Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group.

PURPOSE: To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma. PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were randomly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 (arm A) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 (arm B). Primary end points were tumor response and rate of febrile neutropenia grade. RESULTS: Of 96 randomly assigned patients (49 patients in arm A and 47 patients in arm B), 70 patients were analyzed for response (36 in arm A and 34 in arm B) and 89 patients were analyzed for safety (45 in arm A and 44 in arm B). Confirmed responses were observed in 19.4% (95% CI, 8.2% to 36.0%) of patients in arm A and 23.5% (95% CI, 10.7% to 41.2%) in arm B. In arm A, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0 to 4.7 months), median survival was 7.4 months (95% CI, 5.6 to 11.0 months), and 1-year survival was 30%. In arm B, the median PFS was 2.8 months (95% CI, 2.6 to 4.6 months), median survival was 7.1 months (95% CI, 4.8 to 8.7 months), and 1-year survival was 16%. Febrile neutropenia occurred in 9% and 16% of patients in arms A and B, respectively. CONCLUSION: Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.     

Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate.

PURPOSE: This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. RESULTS: In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. CONCLUSION: IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.     

A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer

Our purpose was to determine the response rate and median and overall survival of gemcitabine as monotherapy versus gemcitabine plus irinotecan in advanced or metastatic pancreatic cancer. Patients with histologically or cytologically confirmed adenocarcinoma who were chemotherapy and radiotherapy naive were enrolled. Patients were centrally randomised at a one-to-one ratio to receive either gemcitabine monotherapy (900 mg m(-2) on days 1, 8 and 15 every 4 weeks (arm G), or gemcitabine (days 1 and 8) plus irinotecan (300 mg m(-2) on day 8) (arm IG), repeated every 3 weeks. The total number of cycles administered was 255 in the IG arm and 245 in the G arm; the median number of cycles was 3. In all, 145 patients (71 in arm IG and 74 in arm G) were enrolled; 60 and 70 patients from arms IG and G, respectively, were evaluable. A complete clinical response was achieved in three (4.3%) arm G patients; nine (15%) patients in arm IG and four (5.7%) in arm G achieved a partial response. The overall response rate was: arm IG 15% and arm G 10% (95% CI 5.96-24.04 and 95% CI 2.97-17.03, respectively; P=0.387). The median time to tumour progression was 2.8 months and 2.9 months and median survival time was 6.4 and 6.5 months for the IG and G arms, respectively. One-year survival was 24.3% for the IG arm and 21.8% for the G arm. No statistically significant difference was observed comparing gemcitabine monotherapy versus gemcitabine plus irinotecan in the treatment of advanced pancreatic cancer, with respect to overall and 1-year survival.     

Use of high-dose cytarabine to enhance cisplatin cytotoxicity-effects on the response and overall survival rates of advanced head and neck cancer patients

It has been reported that cytarabine, acting by at least two different mechanisms, enhances the cytotoxic effect of cisplatin in in vitro systems. The aim of this open, prospective, randomised study was to estimate the eventual benefits from the inclusion of high-dose cytarabine in the cisplatin-5-fluorouracil (5-FU) regimen as first-line treatment of patients with advanced head and neck cancer. The study recruited successive patients with unresectable grade I/II head and neck cancer who were not suitable for irradiation treatment (T any N3 or T4 N2C), metastatic or previously irradiated. All patients gave their informed consent. A joint ear, nose and throat (ENT) oncological committee performed the selection. A total of 170 patients were included in the study. Patients randomised to arm A were given 1000 mg/m(2) cytarabine on day 1 preceding for 6 h cisplatin infusion, 30 mg/m(2)/24 h cisplatin intravenous (i.v.) bolus days 1-4 and 1000 mg/m(2)/24 h 5-FU in a 4-h infusion on days 1-4. Patients in arm B were given cisplatin and 5-FU in the same dosage and schedule as in arm A. Additional irradiation+/-surgery was performed if and when feasible. Patients in both arms were well balanced with regard to clinical variables. The following results were obtained: Arm A: 84 patients were included, 74 were evaluable for activity; Response: complete response (CR) 8 (11%), partial response (PR) 40 (54%), stable disease (SD) 11 (15%), progressive disease (PD) 15 (20%). The overall response rate (RR) based on the evaluable patients was 48/74 (65%, 95% confidence interval (CI) 54-75%); The RR based on an intent-to-treat analysis was 57%, 95% CI 47-67%; Median survival was 13 months; There were 50 episodes of granulocytopenia grade IV and 15 of febrile neutropenia per 316 cycles. Arm B: 86 patients were included, 80 were evaluable for activity; Response: CR 7 (9%), PR 29 (36%), SD 10 (12.5%), PD 34 (42.5%); The overall RR based on the evaluable patients was 36/80 (45%, 95% CI 35-56%); The RR based on an intent-to-treat analysis was 42%, 95% CI 32-52%; Median survival was 8 months; There were 14 episodes of granulocytopenia grade IV and 7 febrile neutropenias per 324 cycles. The RR was significantly higher in arm A (P=0.013), power (one-sided) 80%. The proportion of patients from the appropriate subset who achieved a clinical response making additional treatment feasible was higher in arm A (P=0.00015), as well as the proportion of patients with a performance status 2+3 achieving a response (P<0.0001). Using the Log-rank test, patients from arm A achieved a significantly longer survival (P=0.009), with the probability of survival at 12 months of 0.58 for patients in arm A and 0.28 for patients in arm B. Grade IV granulocytopenia and thrombocytopenia were more frequent in arm A. Due to its haematological side-effects, cytarabine might not be the ideal drug to modulate the cytotoxicity of cisplatin. However, other modulators of its activity could be of interest for further studies in head and neck cancer patients.     

Prolonged gemcitabine infusion in advanced non-small cell lung carcinoma: a randomized phase II study of two different schedules in combination with cisplatin

BACKGROUND: Preclinical and clinical evidence suggests that a fixed infusion rate of 10 mg/m2 per minute may be more effective than the standard 30-minute infusion of gemcitabine. To investigate the activity and toxicity of the cisplatin plus gemcitabine combination with gemcitabine at a fixed infusion rate in patients with advanced non-small cell lung carcinoma (NSCLC), the authors conducted a randomized Phase II trial of cisplatin plus gemcitabine at the 30-minute standard infusion (calibration arm) or cisplatin plus gemcitabine at a fixed infusion rate (experimental arm). METHODS: A total of 112 chemonaive patients with advanced NSCLC entered the study: 57 patients in Arm A and 55 patients in Arm B. The patients were randomly assigned to receive gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 over 30 minutes (Arm A) or at a rate of 10 mg/m2 per minute (Arm B). In both treatment arms, cisplatin at a dose of 80 mg/m2 was administered on Day 15 every 28 days. RESULTS: The overall response rates in Arms A and B were 26% (95% confidence interval [95% CI], 10-42%) and 34% (95% CI, 17-52%) (intent-to-treat-analysis), respectively. The median time to disease progression was 6 months (range, 1-26 months) and 8 months (range, 2-21 months), respectively, for Arms A and B and the median overall survival was 13 months (range, 2-26 months) for each arm. It is interesting to note that a high response rate (67%) of brain metastases was noted in the experimental arm. Toxicity was tolerable and comparable in the two arms. CONCLUSIONS: The results of this randomized Phase II trial demonstrated that cisplatin plus gemcitabine with gemcitabine at fixed infusion rate (10 mg/m2 per minute) is active and well tolerated in patients with advanced NSCLC.     

晚期胰腺癌全身化疗的疗效观察

背景与目的:晚期胰腺癌是恶性程度很高的肿瘤,全身化疗是其主要的治疗方法。本研究拟观察、比较三种不同化疗方案对晚期胰腺癌的客观疗效及其临床受益反应。方法:对我科2000年2月～2001年4月期间收治的经病理检查证实的74例晚期胰腺癌患者的临床资料进行回顾性分析,其中26例采用5-氟尿嘧啶、醛氢叶酸、顺铂方案治疗(A组);23例采用吉西他滨单药治疗(B组);25例采用吉西他滨联合5-氟尿嘧啶、醛氢叶酸方案治疗(C组)。采用Kaplan-Meier法分析患者生存期,Cox比例风险回归模型分析影响预后的因素。结果:A、B、C三组客观缓解率分别为7.7%、17.4%与24.0%,三组间无显著性差异(P=0.261,χ2检验);临床受益反应率分别为19.2%、47.8%与60.0%,B、C组优于A组,差异具有显著性(P<0.05,χ2检验)。A、B、C三组中位生存期分别为6.50个月(95%CI=5.00,7.99)、8.03个月(95%CI=6.72,9.35)、8.79个月(95%CI=7.31,10.26),B、C组长于A组,差异有显著性(Breslow=8.85,P=0.0119)。三组间血液学毒性和非血液学毒性发生率差异无显著性。结论:吉西他滨与5-氟尿嘧啶、醛氢叶酸联合作为一线方案治疗晚期胰腺癌有一定的客观缓解率,可改善患者的生活质量,患者耐受良好,值得进一步研究。     

Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy: A phase II study conducted by the Hellenic Cooperative Oncology Group

Background:Gemcitabine and vinorelbine have shown activity inbreast cancer. A phase II trial was initiated in order to evaluate theresponse rate (RR) and time to progression (TTP) of the combination of the twodrugs in patients with metastatic breast cancer progressing after first-linetaxane-based chemotherapy. Patients and methods:Thirty-one patients were treated with thecombination of gemcitabine 1000 mg/m² days 1 + 8 and vinorelbine30 mg/m² days 1 + 8. The cycles were repeated every three weeks. Results:Of 27 evaluable patients 1 (4%, 95%confidence interval (95% CI): 0.1%–19%) achievedcomplete remission (CR), five (18%; 95% CI:6%–38%) partial remission (PR), eleven (40%;95% CI: 22%–61%) stable disease and ten patientsprogressed. The median duration of response was six months (range 4–10+)and the median duration of disease stabilization was five months (range2–22+). With a median follow-up of 16 months (range 0.4–22+) themedian TTP was 3.5 months (range 0.4–22+) and the median survival was9.5 months (range 0.4–22+). Grade 3–4 toxicities weregranulocytopenia 15 patients (48%), rash 3 patients (10%),neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%).In conclusion the combination of gemcitabine/vinorelbine in the dosesadministered in this group of patients had a response rate of 22% andneeds to be further evaluated in metastatic breast cancer.     

Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel.

BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.     

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses

In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR=1.02; 95% CI=0.85-1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70-0.88), TTP (HR=0.85; 95% CI=0.72-0.99) and overall response rate (RR=0.56; 95% CI=0.46-0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR=1.94; 95% CI=1.32-2.84), leucopenia (RR=1.46; 95% CI=1.15-1.86), neutropenia (RR=1.48; 95% CI=1.07-2.05), nausea (RR=1.77; 95% CI=1.37-2.29), vomiting (RR=1.64; 95% CI=1.24-2.16) and diarrhoea (RR=2.73; 95% CI=1.87-3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity.     

Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan,leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: An AGEO randomised phase II study (FIRGEM)

BackgroundFluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown.MethodsIn this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0–1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N° 2006-005703-34).ResultsBetween October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6–58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9–39.3%]) in arm B.Objective response rates were 37% (23–51%) in arm A and 10% (1–19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR) = 0.59 [0.38–0.90]) and overall survival (11.0 versus 8.2 months, HR = 0.71 [0.46–1.10]) were higher in arm A compared to arm B. The most frequent grade 3–4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred.ConclusionThe FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.     

SCOTROC 2A: carboplatin followed by docetaxel or docetaxel-gemcitabine as first-line chemotherapy for ovarian cancer

The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P=0.102, P=0.056, P=0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% CI: 10.5-20.6); arm B 18.1 months (95% CI: 15.9-20.3); arm C, 13.7 months (95% CI: 12.8-14.6). Neutropenia was the predominant grade 3-4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P=0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.     

Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99

BackgroundHER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated.Patients and methodsOne-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity.ResultsCombination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5–1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6–1.5; P=0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3–5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1–4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related.ConclusionThe outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.     

A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status

OBJECTIVE: We conducted a phase II trial to evaluate the efficacy and toxicity of a combination consisting of second-line docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Eligibility criteria: histologically confirmed advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function. Treatment consisted of docetaxel 36 mg/m(2) i.v. over 60 min followed by gemcitabine 1000 mg/m(2) i.v. over 30 min on days 1 and 8 of each 3-week cycle for a planned six cycles or unacceptable toxicity. RESULTS: Of the 52 patients enrolled, 50 were evaluable for response and toxicity. The mean age was 59 years (range 42-79), 46 male and 4 female. Histology subtypes were: adenocarcinoma 26 patients, bronchioloalveolar 1 patient, large cell carcinoma 5 patients, and squamous cell carcinoma 18 patients. Thirty-eight patients had ECOG PS 1 and 12 patients had PS 0. The median number of cycles administered was four (range 2-6). The overall response rate was 28%. The median follow-up was 9 months (range 5-34 months). The median survival time (MST) was 8.2 months (95% CI, 4-12%), and the 1-year survival was 25%. The median progression-free survival was 4.4 months (95% CI, 2-6%). In the Cox regression model, survival was only significantly affected by the PS. The median survival in patients with PS 0 was 17.8 months (95% CI, 18.8-21.8%) compared with a median survival for patients with PS 1 of 6.1 months (95% CI, 4.1-8.2%) (P=0.0057). Toxicity: three patients had grade 3 anemia, three patients had grade 3 thrombocytopenia, four patients had grade 3 neutropenia and only one patient developed grade 4 febrile neutropenia. Non-hematologic toxicity was also mild; the most frequent was asthenia, with grade 3 in eight patients (16%), and one patient with grade 4. CONCLUSION: This regimen of docetaxel in combination with gemcitabine in advanced second-line NSCLC is an active and safe regimen.     

Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer: a multi-institutional phase II study

Background: This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC).Patients and methods: Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR). Patients received pemetrexed (500 mg/m²) with vitamin supplementation and oxaliplatin (120 mg/m²) every 21 days for six cycles or until disease progression occurred.Results: Median age was 62 years (range 26–76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3–7.5) and median survival was 10.8 months (95% CI 7.7–17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively.Conclusions: PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)–oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules.     

Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: A phase II clinical trial

Purpose: To determine the efficacy of gemcitabine and cisplatin combination therapy in patients with advanced and/or metastatic transitional cell urothelial carcinoma.Patients and methods: Forty-two chemonaïve patients with Karnofsky performance status (KPS) 70 were treated with cisplatin 35 mg/m² followed by gemcitabine 1000 mg/m² (30 min i.v. infusion) on days 1, 8, and 15 every twenty-eight days.Results: Thirty-eight patients were evaluable for efficacy. Half had visceral disease. There were seven complete (18%) and nine partial responses (24%), for a response rate of 42% (95% confidence interval (95% CI): 26%–59%). Responses were independently reviewed. Median response duration was 13.5 months (95% CI: 8.5–18.1 months), median time to progressive disease 7.2 months (95% CI: 4.0–9.1 months) and median survival 12.5 months (95% CI: 8.1–18.7 months); one-year survival was 52%. Laboratory toxicities included leucopenia (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4 symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no grade 4 infections and no toxic deaths.Conclusions: The combination of gemcitabine and cisplatin is active in patients with locally advanced and/or metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered inappropriate.     

Open-label trial on efficacy and security of treatment with gemcitabine and oral modulation with tegafur and levofolinic acid (GEMTG) in patients with advanced pancreatic cancer

Aim

Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4–6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progressionfree survival and OS in advanced pancreatic cancer.

Patients and methods

An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m² was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m²/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined.

Results

Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6–37%). TTP was 3.87 months (CI 95%, 2.1–5.6), time to treatment failure was 2.97 months (CI 95%, 2.43–4.67) and OS 6.3 months (CI 95%, 4–7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%).

Conclusions

The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile.     

Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group.

BACKGROUND: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity. RESULTS: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34-76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1-11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3-4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia. CONCLUSIONS: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.     

Gemcitabine combined with epirubicin in the treatment of patients with locally advanced or metastatic breast cancer: a phase II study

This phase II study of gemcitabine and epirubicin evaluated the activity and toxicity in advanced breast cancer. Female patients with stage IIIB or IV breast cancer received gemcitabine 1000 mg/m2 and then epirubicin 15 mg/m2 on days 1, 8, and 15 of 28-day cycles. Thirty-five patients with stage IV disease, a median age of 59 years (range, 39-73), and a median Karnofsky performance status of 90 (range, 60-100) were enrolled. Fourteen (40.0%) patients received prior chemotherapy (12 adjuvant, 4 metastatic, 2 both). Of 35 evaluable patients, 10 had PR, for an overall RR of 28.6%, and 12 (34.3%) patients had SD. Median time to progression and overall survival were 5.8 months (95% CI, 3.4-9.5 months) and 17.1 months (95% CI, 11.2-19.9 months), respectively. WHO grade 3/4 neutropenia occurred in 51.5% of patients without febrile neutropenia, and grade 3 thrombocytopenia in 29.4% of patients without hemorrhage or platelet transfusions. The most common nonhematologic toxicities were grade 3 alopecia (38.2%) and nausea/vomiting (11.4%). There were no grade 4 nonhematologic toxicities. Gemcitabine plus epirubicin is active and well tolerated in patients with metastatic breast cancer. Future studies should continue to evaluate the impact of various schedules on outcome.     

Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract

Both gemcitabine and weekly 24-h infusion of high-dose 5-fluorouracil/leucovorin (HDFL) have shown promising antitumour activity for patients with locally advanced or metastatic carcinoma of the biliary tract (CBT). From April 1999 through December 2002, 30 patients with inoperable CBT were treated with gemcitabine 800 mg m(-2), intravenous infusion for 30 min, followed by 5-FU, 2000 mg m(-2) and leucovorin, 300 mg m(-2), intravenous infusion for 24 h, on day 1, 8 and 15, every 4 weeks. A total of 166 cycles were given (median of four cycles per patient, range 1-24 cycles). Response was evaluable in 28 patients and toxicity in 29 patients. Partial response was obtained in six patients, stable disease in 13, while progressive disease occurred in nine. The objective response rate was 21.4% (95% CI: 5.2-37.6%). The most common grade 3 or 4 toxicity was infection (nine patients). Other types of grade 3 or 4 toxicity included leucopenia (four patients), thrombocytopenia (three patients), anaemia (three patients), nausea/vomiting (two patients) and elevation of liver transaminases (three patients). As of 30 September 2003, the median progression-free survival was 3.7 months (95% CI: 2.8-4.6 months) and the median overall survival was 4.7 months (95% CI: 0.8-8.6 months). Our data suggest that weekly gemcitabine plus HDFL is modestly active with acceptable treatment-related toxicity for patients with advanced CBT.     

Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer

PurposeThe combination of cisplatin plus gemcitabine is active in metastatic breast cancer. Carboplatin plus gemcitabine, widely used in ovarian and non–small-cell lung cancers, has also been used in breast cancer. This trial examined the efficacy and toxicity of split-dose carboplatin plus gemcitabine in advanced breast cancer.Patients and MethodsPatients with measurable disease, recurrent after adjuvant and ≤ 1 previous treatment for systemic disease, received carboplatin area under the curve = 2.0 (Calvert) plus gemcitabine 800 mg/m², both drugs administered days 1 and 8 every 21 days. Of 15 patients accrued, 13 are fully evaluable.ResultsThere were 2 complete (13.3%) and 6 partial (40%) responses, for an overall response rate by intention to treat of 53.3% (95% CI, 28%-82%). The median time to progression was 4.5 months (95% CI, 2.03-6.97 months), and median overall survival was 28.8 months (95% CI, 9.4-48.2 months). There were 2 patients with grade 3 (13.3%) anemia, 7 patients with grade 3 (46.6%) and 4 patients (26.6%) with grade 4 neutropenia, 4 patients with grade 3 (26.6%) and 3 patients (20%) with grade 4 thrombocytopenia.ConclusionThe repeating doublet of split-dose carboplatin plus gemcitabine reveals activity comparable to that of cisplatin plus gemcitabine, is well tolerated, and warrants evaluation in patients with recurrent breast cancer.