Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.
Evidence (drug and dose schedule):
There has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine. Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
The pooled estimate for overall survival (OS) showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82-0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens versus vinca alkaloid-based regimens (OR, 0.59; 95% CI, 0.38-0.89; P = .013 and OR, 0.68; 95% CI, 0.55-0.84; P < .001, respectively).
There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[14,15] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.
A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
OS for cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine (median survival, 10.3 mo vs. 10.3 mo, respectively; HR, 0.94; 95% CI, 0.84%-1.05%).
OS was statistically superior for cisplatin and pemetrexed versus cisplatin and gemcitabine in patients with adenocarcinoma (n = 847; 12.6 mo vs. 10.9 mo, respectively) and large cell carcinoma histology (n = 153; 10.4 mo vs. 6.7 mo, respectively).
In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 mo vs. 9.4 mo, respectively). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
This study suggests that cisplatin and pemetrexed are another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggests that there may be differences in outcome depending on histology.