Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial

Bramhall, Simon R.; Hallissey, M. T.; Whiting, John; Scholefield, J H; Tierney, Gillian; Stuart, Robert C.; Hawkins, Robert E.; McCulloch, Peter; Maughan, T; Brown, Peter de Nully; Baillet, M; Fielding, J. W. L.

doi:10.1038/sj.bjc.6600310

Cited by 240 publications

(136 citation statements)

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“…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).…”

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confidence: 82%

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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confidence: 82%

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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“…[68][69][70] Some clinical trials have had promising results in gastric cancer and nonsmall cell lung cancer. 71,72 Patients with limited musculoskeletal symptoms have had improved survival in recent studies. 68 A clinical trial of MMP inhibitors in head and neck cancer has not been published, but reports in other cancers imply that broad-spectrum inhibitors will have limited clinical benefit (Table 2) because of dose-limiting musculoskeletal symptoms.…”

Section: Matrix Metalloprotease Inhibitors In Clinical Trialsmentioning

confidence: 99%

Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

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“…1 A prominent example of this group of drugs are synthetic metalloprotease inhibitors, which have received much attention even though only one trial proved clinical therapeutic efficacy recently. 2,3 The difficulty in the design of stromal therapeutics may in part be due to the huge number of potential target molecules and the complicated and still unresolved interactive pathways. As an adjunct to focused mechanistic studies, which are usually performed in vitro, our understanding of the occurring biological processes could be increased by global in vivo gene expression studies.…”

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Global analysis of host tissue gene expression in the invasive front of colorectal liver metastases

Bandapalli

Geheeb

Kobelt

et al. 2005

Intl Journal of Cancer

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Host cell reactions are a crucial determinant for tumor invasion. We analyzed on a genomewide scale gene expression differences between microdissected tissues taken from unaffected liver tissue of a human colorectal tumor (LS174) growing in the livers of nude mice and tissue from the host part of the invasive front. Due to the low degree of interspecies cross‐hybridization of 15% as determined on Affymetrix microarrays, our xenograft model allowed for the distinction of genes of murine versus human origin even if the respective tissues could not be isolated separately. Using the gene ontology (GO) classification, we were able to determine patterns of up‐ and downregulated genes in the liver part of the invasive front. We observed a pronounced overrepresentation, e.g., of the GO terms “extracellular matrix,” “cell communication,” “response to biotic stimulus,” “structural molecule activity” and “cell growth,” indicating a very pronounced host cell response to tumor invasion. On the single gene level, hepatic stellate cell (HSC) activation markers were overrepresented in the liver part of the invasion front. Immunohistochemistry and qPCR confirmed an activation of HSC as well as an increased number of HSC in the invasive front as compared to the noninvaded liver tissue. In summary, our data demonstrate the feasibility of an interspecies differential gene expression approach on a genomewide scale. © 2005 Wiley‐Liss, Inc.

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Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial

Cited by 240 publications

References 23 publications

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

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 metalloproteases in head and neck cancer

Global analysis of host tissue gene expression in the invasive front of colorectal liver metastases

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