Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04 RADAR Trial

CME www.redjournal.org

Clinical Investigation

Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04 RADAR Trial David Joseph, FRANZCR,*,y,z James W. Denham, MD, FRANZCR,x Allison Steigler, BMath,x David S. Lamb, FRANZCR,k Nigel A. Spry, PhD, FRANZCR,y John Stanley, MBBS, FRCS, FRACS(Urol),{ Tom Shannon, MBBS, FRACS(Urol),# Gillian Duchesne, MD, FRANZCR,** Chris Atkinson, FRANZCR,yy John H.L. Matthews, FRANZCR,zz Sandra Turner, FRANZCR,kk Lizbeth Kenny, FRANZCR,{{,## David Christie, FRANZCR,*** Keen-Hun Tai, FRANZCR,** Nirdosh Kumar Gogna, FRANZCR,yyy Rachel Kearvell, DipHealthAdmin,zzz Judy Murray, DipHealthSc,k Martin A. Ebert, PhD,z,xxx Annette Haworth, PhD,kkk Brett Delahunt, MD,k Christopher Oldmeadow, PhD,x,{{{ and John Attia, MD, PhDx,{{{ *Department of Medicine and Surgery, University of Western Australia, Western Australia, Australia; y GenesisCare, Joondalup, Western Australia, Australia; z5D Clinics, Claremont, Western Australia, Australia; xSchool of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia; kWellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; {Hollywood Specialist Centre, Nedlands, Western Australia, Australia; # The Prostate Clinic, Nedlands, Western Australia, Australia; **Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia; yySt Georges Cancer Care Centre, Christchurch, New Zealand; zzCancer and Blood Services, Auckland District Health Board, Auckland, New Zealand; kk Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia; {{ Royal Brisbane and Women’s Hospital, Brisbane, Australia; ##School of Medicine, University of Queensland, Queensland, Australia; ***Genesiscare, Tugun, Queensland, Australia; yyyMater Radiation Oncology Centre, Princess Alexandra Hospital, Brisbane, Queensland, Australia; zzz GenesisCare, St Andrew’s Hospital, Adelaide, South Australia, Australia; xxxDepartment of Physics, NotedAn online CME test for this article can be taken at https:// academy.astro.org. Corresponding author: James W. Denham, MD, FRANZCR; E-mail: [email protected] This work was supported by the National Health and Medical Research Council of Australia (Project Application ID 300705, 455521 and 1099149); The Goodfellow Foundation, Auckland (New Zealand); Cancer Int J Radiation Oncol Biol Phys, Vol. 106, No. 4, pp. 693e702, 2020 0360-3016/$ - see front matter Ó 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ijrobp.2019.11.415

Standards Institute of New Zealand; Novartis Pharmaceuticals Australia; and AbbVie Pharmaceuticals Australia. Disclosures: J.W.D. reports grants from Novartis Pharmaceuticals and grants and nonfinancial support from AbbVie during the conduct of the study. All other authors declare no competing interests. Supplementary material for this article can be found at https://doi.org/ 10.1016/j.ijrobp.2019.11.415.

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International Journal of Radiation Oncology  Biology  Physics

University of Western Australia, Crawley, Western Australia, Australia; kkkSchool of Physics, University of Sydney, Sydney, New South Wales; and {{{Hunter Medical Research Institute, Newcastle, New South Wales, Australia Received Nov 17, 2019. Accepted for publication Nov 21, 2019.

Purpose: To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer. Methods and Materials: Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS  18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group. Results: A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P Z .002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P Z .76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P < .0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups. Conclusions: Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial. Ó 2019 Elsevier Inc. All rights reserved.

Introduction Opinion remains divided on how much androgen suppression (AS) is necessary for men with locally advanced prostate cancer if they are treated with escalated radiation (RT) doses. In our first report of our RT dose escalation substudy for the RADAR trial, we found that increasing AS and RT dose escalation independently reduced local progressions.1 We had insufficient data at that time, with minimum follow-up of 6.5 years after randomization, to determine whether a reduction in distant progressions and prostate cancer deaths had been achieved by either treatment modality. With minimum followup of 10 years, we now have sufficient data to address these outcomes. In this report our aims are (1) to test if longer AS influences distant progression and the other secondary endpoints independently of RT dose, (2) to estimate the effect of AS duration within strata of RT doses, and (3) to assess if there is an independent ordered effect of RT dose on outcomes.

Methods and Materials Patients and treatment Men with histologically confirmed adenocarcinoma of the prostate without lymph node or systemic metastases, and with cT2b-4 stage primary tumors or cT2a stage primary

tumors with Gleason score 7 and baseline prostatespecific antigen (PSA) levels 10 ng/mL, were eligible to participate after providing informed consent. All subjects received the standard treatment of 6 months of leuprorelin (22.5 mg every 3 months, intramuscularly) commencing at randomization, 5 months before RT to the prostate and seminal vesicles. Subjects allocated to the experimental treatments received either an additional 12 months of leuprorelin (22.5 mg every 3 months, intramuscularly), or 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomization, or both. A regulated radiation dose escalation program was achieved by requiring participating centers to select their preferred dosing options from a predetermined range of doses and techniques. The dosing options were 66, 70, and 74 Gy using 2 Gy fractional increments to the International Commission on Radiation Units and Measurements (ICRU) point using external beam radiation therapy alone (EBRT only), and 46 Gy in 2 Gy fractions to the ICRU point using external beams followed by a high-dose-rate brachytherapy (HDRB) boost dose of 19.5 Gy using 3 fractions of 6.5 Gy (HDRB). Assuming an a/b ratio of 1.8 Gy without an overall time adjustment, this dosing option was estimated to be equivalent to 88 Gy in 2 Gy fractions. Brachytherapy dose was prescribed to the isodose encompassing the prostate gland and any identified extracapsular extensions. Dose constraints were 120% to the prostatic urethra and

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70% to the anterior rectal wall. No more than 50% of the prescription volume should receive 150% of the prescribed dose. Full details of the methodology used for dose escalation, derivation of radiation target volumes, dose volume histogram constraints, and set-up accuracy requirements are provided in our earlier report2 and in the relevant sections of the RADAR protocol (reproduced in the web appendix of that report). The stratification scheme used ensured that radiation dose and technique were balanced across trial arms. However, because assignment to dose and technique was not a random process in the trial, balance in baseline prognostic factors across RT groups could not be assumed. Consistency in EBRT dose delivery was assessed via dosimetric audit of centers3-7 and adherence to trial planning protocol via expert review of each treatment plan.8

Follow-up After treatment, all patients were followed up in clinic every 3 months for 18 months, then every 6 months up to 5 years post randomization, and then annually for another 5 years. At each visit, PSA levels, patient-reported outcomes, and clinician-assessed outcomes were collected and clinical examinations, including digital rectal examination, were performed. Serial rising PSAs every 2 months were used to determine the possibility of prostatic recurrence or metastatic progression. Investigations to diagnose metastases, including computed tomography (CT) scans of the abdomen and pelvis, chest x-ray, and isotopic whole-body bone scintigraphy, were mandated if symptoms suggested a need or if the PSA reached 20 ng/mL. Although the protocol did not mandate the type of secondary therapeutic intervention, it recommended that it be delayed until clinical progression was diagnosed or PSA had reached 20 ng/ mL. The closeout date was August 31, 2017, 10 years after the last subject was randomized.

Endpoints The primary endpoint of this study report was distant progression owing to its prognostic importance as a prelude to prostate cancerespecific mortality. Moreover, distant progression usually leads to secondary therapeutic intervention and frequently impairs quality of life. Secondary endpoints were local progression, bone progression, prostate cancerespecific mortality, and all-cause mortality. Time to event was measured from randomization. Distant progression was defined as metastasis at anatomic sites outside of the prostatic region, namely bones, lymph nodes, and other sites diagnosed by bone scintigraphy, CT scanning, or plain radiology. Local progression was defined as a recurrent prostatic mass diagnosed by digital rectal examination or by imaging techniques. Death was attributed to prostate cancer if it occurred in the context of progressive metastatic disease or recurrent primary cancer causing

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urinary obstruction, without reasonable alternative unrelated causes. All oncologic endpoints were reviewed annually by the Trial Endpoints Committee, blinded to subject identity and treatment allocation, who reviewed copies of all deidentified imaging, pathology, and endpoint correspondence.

Analyses In our 2014 main endpoints analyses9 we identified an interaction between the use of zoledronic acid and Gleason score that influenced all distant progression related endpoints. Our 10-year main endpoints analyses10 indicated that these interactions had dissipated substantially and no longer reached significance on the multiplicative scale. In addition, global testing for interactions found no significant differences between the 4 treatment arms, hence arms could be collapsed to compare treatment factors separately (ie, 6 months of leuprorelin [6AS] versus 18 months of leuprorelin [18AS], and 18 months of Z versus no Z). Treatment effects for AS duration (6AS vs 18AS) and RT dose (66 Gy, 70 Gy, 74 Gy, and HDRB) were assessed in multivariable models adjusted for use of 18 months of Z (no vs yes); patient age at randomization; tumor stage (T2 vs T3 or T4); Gleason grade group (1-5); and baseline PSA (<10 vs 10-20 vs >20 ng/mL). Analyses were adjusted for correlation of patients within treatment centers using the robust standard error estimator with center as the cluster term. The Wald test was performed to test for interaction between AS duration and RT dose. Descriptive statistics were used to compare baseline clinicopathologic factors across treatment groups. Associations between RT dose group and baseline factors were assessed using c2 tests for categoric variables and Kruskal-Wallis tests for continuous variables. The effect of the exposure and covariates on the probability of each endpoint in the presence of competing risks was modelled via multivariable proportional subhazards models using the method of Fine and Gray.11 Competing risks for local progression were defined as distant progression diagnosed more than 2 months before local progression and death owing to any cause. Competing risks for prostate cancerespecific mortality were defined as deaths due to other or unknown causes. For all other endpoints, the competing risk was death due to any cause. Cox regression was used to assess all-cause mortality. The proportional hazards assumption was tested in competing risks models by including interaction terms between time and each variable; the interaction term was retained in the model if the associated variable violated the assumption. For Cox regression, the proportional hazards assumption was tested by using Schoenfeld residuals. Covariates that violated the assumption were stratified for in this model. For the primary endpoint, subgroup analyses were performed to compare duration of AS within each of the RT dose groups and presented in a forest plot. A dose-response curve comparison between subjects treated with 6 months

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AS and 18 months AS was also derived from subgroup analyses using separate models of the 2 AS treatment groups. Cumulative incidence functions using the direct adjustment method were estimated and plotted for each RT dose, adjusted for all other covariates. Adjusted cumulative incidence estimates at 10 years after randomization were used to derive dose response. Subhazard ratios and cumulative incidences were estimated using 70 Gy as the reference level because this group contained the largest number of participants (n Z 427). For comparative purposes, the same models were run with 74 Gy as the reference level. A 2-sided P value of <.05 was considered statistically significant for the primary and secondary endpoints. Statistical analyses were programmed using Stata/IC version 14.2 (StataCorp LLC, College Station, TX) and SAS version 9.4 (SAS Institute, Cary, NC).

Results Of the 1071 trial subjects, 1051 subjects who received radiation therapy as specified in the trial protocol were eligible for inclusion in these analyses. Four out of the 23 participating centers were equipped with HDRB facilities. Median follow-up duration from randomization was 10.5 years (interquartile range, 8.2-11.8 years). Baseline characteristics and RT dose assignment were well balanced between the AS groups (Table 1). There were some imbalances in baseline characteristics according to the RT dose groups (Table E1, available online at https://doi.org/ 10.1016/j.ijrobp.2019.11.415). Tumor prognostic factors and age were similar across the 3 EBRT (only) groups except for National Comprehensive Cancer Network (NCCN) risk classification. A larger proportion of subjects with high-risk tumors were treated with 74 Gy (69.1%) compared with the other 2 EBRT groups (56.0%-56.9%; P Z .01). The HDRB group comprised 85.7% high-risk tumors. In comparison with the EBRT groups, subjects selected for HDRB boost were 2 to 3 years younger and more likely to have tumors with stage T3 or T4 (64.1% vs 24.8%-31.7%) and grade group 4 to 5 (51.1% vs 27.2%34.3%). The EBRT dose groups also differed in recruitment patterns, with subjects randomized in the earlier years more likely to be assigned 66 Gy, whereas those randomized in the latter years were more likely to be treated with higher doses. Distant progression was diagnosed in 291 of 1051 subjects (27.7%). There was no evidence of an interaction between AS duration and RT dose (P Z .76). After adjusting for RT dose, the 525 men who received 18AS experienced a reduced hazard of distant progression compared with the 526 men who received 6AS (subhazard ratio [sHR] 0.70 [0.56-0.87], P Z .002). Full results for the multivariable model are shown in Table E2 (available online at https://doi.org/10.1016/j.ijrobp.2019.11.415). The effect of AS duration within RT dose groups is summarized in Figure 1. The longer duration of AS achieved significant

International Journal of Radiation Oncology  Biology  Physics Table 1 Baseline characteristics and radiation dose assignment according to duration of androgen suppression 6 mo AS (Z) 18 mo AS (Z) (n Z 526) Age (y) Median IQR Range Radiation dose 66 Gy 70 Gy 74 Gy HDRB PSA (ng/mL) Median IQR Range <10 10-20 >20 Clinical T stage T2 T3, T4 Grade group 1 (GS 6) 2 (GS 3 þ 4) 3 (GS 4 þ 3) 4 (GS 8) 5 (GS 9,10) NCCN risk group Favorable intermediate Unfavorable intermediate High D’Amico risk group Intermediate High

(n Z 525)

69.3 63.9-73.3 49.1-84.5

68.4 63.2-72.8 47.7-83.9

60 219 133 114

65 208 129 123

(11.4) (41.6) (25.3) (21.7)

(12.4) (39.6) (24.6) (23.4)

Total (n Z 1051) 68.7 63.4-73.0 47.7-84.5

125 427 262 237

(11.9) (40.6) (24.9) (22.6)

14.3 9.6-24.0 1.6-140.0 143 (27.2) 218 (41.4) 165 (31.4)

14.5 9.4-25.0 2.0-110.0 143 (27.2) 216 (41.1) 166 (31.6)

14.5 9.5-24.6 1.6-140.0 286 (27.2) 434 (41.3) 331 (31.5)

334 (63.5) 192 (36.5)

335 (63.8) 190 (36.2)

669 (63.7) 382 (36.4)

50 172 133 89 82

49 170 114 91 101

99 342 247 180 183

(9.5) (32.7) (25.3) (16.9) (15.6)

(9.3) (32.4) (21.7) (17.3) (19.2)

(9.4) (32.5) (23.5) (17.1) (17.4)

9 (1.7)

15 (2.9)

24 (2.3)

177 (33.7)

153 (29.1)

330 (31.4)

340 (64.6)

357 (68.0)

697 (66.3)

112 (21.3) 414 (78.7)

102 (19.4) 423 (80.6)

214 (20.4) 837 (79.6)

Data are n (%) unless otherwise stated. Percentages may not add to 100 due to rounding. Abbreviations: AS Z androgen suppression; GS Z Gleason score; Gy Z Gray; HDRB Z high-dose-rate brachytherapy; IQR Z interquartile range; NCCN Z National Comprehensive Cancer Network; PSA Z prostate-specific antigen; Z Z zoledronic acid.

reductions in distant progression in 70 Gy (sHR 0.67 [0.460.98], P Z .039) and HDRB (sHR 0.61 [0.38-0.97], P Z .036). Nonsignificant reductions were observed in the 66 Gy and 74 Gy groups (sHR 0.55 [0.24-1.29], P Z .24 and sHR 0.83 [0.50-1.38], P Z .47, respectively). At 10 years the adjusted cumulative incidence rates for distant progression in the RT dose groups were 26.1% (95% CI, 18.9-33.2%) for 66 Gy, 26.7% (22.9%-30.6%) for 70 Gy, 24.9% (20.0%-29.8%) for 74 Gy, and 19.7% (15.5%-23.8%) for HDRB. Compared with the 427 men in

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Events/Subjects

RT Dose n

6AS

18AS

sHR (95% CI)

13/65

0.55 (0.24, 1.29)

66 Gy

125 21/60

70 Gy

427 66/219 51/208

0.67 (0.46, 0.98)

74 Gy

262 35/133 30/129

0.83 (0.50, 1.38)

HDRB

237 42/114 33/123

0.61 (0.38, 0.97)

.2

.5

1

FAVOURS 18AS

2

FAVOURS 6AS

Fig. 1. Effect of duration of androgen suppression on distant progression by radiation dose group. *Models adjusted for 18 months of zoledronic acid (no, yes); T stage (T2, T3 and T4); Gleason grade group (1-5); prostatespecific antigen (<10, 10-20, >20 ng/mL); age (years continuous). Abbreviations: CI Z confidence interval; HDRB Z high-dose-rate brachytherapy; RT Z radiation therapy; sHR Z subhazard ratio.

Adjusted cumulative incidence (%) Distant progression

the 70 Gy reference level, the 237 men who received the HDRB boost had a significantly lower hazard of distant progression (sHR 0.68; 95% CI, 0.57-0.80; P < .0001). The dose-response relationships for distant progression within the AS treatment groups are shown in Figure 2. Local progression was diagnosed in 93 (8.9%) subjects. Significant reductions in the hazard of local progression were achieved independently by 18AS (sHR 0.60 [0.380.95], P Z .03) and by HDRB (sHR 0.28 [0.19-0.41], P < .0001). Adjusted cumulative incidence rates were 12.3% for 66 Gy, 7.5% for 70 Gy, 7.3% for 74 Gy, and 2.2% for HDRB. Bone progression was diagnosed in 227 (21.6%) subjects. Significant reductions in the hazard of bone progression were achieved independently by 18AS (sHR 0.62 40

30

20

10

0 66

70

74

[0.49-0.78], P Z .0001) and by HDRB (sHR 0.63 [0.480.81], P Z .0004). Adjusted cumulative incidence rates were 22.4% for 66 Gy, 22.0% for 70 Gy, 20.4% for 74 Gy, and 14.9% for HDRB. The total number of deaths was 368, with 142 (38.6%) attributable to prostate cancer. Significant reductions in prostate cancerespecific mortality were achieved independently by 18AS (sHR 0.70 [0.53-0.92], P Z .009) and by HDRB (sHR 0.65 [0.51-0.82], P Z .0004). Adjusted cumulative incidence rates for prostate cancerespecific mortality were 14.5% for 66 Gy, 13.0% for 70 Gy, 11.5% for 74 Gy, and 8.9% for HDRB. For all-cause mortality, 18AS reduced the hazard compared with 6AS, but this did not reach significance (HR 0.84 [0.71-1.01], P Z .06). Compared with 70 Gy, HDRB was the only RT dose group associated with a significant hazard reduction (0.65 [0.520.82], P Z .0002). Adjusted cumulative incidence rates for all-cause mortality were 29.9% for 66 Gy, 32.6% for 70 Gy, 31.3% for 74 Gy, and 23% for HDRB. For the same models using 74 Gy as the reference level, HDRB achieved significant reductions in local progression and all-cause mortality; however, reductions in bone progression, distant progression, and prostate cancerespecific mortality that strongly favored HDRB did not reach statistical significance. To explore the finding of a reduction in all-cause mortality associated with HDRB, we also analyzed other-cause mortality. This showed no difference between the AS groups (sHR 1.01 [0.84-1.21], P Z .92) and a significant reduction in HDRB compared with both 70 Gy (sHR 0.67 [0.49-0.91], P Z .01) and 74 Gy (sHR 0.71 [0.53-0.96], P Z .03). The relative treatment effects of AS duration and radiation therapy dose derived from the multivariable models are summarized in Table 2 (treatment effects within the 66 Gy subgroup have not been reported owing to its relatively small size, resulting in very large confidence intervals). Figure 3 displays adjusted cumulative incidence plots for each endpoint by RT dose. Treatment effects of AS duration within the RT dose subgroups for each endpoint are summarized in Table E3 (available online at https://doi.org/ 10.1016/j.ijrobp.2019.11.415; local progression is not presented owing to small event numbers). In men treated with HDRB, 18AS provided similar reductions across all endpoints. However, the reductions in secondary endpoints did not reach statistical significance with the exception of allcause mortality.

//

HDRB

Radiation dose escalation group (Gy) 6 months AS

697

18 months AS

Fig. 2. A dose response comparison for distant progression between radiation dose escalation groups of men treated with 6 months androgen suppression and 18 months androgen suppression at 10 years post randomization. The error bars represent standard errors. Abbreviation: HDRB Z high-dose-rate brachytherapy.

Discussion This study explores the duration of AS in the context of dose-escalated radiation therapy using 10-year data from the RADAR trial for locally advanced, high-risk PC. To our knowledge, RADAR is the first RCT to randomize subjects to short or longer AS after stratifying by radiation dose. Subjects received either 6AS or 18AS in combination with one of 4 RT dosing options: 66 Gy, 70 Gy, 74 Gy, or

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Table 2

Treatment effects of AS duration and radiation dose on the cumulative incidence of endpoints at 10 years (n Z 1051) Endpoint

Distant progression

Local progression

Bone progression

Prostate cancer-specific mortality

All-cause mortality

sHR*

95% CI

P value

mo

0.70

0.560.87

.002

mo

0.90 0.68 0.75 0.60

0.641.27 0.570.80 0.561.01 0.370.96

.54 <.0001 .06 .03

mo

0.97 0.28 0.29 0.62

0.432.19 0.190.40 0.130.63 0.490.78

.94 <.0001 .002 .0001

mo

0.90 0.63 0.69 0.70

0.541.50 0.480.81 0.451.07 0.530.92

.69 .0004 .10 .009

mo

0.87 0.65 0.75 0.84

0.561.34 0.510.82 0.511.09 0.711.01

.52 .0004 .13 .06

0.95 0.65 0.69

0.701.29 0.520.82 0.540.87

.73 .0002 .002

Treatment comparisons AS duration: 18 vs 6 RT dose 74 vs 70 Gy HDRB vs 70 Gy HDRB vs 74 Gyy AS duration: 18 vs 6 RT dose 74 vs 70 Gy HDRB vs 70 Gy HDRB vs 74 Gyy AS duration: 18 vs 6 RT dose 74 vs 70 Gy HDRB vs 70 Gy HDRB vs 74 Gyy AS duration: 18 vs 6 RT dose 74 vs 70 Gy HDRB vs 70 Gy HDRB vs 74 Gyy AS duration: 18 vs 6 RT dose 74 vs 70 Gy HDRB vs 70 Gy HDRB vs 74 Gyy

Model covariates: radiation therapy (RT) dose (66 Gy, 70 Gy, 74 Gy, HDRB); AS duration (6 mo, 18 mo); 18 months of zoledronic acid (no, yes); T stage (T2, T3 and T4); Gleason grade group (1-5); prostate-specific antigen (<10, 10-20, >20 ng/mL); age (years continuous). Treatment site was adjusted for by using cluster-robust standard errors. Abbreviations: AS Z androgen suppression; CI Z confidence interval; Gy Z Gray; HDRB Z high-dose-rate brachytherapy; sHR Z sub hazard ratio. * Hazard ratio presented for all-cause mortality. y Same model with reference level as 74 Gy.

HDRB. Our study showed no evidence of an interaction between AS duration and RT dose and that intermediateterm AS improved clinically meaningful endpoints independently of dose. Compared with 6AS, 18AS significantly reduced distant progression and the secondary endpoints local progression, bone progression, and prostate cancerespecific mortality, irrespective of RT dose. The reduction in all-cause mortality owing to longer AS did not reach significance. Importantly, no difference in othercause mortality was observed between the AS groups. In subgroup analyses men treated with HDRB showed a significant benefit from the additional year of AS, with a 40% relative reduction in distant progression. A similar significant reduction of 33% was observed in men treated with 70 Gy, but reductions in the smaller EBRT groups, 66 Gy and 74 Gy, did not reach significance. There may be a number of reasons why no difference between 6AS and 18AS was shown in men treated with 74 Gy. First, there was a chance imbalance of high-risk tumors within this subgroup (64% assigned 6AS vs 74% assigned 18AS). Second, subjects who received 74 Gy were more likely to be randomized during the latter years of the recruitment phase, resulting in their potential median follow-up being

shorter than the 70 Gy and HDRB groups by 12 and 10 months, respectively. Additional exploratory analyses of the HDRB subgroup provided evidence of a benefit from 18AS for the secondary endpoints, with relative reductions of approximately 33% to 40%. However, these reductions did not reach statistical significance for bone progression and prostate cancerespecific mortality owing to insufficient event numbers. The finding of a significant reduction in all-cause mortality by 18AS suggests chance imbalances at baseline in preexisting comorbidities. The role of AS in patients undergoing extreme doseescalation RT for high-risk tumors has remained unclear owing to a lack of randomized evidence, with some nonrandomized studies showing no benefit from AS.12-14 This uncertainty has been reflected in clinical practice, with 2 studies, using data from the National Cancer Database, reporting that patients with unfavorable intermediate and high-risk PC were significantly less likely to receive AS if they were treated with dose-escalation via brachytherapy (BT) boost rather than EBRT alone.15,16 The findings from the RADAR trial help to resolve this uncertainty by providing evidence from an AS randomized trial that men

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B 40

Adjusted cumulative incidence of local progression (%)

Adjusted cumulative incidence of distant progression (%)

A sHR 0.68 [0.57-0.80], P < .0001†

66 Gy 70 Gy 74 Gy HDRB

30

20

10

30

66 Gy 70 Gy 74 Gy HDRB

sHR 0.28 [0.19-0.40], P < .0001†

20

10

0

0 0

1

2

3

4

5

6

7

8

9

0

10

1

2

3

4

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6

7

8

9

10

Time from randomisation (years)

Time from randomisation (years)

D 30

66 Gy 70 Gy 74 Gy HDRB

Adjusted cumulative incidence of prostate cancer-speciffic mortality (%)

C Adjusted cumulative incidence of bone progression (%)

699

sHR 0.63 [0.48-0.81], P = .0004†

20

10

0 0

1

2

3

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6

7

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66 Gy 70 Gy 74 Gy HDRB

15

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0 0

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Time from randomisation (years)

E

40

3

4

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6

7

8

9

10

Time from randomisation (years)

66 Gy

sHR 0.65 [0.52-0.82], P = .0002†

70 Gy

Adjusted cumulative incidence of all-cause mortality (%)

sHR 0.65 [0.51-0.82], P = .0004†

74 Gy HDRB

30

20

10

0 0

1

2

3

4

5

6

7

8

9

10

Time from randomisation (years)

Fig. 3. Ten-year adjusted cumulative incidence rates by radiation dose escalation group.* (A) Distant progression. (B) Local progression. (C) Bone progression. (D) Prostate cancer-specific mortality. (E) All-cause mortality. *Models adjusted for androgen suppression duration (6 months, 18 months); 18 months of zoledronic acid (no, yes); T stage (T2, T3 and T4); Gleason grade group (1-5); prostate-specific antigen (<10, 10-20, >20 ng/mL); age (years continuous). yTreatment effect for high-dose-rate brachytherapy versus 70 Gy. Abbreviation: sHR Z subhazard ratio.

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treated with extreme dose-escalated RT do benefit from a longer duration of AS in a clinically meaningful outcome such as distant progression. Our exploratory analyses comparing RT doses showed that, despite adverse tumor selection bias, HDRB achieved superior outcomes to 70 Gy independently of AS duration, providing significant reductions in local, bone, and distant progressions and prostate cancerespecific mortality. However, reductions in other-cause and all-cause mortality indicate confounding owing to the selection of younger, and presumably healthier, men for HDRB. Although posttreatment prostate biopsies were not mandated in this trial and local recurrences were underdiagnosed, the major improvement in local control associated with HDRB could be one mechanism for the reduction in distant metastasis.17,18 In the future, better noninvasive diagnostic tests, such as magnetic resonance imaging and prostate-specific membrane antigen scans, will be required to quantify these reductions more accurately and to understand how HDRB effects metastatic disease control. Long-term benefits for EBRT plus a brachytherapy boost (EBRT and BT) have also been shown in multiple retrospective and observational studies.19-22 Although promising, results from these studies and from the RADAR trial must be considered hypothesis generating, as dose was not randomized. Three RCTs comparing EBRT and BT to EBRT alone reported significant improvements in biochemical progression-free survival for EBRT and BT23-25 but failed to demonstrate a difference in metastasis, causespecific survival, or overall survival. In the androgen suppression combined with elective nodal and dose escalated radiation therapy (ASCENDE-RT) trial, the largest of the trials with 398 subjects (69% high-risk PC) and the only one to use dose-escalated RT as the control, all subjects received 1 year of AS and were randomized to either dose-escalated EBRT to 78 Gy or a combination of EBRT to 46 Gy followed by a low dose rate (LDR) brachytherapy boost. After median follow-up of 6.5 years, the risk of biochemical failure was halved by the LDR boost.25 It should be noted that 2 retrospective studies reported a survival advantage for a BT boost using population-based data sets to match the ASCENDE-RT cohort,20,21 suggesting the large improvement in biochemical control for LDR boost reported in this trial may translate into survival benefits with further follow-up. Toxicity due to RT in the RADAR trial has been reported previously2 and is summarized in this report to balance the oncologic gains achieved by HDRB against treatment side effects and effect on quality of life. Rectal and urinary symptoms were measured by clinician assessment and by patient-reported outcome questionnaires, which included the EORTC QLQ-PR25 and International Prostate Symptom Score. There were 8 serious adverse events attributable to RT, 3 of which occurred in men receiving HDRB (2 cases of urinary retention and one case of urinary stricture). Overall toxicity rates within the first 3 years were very low, with 6 patients (1%) experiencing grade 3 events. Men treated with EBRT alone

International Journal of Radiation Oncology  Biology  Physics

experienced significantly worse rectal symptoms, although men treated with HDRB reported worse urinary symptoms. Compared with EBRT alone, HDRB was associated with statistically increased dysuria (grade 1) within the first 18 to 36 months of randomization and a transient increase of 3 points in International Prostate Symptom Score at 18 months, which dissipated by 36 months.2 As a result of this earlier report, we collected data retrospectively to determine whether urethral strictures were the cause of increased urinary problems associated with HDRB. At median follow-up of 7.4 years the rate of urethral strictures was 12.7% for HDRB compared with 0.8%, 0.9% and 3.8% for men receiving 66, 70, and 74 Gy, respectively. Unfortunately, updated stricture rates at 10 years of follow-up are not available, as collection of toxicity data was stopped in 2014 owing to limited trial funding and resources. In comparison to RADAR, overall toxicity rates reported in the ASCENDE-RT trial were much higher, possibly owing to whole pelvic irradiation. Strictures were the main cause of the higher rates of genitourinary morbidity observed in the LDR boost arm compared with the EBRT alone.26 After median follow-up of 6.5 years stricture rates were 8.5% and 1.0% in the LDR boost and EBRT alone arms, respectively. Major strengths of this study are that the data come from a large, multicenter, randomized control trial with over 1000 subjects recruited from 23 centers and median follow-up of 10 years. Data also were collected prospectively for patient-reported outcomes, and oncologic outcomes were analyzed appropriately using competing risks methodology. However, the study does have some limitations. Of most importance, radiation dose was not randomly allocated in the RADAR trial, and thus the doserelated comparisons cannot be regarded as definitive evidence. Randomization according to radiation dose was not feasible because at the time the trial was being designed, very few treatment centers around Australia and New Zealand were equipped with HDRB facilities. Although a stratification scheme ensured radiation dose and technique were balanced across trial arms, biases were evident with younger men presenting with high-stage, high-grade tumors being selected for HDRB. Attempts to address these selection biases were made by adjusting for the known confounders and treatment center in the multivariable models. Nevertheless, unknown selection biases could still be present (eg, the trial did not collect baseline data on socioeconomic status, comorbidity score, and prostate gland size). It should be noted that although comorbidity scores were not collected, eligible men had to be reasonably healthy with an Eastern Cooperative Oncology Group <2 to participate in the trial. Another limitation to the study, and a common challenge for PC trials requiring long-term follow-up to assess survival outcomes, was that the external beam dosing options chosen (66, 70, and 74 Gy using 2 Gy fractional increments to the ICRU point), although reflecting practices at the time RADAR was designed, were low compared with contemporary practice.

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Conclusions Our study showed that 18 months of AS significantly reduced distant progression compared with 6 months AS independently of RT dose. It also provides the first definitive evidence of the benefit of a longer duration of AS in men treated with EBRT plus HDR boost, confirming that extreme-dose escalated RT does not obviate the need for AS. Based on these findings, 18 months of AS together with EBRT plus HDR boost should be considered an effective option for men with locally advanced, high-risk PC. Evidence of improved oncologic outcomes for HDRB compared with conventionally fractionated, dose-escalated EBRT needs to be confirmed in a randomized trial. If such a trial were to eventuate, we would recommend a robust primary endpoint such as metastasis-free survival and that patient-reported outcomes are included. We would also suggest the trial be stratified by risk group and that all participants receive 18 months of AS, which has been shown by the RADAR and Prostate Cancer Study IV trials to be an effective treatment with limited toxicity.10,27 The control treatment would be conventionally fractionated dose-escalated EBRT to the commonly used 78 Gy in 39  2 Gy fractions over 8 weeks, or alternatively the bioequivalent hypofractionated EBRT regimen using 20 daily fractions of approximately 3 Gy (using a time dependent correction) over 4 weeks. The experimental treatment arm would be the RADAR HDRB boost of 3  6.5 Gy over 24 hours, or a suitable stereotactic EBRT alternative, after conventionally fractionated EBRT to 46 Gy in 23  2 Gy fractions (using a time dependent correction).

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