title: The effect of salvage therapy on survival in a longitudinal study with treatment by indication.
abstract: We consider using observational data to estimate the effect of a treatment on disease recurrence, when the decision to initiate treatment is based on longitudinal factors associated with the risk of recurrence. The effect of salvage androgen deprivation therapy (SADT) on the risk of recurrence of prostate cancer is inadequately described by the existing literature. Furthermore, standard Cox regression yields biased estimates of the effect of SADT, since it is necessary to adjust for prostate-specific antigen (PSA), which is a time-dependent confounder and an intermediate variable. In this paper, we describe and compare two methods which appropriately adjust for PSA in estimating the effect of SADT. The first method is a two-stage method which jointly estimates the effect of SADT and the hazard of recurrence in the absence of treatment by SADT. In the first stage, PSA is predicted in the absence of SADT, and in the second stage, a time-dependent Cox model is used to estimate the benefit of SADT, adjusting for PSA. The second method, called sequential stratification, reorganizes the data to resemble a sequence of experiments in which treatment is conditionally randomized given the time-dependent covariates. Strata are formed, each consisting of a patient undergoing SADT and a set of appropriately matched controls, and analysis proceeds via stratified Cox regression. Both methods are applied to data from patients initially treated with radiation therapy for prostate cancer and give similar SADT effect estimates.
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Kennedy
authors.forename: Jeremy M G
authors.initials: JM
authors.lastname: Taylor
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Schaubel
authors.forename: Scott
authors.initials: S
authors.lastname: Williams
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D015986:Confounding Factors, Epidemiologic; D003627:Data Interpretation, Statistical; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D018570:Risk Assessment; D016879:Salvage Therapy; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D017430:Prostate-Specific Antigen
references.citation: Eur Urol. 1998;33(1):39-53
references.pmid: 9471040
references.citation: J Am Stat Assoc. 2001;96(455):
references.pmid: 24204084
references.citation: Am J Epidemiol. 2007 Nov 1;166(9):985-93
references.pmid: 17875580
references.citation: Biometrics. 1997 Mar;53(1):330-9
references.pmid: 9147598
references.citation: J Clin Endocrinol Metab. 1991 Nov;73(5):1016-25
references.pmid: 1719016
references.citation: Int J Biostat. 2007;3(1):Article 3
references.pmid: 19122793
references.citation: Cochrane Database Syst Rev. 2002;(1):CD003506
references.pmid: 11869665
references.citation: Stat Med. 1989 Jun;8(6):679-701
references.pmid: 2749074
references.citation: Biometrics. 2005 Sep;61(3):721-8
references.pmid: 16135023
references.citation: Basic Clin Pharmacol Toxicol. 2006 Mar;98(3):237-42
references.pmid: 16611197
references.citation: Cancer. 1993 Jul 15;72(2):538-48
references.pmid: 7686443
references.citation: JAMA. 2005 Jul 13;294(2):238-44
references.pmid: 16014598
references.citation: Stat Med. 1998 Sep 30;17(18):2061-77
references.pmid: 9789914
references.citation: Cancer. 2008 Jan 15;112(2):307-14
references.pmid: 18050294
references.citation: Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):782-91
references.pmid: 19014779
references.citation: JAMA. 1999 May 5;281(17):1598-604
references.pmid: 10235152
references.citation: Biometrics. 2006 Sep;62(3):910-7
references.pmid: 16984335
references.citation: J Androl. 1991 Nov-Dec;12(6):376-80
references.pmid: 1722793
references.citation: J Clin Oncol. 2006 Sep 20;24(27):4448-56
references.pmid: 16983113