title: Joint modeling of longitudinal health-related quality of life data and survival.
abstract: OBJECTIVE
  In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival.
  
  
  METHODS
  Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)].
  
  
  RESULTS
  The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58-1.00) for M1, 0.72 (0.55-0.96) for M2, and 0.69 (0.52-0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01-1.12) for M2 and 1.13 (1.03-1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2.
  
  
  CONCLUSIONS
  Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients' HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling.
authors.affiliation: Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium, ediebahdivine@gmail.com.
authors.forename: Divine E
authors.initials: DE
authors.lastname: Ediebah
authors.forename: Francisca
authors.initials: F
authors.lastname: Galindo-Garre
authors.forename: Bernard M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: Jolie
authors.initials: J
authors.lastname: Ringash
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
authors.forename: Linda
authors.initials: L
authors.lastname: Dirven
authors.forename: Efstathios
authors.initials: E
authors.lastname: Zikos
authors.forename: Corneel
authors.initials: C
authors.lastname: Coens
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Andrew
authors.initials: A
authors.lastname: Bottomley
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000532:radiotherapy; D005260:Female; D006801:Humans; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009837:Oligodendroglioma / Q000188:drug therapy / Q000401:mortality* / Q000532:radiotherapy; D017063:Outcome Assessment, Health Care; D011344:Procarbazine / Q000627:therapeutic use; D011788:Quality of Life; D011795:Surveys and Questionnaires; D013995:Time; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine