Abstract: 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 modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT;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 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence). With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens. We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.

Plain-language summary: The evidence is current to May 2016. In this updated review, we identified 34 clinical trials that compared second-line therapy with either no chemotherapy (best supportive care) or an alternative second-line therapy, so addressing the issue of second-line therapy performance in people with metastatic colorectal cancer. Available evidence seemed to support the use of second-line therapy because it improved survival expectations as compared to best supportive care, although this was reported in only one small trial and the result would need to be confirmed in further research. Moreover, we found that modern chemotherapy regimens were more effective than older ones that contained a drug called 5-fluorouracil, that combination chemotherapy was more effective than single agent chemotherapy and that targeted agents (so called 'smart drugs' that attack the cancer cells and do little damage to normal cells) increased the effectiveness of conventional chemotherapy. Generally, toxicity increased as effectiveness increased. The main conclusions of this review were based on moderate to high quality evidence. When the quality of the evidence was considered low or moderate, this was generally due to inconsistency in the main results (i.e. the result for progression-free survival (time from the start of second-line treatment to progression of the cancer) was not confirmed by overall survival (time from the start of second-line treatment to death from any cause)) and the low numbers of participants included in the analyses. Nevertheless, it should be remembered that progression-free survival nowadays is considered a reliable surrogate of overall survival (which includes all deaths, not just cancer-related, and requires longer follow-up to obtain an accurate estimate) in the setting of second-line therapy for metastatic colorectal cancer. Most of the trials did not report quality of life, which prevented us formally investigating the balance between survival benefits provided by second-line systemic therapy and treatment-related toxicity.