title: Association between treatment toxicity and outcomes in oncology clinical trials.
abstract: BACKGROUND
  Whether or not toxicity predicts clinical outcomes has long been a question regarding cancer treatments. While prior studies have focused on specific cancers, therapies, and toxicities, no comprehensive evidence exists on whether treatment toxicity predicts favorable outcomes.
  
  
  METHODS
  We abstracted treatment toxicity and clinical outcome data from a sample of phase III oncology randomized clinical trials (n = 99 trials). We investigated whether treatments with relatively greater toxicity compared with their controls had relatively higher, lower, or equivocal rates of clinical efficacy, measured by progression-free survival (PFS) and overall survival (OS). Several toxicities were assessed (all grades, grades III/IV, cutaneous rash, gastrointestinal toxicity, and myelosuppression).
  
  
  RESULTS
  Toxicity and efficacy were greater among treatments than controls (e.g. 3.5 instances of all-grade toxicity per patient in treatment arms versus 2.8 instances in controls, P < 0.001; mean PFS of 9.1 months across treatment arms versus 7.1 months across controls, P < 0.001; mean OS of 18.6 months across treatment arms versus 16.9 months across controls, P < 0.001). Across trials, greater relative treatment toxicity was strongly associated with greater PFS in treatments versus controls (P < 0.001), but not OS (P = 0.44). Although higher relative rates of myelosuppression and cutaneous rash among treatments were not associated with greater treatment efficacy, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007).
  
  
  CONCLUSIONS
  Across trials, treatments with relatively greater all-grade toxicity compared with controls are associated with relatively greater PFS but not OS.
authors.affiliation: Department of Family Medicine, Case Western Reserve University School of Medicine, Cleveland.
authors.forename: M V
authors.initials: MV
authors.lastname: Abola
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda.
authors.forename: V
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Department of Health Care Policy, Harvard Medical School, Boston; Department of Medicine, Massachusetts General Hospital, Boston, USA. Electronic address: jena@hcp.med.harvard.edu.
authors.forename: A B
authors.initials: AB
authors.lastname: Jena
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: clinical trials; treatment toxicity