title: Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer.
abstract: BACKGROUND
  Chemotherapy is the treatment of choice in patients with advanced or metastatic colorectal cancer (CRC) where surgical resection of metastases is not an option. Both irinotecan (IRI) and fluoropyrimidines are often included in first- or second- line chemotherapy treatment regimens in such patients. However, it is not clear whether combining these agents is superior to irinotecan alone.
  
  
  OBJECTIVE
  To compare the efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced CRC when administered in the first or second-line settings.
  
  
  METHODS
  We searched the following electronic databases to identify randomized controlled trials: Cochrane Colorectal Cancer Group Specialised Register (January 13, 2016), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 12, 2016), Ovid MEDLINE (1950 to January 13, 2016), Ovid EMBASE (1974 to January 13, 2016), registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field were contacted when necessary. The search from January 2016 identified one eligible study, an ongoing trial currently presented as an abstract, to be considered in an update of this review.
  
  
  METHODS
  Randomized controlled trials (RCTs) investigating the efficacy and safety of IRI chemotherapy combined with fluoropyrimidine compared with IRI alone for the treatment of patients with advanced CRC, regardless of treatment line settings.
  
  
  METHODS
  Study eligibility and methodological quality were assessed independently by the two authors, and any disagreement was solved by a third author. The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.3.
  
  
  RESULTS
  Five studies were included in this review with a total of 1,726 patients. The top-up search resulted in an additional ongoing trial, the results of which have not been incorporated in this review. Among five included studies, no reduction in all-cause mortality was observed in the combination arm, with a summary hazard ratio (HR) of 0.91 (95% CI: 0.81-1.02). Longer progression-free survival was observed in those treated with the combination chemotherapy (HR: 0.68, 95% CI: 0.53-0.87), however, this result may have been driven by findings from the single first-line treatment setting study.The quality of evidence for overall survival was low and for progression-free survival was moderate, mainly due to study limitation from the lack of information on randomisation methods and allocation concealment.There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia, and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group. Evidence for toxicity has been assessed to be low to moderate quality.
  
  
  CONCLUSIONS
  There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone, thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC. Given the low and moderate quality of the evidence, future studies with sufficient numbers of patients in each treatment arms are needed to clarify the benefit observed in progression-free survival with combination irinotecan and fluoropyrimidines.
authors: Cancer Epidemiology Group, Division of Studies, Faculty of Life Sciences and Medicine, King's College London, Research Oncology, 3rd floor Bermondsey Wing, Guy's Hospital, London, England, UK, SE1 9RT.
authors: Wahyu
authors: W
authors: Wulaningsih
authors: Ardyan
authors: A
authors: Wardhana
authors: Johnathan
authors: J
authors: Watkins
authors: Naomi
authors: N
authors: Yoshuantari
authors: Dimitra
authors: D
authors: Repana
authors: Mieke
authors: M
authors: Van Hemelrijck
mesh_terms: D000505:Alopecia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin