDR arm) and neutropenia (24% in the standard arm and 33% in the FDR arm). Although hematological toxicity occurred in a little higher percent of patients in the FDR arm than in the standard arm, there were no discernible differences by statistical analysis in both treatment arms (P > 0.05). And significant nonhematologic toxicities were infrequent and tolerable in both arms. No significant difference existed also (P > 0.05). Conclusion In this phase II study, gemcitabine in combination with carboplatin either at standard rate or fixed dose rate infusion was clinically effective and well tolerated in patients with advanced NSCLC.     

S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study

A pilot phase II study showed S-1 monotherapy to be safe and active against biliary tract cancer (BTC). We, therefore, conducted a multicenter phase II study to evaluate the antitumor effect and safety of S-1 in previously untreated patients with advanced BTC. Eligible patients had pathologically proven, unresectable adenocarcinoma with no prior chemotherapy or radiotherapy. Patients received S-1 orally at 80 mg/m2 total daily dose divided b.i.d. for 28 days followed by 14 days of rest. Of the 41 enrolled patients, 40 were assessable. The primary tumor sites were as follows: gallbladder (n = 20), extrahepatic bile duct (n = 15), and the ampulla of Vater (n = 5). One patient (2.5%) achieved a complete response, 13 patients (32.5%) had partial responses, 17 patients (42.5%) had no change, 7 patients (17.5%) had progressive disease, and 2 patients (5.0%) were not evaluable. The overall objective response rate was 35.0%. The median overall survival (median OS) was 9.4 months, and the median time to progression was 3.7 months. Grade 3 or 4 toxicities included fatigue (7.5%), anorexia (7.5%) and T-Bil elevation (7.5%). Significant antitumor activity combined with a mild toxicity profile was observed. This monotherapy warrants further evaluation in a randomized study.     

奥沙利铂联合吉西他滨治疗晚期胆道系统肿瘤的临床观察

目的 观察奥沙利铂联合吉西他滨治疗晚期胆道系统肿瘤的疗效及不良反应。方法 收集2008年1月至2011年3月均经影像和病理组织学确诊的晚期胆道系统肿瘤38例,具体用药方案：奥沙利铂85mg/m²静滴2h,d₁;吉西他滨835 mg/m2静滴30min,d_¹、d₈,21天为1周期。化疗2个周期评价疗效,并记录不良反应。结果 38例均可评价疗效,获CR 1例,PR 7例,有效率（RR）为21.1%(8/38)。主要不良反应包括骨髓抑制、外周神经毒性及恶心呕吐,均未出现重度不良反应。结论 奥沙利铂联合吉西他滨治疗晚期胆道系统肿瘤患者的近期疗效较好,不良反应可以耐受,值得深入研究。     

Phase II study of single-agent gemcitabine in heavily pretreated Japanese patients with recurrent ovarian cancer

BACKGROUND: Gemcitabine has been recommended as an active agent for salvage chemotherapy in patients with recurrent epithelial ovarian cancer, but no clinical study of this agent has been conducted for Japanese women with ovarian cancer. To evaluate the efficacy and feasibility of gemcitabine for heavily pretreated Japanese patients with recurrent epithelial ovarian cancer, we conducted a single-institute phase II clinical trial. METHODS: All patients had received a minimum of two previous chemotherapy regimens, In this study, gemcitabine was administered at 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 28 patients participated in this study. Although 5 patients (17.9%) needed dose reduction to 800 mg/m(2) because of thrombocytopenia and granulocytopenia, all patients completed an average of 6.7 courses (range, 2-24 courses). The overall response rate, including five partial responses, was 17.9% (95% confidence interval [C I], 6.0-36.9). The median time to progression was 8.8 months and the median survival period was 11.2 months. Grade 3/4 hematological toxicities included leucopenia, 35.7%; granulocytopenia, 39.3%; anemia, 46.4%; and thrombocytopenia, 10.7%. However, no grade 3/4 nonhematological toxicity was observed. The mean delay in treatment was 5.0 +/- 7.7 days (range, 0-15 days) in a total of 562 cycles. CONCLUSION: Single-agent gemcitabine is an effective salvage chemotherapy regimen in heavily pretreated Japanese patients with recurrent epithelial ovarian cancer.     

Phase II study of S-1 in patients with advanced biliary tract cancer

The aim of this study was to investigate the efficacy and safety of an oral fluoropyrimidine derivative, S-1, in patients with advanced biliary tract cancer. Patients with pathologically confirmed advanced biliary tract cancer, a measurable lesion, and no history of radiotherapy or chemotherapy were enrolled. S-1 was administered orally (40 mg m(-2) b.i.d.) for 28 days, followed by a 14-day rest period. A pharmacokinetic study was performed on day 1 in the initial eight patients. In all, 19 consecutive eligible patients were enrolled in the study between July 2000 and January 2002. The site of the primary tumour was the gallbladder (n=16), the extrahepatic bile ducts (n=2), and the ampulla of Vater (n=1). A median of two courses of treatment (range, 1-12) was administered. Four patients achieved a partial response, giving an overall response rate of 21.1%. The median time-to-progression and median overall survival period were 3.7 and 8.3 months, respectively. Although grade 3 anorexia and fatigue occurred in two patients each (10.5%), no grade 4 toxicities were observed. The pharmacokinetic parameters after a single oral administration of S-1 were similar to those of patients with other cancers. S-1 exhibits definite antitumour activity and is well tolerated in patients with advanced biliary tract cancer.     

Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease

IntroductionThe advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1^st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin.MethodsPatients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected.ResultsThirty-three patients of 545 screened; median age 59 years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS).ConclusionFor PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.     

Phase II study with gemcitabine, ifosfamide and cisplatin in advanced non-small cell lung cancer

The aim of the present study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine, ifosfamide and cisplatin (GIP), administered every 3 weeks, in patients with inoperable non-small cell lung cancer (NSCLC). From October 1998 to July 1999, 18 previously untreated stages IIIb (4) and IV (14) patients were enrolled into the study. Gemcitabine and ifosfamide (with mesna as uroprotection) was administered on days 1 and 6, at a dose of 1000 and 1500 mg/m², respectively; and cisplatin was given on day 1 at a dose of 60 mg/m², every 3 weeks. All 18 patients were evaluable for response and toxicity profiles. One patient achieved a complete response, and 11 patients achieved a partial response, with an overall response rate of 66.7% (95% CI, 45–89%). The main toxicity was hematological, a NCI grade 3–4 neutropenia in 16 patients (88.9%) during the treatment course. Febrile neutropenia occurred in three patients (16.6%). Grade 3 anemia occurred in eight patients (44.4%) and grade 3–4 thrombocytopenia occurred in 11 patients (61.1%). Non-hematological toxicity was mild and tolerable. No toxic death occurred. The median survival was 12.7 months and 1 year survival was 58.4%. The GIP combination chemotherapy produced a high response rate in advanced NSCLC; however, there was a relatively high percentage of hematological toxicity that still could be tolerated. A randomized trial comparing GIP to a two-drug combination of gemcitabine and cisplatin is planned.     

A phase II study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer

PURPOSE: This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles. RESULTS: A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent. CONCLUSION: The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.     

GEMOX方案一线治疗晚期转移性胆道系统肿瘤的临床观察

目的 探讨吉西他滨联合奥沙利铂（GEMOX）方案一线治疗晚期转移性胆道系统肿瘤的疗效及安全性。方法 收集2005年7月至2012年4月共49例接受GEMOX方案一线治疗的晚期胆道系统肿瘤患者,具体方案为：吉西他滨 1000mg／m2 静滴,d1、d8;奥沙利铂 100mg／m2 静滴,d2,21天为1周期,2个周期后评价疗效。结果 49例患者共接受了239个周期化疗,平均4.88个周期（2～10个周期）。49例患者均可评价疗效和毒副反应,获CR 2例（4.1％）,PR 8例（16.3％）,SD 26例（53.1％）,PD 13例（26.5％）,总有效率（RR）为20.4％,疾病控制率（DCR）为73.5％。中位疾病进展时间（mTTP）为6.0个月,中位生存时间（mOS）为11.0个月。主要毒副反应为白细胞减少、血小板减少、恶心呕吐和肝功能损害,均以1～2级为主。结论 GEMOX方案治疗晚期转移性胆道系统肿瘤疗效较好,毒副反应可耐受,值得临床进一步应用。     

Toxicity of a 24-hour infusion of gemcitabine in biliary tract and pancreatic cancer: a pilot study

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with non-small-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m². One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m².     

干扰素在胆系肿瘤治疗中的作用及其研究进展

干扰素是一种具有广泛生物活性的细胞因子,具有多方面的抗肿瘤作用。干扰素家族包括Ⅰ、Ⅱ、Ⅲ 3种类型。研究表明,Ⅰ型干扰素尤其是INF-α2b联合单药氟尿嘧啶（5-FU）或以其为基础的化疗方案对胆系肿瘤有效, 联合HELF方案（羟基喜树碱+足叶乙甙+亚叶酸钙+5-FU）对晚期胆囊癌疗效较好;Ⅱ型干扰素除有较好的免疫调节作用外,可有效抑制胆系肿瘤细胞生长和促进细胞凋亡,在与钙调素（CaM）拮抗剂、米非司酮及中药等联合运用时可增效;Ⅲ型干扰素目前仅用于病毒性疾病的治疗,但基础研究证实其抗肿瘤作用明确,值得进一步研究。本文就干扰素在胆系肿瘤治疗中的作用及其研究进展作一综述。     

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

Phase II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer

PURPOSE: To evaluate the efficacy and safety of the combination of gemcitabine at a low dose of 250 mg/m(2) in 6h prolonged infusion with cisplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-eight chemonaive patients with stage IIIB or IV NSCLC were included, 39 males and 19 females, with a median age 61 years (range 28-73). Thirty-four (58.6%) patients had adenocarcinoma, 18 (31.0%) squamous cell, and 6 (10.4%) others. Seventeen (29.3%) had stage IIIB and 41 (70.7%) stage IV. Treatment consisted of 250 mg/m(2) gemcitabine in a 6h infusion on days 1 and 8, and cisplatin at 75 mg/m(2) on day 2 of a 3-week cycle. A total of 219 chemotherapy cycles were administered, with a median of 4 cycles per patient (range 1-6). RESULTS: Of the 58 patients enrolled, all were evaluated for toxicity and 56 assessed for response. The overall response rate was 39.3% (95% confidence interval, 26.5-52.1%) with complete and partial responses of 3.6 and 35.7%, respectively. The median time to disease progression was 5.5 months (95% CI, 4.3-6.7 months), and median overall survival time was 10.5 months (95% CI, 8.5-12.5 months). One-year survival rate was 41.4%. Hematologic toxicity was fairly mild, and grades 3-4 hematologic toxicities consisted of neutropenia in 18.9% of patients, thrombocytopenia in 10.3%, and anemia in 6.9%. No patients required platelet transfusions, no bleeding episodes were recorded, and three patients received packed red blood cells (RBC) transfusions. The main nonhematologic toxicities included grade 3 nausea/vomiting in 27.6% of patients, grade 1-2 alopecia in 63.8%, and grade 1-2 skin rash in 17.3 %. CONCLUSIONS: Low-dose gemcitabine in 6h prolonged infusion plus cisplatin is effective in NSCLC treatment. Toxicity, especially myelosuppression, is remarkably mild.     

Biweekly cisplatin and gemcitabine in patients with advanced biliary tract cancer

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m²/min) and cisplatin 20 mg/m² on days 1 and 15 of every 28‐day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico‐pathologic features, toxicities, and survival. Kaplan‐Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1–27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies.     

Alternating weekly administration of paclitaxel and gemcitabine: a phase II study in patients with advanced non-small-cell lung cancer

Background We sought to evaluate toxicity and efficacy of an alternating week schedule of paclitaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC).Methods Patients (n=27, mean age 56 years, range 27–73 years) received paclitaxel (100 mg/m² i.v. infusion over 1 h) on days 1 and 15 alternating with gemcitabine (1000 mg/m²) on days 8 and 22 of a 36-day cycle. Responses were evaluated after three cycles, and after the proposed six cycles.Results In total, 116 cycles were administered (mean 4.25 cycles per patient). Haematological toxicity was slight: febrile neutropenia (n=1) and neutropenia grade III–IV (n=5). Non-haematological toxicities included arthromyalgia grade II (n=6) and neurotoxicity grade III (n=1). Objective response was 29%, stable disease 25% and disease progression 46%. Median duration of response was 8 months (95% CI 5–11 months), median progression-free survival was 7 months (95% CI 4–11 months), median overall survival was 13 months (95% CI 7–17 months) and survival at 1 year was 52%.Conclusions A regimen of alternating weekly paclitaxel and gemcitabine is feasible in patients with advanced NSCLC, showing a lower toxicity profile compared with other platinum-based combinations, which makes this novel scheme attractive for these patients.     

Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial

Background:

Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-β, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma.

Methods:

We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks.

Results:

A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0–12 months), and the median overall survival was 4.4 months (range: 0–22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients.

Conclusions:

Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.     

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.