title: Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.
abstract: BACKGROUND
  Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy.
  
  
  METHODS
  Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS).
  
  
  RESULTS
  The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively.
  
  
  CONCLUSIONS
  Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.
authors: National Institute for Health and Medical Research (INSERM) Unit 776, "Biological Rhythms and Cancers," Villejuif, France.
authors: Pasquale F
authors: PF
authors: Innominato
authors: Sylvie
authors: S
authors: Giacchetti
authors: Thierry
authors: T
authors: Moreau
authors: Georg A
authors: GA
authors: Bjarnason
authors: Rune
authors: R
authors: Smaaland
authors: Christian
authors: C
authors: Focan
authors: Carlo
authors: C
authors: Garufi
authors: Stefano
authors: S
authors: Iacobelli
authors: Marco
authors: M
authors: Tampellini
authors: Salvatore
authors: S
authors: Tumolo
authors: Carlos
authors: C
authors: Carvalho
authors: Abdoulaye
authors: A
authors: Karaboué
authors: Antoine
authors: A
authors: Poncet
authors: David
authors: D
authors: Spiegel
authors: Francis
authors: F
authors: Lévi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D055870:Drug Chronotherapy; D005221:Fatigue; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D015431:Weight Loss
chemical_list: D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil
keywords: chemotherapy; circadian; colorectal cancer; prognostic factor; toxicity