Anti-Tumour TreatmentMolecularly targeted therapies in unresectable-metastatic gastric cancer. A systematic review
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.
References (116)
- et al.
Cancer statistics
CA Cancer J Clin
(2008) - et al.
Global cancer statistics, 2002
CA Cancer J Clin
(2005) - et al.
Global cancer statistics
CA Cancer J Clin
(1999) - et al.
Capecitabine and oxaliplatin for advanced esophagogastric cancer
N Engl J Med
(2008) - et al.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration
J Clin Epidemiol
(2009) - et al.
AVAGAST: A randomized double-blind, placebo-controlled, phase III study of first-line capecitabine/cisplatin + bevacizumab or placebo in patients with advanced gastric cancer (AGC)
J Clin Oncol
(2010) - Shah M, Kang Y, Ohtsu A, et al. Tumor and blood biomarker analyses in the AVAGAST phase III randomized study of...
- et al.
Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma
J Clin Oncol
(2006) - Enzinger P, Fidias P, Meyerhardt J, et al. Phase II study of bevacizumab and docetaxel in metastatic esophageal and...
- et al.
BECAM: a salvage protocol with bevacizumab, capecitabine, mitomycin C for patients with refractory metastatic colorectal cancer (CRC) or gastric cancer (GC)
J Clin Oncol
(2006)
Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: results of a phase II clinical trial
J Clin Oncol
Phase II trial of docetaxel, cisplatin, irinotecan, bevacizumab in metastatic esophagogastric cancer
J Clin Oncol
Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Br J Cancer
Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer
Br J Cancer
Predictive factors for the efficacy of cetuximab plus chemotherapy as salvage therapy in metastatic gastric cancer patients
Cancer Chemother Pharmacol
Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study)
Br J Cancer
Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study)
Ann Oncol
Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: A nonrandomized multicenter AIO phase II study
J Clin Oncol
Oxaliplatin, irinotecan, cetuximab in advanced gastric cancer. First efficacy results of a multicenter phase II trial (AGMT Gastric-2) of the arbeitsgemeinschaft medikamentoese tumortherapie (AGMT)
J Clin Oncol
Phase II study of cetuximab plus weekly cisplatin, 24-hour infusion of high-dose 5-fluorouracil, leucovorin for the first-line treatment of advanced gastric cancer
J Clin Oncol
Cetuximab as second-line therapy in patients with metastatic esophageal cancer: a phase II southwest oncology group study
J Clin Oncol
Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer
Br J Cancer
Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification
J Clin Oncol
A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies
Mol Cancer Ther
Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in firstline human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC)
J Clin Oncol
S0413: a phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer
J Clin Oncol
Target-specific, histologyindependent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors
J Clin Oncol
Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esophageal, gastric, and gastroesophageal cancer phase ii results from the north central cancer treatment group (N044B)
J Thorac Oncol
Phase II study of the cyclindependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma
J Clin Oncol
Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors
J Clin Oncol
Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors
Clin Cancer Res
A phase I study of weekly irinotecan (CPT), cisplatin (CIS), flavopiridol (F)
J Clin Oncol
An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: the GC4 study
Cancer
A phase II study of G17DT in gastric carcinoma
Eur J Surg Oncol
Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203
J Clin Oncol
Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127
J Clin Oncol
Efficacy, tolerability, pharmacokinetics of gefitinib (ZD1839) in pretreated patients with metastatic gastric cancer
J Clin Oncol
Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer
J Clin Oncol
Cited by (31)
Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight
2015, Critical Reviews in Oncology/HematologyCitation Excerpt :In gastrointestinal malignancies, angiogenesis is a well-known underlying promoter of tumor growth, invasion, and metastases. Based on a solid biologic background [16–18], the role of antiangiogenic drugs has been extensively investigated in gastric cancers [19]. Among many other molecules, bevacizumab, sorafenib, and sunitinib have been tested in clinical trials.
Targeted therapy for advanced esophagogastric adenocarcinoma
2014, Critical Reviews in Oncology/HematologyCitation Excerpt :It induces antiangiogenic effects via inhibition of the VEGFR signaling pathway. Common side effects are hypertension and proteinuria and less common, but potentially life-threatening are arterial thrombo-embolisms, gastrointestinal bleeding and–perforations [39]. Phase II studies showed promising data for response (65–67%) and survival (12.3–16.8 months) in advanced EGC when bevacizumab was combined with chemotherapy and led to the internationally, multicenter AVAGAST trial [40–42].
Polypharmacology: Principles and methodologies
2022, Polypharmacology: Principles and MethodologiesLncRNA ADAMTS9-AS2 suppresses the proliferation of gastric cancer cells and the tumorigenicity of cancer stem cells through regulating SPOP
2020, Journal of Cellular and Molecular MedicineCelastrol induces necroptosis and ameliorates inflammation via targeting biglycan in human gastric carcinoma
2019, International Journal of Molecular Sciences