The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. Sixty-five trials (13,601 patients) were identified.
In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37- 0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70-0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens.
There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85-1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94-1.06; P = .97).
Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior with variable results.[7,8,9] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.
The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% vs. 24%, respectively; OR, 1.37; 95% CI, 1.16-1.61; P < .001).
Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (hazard ratio [HR], 1.07; 95% CI, 0.99-1.15; P = .100).
In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01-1.23 and HR, 1.11; 95% CI, 1.01-1.21, respectively).
Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71-3.01; P < .001), while cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33-0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15-0.88; P = .018).
The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.
Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10,11,12]
The first meta-analysis identified 37 assessable trials that included 7,633 patients.
A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46-1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09-1.35; P = .003).
No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96-1.28; P = .17).
The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
The second meta-analysis identified 17 trials that included 4,920 patients.
The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%-1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02-1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects.
In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06-1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08-4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07-1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea.
Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85-1.07; P = .43).
The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials. Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 and 2,304 patients in platinum-based and nonplatinum arms, respectively).
Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78-0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73-0.99; P = .049).
Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and nonplatinum regimens, respectively (OR, 1.53; CI, 0.96-2.49; P = 0.08). An increased risk of grade 3-4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in risk of febrile neutropenia (OR, 1.23; CI, 0.94-1.60; P = .063).