Histology as a treatment effect modifier in advanced non-small cell lung cancer: A systematic review of the evidence

ABSTRACT Background and objective: We conducted a systematic review of prospective, randomized, controlled trials (RCT) to examine whether histology had a treatment modifying effect (TME) on the efficacy outcomes of chemotherapeutic agents in patients with advanced (stage IIIB‐IV) non‐small cell lung cancer (NSCLC). Methods: Potentially pertinent publications were reviewed in full to determine if there was any TME by histology for overall survival (OS), progression‐free survival (PFS) or treatment response rate (TRR). Results: Data from three pemetrexed RCT, comparing (i) pemetrexed versus docetaxel, (ii) pemetrexed and cisplatin versus gemcitabine and cisplatin, and (iii) pemetrexed versus placebo, showed a statistically significant TME by histology for OS and PFS. One trial comparing pemetrexed and carboplatin versus gemcitabine and carboplatin found no significant associations between histology and OS. The results of this systematic review indicate that pemetrexed appears to have the most consistent treatment‐by‐histology interaction effect on the efficacy outcomes of chemotherapeutic agents in patients with advanced or metastatic NSCLC. Patients with non‐squamous histology gain the greatest benefit from treatment with pemetrexed. Conversely, patients with squamous cell disease appeared to experience poorer OS when pemetrexed was compared with other active treatments, and similar OS when compared with placebo. Reproducible patterns of TME effect by histology with other chemotherapeutic agents are less clear. Conclusions: We consider that the historical approach to treating all NSCLC patients with the same chemotherapy regimen is now no longer acceptable. We conducted a systematic review of prospective, randomized, controlled trials to examine whether histology had a treatment modifying effect on the efficacy outcomes of chemotherapeutic agents in patients with advanced non‐small cell lung cancer. A treatment‐by‐histology interaction effect has been observed for pemetrexed, but is less clear for other chemotherapeutics.