title: Second-line systemic therapy for metastatic colorectal cancer.
abstract: The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge.
  
  
  
  To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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 modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT;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.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, Padova, Veneto, Italy, 35128.|Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy, 35100.
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
authors.affiliation: U.O.C. di Oncologia ULSS5 Ovest Vicentino, Ospedale di Montecchio, Montecchio Maggiore, Vicenza, Italy.
authors.forename: Zora
authors.initials: Z
authors.lastname: Baretta
authors.affiliation: Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Sant Antoni Maria Claret 171, Edifici Casa de Convalescència, Barcelona, Catalunya, Spain, 08041.
authors.forename: Marta
authors.initials: M
authors.lastname: Roqué I Figuls
authors.affiliation: Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP) - Universitat Autònoma de Barcelona, Sant Antoni Maria Claret 167, Pavilion 18, Barcelona, Catalunya, Spain, 08025.
authors.forename: Ivan
authors.initials: I
authors.lastname: Solà
authors.affiliation: Clinical Oncology, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, Barcelona, Spain, 08025.
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Richard
authors.affiliation: Cochrane Colorectal Cancer Group, Cochrane, 23 Bispebjerg Bakke, Copenhagen, Denmark, DK 2400 NV.
authors.forename: Sara
authors.initials: S
authors.lastname: Hallum
authors.affiliation: Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Sant Antoni Maria Claret 171, Edifici Casa de Convalescència, Barcelona, Catalunya, Spain, 08041.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bonfill Cosp
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin