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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 modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT;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 0.60 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). Authors' conclusions 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.

Background Combination chemotherapy has been the mainstay of treatment for extensive stage small cell lung cancer (SCLC) over the last 30 years even though it only gives a short prolongation in median survival time. The main goal for these patients should be palliation with the aim of improving their quality of life. Objectives To evaluate the effectiveness of chemotherapy in extensive SCLC compared with best supportive care (BSC) or placebo treatment. Search strategy MEDLINE (1966 to July 2008), EMBASE (1974 to week 31, 2008), and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2008). Experts in the field were contacted. Selection criteria Randomised controlled trials in which any chemotherapy treatment was compared with placebo or BSC in patients with extensive SCLC, as first or second therapy at relapse. Data collection and analysis Two authors independently extracted data and assessed study quality. We resolved disagreements by discussion. Additional information was obtained from one study author. Main results Two studies were included for first-line chemotherapy. A total of 65 patients were randomised to receive either placebo or ifosfamide. Ifosfamide gave an extra mean survival of 78.5 days compared with placebo. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group. Two studies were included for second-line chemotherapy at relapse. A total of 531 patients were randomised to receive either methotrexate-doxorubicin or symptomatic treatment, or to receive oral topotecan versus BSC. The methotrexate-doxorubicin treatment gave a median survival of 63 days longer than in the symptomatic treatment group, and 21 days longer for patients allocated to receive four or eight cycles of first-line chemotherapy, respectively. Treatment with topotecan gave a median survival of 84 days longer than in the BSC group (log-rank P = 0.01). The adjusted hazard ratio for overall survival was 0.61 (95% CI, 0.43 to 0.87). Partial or complete response in the methotrexate-doxorubicin group was 22.3%. Five patients (7%, 95% CI, 2.33 to 15.67) showed a partial response with topotecan. Toxicity was worst in the chemotherapy group. Quality of life was better in the topotecan group. Authors' conclusions Chemotherapeutic treatment prolongs survival in comparison with placebo in patients with advanced SCLC. Nevertheless, the impact of first-line chemotherapy on quality of life and in patients with poor prognosis is unknown. Well-designed, controlled trials are needed to further evaluate the risks and benefits of different chemotherapeutic schedules in patients with advanced SCLC.