Marimastat as First-Line Therapy for Patients With Unresectable Pancreatic Cancer: A Randomized Trial

Bramhall, Simon R.; Rosemurgy, Alexander S.; Brown, Peter de Nully; Bowry, C.; Buckels, J. A. C.

doi:10.1200/jco.2001.19.15.3447

Cited by 400 publications

(195 citation statements)

References 24 publications

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“…27 The synthetic MMPIs are predominantly growth inhibitory rather than cytotoxic as the present study showed. Thus, their antitumor activity might be enhanced when used in combination with conventional chemotherapeutic agents.…”

Section: Discussionsupporting

confidence: 49%

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Osuga

Matono

Nakajima

et al. 2005

Intl Journal of Cancer

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We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat. ' 2005 Wiley-Liss, Inc.Key words: preclinical lung metastases model; angiogenesis; apoptosis; postoperative adjuvant therapy Colorectal cancer remains one of the major causes of cancer death worldwide. The mainstay of treatment for colorectal cancer with curative intent is surgical resection. However, recurrences to the liver or lung may occur in some patients even after a potentially curative operation. 1 For instance, the overall 5-year-survival rate for stage III cancer is approximately 60 % 2 due to postoperative recurrences even if the patients receive adjuvant chemotherapy. It is thought that the development of distant metastases depends on the spread of cancer cells from the primary tumor and that micrometastases already established prior to primary tumor resection appear as recurrent tumors after the operation. Therefore, to improve the postoperative prognosis of patients with colorectal cancer, effective adjuvant therapies against the micrometastases such as chemotherapy and immunotherapy should be considered. Since the 1990s, chemotherapy using 5-fluorouracil and leucovorin (5-FU/LV) has become standard treatment for stage III colon cancer after successful surgery. 3,4 However, this chemotherapy is still insufficient for patients at a high risk to recurrence who have biologically aggressive tumors, and the need to improve the outcome in such patients has increased the interest in developing more intensive or more targeted therapeutic strategies.It has been shown that solid tumor growth beyond a certain size requires neovascularization to supply the tumor with oxygen and nutrients. 5 In other words, without neovascularization, micrometastasis cannot grow. Therefore, it has been suggested that antiangiogenic therapy is effective against various solid tumors by inhibiting neovascularizat...

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Section: Discussionsupporting

confidence: 49%

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Osuga

Matono

Nakajima

et al. 2005

Intl Journal of Cancer

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“…Progression free survival was significantly better for patients treated with gemcitabine (P=0.0001) but this was predicted based on the mode of action of the two drugs. Exploratory analysis of these data suggested that survival in patients treated with marimastat with non-metastatic pancreatic cancer was significantly better than in patients with metastatic disease (P=0.035) but this was not the case in patients treated with gemcitabine (P=0.456) (Bramhall et al, 2001b). These data suggest that marimastat might be more beneficial in patients with low volume disease and this was also supported in a placebo-controlled study of marimastat in gastric and gastro-oesophageal cancer (Bramhall et al, 2001a).…”

mentioning

confidence: 86%

“…A pivotal international multi-center randomised study compared the effect of three different doses of marimastat with gemcitabine in patients with advanced pancreatic cancer. The study failed to reach its primary endpoint but did show a dose-dependent effect of marimastat and reported a 1-year survival of 19% for patients treated with gemcitabine and 20% for patients receiving 25 mg b.i.d of marimastat (P=ns) (Bramhall et al, 2001b). Progression free survival was significantly better for patients treated with gemcitabine (P=0.0001) but this was predicted based on the mode of action of the two drugs.…”

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confidence: 98%

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

et al. 2002

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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.

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“…In a phase III randomised trial in unresectable pancreatic cancer, no difference in 1-year survival was found between patients treated with 25 mg of marimastat or gemcitabine. 121 In a study by British Biotech (study 186), treatment of advanced ovarian cancer patients with the combination of carboplatin and marimastat showed no statistically significant advantage over carboplatin alone. 122 Two SCLC clinical trials with marimastat (studies 140 and 117) have been completed.…”

Section: Peptidomimetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Vihinen

Kähäri

2002

Intl Journal of Cancer

580

484

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Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.

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Marimastat as First-Line Therapy for Patients With Unresectable Pancreatic Cancer: A Randomized Trial

Cited by 400 publications

References 24 publications

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

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