Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study

Advanced biliary tract carcinomas (BTCs) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) has shown promising activity in this setting. This international phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTC received gemcitabine 1000 mg m⁻² (day 1) and oxaliplatin 100 mg m⁻² (day 2), every 2 weeks. Seventy patients were enroled; 72.9% had metastatic disease. Sixty-seven patients were treated. There were 10 confirmed partial responses (14.9%; 95% confidence interval (CI), 7.4–25.7%) in the treated population (RECIST). Twenty-four patients (35.8 %) had stable disease. The objective response rate was 20.5% in patients with non-gallbladder cancers (9/44 patients) and 4.3% in patients with gallbladder cancers (1/23). Median overall survival for the intent-to-treat population was 8.8 months (95% CI, 6.9–11.1%) and progression-free survival was 3.4 months (95% CI, 2.5–4.6%). Grade 3/4 toxicities included thrombocytopenia (14.9% of patients), alanine aminotransferase elevation (13.4%), anaemia (10.4%), neutropenia (11.9%) and pain (11.9%). In this study, GEMOX demonstrated activity in non-gallbladder carcinoma, but poor activity in gallbladder carcinoma. GEMOX is well tolerated in advanced BTCs.     

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.     

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.     

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.     

Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma.

OBJECTIVES: The prognosis for patients with unresectable biliary tract cancer is poor and existing chemotherapy is relatively ineffective. Therefore, a need exists for new, effective chemotherapeutic regimens. The aim of this study was to determine the efficacy and safety profile of gemcitabine plus cisplatin in patients with unresectable biliary tract cancer (cholangiocarcinoma) and gall bladder cancer. METHODS: From December 2000 to July 2002, 43 patients received gemcitabine 1250 mg/m(2) in a 30-min i.v. infusion on d1, 8 and cisplatin 75 mg/m(2) in a 2-h i.v. infusion on d1 (with appropriate hydration), every 3 weeks. ELIGIBILITY: Normal hematologic parameters and creatinine levels; serum bilirubin < 5 mg/dl. RESULTS: Forty-three patients enrolled; 40 were assessable (three patients were not assessable due to incomplete treatment; they chose to discontinue chemotherapy after the first cycle). There were 23 males and 17 females, median age 50 years (range 31-69), median Karnofsky PS 80%. Tumor types: cholangiocarcinoma (39), gall bladder cancer (1). Median number of chemotherapy courses was four (range 1-8). Overall response rate was 27.5% (PR in 11 pts), with 32.5% SD and/or minor response. Median survival time was 36 weeks. Grade 3 hematologic toxicity: anemia (4.33%), leukopenia (1.73%). Non-hematologic toxicity (i.e. rash, nausea, vomiting, neuropathy and myalgia) ranged from mild to moderate. CONCLUSIONS: Gemcitabine plus cisplatin is active in biliary tract carcinoma. These data warrant further investigation of single-agent gemcitabine versus gemcitabine plus cisplatin or its derivative, i.e. oxaliplatin.     

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.     

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.     

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.     

MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers

Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O ⁶‐methylguanine‐DNA methyltransferase (MGMT) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA‐seq) data from the BTC subcohort of the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Among 164 Italian cases, 18% presented MGMT promoter hypermethylation (> 14%) and 73% had negative MGMT protein expression. Both were associated with worse overall survival (OS; HR 2.31; P < 0.001 and HR 1.99, P = 0.012, respectively). In the MASTER cohort, patients with lower MGMT mRNA expression showed significantly poorer OS (median OS [mOS] 20.4 vs 31.7 months, unadjusted HR 1.89; P = 0.043). Our results suggest that MGMT inactivation is a frequent epigenetic alteration in BTC, with a significant prognostic impact, and provide the rationale to explore DNA‐damaging agents in MGMT‐inactivated BTCs.     

Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials

Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.     

Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience.

BACKGROUND: Unresectable biliary tract cancer has a very poor prognosis. A combination of weekly gemcitabine plus continuous infusional 5-fluorouracil (5-FU) (GEM/CVI 5-FU) was evaluated as therapy for this cancer. PATIENTS AND METHODS: The charts of 27 patients with advanced biliary tract adenocarcinoma treated with GEM/CVI 5-FU at the Princess Margaret Hospital were evaluated for response, survival and toxicity. The treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m(2) on days 1, 8 and 15 of a 28-day cycle plus 5-FU given via a peripherally inserted central line at 200 mg/m(2)/day continuously for 21 days, every 28 days. RESULTS: Objective responses were observed in nine patients (33%; 95% confidence interval 17% to 54%). An additional eight patients (30%) achieved stable disease for a median of 4 months (range 2.3-11). Median time to progression and overall survival were 3.7 and 5.3 months, respectively. Direct chemotherapy-related toxicity was mild, with only 11% grade > or =3 myelosuppression. Central venous catheter complications were common (26%). There were no treatment-related deaths. CONCLUSIONS: This study shows that GEM/CVI 5-FU is active and well tolerated in advanced and metastatic biliary tract cancers.     

Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer

BACKGROUND: A phase 2 trial of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer led to an objective response in approximately 30% of patients and a median survival of 14 months. In the current study, the authors report further efficacy data of a larger cohort of such patients treated with the GemCap regimen. METHODS: Patients aged >18 years and who had a diagnosis of locally advanced biliary cancer received first-line treatment with capecitabine at a dose of 650 mg/m(2) twice daily for 14 days and gemcitabine at a dose of 1,000 mg/m(2) on Day 1 and Day 8, every 3 weeks until disease progression. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RESULTS: Between July 2001 and January 2005, 75 patients were enrolled in the study. At a median follow-up of 9.5 months, the overall response rate was 29% (95% confidence interval [95% CI], 19.4-41%), with a median duration of 9.7 months (range, 3-36 months). Three patients achieved complete responses, with a median duration of 17 months (range, 9-27 months). The median progression-free survival and overall survivals were 6.2 months (95% CI, 4.4-8.3 months) and 12.7 months (95% CI, 9.5-31 months), respectively. CONCLUSIONS: The GemCap regimen is active in patients with biliary cancer. Randomized trials are warranted to define the impact of such a regimen on patient survival and quality of life.     

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。     

Phase II study of gemcitabine,oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer

Background:

Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.

Methods:

Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg⁻¹, GEM 1000 mg m⁻² (10 mg m⁻² min⁻¹) and OX 85 mg m⁻² on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.

Results:

Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.

Conclusions:

The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.     

Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer

This phase II study was conducted to determine the efficacy and toxicity of a gemcitabine (GEM) and oxaliplatin (OX) chemotherapy protocol in patients with unresectable biliary tract cancer (BTC). Patients were treated with GEM 1000 mg m-2 (30 min infusion) on days 1, 8, 15, and OX 100 mg m-2 (2 h infusion) on days 1 and 15 (gemcitabine and oxaliplatin (GEMOX-3 protocol), repeated every 28 days. The data were collected according to the Simon 2-stage design for a single centre phase II study (alpha=0.05; beta=0.2). Primary end point was response rate; secondary end points were time-to-progression (TTP), median survival, and safety profile. Thirty-one patients were enrolled in the study between July 2002 and April 2005. Therapeutic responses were as follows: partial response in eight patients (26%, 95% confidence interval (CI) 14-44), stable disease in 14 patients (45%, 95%CI 29-62), resulting in a disease control rate of 71%. Nine patients (29%, 95%CI 16-47) had progressive disease. Median TTP was 6.5 months. Median overall survival was 11 months. Common Toxicity Criteria (CTC) Grade 3-4 toxicities were transient thrombocytopenia (23%), peripheral sensory neuropathy (19%), leucopenia (16%), and anaemia (10%). In conclusion the GEMOX-3 protocol is active and well tolerated in patients with advanced BTC. It can be applied in an outpatient setting with three visits per month only.     

Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer

Purpose: This phase II study was conducted to evaluate the efficacy and toxicity of single-agent gemcitabine in patients with advanced or metastatic biliary tract cancer. Patients and methods: Gemcitabine 1,000 mg/m² was administered as an intravenous 30-min infusion on days 1, 8, and 15 for every 28 days. Results: Forty chemonaive patients with a median age of 61 (range 33–73) were enrolled, and all 40 patients were involved in efficacy and safety analyses. Seven (17.5%) achieved partial response; 15 (37.5%) had stable disease; 17 (42.5%) had progressive disease; and 1 (2.5%) was not evaluated. The median survival time was 7.6 months, and the 1-year survival rate was 25.0%. Grade 3/4 neutropenia occurred in 12 patients (30.0%), leukopenia in five patients (12.5%), and anemia in four patients (10.0%). The most common grade 3/4 nonhematologic toxicities were elevated ALT (15.0%) and elevated γ-GTP (12.5%). One patient had grade 4 hemolytic uremic syndrome and recovered after discontinuation of gemcitabine. Conclusions: In single-agent therapy, gemcitabine demonstrated moderate efficacy with manageable toxicity in patients with advanced or metastatic biliary tract cancer. Further evaluations are warranted, including the exact impact of gemcitabine on the management of advanced or metastatic biliary tract cancer.     

Single-agent gemcitabine versus cisplatin-etoposide: Early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer

Background: This randomised study was designed to determine the responserate, survival and toxicity of single-agent gemcitabine andcisplatin–etoposide in chemo-naïve patients with locally advancedor metastatic non-small-cell lung cancer.Patients and methods: Gemcitabine 1,000 mg/m² was given asa 30 min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin100 mg/m² on day 1, and etoposide 100 mg/m²on days 1 (following cisplatin), 2 and 3. Major eligibility criteria includedhistologically confirmed non-small-cell lung cancer, measurable disease,Zubrod PS 0–2; no prior chemotherapy, no prior radiation of the measuredlesion, and no CNS metastases.Results: 146 patients were enrolled, 71 patients on gemcitabine and 75patients on cisplatin–etoposide. Patient characteristics were wellmatched across both arms. Sixty-six gemcitabine patients and 72cisplatin–etoposidepatients were evaluable. Partial responses were seen in 12 gemcitabinepatients (18.2%; 95% CI: 9.8–30) and 11cisplatin–etoposide patients (15.3%; 95% CI:7.9–25.7).Early indications show no statistical differences between the two treatmentswith respect to time to disease progression or survival. Haematological andlaboratory toxicity were moderate and manageable. However, hospitalisationbecause of neutropenic fever was required for 6 (8%)cisplatin–etoposide patients but not for any gemcitabine patients.Non-haematological toxicity was more pronounced with significant differencesin nausea and vomiting (grade 3 and 4: 11% gemcitabine vs. 29%cisplatin–etoposide; despite the allowance for 5-HT^-3antiemetics during the first cycle of cisplatin–etoposide), and alopecia(grade 3 and 4: 3% gemcitabine vs. 62%cisplatin–etoposide).Conclusions: In this randomised study, single-agent gemcitabine was atleast as active but better tolerated than the combinationcisplatin–etoposide.