Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer

TY - JOUR

T1 - Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer

T2 - A Patient-Level Data Analysis of 3 Cohorts

AU - Kishan, Amar U

AU - Steigler, Alison

AU - Denham, James W

AU - Zapatero, Almudena

AU - Guerrero, Araceli

AU - Joseph, David

AU - Maldonado, Xavier

AU - Wong, Jessica K

AU - Stish, Bradley J

AU - Dess, Robert T

AU - Pilar, Avinash

AU - Reddy, Chandana

AU - Wedde, Trude B

AU - Lilleby, Wolfgang A

AU - Fiano, Ryan

AU - Merrick, Gregory S

AU - Stock, Richard G

AU - Demanes, D Jeffrey

AU - Moran, Brian J

AU - Tran, Phuoc T

AU - Martin, Santiago

AU - Martinez-Monge, Rafael

AU - Krauss, Daniel J

AU - Abu-Isa, Eyad I

AU - Pisansky, Thomas M

AU - Choo, C Richard

AU - Song, Daniel Y

AU - Greco, Stephen

AU - Deville, Curtiland

AU - McNutt, Todd

AU - DeWeese, Theodore L

AU - Ross, Ashley E

AU - Ciezki, Jay P

AU - Tilki, Derya

AU - Karnes, R Jeffrey

AU - Tosoian, Jeffrey J

AU - Nickols, Nicholas G

AU - Bhat, Prashant

AU - Shabsovich, David

AU - Juarez, Jesus E

AU - Jiang, Tommy

AU - Ma, T Martin

AU - Xiang, Michael

AU - Philipson, Rebecca

AU - Chang, Albert

AU - Kupelian, Patrick A

AU - Rettig, Matthew B

AU - Feng, Felix Y

AU - Berlin, Alejandro

AU - Tward, Jonathan D

AU - Davis, Brian J

AU - Reiter, Robert E

AU - Steinberg, Michael L

AU - Elashoff, David

AU - Boutros, Paul C

AU - Horwitz, Eric M

AU - Tendulkar, Rahul D

AU - Spratt, Daniel E

AU - Romero, Tahmineh

PY - 2022/3/1

Y1 - 2022/3/1

N2 - IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

AB - IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

KW - Androgen Antagonists/adverse effects

KW - Androgens

KW - Brachytherapy/adverse effects

KW - Data Analysis

KW - Humans

KW - Male

KW - Middle Aged

KW - Prostatic Neoplasms/drug therapy

KW - Retrospective Studies

U2 - 10.1001/jamaoncol.2021.6871

DO - 10.1001/jamaoncol.2021.6871

M3 - SCORING: Journal article

C2 - 35050303

VL - 8

SP - e216871

JO - JAMA ONCOL

JF - JAMA ONCOL

SN - 2374-2437

IS - 3

ER -