Combination chemotherapy

Certain three-drug combinations that add so-called targeted agents may result in superior survival.

EGFR inhibitors may benefit selected patients with EGFR variants.

Maintenance chemotherapy after four cycles of platinum combination chemotherapy may improve PFS and OS.

Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, protein-bound paclitaxel, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.

Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.

Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.

Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

The Cochrane Collaboration 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.[24] Sixty-five trials (13,601 patients) were identified.

The Cochrane Collaboration 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.[24] Sixty-five trials (13,601 patients) were identified.

In the trials that compared a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% 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 after single-agent therapy, with ORs ranging from 1.2 to 6.2. Infection rates did not increase in doublet regimens.

The Cochrane Collaboration 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.[24] Sixty-five trials (13,601 patients) were identified.

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.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

The objective response rate was higher for patients treated with cisplatin (30%) than for patients treated with carboplatin (24%); (OR, 1.37; 95% CI, 1.16–1.61; P < .001).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR, 1.07; 95% CI, 0.99–1.15; P = .100).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

In patients with nonsquamous cell tumors and in patients 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 in patients with nonsquamous cell tumors and HR, 1.11; 95% CI, 1.01–1.21 in patients treated with third-generation chemotherapy).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

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), but 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).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

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 that were based on essentially the same clinical trials, but which used only published data.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

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).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

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).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurological toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The second meta-analysis identified 17 trials that included 4,920 patients.[29]

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The second meta-analysis identified 17 trials that included 4,920 patients.[29]

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 neurological toxic effects.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The second meta-analysis identified 17 trials that included 4,920 patients.[29]

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, neurological toxic effects, and nausea.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The second meta-analysis identified 17 trials that included 4,920 patients.[29]

Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] 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 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] 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 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).

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).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] 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 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).

Forty-four (1.9%) toxic-related deaths were reported for platinum-based regimens and 29 (1.3%) toxic-related deaths were reported for nonplatinum regimens (OR, 1.53; CI, 0.96–2.49; P = .08). An increased risk of grade 3 to 4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in the risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).