|
IntroductionLung cancer, with its high incidence and grim prognosis, remains a major public health menace for both men and women worldwide. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of all lung tumors. For early stage NSCLC, surgical resection continues to be the standard treatment with curative intent. Unfortunately, approximately 70% of NSCLC patients are diagnosed in advanced stage of the disease (locoregionally advanced or distant metastatic disease).Palliative chemotherapy has been the mainstay of treatment in advanced NSCLC. It has been well documented that platinum containing arms show a highly significant 27% lower risk for death and an absolute 10% greater 1-year survival rate over best supportive care (BSC). One individual patient data meta-analysis found that cisplatin-based chemotherapy is superior to carboplatin-based arms in terms of RR; however, the increased RR does not translate into an OS benefit.Within the past decade, new cytotoxic drugs with promising activity in NSCLC have been developed. These so-called third-generation agents include gemcitabine, paclitaxel, docetaxel, and vinorelbine. Despite some conflicting results, a good number of trials and two meta-analyses have established the superiority of modern platinum doublets over BSC and old-fashioned regimens. Several randomized studies, as well as two independent meta-analyses, have consistently shown that two-drug regimens provide superior response and survival rates compared with mono-therapy, whereas three-drug combinations may improve the objective response rate (ORR) but do not yield any survival benefit and are associated with higher toxic events.In summary, based on this body of evidence, a two-drug regimen in which cisplatin or carboplatin is combined with a third-generation agent currently represents the worldwide standard treatment of chemotherapy-naive patients with a good performance status and advanced disease. However, the optimal selection of a third-generation agent to combined with platinum remains controversial.Gemcitabine as a nucleoside analog, has shown better antitumor activity because of stronger cell-membrane penetration, higher affinity for deoxycytidine kinase, and longer intracellular retention time. Several studies comparing gemcitabine arms with other third-generation agents, have yielded a significantly longer time to progression (TTP) than in controls, and the 2-year survival rate was numerically higher; but these results are not substantiated by other studies. Furthermore, comparisons have been mainly based on small sample size data with inadequate statistical power to detect modest therapeutic advances.Gemcitabine:is this the best third-generation agent to choose for platinum-based doublets in advanced NSCLC? The clinical data, which produce mixed results, warrant a systematic review that will provide a new estimate of efficacy and have greater scientific value.ObjectiveThe aim of this study was to assess the relative impact of gemcitabine plus platinum chemotherapy on the activity of first-line chemotherapy in advanced NSCLC—as measured by overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and side-effects rates—using literature data from randomized trials of gemcitabine-containing doublets versus gemcitabine-free regimens.MethodsBoth published and unpublished trials that had completed recruitment by December 31,2009 were identified through a computer-based search of the CCTR, Embase, PubMed, CNKI, and CBM database and abstracts from Proceedings of American Society of Clinical Oncology (ASCO) or Proceedings of European Society of Medical Oncology (ESMO). The search strategy included the Medical Subject Headings terms or text word terms "non-small cell lung carcinoma", "NSCLC", "clinical trial", "randomized trial," "gemcitabine", "vinorelbine", "docetaxel", "paclitaxel", and "third-generation". Reference lists of original articles, review articles, and relevant books were also checked to identify additional studies.We evaluated these trials for inclusion, rated methodologic quality, and abstracted relevant data from randomized trials comparing a gemcitabine containing regimen with platinum plus other novel agents. A meta-analysis was conducted, and primary end points were overall survival (OS) and progression-free survival (PFS). Pooled relative risks (RRs) for the objective response rate, disease control rate (DCR), and toxic events were calculated using the Mantel-Haenszel estimate.ResultsData from a total of 4470 patients from 17 randomized trials investigating gemcitabine in combination with platinum versus any other drug regimen containing the same platinum plus a new agent were included. A non-significant reduction in overall mortality in favor of gemcitabine-platinum regimens (GC arms), hazard ratio (HR) 0.95 (95%CI:0.89-1.02) with an absolute benefit at 1 year of 1.9%. Median survival was 9.7 months for the gemcitabine-platinum regimens and 9.3 months for the comparator regimens. However,1-,2-, and 3-year survival rates were significantly different favoring GC arms (RR1 year=1.09,95%CI:1.01-1.19; RR2 year=1.25,95%CI: 1.04-1.52; RR3 year=1.64,95%CI:1.14-2.36).There was a significant decrease in the risk of disease progression in favor of GC arms, HR 0.92, (95%CI:0.86-0.98). An absolute benefit of 1.7% at 1 year was estimated. Median progression-free survival was 4.9 months for GC arms and 4.2 months for the comparator regimens. The objective response rates between GC arm and comparator regimen were not significantly different (RR=1.02,95%CI:0.92-1.12); however, gemcitabine-based chemotherapy was associated with a 7% lower risk for disease progression (RR=1.07, 95%CI:1.01-1.17), especially when compared to vinorelbine (RR=1.09,95%CI: 1.01-1.17).Patients on GC arm frequently developed anemia and thrombocytopenia. However, the incidence rate of grade 3-4 neutropenia, diarrhea, constipation, local toxicity in GC arms is statistically lower than that in comparator regimens. No significant differences in treatment related vomiting, fatigue, hair loss, neuropathy, liver toxic, and renal toxic, were observed.ConclusionsWe found that combination chemotherapy consisting of platinum plus gemcitabine yields a substantial PFS,1-,2-,3-year survival rate, and DCR advantage compared with platinum plus other novel agents in patients with advanced NSCLC. However, it’s quite different from each other in side effects, which provides important evidence on selecting individual chemotherapy regimen. The strength of our conclusion is limited because we used abstracted data, and careful interpretation is thus required.
|