A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU).Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m². Gemcitabine was administered prior to leucovorin (25 mg/m²) followed by bolus 5-FU (600 mg/m²) every week for 3 weeks followed by 1 week of rest.Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m² systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m², full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m² was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels.Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m². Initial evidence of clinical activity was seen in a variety of tumor types.     

Phase II study of gemcitabine in advanced colorectal adenocarcinoma

Summary A phase II trial of gemcitabine (difluorodeoxycytidine) was conducted in 14 patients with advanced colorectal adenocarcinoma. Gemcitabine was administered intravenously over 30 minutes at weekly intervals for 3 consecutive weeks each month. The starting dose was 800 mg/m², with dose escalation as tolerated. No complete or partial response were observed. Ten patients experienced progressive disease while on therapy. Toxic effects were primarily hematologic in nature. Grade 3 toxicities included leukopenia (one patient at 1000 mg/m²), granulocytopenia (two patients at 800 mg/m²), anemia (two patients at 800 mg/m²), and myalgia (one patient at 800 mg/m²). No grade 4 toxic effects or treatment-associated deaths were observed. Gemcitabine, at the doses and schedule used in this study, did not demonstrate activity against advanced colorectal adenocarcinoma.     

Phase I study of eniluracil,oral 5-fluororacil and gemcitabine in patients with advanced malignancy

Purpose: The objectives of this trial wereto assess the maximal tolerated dose andtoxicity of the combination of oraleniluracil and 5-fluorouracil andintravenous gemcitabine. Patients and methods: Patients withhistologically confirmed, incurablemalignancy (solid tumor or lymphoma)refractory to standard therapy or for whichno standard therapy exists were enrolled. The treatment plan consisted of weeklygemcitabine for three weeks with twicedaily dosing of 5-FU and eniluracil for 21days beginning on day one of gemcitabine. Cycles repeated on an every four weekschedule. The initial cohort receivedgemcitabine 800 mg/m², oral 5-FU 0.6 mg/m²and eniluracil 6.0 mg/m². Results: Twenty-six patients were enrolled. Eight patients received less than 2 cyclesof therapy. Hematologic andgastrointestinal toxicity predominated,with 48% of courses resulted in grade oneor two neutropenia. Hematologic toxicitywas dose limiting. One treatment relateddeath occurred. Conclusions: The combination of eniluracil,5-fluorouracil and gemcitabine offers anoral alternative for 5-FU administration.The recommended phase II dose isgemcitabine 1000 mg/m², 5FU 1.2 mg/m² andeniluracil 12 mg/m².     

A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

INTRODUCTION: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU). METHODS: Standard eligibility criteria were required for patients with advanced malignancy to enroll. Gemcitabine was escalated from an initial dose of 800 mg/m2. Gemcitabine was administered prior to leucovorin (25 mg/m2) followed by bolus 5-FU (600 mg/m2) every week for 3 weeks followed by 1 week of rest. RESULTS: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m2 systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m2, full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m2 was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels. CONCLUSIONS: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m2. Initial evidence of clinical activity was seen in a variety of tumor types.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

胆管或胰腺癌并肝功能异常15例应用吉西他滨治疗的剂量选择

目的 肝功能障碍时胆管或胰腺癌病人应用吉西他滨治疗的剂量标准。方法 20112015年间鹤壁市传染病医院收治的胆管或胰腺癌成人病人15例,分为3组,根据其肝功能损伤程度(轻、中、重),依血清胆红素和肝脏转氨酶进行评价。吉西他滨按800或1 000 mg/m²静脉用药1周1次共3周,间隔1周后进行下一周期治疗,共用药4个周期。第一周期中评价病人的不良事件,吉西他滨药物动力学及其无效代谢物,确定最佳初始剂量。结果 15例病人纳入研究。肝功能轻度异常1例,中度异常6例,重度异常8例。15例病人均行胆管引流并接受吉西他滨治疗。1例中度肝功能障碍病人发生3级胆管炎,其接受剂量为1 000 mg/m²。无其他病人发生严重的治疗相关事件。本组病人间吉西他滨的血浆浓度和氟尿嘧啶脱氧核苷的血浆浓度差异无统计学意义。结论 轻或中度肝功能异常的胆管或胰腺癌病人吉西他滨单药治疗初始剂量无需减量。     

A phase I study of topotecan and gemcitabine in advanced solid tumors

Purpose Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined. Patients and Methods Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m² days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m² given on days 2 through 5 every 21 days. Results The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m² and topotecan 1 mg/m². A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients. Conclusion The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m² on days 1 and 5 with topotecan at 0.8 mg/m² on days 2 to 5.     

Tirofiban: an investigational plateletglycoprotein IIb/IIIa receptor antagonist

Introduction: Fluoropyrimidines with oxaliplatin or irinotecan plus bevacizumab is the standard chemotherapy combination in patients with advanced colorectal cancer (CRC). Gemcitabine acts synergistically with fluoropyrimidines to enhance the binding of thymidylate synthase and increase inhibition of DNA synthesis. The objective of this review is to evaluate the literature for evidence of efficacy and safety of fluoropyrimidine plus gemcitabine (FG) in patients with advanced CRC. Methods: Relevant studies were identified in PubMed, Ovid, Cochrane database and the American Society of Clinical Oncology abstracts using the following search terms: gemcitabine, fluorouracil, capecitabine and colorectal cancer. Only studies using the FG combination were selected. Results: Forty-two advanced CRC patients were evaluated in two Phase I studies and the maximum tolerated dose of gemcitabine was 900 – 1,000 mg/m² weekly with either bolus 5-fluorouracil (5-FU) or capecitabine. A total of 216 advanced CRC patients were evaluated in six Phase II studies. Gemcitabine (750 – 1,250 mg/m²) with either 5-FU (continuous infusion or bolus) or capecitabine was administered as first-line therapy in two studies and as third-line therapy in three studies. The range reported for overall response rate was 30 – 38.3%, median time to progression was 4 – 8.3+ months and median survival was 9.8 – 18+ months. The most commonly reported grade 3 – 4 toxicities were neutropenia, thrombocytopenia and mucositis. Conclusions: Fluoropyrimidine plus gemcitabine is clinically active in patients with refractory CRC demonstrating prolonged median time to progression and acceptable toxicity only when bolus 5-FU was not used. Studies are underway to evaluate the combinations of FG with other chemotherapy or targeted agents. Meanwhile, FG may be considered for patients with advanced CRC who are refractory to primary treatment without other options or who are not eligible for clinical studies.     

Prolonged infusion of gemcitabine in advanced solid tumors: A phase-I-study

Summary Background: Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that prolonged administration of gemcitabine might result in higher intracellular concentrations of active metabolites. This phase I trial was therefore initiated to determine the optimal dose of gemcitabine administered over 4h in patients with advanced solid tumors. Patients and Methods: Patients were treated with gemcitabine as 4h-infusion on day 1, 8 and 15 in 4 week intervals. The starting dose was 350 mg/m². Doses were escalated in 50 mg/m² increments.Results: Twenty-one patients were treated at doses ranging from 350 to 450 mg/m². The maximum tolerated dose was 400 mg/m² with neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes being dose limiting toxicities (DLTs). Hematologic and nonhematological toxicities were generally mild to moderate. Most common side effects were myelosuppression, nausea, elevation of liver enzymes and asthenia. Objective responses were noted in patients with hepatocellular carcinoma and cholangio-carcinoma.Conclusion: In this phase I study of gemcitabine as 4h-infusion, DLTs were neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes. The recommended dose for phase II studies is 400 mg/m².     

A Phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors

Purpose: Pharmacological studies of gemcitabine (2,2-difluorodeoxycytidine) have shown that increased levels of the active triphosphate metabolite are achieved by prolonging infusion time while holding the dose rate constant. The primary aim of this study was to determine the maximum tolerated dose (MTD) of gemcitabine administered as a fixed rate infusion (10 mg/m²/min) on a weekly schedule in patients with untreated non-hematologic malignancies.Patients and methods: Twenty-seven patients (21 pancreatic adenocarcinoma, 3 hepatoma, 1 neuroendocrine tumor, and 2 adenocarcinoma of unknown primary) were enrolled in this open-label, non-randomized study. Three different entry dose levels (1200 mg/m², 1500 mg/m² and 1800 mg/m²) were evaluated for gemcitabine administered on days 1, 8, and 15 of a 28-day cycle.Results: The MTD was defined as 1500 mg/m² with granulocytopenia and thrombocytopenia being dose-limiting. There were no non-hematological dose limiting toxicities. The maximum WHO grade 3 or 4 toxicities for hemoglobin, leukocytes, neutrophils, and platelets for all doses of gemcitabine administered were 11.5%, 30.8%, 57.7%, and 26.9%, respectively. Non-hematologic toxicities included nausea, vomiting and fever. Four patients were withdrawn from the study for non-hematological toxicities: pneumonitis, ascites, disabling fatigue, and an acute myocardial infarction. Two of these events were severe (pneumonitis and myocardial infarction) but these may not be related to drug administration.Conclusion: Gemcitabine administered at a rate of 10 mg/m²/min was tolerated up to 1500 mg/m² in patients with previously untreated non-hematologic malignancies. Myelosuppression seen in this study is more severe than anticipated based on previous reports of bolus administration of similar doses of gemcitabine. This supports earlier studies suggesting that prolonged duration of infusion increases the intracellular accumulation of active metabolites of gemcitabine.     

A Phase II study of celecoxib,gemcitabine, and cisplatin in advanced pancreatic cancer

Summary Background. Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m² over 100 minutes, cisplatin 35 mg/m² I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results. Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6–7.6 months). The probability of survival at 6 months was 46% (90% CI, 27–62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.     

Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors

Purpose: In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib. Experimental Design: Imatinib was administered at 400 mg daily on days 1–5, 8–12 and 15–19. Gemcitabine was started at 600 mg/m² at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m² on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients. Results: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m² on days 3 and 10 for gemcitabine, 30 mg/ m² on day 10 for docetaxel, and 400 mg daily on days 1–5 and 8–12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles. Discussion: An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control.     

Phase I/II study of gemcitabine and vinorelbine plus cisplatin in non-small cell lung cancer

Purpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m² andvinorelbine 25 mg/m² intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m² and 5 mg/m²,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m² on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m²).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000–1250/25 mg/m²)followed (24 hours later) by cisplatin50 mg/m². Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5–12) and 11 months (95 % CI:9–13), respectively. World HealthOrganization toxicity grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting( grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000–1250 mg/m plus vinorelbine25 mg/m² on days 1 and 8, followed bycisplatin 50 mg/m² 24 hours later, issafe for outpatient administration andactive in patients with NSCLC.     

Phase II trial of gemcitabine (2,2′-difiuorodeoxycytidine) in patients with adenocarcinoma of the pancreas

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m² was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 10³/l (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 10³/l (range 0.4–7.2). Thrombocytopenia - 100.0 × 10³/l was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.     

Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer

Background: Because gemcitabine andvinorelbine have demonstrated single-agentactivity in non-small cell lung cancer(NSCLC), we conducted this phase I/II studyto determine the maximum tolerated dose(MTD) and activity of these drugs combined. Patients and methods: Patients withinoperable or advanced NSCLC and no priorchemotherapy were treated with gemcitabineplus vinorelbine on days 1 and 8 every 21days. The initial doses of gemcitabine1,000 mg/m² and vinorelbine25 mg/m² were escalated by250 mg/m² and 5 mg/m²,respectively, in separate patient cohortsuntil the MTD was established. Results: In phase I, 32 patientsreceived a total of 115 cycles. Dose-limiting toxicities were neutropeniaand hepatotoxicity, occurring at the doselevel of 1,500 mg/m² and30 mg/m². Thus, the MTD used forphase II was 1,250 mg/m² and30 mg/m². Of 41 patients in phase II,16 (39%) achieved objective responses(95% confidence interval [CI] 24% to54%), with a median time to progression of4.2 months. Overall survival was 9 months(95% CI 5.7 to 12.7 months) and the 1-yearsurvival rate was 31%. World HealthOrganization (WHO) grade 3neutropenia and reversible thrombocytosisoccurred in 15% and 65% of patients,respectively. Non-hematologic toxicity wasmild at all dose levels. Grades 3 and 4hepatotoxicity were reported in one patienteach. Conclusion: The combination of1,250 mg/m² gemcitabine and30 mg/m² vinorelbine on days 1 and 8every 21 days is well tolerated and activein patients with NSCLC. These resultsshould be confirmed in comparativestudies.     

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium

Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-na?ve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m² on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.     

Second-line treatment with oxaliplatin,leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: A phase II study

Study objectives: The present study was conducted to evaluate the efficacy and safety of the combination of Oxaliplatin, Leucovorin and 5-FU as second line therapy, following relapse to Gemcitabine, in patients with advanced adenocarcinoma of the pancreas. Patients and methods: Patients with advanced pancreatic cancer previously treated with Gemcitabine were included in the study. All patients had histologically or cytologically confirmed adenocarcinoma of the pancreas that was unresectable, locally advanced or metastatic. Treatment consisted of Oxaliplatin 50 mg/m² (2-hour iv infusion), followed by Leucovorin 50 mg/m² (i.v. bolus) and 500 mg/m² 5-FU (1-hour iv infusion), administered weekly, until unacceptable toxicity or disease progression. Objective tumour response and toxicity were evaluated according to World Health Organisation (WHO) criteria. Results: A total of 30 patients, 20 men and 10 women, median age 63 years (range 52–71 years) and Karnofsky Performance Status (PS) of ≥50 entered the study. The majority of patients (96%) had locally advanced disease. A total of 380 doses of chemotherapy were delivered, a median of 12 doses per patient. Partial responses were observed in 7 patients (PR 23.3%), stable disease in 9 (SD 30.0%), while 14 patients progressed (PD 46.7%). Improved PS was observed in 18 (42.8%) patients. Patients that had responded to first-line Gemcitabine treatment were found more likely to respond or stabilize their disease with second-line treatment. The median duration of response was 22 weeks, and median overall survival was 25 weeks, Grade 3/4 toxicity expressed per chemotherapy dose included leukopenia 16%, anemia 3.2%, thrombocytopenia 3.2%, diarrhea 14.2%, fatigue 16.1% and neurotoxicity 4.2%. Eight patients (27%) suffered a febrile neutropenic event managed successfully with oral antibiotic home therapy, while 17 patients required G-CSF support. There were no treatment related deaths. Conclusions: The combination of Oxaliplatin, Leucovorin and 5-FU was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced or metastatic pancreatic adenocarcinoma, previously treated with Gemcitabine. Additional studies are warranted with this regimen in Gemcitabine relapsed pancreatic cancer patients. An erratum to this article is available at .     

Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium

Summary Objectives: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P + G in patients with metastatic TCC. Methods: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800–1,000 mg/m² on days 1 and 15; P 400–500 mg/m² on day 15; and C 50–70 mg/m² on day 1. All patients received folic acid, vitamin B₁₂, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. Results: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53–82); 11/15 had KPS ≥ 90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed <1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3–4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). Conclusion: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.     

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study

A phase II trial of gemcitabine(Gemzar®), a nucleoside analogue with broadactivity in solid tumors, was performed inpatients with recurrent or metastaticsquamous cell carcinoma of the head andneck. A total of 26 eligible patients wereregistered to receive a dose of1250 mg/m² weekly for 3 weeks,followed by a 1 week rest. Toxicity wasevaluable in 26 patients. Nausea andvomiting occured in 11 and 6 patients,repectively. Grade 3 or 4 hematologictoxicities were infrequent. Two patientsdeveloped neutropenic infections. Onepatient developed fatal liver failure whichwas thought due to progressive livermetastases or infection 14 days after asingle dose of gemcitabine. There were noobjective treatment responses (95% CI0–13%), with a median survival of 6 monthsin this highly resistant diseasepopulation. Gemcitabine is not consideredactive enough as monotherapy for furtherevaluation in this disease population.     

5-Fluorouracil and Folinic Acid: a Phase I–II trial in gastrointestinal malignancy

Summary Fifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I–II clinical trial. Two different schedules were used: (a) bolus infusion — 5FU 7 –12 mg/kg/d I.V. d1–5, FA 1.6 mg/kg/d I.V. d1–5; (b) continuous infusion — 5FU 600–1200 mg/m²/d I.V. d1–4, FA 60 mg/m²/d I.V. d1–4. Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg/d I.V. d1–5 and 1000 mg/m²/d I.V. d1–4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), including responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equivalent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The possibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.