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Research Letter |

Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer FREE

Anthony V. D’Amico, MD, PhD1; Ming-Hui Chen, PhD2; Andrew Renshaw, MD3; Marian Loffredo, RN, OCN1; Philip W. Kantoff, MD4
[+] Author Affiliations
1Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts
2Department of Statistics, University of Connecticut, Storrs
3Department of Pathology, Miami Baptist Hospital, Miami, Florida
4Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts
JAMA. 2015;314(12):1291-1293. doi:10.1001/jama.2015.8577.
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Published online

Six months of androgen deprivation therapy (ADT) and radiation therapy (RT) vs RT alone prolongs survival1 and is the standard treatment for unfavorable-risk prostate cancer. A postrandomization hypothesis-generating analysis1 suggested that men with moderate or severe comorbidity had no survival benefit from combined therapy.

In addition, ADT use in men with unfavorable-risk prostate cancer was not associated with increased cardiac mortality in a meta-analysis,2 but whether men with moderate or severe comorbidity experience increased cardiac mortality with ADT remains unknown. Using updated data from our randomized trial,1 we compared overall survival and mortality from prostate cancer, cardiac, or other causes in all men and those within comorbidity subgroups by randomized treatment group.

Between December 1, 1995, and April 15, 2001, 206 men with unfavorable-risk prostate cancer were randomized to receive RT alone or RT and 6 months of ADT at 3 academic and 3 community-based centers in Massachusetts.1 Using information collected before randomization, a comorbidity score was assigned using the Adult Comorbidity Evaluation 27. The patient’s oncologist determined the cause of death, which was updated through February 21, 2015. To assign prostate cancer as the cause of death, castration-resistant metastatic disease, prostate-specific antigen test results with increasing levels despite hormonal manipulation, and usually chemotherapy before death was required; a lethal myocardial infarction defined cardiac mortality. Men signed an informed consent form approved by the institutional review boards at St Anne’s Hospital and the Dana Farber Harvard Cancer Center, and a waiver of consent was obtained for long-term follow-up.

Kaplan-Meier3 survival and cumulative incidence4 cause-specific mortality estimates stratified by randomized treatment and comorbidity were compared using log-rank and k-sample P values. For the postrandomization analyses, Cox regression methods5 and the methods of Fine and Gray6 were used to evaluate whether a significant interaction existed between ADT and comorbidity regarding overall mortality and prostate cancer, cardiac, and other-cause mortality, adjusting for randomized treatment, age, comorbidity, and prostate cancer prognostic factors. R version 3.0.1 (R Foundation for Statistical Computing) was used for calculations pertaining to the k-sample test of Gray and the regression methods of Fine and Gray. SAS version 9.3 (SAS Institute Inc) was used for the remaining statistical analyses. A 2-sided P value <.05 was considered statistically significant.

After a median follow-up of 16.62 years (interquartile range, 15.42-17.67 years), 156 men died (76%); 29 died of prostate cancer (19%), 39 of cardiac causes (25%), and 88 of other causes (56%). Of men with moderate or severe comorbidity, 46 of 49 died (94%) vs 110 of 157 (70%) with none or minimal comorbidity. Survival did not differ in the RT alone group vs the RT and ADT group, but opposite effects of treatment on survival were observed in the comorbidity subgroups (Figure). Treatment with RT alone did not increase mortality (80 vs 76 deaths; hazard ratio [HR], 1.22 [95% CI, 0.89-1.67]; P = .22) as previously reported (HR, 1.8 [95% CI, 1.1-2.9])1 and it did not significantly affect cardiac mortality (HR, 0.74 [95% CI, 0.40-1.39]; P = .36).

Place holder to copy figure label and caption
Figure.
Overall Survival Stratified by Randomized Treatment Group

The 15-year survival estimates for panel A were 27.58 (95% CI, 19.16-36.64) for radiation therapy (RT) alone vs 35.47 (95% CI, 26.20-44.84) for RT and androgen deprivation therapy (ADT); panel B, 30.52 (95% CI, 20.52-41.09) for RT alone vs 43.77 (95% CI, 32.41-54.56) for RT and ADT; panel C, 20.00 (95% CI, 7.28-37.20) for RT alone vs 8.33 (95% CI, 1.44-23.30) for RT and ADT. The 2-sided log-rank P value comparing survival in men across the 2 treatment groups was .22 for panel A, .04 for panel B, and .07 for panel C.

aDescription of comorbidity based on the 4 grades (grade 0, none; grade 1, minimal; grade 2, moderate; and grade 3, severe) of the Adult Comorbidity Evaluation 27; the grade corresponds to the severity of the individual organ system decompensation and prognostic effect.

Graphic Jump Location

In multivariable analyses, RT alone vs RT and ADT in men with none or minimal comorbidity was associated with significantly increased overall mortality (HR, 1.51 [95% CI, 1.03-2.21]; P = .04) and prostate cancer mortality (HR, 4.30 [95% CI, 1.60-11.50]; P = .004), no difference in cardiac mortality (HR, 1.72 [95% CI, 0.64-4.58]; P = .28), and decreased other cause mortality (HR, 0.60 [95% CI, 0.36-0.99]; P = .04) (Table). Conversely, in men with moderate or severe comorbidity, RT alone vs RT and ADT was associated with significantly decreased overall mortality (HR, 0.36 [95% CI, 0.19-0.67]; P = .001) and cardiac mortality (HR, 0.17 [95% CI, 0.06-0.46]; P < .001), no difference in prostate cancer mortality (HR, 2.41 [95% CI, 0.23-25.21]; P = .46), and increased other cause mortality (HR, 2.79 [95% CI, 1.02-7.60]; P = .05).

Table Graphic Jump LocationTable.  All-Cause, Prostate Cancer, Cardiac, and Other-Cause Mortality Hazard Ratios by Patient, Prostate Cancer, and Treatment Factors

At a median follow-up of 16.62 years, RT alone vs RT and ADT was associated with significantly decreased overall and cardiac mortality in men with moderate or severe comorbidity, in contrast to no association with overall mortality at a median follow-up of 7.6 years (HR, 0.54 [95% CI, 0.27-1.10]; P = .08).1 Although RT alone vs RT and ADT was associated with increased mortality in men with none or minimal comorbidity, mortality among all men randomized to RT alone was not significantly increased.

Limitations include that the results from postrandomization analyses are hypothesis-generating and in some cases based on low event rates and therefore require validation. Nevertheless, the association of treatment with RT alone with decreased cardiac and overall mortality in men with moderate or severe comorbidity suggests that administering ADT to treat unfavorable-risk prostate cancer in these men should be carefully considered.

Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Anthony V. D’Amico, MD, PhD, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (adamico@partners.org).

Author Contributions: Dr D’Amico had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: D’Amico, Kantoff.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: D’Amico, Chen.

Critical revision of the manuscript for important intellectual content: D’Amico, Chen, Renshaw, Loffredo.

Statistical analysis: Chen.

Administrative, technical, or material support: D’Amico, Loffredo.

Study supervision: D’Amico, Kantoff.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Trial Registration: clinicaltrials.gov Identifier: NCT00116220

D’Amico  AV, Chen  MH, Renshaw  AA, Loffredo  M, Kantoff  PW.  Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289-295.
PubMed   |  Link to Article
Nguyen  PL, Je  Y, Schutz  FA,  et al.  Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306(21):2359-2366.
PubMed   |  Link to Article
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457-481.
Link to Article
Gaynor  JJ, Feuer  EJ, Tan  CC,  et al.  On the use of cause-specific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc. 1993;88(422):400-409.
Link to Article
Klein  JP, Moeschberger  ML. Semiparametric proportional hazards regression with fixed covariates. In: Survival Analysis—Techniques for Censored and Truncated Data: Second Edition. New York, NY: Springer; 2003:243-293.
Fine  JP, Gray  RJ.  A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509.
Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Overall Survival Stratified by Randomized Treatment Group

The 15-year survival estimates for panel A were 27.58 (95% CI, 19.16-36.64) for radiation therapy (RT) alone vs 35.47 (95% CI, 26.20-44.84) for RT and androgen deprivation therapy (ADT); panel B, 30.52 (95% CI, 20.52-41.09) for RT alone vs 43.77 (95% CI, 32.41-54.56) for RT and ADT; panel C, 20.00 (95% CI, 7.28-37.20) for RT alone vs 8.33 (95% CI, 1.44-23.30) for RT and ADT. The 2-sided log-rank P value comparing survival in men across the 2 treatment groups was .22 for panel A, .04 for panel B, and .07 for panel C.

aDescription of comorbidity based on the 4 grades (grade 0, none; grade 1, minimal; grade 2, moderate; and grade 3, severe) of the Adult Comorbidity Evaluation 27; the grade corresponds to the severity of the individual organ system decompensation and prognostic effect.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  All-Cause, Prostate Cancer, Cardiac, and Other-Cause Mortality Hazard Ratios by Patient, Prostate Cancer, and Treatment Factors

References

D’Amico  AV, Chen  MH, Renshaw  AA, Loffredo  M, Kantoff  PW.  Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289-295.
PubMed   |  Link to Article
Nguyen  PL, Je  Y, Schutz  FA,  et al.  Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306(21):2359-2366.
PubMed   |  Link to Article
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457-481.
Link to Article
Gaynor  JJ, Feuer  EJ, Tan  CC,  et al.  On the use of cause-specific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc. 1993;88(422):400-409.
Link to Article
Klein  JP, Moeschberger  ML. Semiparametric proportional hazards regression with fixed covariates. In: Survival Analysis—Techniques for Censored and Truncated Data: Second Edition. New York, NY: Springer; 2003:243-293.
Fine  JP, Gray  RJ.  A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509.
Link to Article
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