Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate Cancer | Oncology | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Kuban  DA, Tucker  SL, Dong  L,  et al.  Long-term results of the MD Anderson randomized dose-escalation trial for prostate cancer.  Int J Radiat Oncol Biol Phys. 2008;70(1):67-74.PubMedGoogle ScholarCrossref
Heemsbergen  WD, Al-Mamgani  A, Slot  A, Dielwart  MF, Lebesque  JV.  Long-term results of the Dutch randomized prostate cancer trial: impact of dose-escalation on local, biochemical, clinical failure, and survival.  Radiother Oncol. 2014;110(1):104-109.PubMedGoogle ScholarCrossref
Zietman  AL, Bae  K, Slater  JD,  et al.  Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09.  J Clin Oncol. 2010;28(7):1106-1111.PubMedGoogle ScholarCrossref
Beckendorf  V, Guerif  S, Le Prisé  E,  et al.  70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial.  Int J Radiat Oncol Biol Phys. 2011;80(4):1056-1063.PubMedGoogle ScholarCrossref
Dearnaley  DP, Jovic  G, Syndikus  I,  et al.  Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial.  Lancet Oncol. 2014;15(4):464-473.PubMedGoogle ScholarCrossref
Andriole  GL, Crawford  ED, Grubb  RL  III,  et al; PLCO Project Team.  Mortality results from a randomized prostate-cancer screening trial.  N Engl J Med. 2009;360(13):1310-1319.PubMedGoogle ScholarCrossref
Schröder  FH, Hugosson  J, Roobol  MJ,  et al; ERSPC Investigators.  Screening and prostate-cancer mortality in a randomized European study.  N Engl J Med. 2009;360(13):1320-1328.PubMedGoogle ScholarCrossref
Lu-Yao  GL, Albertsen  PC, Moore  DF,  et al.  Outcomes of localized prostate cancer following conservative management.  JAMA. 2009;302(11):1202-1209.PubMedGoogle ScholarCrossref
Stattin  P, Holmberg  E, Johansson  J-E, Holmberg  L, Adolfsson  J, Hugosson  J; National Prostate Cancer Register (NPCR) of Sweden.  Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study.  J Natl Cancer Inst. 2010;102(13):950-958.PubMedGoogle ScholarCrossref
Daskivich  TJ, Fan  KH, Koyama  T,  et al.  Effect of age, tumor risk, and comorbidity on competing risks for survival in a U.S. population-based cohort of men with prostate cancer.  Ann Intern Med. 2013;158(10):709-717.PubMedGoogle ScholarCrossref
Michalski  JM, Moughan  J, Purdy  JA,  et al.  Initial results of a phase III randomized study of high-dose 3DCRT/IMRT vs standard-dose 3DCRT/IMRT in patients treated for localized prostate cancer (RTOG 0126).2014. Accessed June 9, 2015.
American College of Surgeons.  About the National Cancer Database. Accessed January 25, 2015.
American College of Surgeons Commission on Cancer.  Participant User Files. Accessed January 15, 2015.
Swisher-McClure  S, Mitra  N, Woo  K, Smaldone  M, Uzzo  R, Bekelman  JE.  Increasing use of dose-escalated external beam radiation therapy for men with nonmetastatic prostate cancer.  Int J Radiat Oncol Biol Phys. 2014;89(1):103-112.PubMedGoogle ScholarCrossref
NCCN Clinical Practice Guidelines in Oncology.  Prostate Cancer. Version 1.2015. Accessed June 15, 2015.
Hill  AB.  The environment and disease: association or causation?  Proc R Soc Med. 1965;58:295-300.PubMedGoogle Scholar
Kalbasi  A, Swisher-McClure  S, Mitra  N,  et al.  Low rates of adjuvant radiation in patients with nonmetastatic prostate cancer with high-risk pathologic features.  Cancer. 2014;120(19):3089-3096.PubMedGoogle ScholarCrossref
Taksler  GB, Keating  NL, Cutler  DM.  Explaining racial differences in prostate cancer mortality.  Cancer. 2012;118(17):4280-4289.PubMedGoogle ScholarCrossref
Curtis  LH, Hammill  BG, Eisenstein  EL, Kramer  JM, Anstrom  KJ.  Using inverse probability-weighted estimators in comparative effectiveness analyses with observational databases.  Med Care. 2007;45(10)(suppl 2):S103-S107.PubMedGoogle ScholarCrossref
Rubin  DB.  Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127(8 Pt 2):757-763.PubMedGoogle ScholarCrossref
Rubin  DB, Thomas  N.  Matching using estimated propensity scores: relating theory to practice.  Biometrics. 1996;52(1):249-264.PubMedGoogle ScholarCrossref
Collett  D.  Modelling Survival Data in Medical Data.2nd ed. New York, NY: Chapman & Hall CRC Texts in Statistical Science; 2003.
Mattei  A.  Estimating and using propensity score in presence of missing background data: an application to assess the impact of childbearing on wellbeing.  Stat Methods Appl. 2009;18:257-273. doi:10.1007/s10260-007-0086-0.Google ScholarCrossref
Klein  JP, Moeschberger  ML.  Survival Analysis: Techniques for Censored and Truncated Data. 2nd ed. New York, NY: Springer Science & Business Media; 2003.
Imbens  GW.  The role of the propensity score in estimating dose-response functions.  Biometrika. 2000;87(3):706-710. doi:10.1093/biomet/87.3.706.Google ScholarCrossref
Mitra  N, Heitjan  DF.  Sensitivity of the hazard ratio to nonignorable treatment assignment in an observational study.  Stat Med. 2007;26(6):1398-1414.PubMedGoogle ScholarCrossref
Lin  DY, Psaty  BM, Kronmal  RA.  Assessing the sensitivity of regression results to unmeasured confounders in observational studies.  Biometrics. 1998;54(3):948-963.PubMedGoogle ScholarCrossref
Spillman  BC.  Changes in elderly disability rates and the implications for health care utilization and cost.  Milbank Q. 2004;82(1):157-194.PubMedGoogle ScholarCrossref
Cawthon  PM, Marshall  LM, Michael  Y,  et al; Osteoporotic Fractures in Men Research Group.  Frailty in older men: prevalence, progression, and relationship with mortality.  J Am Geriatr Soc. 2007;55(8):1216-1223.PubMedGoogle ScholarCrossref
Brookhart  MA, Rassen  JA, Schneeweiss  S.  Instrumental variable methods in comparative safety and effectiveness research.  Pharmacoepidemiol Drug Saf. 2010;19(6):537-554.PubMedGoogle ScholarCrossref
Rassen  JA, Brookhart  MA, Glynn  RJ, Mittleman  MA, Schneeweiss  S.  Instrumental variables, I: instrumental variables exploit natural variation in nonexperimental data to estimate causal relationships.  J Clin Epidemiol. 2009;62(12):1226-1232.PubMedGoogle ScholarCrossref
Klotz  L, Vesprini  D, Sethukavalan  P,  et al.  Long-term follow-up of a large active surveillance cohort of patients with prostate cancer.  J Clin Oncol. 2015;33(3):272-277.PubMedGoogle ScholarCrossref
Spratt  DE, Zumsteg  ZS, Ghadjar  P,  et al.  Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.  BJU Int. 2014;114(3):360-367.PubMedGoogle Scholar
Warde  P, Mason  M, Ding  K,  et al; NCIC CTG PR.3/MRC UK PR07 investigators.  Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.  Lancet. 2011;378(9809):2104-2111.PubMedGoogle ScholarCrossref
Widmark  A, Klepp  O, Solberg  A,  et al; Scandinavian Prostate Cancer Group Study 7; Swedish Association for Urological Oncology 3.  Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.  Lancet. 2009;373(9660):301-308.PubMedGoogle ScholarCrossref
Koshy  M, Malik  R, Weichselbaum  RR, Sher  DJ.  Increasing radiation therapy dose is associated with improved survival in patients undergoing stereotactic body radiation therapy for stage I non-small-cell lung cancer.  Int J Radiat Oncol Biol Phys. 2015;91(2):344-350.PubMedGoogle ScholarCrossref
Original Investigation
October 2015

Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate Cancer

Author Affiliations
  • 1Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 2Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 3Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 4Leonard Davis Institute of Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 5Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
  • 6Department of Statistics, The Wharton School at the University of Pennsylvania, Philadelphia
  • 7Department of Medical Ethics and Health Policy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
JAMA Oncol. 2015;1(7):897-906. doi:10.1001/jamaoncol.2015.2316

Importance  In 5 published randomized clinical trials, dose-escalated external-beam radiation therapy (EBRT) for prostate cancer resulted in improved biochemical and local control. However, scarce evidence addresses whether dose escalation improves overall survival.

Objective  To examine the association between dose-escalated EBRT and overall survival among men with nonmetastatic prostate cancer.

Design, Setting, and Participants  We conducted a retrospective, nonrandomized comparative effectiveness study of dose-escalated vs standard-dose EBRT for prostate cancer diagnosed from 2004 to 2006 using the National Cancer Database (NCDB), which includes data from patients treated at Commission on Cancer–accredited community, academic, and comprehensive cancer facilities. Three cohorts were evaluated: men with low-risk (n = 12 229), intermediate-risk (n = 16 714), or high-risk (n = 13 538) prostate cancer.

Exposures  We categorized patients in each risk cohort into 2 treatment groups: standard-dose (from 68.4 Gy to <75.6 Gy) or dose-escalated (≥75.6 Gy to 90 Gy) EBRT (1 Gy = 100 rad).

Main Outcomes and Measures  We compared overall survival between treatment groups in each analytic cohort using Cox proportional hazard models with an inverse probability weighted propensity score (IPW-PS) approach. In secondary analyses, we evaluated dose response for survival.

Results  Dose-escalated EBRT was associated with improved survival in the intermediate-risk (IPW-PS adjusted hazard ratio [HR], 0.84; 95% CI, 0.80-0.88; P < .001) and high-risk groups (HR, 0.82; 95% CI, 0.78-0.85; P < .001) but not the low-risk group (HR, 0.98; 95% CI, 0.92-1.05; P = .54). For every incremental increase of about 2 Gy in dose, there was a 7.8% (95% CI, 5.4%-10.2%; P < .001) and 6.3% (95% CI, 3.3%-9.1%; P < .001) reduction in the hazard of death for intermediate- and high-risk patients, respectively.

Conclusions and Relevance  Dose-escalated EBRT is associated with improved overall survival in men with intermediate- and high-risk prostate cancer but not low-risk prostate cancer. These results add to the evidence questioning aggressive local treatment strategies in men with low-risk prostate cancer but supporting such treatment in men with greater disease severity.