Elsevier

Cancer Treatment Reviews

Volume 37, Issue 8, December 2011, Pages 599-610
Cancer Treatment Reviews

Anti-Tumour Treatment
Molecularly targeted therapies in unresectable-metastatic gastric cancer. A systematic review

https://doi.org/10.1016/j.ctrv.2011.03.007Get rights and content

Summary

Gastric cancer is the second leading cause of cancer related-death. Most patients present with an advanced stage of disease that has a dismal outcome. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in the treatment of this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, such as angiogenesis inhibitors and agents targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the stomach, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable.

Introduction

Gastric cancer is the second leading cause of cancer related-death,1 with approximately 930,000 new cases diagnosed annually (8.6% of all new cancer cases)1 and more than 700,000 deaths recorded in 2006.[1], [2] The case fatality ratio for gastric cancer of 0.75 is considerably higher than that for other common malignancies like colorectal cancer (0.52), breast cancer (0.36) and prostate cancer (0.33).2

Surgical resection is considered the mainstay of curative treatment, though it can only be performed in a small subgroup of patients.3 Unfortunately, most patients present with an advanced stage of disease that has a dismal outcome. In the metastatic setting, chemotherapy is the gold standard of palliative therapy, achieving objective response rates (ORRs) of only 20–40% and median overall survivals (OS) of 8–10 months.[3], [4] Recent investigations have focused on the incorporation of a third chemotherapy agent with two-drug regimens; although a modest improvement in survival was noted, it was not without considerable additional toxicity.4

Evidently, there is a clear need for the development of new agents with novel mechanisms of action in the treatment of this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development. These agents inhibit angiogenesis and target epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) or proteasome.

This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer.

Section snippets

Search strategy

This systematic review was performed in accordance with the PRISMA guidelines.5 The protocol of this systematic review has been submitted to the Institutional Review Board of Hippokration Hospital, Medical University of Athens, Greece and is available upon request. Eligible articles were identified by a search of MEDLINE bibliographical database for the period up to August 07, 2010. The search strategy was the following: (gastric or stomach) and (cancer or carcinoma or adenocarcinoma) and

Results

The search strategy retrieved 129 articles. Of these articles 60 were irrelevant, 40 were reviews and 6 were case reports. After searching the references of all reviews and remaining articles, 24 conference abstracts were also included. Overall, 47 studies were eligible for the systematic review. The aforementioned stages are illustrated in detail in Fig. 1. The main pathways of gastric carcinogenesis are depicted in Fig. 2.

In relation to bevacizumab, 7 articles were retrieved (980 patients); 6

Anti-VEGF therapy

Pathological angiogenesis is the abnormal proliferation of blood vessels from pre-existing vessels. Activation of angiogenesis is a necessary condition for tumor growth and subsequent production of metastases. Vascular endothelial growth factor (VEGF) is a mitogenic protein for endothelial cells derived from arteries, veins and lymphatics, but not for other cell types.54 In addition to VEGF, six other closely related factors have been detected, namely VEGFA (VEGF), VEGFB, VEGFC, VEGFD, VEGFE

Conclusion and future perspectives

Molecularly targeted agents seem to mark the beginning of a new era in the context of unresectable and metastatic gastric cancer. It would be tempting to hypothesize an analogy in developments following the introduction of imatinib for the treatment of gastrointestinal stromal tumors. In any event, as molecular profiling surpasses the borders of morphological classifications, direct consequent molecularly targeted therapy may well contribute to the individualization of treatment in the

Conflict of interest statement

The authors declared no conflict of interest.

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