title: Colorectal Cancer Survival Gains and Novel Treatment Regimens: A Systematic Review and Analysis.
abstract: OBJECTIVE
  The past 2 decades have witnessed progress in the management of metastatic colorectal cancer (mCRC) with more effective agents and better surgical, medical, and supportive care. While substantial progress has been made, much more must be achieved to prolong the lives of patients.
  
  
  OBJECTIVE
  To conduct a systematic review to ascertain what percentage of the life expectancy gain in locally advanced and mCRC over the past 2 decades is due to novel therapies vs improvements in supportive care or secular trends and to thus inform treatment development strategies.
  
  
  METHODS
  We searched Cochrane Controlled Trials Register, Medline, Embase, CancerLit, and Healthstar electronic databases for trials covering the period 1993 to 2015, scanned reference lists of articles, and searched recent conference abstracts. Ninety-six phase 3 trials and large (>50 patients) phase 2 trials in mCRC were examined. Outcomes evaluated in the experimental arms (EAs) and control arms (CAs) included overall response rate, stable disease, progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  Over the period covered by the studies, the OS in EAs increased at a mean (95% CI) rate of 0.80 (0.67-0.93) mo/y. Importantly, OS in the CAs improved 0.63 (0.51-0.75) mo/y, reflecting in part the use of experimental regimens in subsequent studies. Chemotherapy contributed only partly to the gains in OS, given that (1) mean (95% CI) improvements in PFS were only 0.31 (0.22-0.39) mo/y in the EAs and 0.23 (0.15-0.31) mo/y in CAs; (2) gains in survival not directly attributable to the protocol were greater than gains in PFS (0.46 [0.36-0.57] mo/y in EAs and 0.39 [0.29-0.49] mo/y in CAs; and (3) effects on OS were much lower in second-line trials (median [interquartile range] response rates, 8.6% [0%-11.0%] in EAs and 7.5% [3.8%-12.8%] in CAs) compared with first-line trials (39.5% [24.0%-50.2%] for EAs and 29.4% [16.4%-39.4%] for CAs).
  
  
  CONCLUSIONS
  The OS of patients with mCRC has improved gradually over the past 2 decades, with gains from chemotherapy occurring alongside gains from lead-time bias and improved locoregional approaches and supportive care. Gains from first-line therapies have been modest but consistent; however, gains from second-line therapies have been disappointing. We believe that future progress will be greater if emphasis is placed on enrolling patients in experimental trials to explore and develop alternative first-line regimens and better second-line therapies.
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland2Lawrence Memorial Hospital Oncology Center, Lawrence, Kansas.
authors.forename: Irfan
authors.initials: I
authors.lastname: Jawed
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Vinay
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Duffy
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D005544:Forecasting; D006801:Humans; D008495:Medical Oncology / Q000639:trends*; D009362:Neoplasm Metastasis; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome