Optimal firstline chemotherapeutic treatment in p

Authors: N Haj Mohammad E ter Veer L Ngai R Mali M G H van Oijen H W M van Laarhoven

Publish Date: 2015/08/13

Volume: 34, Issue: 3, Pages: 429-441

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Abstract

There is a debate whether triplet or doublet chemotherapy should be used as a firstline treatment in patients with advanced or metastatic esophagogastric cancer Therefore here we will review the available literature to assess the efficacy and safety of triplet versus doublet chemotherapy as a firstline treatment in patients with advanced esophagogastric cancer We searched MEDLINE Embase and CENTRAL Cochrane Central Register of Controlled Trials between 1980 and March 2015 for randomized controlled phase II and III trials comparing triplet with doublet chemotherapy and abstracts of major oncology meetings from 1990 to 2014 Twentyone studies with a total of 3475 participants were included in the metaanalysis for overall survival An improvement in overall survival OS hazard ratio HR 090 95  confidence interval CI 083–097 and progressionfree survival PFS HR 080 95  CI 069–093 was observed in favor of triplet In addition the use of triplet was associated with better objective response rate ORR risk ratio 125 95  CI 109–144 compared to doublet The risks of grade 3–4 thrombocytopenia 62 vs 38  infection 102 vs 64  and mucositis 97 vs 47  were statistically significantly increased with triplet compared to doublet This review shows that firstline triplet therapy is superior to doublet therapy in patients with advanced esophagogastric cancer However the survival benefit is limited and the risks of grade 3–4 thrombocytopenia infection and mucositis are increasedGastric and esophageal cancers are respectively the second and the sixth most common cause of cancerrelated deaths worldwide The only potentially curative option involves resection Unfortunately the majority of patients presents with advanced disease or develops metastases after treatment with curative intent In these patients palliative systemic chemotherapy improves survival and quality of life compared to best supportive care 1 2 3Combination therapies have been associated with substantially higher response rates and survival compared to monotherapy 4 5 However the optimal regimen for firstline palliative chemotherapy has yet to be clearly established and the question whether a threedrug regimen is more effective than a potentially less toxic doublet is a point of debate A Cochrane review published in 2010 concluded that “two and threedrug regimens including 5FU cisplatin with or without an anthracycline are reasonable treatment options 6” This ambiguity is reflected in various guidelines According to the National Comprehensive Cancer Network NCCN guidelines of 2015 twodrug regimens are preferred and threedrug cytotoxic regimens should be reserved for medically fit patients with good performance scores and access to frequent toxicity evaluation 7 The European Society for Medical Oncology ESMO guidelines of 2013 state that “combination regimens incorporating a platinum agent and a fluoropyrimidine are generally used It remains controversial whether a triplet regimen is needed 8” In recently published randomized trials introducing targeted therapies in firstline treatment mainly doublets have been used as the backbone chemotherapy 9 10 11 although one trial used a triplet 12A search was conducted at the Cochrane Central Register of Controlled Trials CENTRAL MEDLINE and EMBASE up to March 2015 The search strategy contained medical subject headings MESH and text words for esophageal and gastric cancer and all established chemotherapy compounds in esophageal and gastric cancer We searched all abstracts from the American Society of Clinical Oncology ASCO and the ESMO conferences held between 1990 and 2014 The research question was registered in PROSPERO in September 2014 registration CRD42014014480Randomized phased II or III studies were included We included studies in abstract form only if information on study design characteristics of participants interventions and outcomes was available in English We excluded crossover studies and quasi randomized studies Patients had advanced recurrent or metastatic adenocarcinoma of the distal esophagus gastroesophageal junction or stomach They were not previously treated with chemotherapy or ≥6 months ago in adjuvant setting Treatment was defined as intravenous or oral chemotherapy and we excluded targeted therapy/biological therapy Subgroups were made and named after the third compound that was added to the identical backbone in both arms One subgroup “other” was created that contained a triplet and a doublet without the presence of an identical doublet backboneNHM MA and EV conducted the search NHM and EV independently scrutinized titles and abstracts and if applicable the full articles HvL decided in case of disagreement between NHM and EV NHM RM and EV extracted the study characteristics and outcome data The primary outcome was overall survival OS Overall survival was defined as the time between date of randomization and date of death or last date of followup

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