Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor. Recent advances in conventional chemotherapy and the development of novel 'molecular' treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies. This randomised study in pancreatic cancer compares marimastat (orally administered matrix metalloproteinase inhibitor) in combination with gemcitabine to gemcitabine alone. Two hundred and thirty-nine patients with unresectable pancreatic cancer were randomised to receive gemcitabine (1000 mg m 72 ) in combination with either marimastat or placebo. The primary end-point was survival. Objective tumour response and duration of response, time to treatment failure and disease progression, quality of life and safety were also assessed. There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo (P=0.95 log-rank test). Median survival times were 165.5 and 164 days and 1-year survival was 18% and 17% respectively. There were no significant differences in overall response rates (11 and 16% respectively), progression-free survival (P=0.68 log-rank test) or time to treatment failure (P=0.70 log-rank test) between the treatment arms. The gemcitabine and marimastat combination was well tolerated with only 2.5% of patients withdrawn due to presumed marimastat toxicity. Grade 3 or 4 musculoskeletal toxicities were reported in only 4% of the marimastat treated patients, although 59% of marimastat treated patients reported some musculoskeletal events. The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer. The combination of marimastat with gemcitabine was well tolerated. Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified.

Despite chemotherapy, median survival of patients with advanced pancreatic cancer (APC) remains poor. Gemcitabine (GEM) remains standard treatment. Numerous phase II studies have suggested that combination therapies may improve response rates. Mitomycin C (MMC) when used as a single agent may have response rates comparable to other cytotoxic drugs. Therefore, MMC could be an interesting drug to be combined with GEM. This study aimed to assess the feasibility, toxicity and efficacy of GEM combined with MMC in patients with APC. Between April 1997 and January 2002, 55 consecutive patients were treated with GEM 800 mg/m2 i.v., days 1, 8 and 15, and MMC 8 mg/m2 i.v., day 1, every 4 weeks in an outpatient setting. Patient characteristics included: M/F 34/21, median age of 58 years, ECOG PS 0-2. A median of 3 cycles was administered. The most frequent toxicity was thrombocytopenia grade III/IV in 54% of patients. Ten patients experienced dyspnea+/-X-ray-proven pneumonitis (n=2). One of these patients developed a hemolytic uremic syndrome after the sixth application of MMC. There was one early death as a consequence of a stroke. The objective response rate was 29% (95% confidence interval: 17-43). Eighteen patients had stable disease resulting in an overall tumor growth control of 62%. Time to progression was 4.7 months and median overall survival was 7.25 months. We conclude that, except for thrombocytopenia, the combination of GEM and MMC is well tolerated. These results compare favorably to single-agent chemotherapy with GEM or the combination of 5-fluorouracil plus MMC. Furthermore, this regimen is cost-effective and, since it can be given on an outpatient basis, contributes to the quality of life.

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