title: Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity?
abstract: BACKGROUND
  Adverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy.
  
  
  METHODS
  Data from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05 years.
  
  
  RESULTS
  47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome.
  
  
  CONCLUSIONS
  Specific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. Electronic address: leena-maija.soveri@hus.fi.
authors.forename: L M
authors.initials: LM
authors.lastname: Soveri
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Hermunen
authors.affiliation: Department of Oncology, Hôpital Saint-Antoine, Paris, France; University Pierre et Marie Curie, Paris VI, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: de Gramont
authors.affiliation: STAT-Consulting, Nokia, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Poussa
authors.affiliation: International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Quinaux
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Bono
authors.affiliation: Department of Oncology, Hôpital Saint-Antoine, Paris, France; University Pierre et Marie Curie, Paris VI, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: André
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Österlund
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003967:Diarrhea / Q000139:chemically induced / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D060831:Hand-Foot Syndrome / Q000209:etiology / Q000401:mortality; D006402:Hematologic Diseases / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced / Q000401:mortality; D009325:Nausea / Q000139:chemically induced / Q000401:mortality; D011446:Prospective Studies; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced / Q000401:mortality
chemical_list: D002955:Leucovorin; D005472:Fluorouracil
keywords: 5-Fluorouracil; Adjuvant therapy; Adverse events; Colorectal cancer; Prognosis