Second‐line systemic therapy for metastatic colorectal cancer

Background The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first‐line treatment represents a formidable challenge. Objectives To determine the efficacy and toxicity of second‐line systemic therapy in people with metastatic CRC. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In‐process & Other Non‐Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. Selection criteria Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second‐line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first‐line systemic therapy. Data collection and analysis Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta‐analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random‐effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression‐free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). Main results Thirty‐four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second‐line systemic therapy of people with metastatic CRC. 1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate‐quality evidence); 2. modern chemotherapy (FOLFOX (5‐fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5‐fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high‐quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate‐quality evidence); 3. irinotecan‐based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0