Accepted Manuscript

*ASCENDE-RT: An Analysis of Survial Endpoints for a Randomized Trial Comparing

a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for
High- And Intermediate-Risk Prostate Cancer

W. James Morris, MD FRCPC, Scott Tyldesley, MD FRCPC, Sree Rodda, MBBS

MRCP FRCR, Ross Halperin, MD FRCPC, Howard Pai, MD FRCPC, Michael
McKenzie, MD FRCPC, Graeme Duncan, MB ChB FRCPC, Gerard Morton, MB
MRCPI FRCPC FFRRCSI, Jeremy Hamm, MSC, Nevin Murray, MD FRCPC
PII: S0360-3016(16)33484-8
DOI: 10.1016/j.ijrobp.2016.11.026
Reference: ROB 23915

To appear in: International Journal of Radiation Oncology • Biology • Physics

Received Date: 25 August 2016

Revised Date: 12 November 2016
Accepted Date: 16 November 2016

Please cite this article as: Morris WJ, Tyldesley S, Rodda S, Halperin R, Pai H, McKenzie M, Duncan G,
Morton G, Hamm J, Murray N, *ASCENDE-RT: An Analysis of Survial Endpoints for a Randomized Trial
Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High-
And Intermediate-Risk Prostate Cancer, International Journal of Radiation Oncology • Biology • Physics
(2016), doi: 10.1016/j.ijrobp.2016.11.026.

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 ACCEPTED MANUSCRIPT

TITLE:

*ASCENDE-RT: AN ANALYSIS OF SURVIAL ENDPOINTS FOR A RANDOMIZED

TRIAL COMPARING A LOW-DOSE-RATE BRACHYTHERAPY BOOST TO A DOSE-

ESCALATED EXTERNAL BEAM BOOST FOR HIGH- AND INTERMEDIATE-RISK

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PROSTATE CANCER

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AUTHORS:

1. W. James Morris, MD FRCPC (corresponding)

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B C Cancer Agency - Vancouver Centre

Department of Surgery, University of British Columbia

Mailing address:
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600 west 10th Ave

Vancouver, BC
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Canada, V5Z 4E6

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Work phone: 604-877-6000, local 672673

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Mobile phone: 604-551-8906

Email: jmorris@bccancer.bc.ca
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2. Scott Tyldesley, MD FRCPC

B C Cancer Agency - Vancouver Centre

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Department of Surgery, University of British Columbia

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3. Sree Rodda, MBBS MRCP FRCR

B C Cancer Agency - Vancouver Centre

4. Ross Halperin, MD FRCPC

B C Cancer Agency - Centre for the Southern Interior

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Department of Surgery, University of British Columbia

5. Howard Pai, MD FRCPC

B C Cancer Agency - Vancouver Island Centre

Department of Surgery, University of British Columbia

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6. Michael McKenzie, MD FRCPC

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B C Cancer Agency - Vancouver Centre

Department of Surgery, University of British Columbia

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7. Graeme Duncan, MB ChB FRCPC

B C Cancer Agency - Vancouver Centre

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Department of Surgery, University of British Columbia
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8. Gerard Morton, MB MRCPI FRCPC FFRRCSI

Sunnybrook Health Sciences Centre, Toronto

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Dept of Radiation Oncology, University of Toronto

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9. Jeremy Hamm, MSC

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B C Cancer Agency - Dept of Population Oncology,

10. Nevin Murray, MD FRCPC

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BC Cancer Agency - Vancouver Centre

Department of Medicine, University of British Columbia

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*ASCENDE-RT stands for Androgen Suppression Combined with Elective Nodal and

Dose Escalated Radiation Therapy and is a NCI registered trial (NCT00175396) and

was supported by unrestricted educational grants to the British Columbia Cancer

Agency (BCCA) received from Oncura Corporation and Sanofi-Aventis Canada.

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ACKNOWLEDGEMENTS:

1. The British Columbia Cancer Agency (BCCA) received unrestricted educational

grants from Oncura corporation, a division of GE Healthcare which manufactures

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the model 6711 125Iodine RapidStrand® sources used in this trial, and Sanofi-

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Aventis Canada, the maker of the Suprefact® and Eligard® LHRH depot

injections used in this trial. Without these grants ASCENDE-RT would not have

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been possible.

2. The authors wish to acknowledge the members of the BCCA Provincial Prostate

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Brachytherapy Program who accrued patients and participated in follow up.
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Without the efforts Vincent Lapointe who designed the ASCENDE-RT database

and the efforts of three data managers (Adam Kahnamelli, Devon Poznanski,
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and Lorenz Yeung), ASCENDE-RT would not have been possible.

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ABSTRACT

Purpose: To report the primary endpoint of biochemical progression free survival (b-

PFS) and secondary survival endpoints for a randomized trial comparing two methods

of dose escalation for intermediate- and high-risk prostate cancer.

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Materials and Methods: The trial enrolled 398 men, median age 68; 69% (N =276) had

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high-risk disease. After stratification by risk group, subjects were randomized to either a

standard arm with 12 months of androgen deprivation therapy (ADT), pelvic irradiation

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to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT)

boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate

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brachytherapy (LDR-PB) boost. Two hundred trial subjects were assigned to DE-EBRT
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boost and 198 to LDR-PB boost. Median follow-up is 6.5 years.

Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as

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likely to experience biochemical failure (MVA HR: 2.04, p =0.004). The 5-, 7-, and 9-
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year Kaplan-Meier b-PFS estimates were 89%, 86% and 83% for those randomized to
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LDR-PB boost versus 84%, 75% and 62% for DE-EBRT boost (log rank p <0.001). The

LDR-PB boost benefited both intermediate- and high-risk patients. Since the b-PFS
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curves for the treatment arms diverge sharply after 4 years, the relative advantage of

the LDR-PB should increase with longer follow up.

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In MVA, the only variables correlated with reduced overall survival (OS) were age (MVA
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HR: 1.06/year, p =0.004) and biochemical failure (MVA HR: 6.30, p <0.001). Although

biochemical failure was associated with increased mortality and randomization to DE-

EBRT doubled the rate of biochemical failure, no significant OS difference was

observed between arms (MVA HR 1.13, p =0.62).

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Conclusions: Compared to 78 Gy EBRT, men randomized to LDR-PB boost were

twice as likely to be free of biochemical failure at 6.5 years median follow-up.

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INTRODUCTION

In multiple randomized studies, dose-escalated external beam radiation therapy (DE-

EBRT) is associated with improved biochemical progression free survival (b-PFS)

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compared to standard dose EBRT using prostate specific antigen (PSA) endpoints (1-

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5). However, randomized data comparing different methods of dose escalation are

sparse with just two randomized trials comparing EBRT plus a brachytherapy boost to

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EBRT alone (6,7). As in the present trial, both involved brachytherapy boost and

intermediate- and high-risk localized tumors. But, beyond these similarities, they differ

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fundamentally from this trial since neither used DE-EBRT for the standard arm nor a
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low-dose-rate prostate brachytherapy (LDR-PB) for the experimental arm. By

randomizing men with National Comprehensive Cancer Network (NCCN) high- and
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intermediate-risk prostate cancer to receive either a LDR-PB boost or a DE-EBRT

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boost, this trial is the only randomized comparison of LDR-BP to any other form of
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curative-intent radiation therapy for prostate cancer. This is important because LDR-PB

is widely used with multiple retrospective studies demonstrating excellent rates of b-

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PFS when a LDR-PB boost is combined with modest doses of EBRT (8-10).
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MATERIALS AND METHODS

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Protocol interventions

All trial subjects received androgen deprivation therapy (ADT) consisting of 12 months

of luteinizing hormone releasing hormone (LHRH) agonist using three-month depot

injections (either buserelin acetate [Suprefact Depot®] 9.45 mg or leuprolide acetate

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[Eligard®] 22.5 mg) given concurrent with four weeks of oral non-steroidal anti-

androgen (flutamide 250 mg Q8h or bicalutamide 50 mg daily) (item 3 supplementary

on-line material). After 8 months of neo-adjuvant ADT, all trial subjects were to receive

46 Gy/23 fractions of pelvic irradiation encompassing the prostate, seminal vesicles,

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and regional lymph nodes.

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Directly after completion of pelvic irradiation, DE-EBRT boost subjects (standard arm)

received an additional 32 Gy/16 fractions using a two phase 3-D conformal boost

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(EBRT details in items 4-6, supplemental on-line material).

Two to three weeks following pelvic irradiation, LDR-PB boost subjects (experimental

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arm) received a 125-Iodine brachytherapy implant (minimal peripheral dose =115 Gy).
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All implants used Oncura model 6711 sources (0.32-0.51 U) supplied as RapidStrand®

(item 7, supplemental on-line material).

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Eligibility, accrual, registration, stratification and randomization

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A consort diagram is given in Figure 1. The trial was approved by the appropriate

institutional research ethics board at each participating cancer center. Only NCCN high-
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and intermediate-risk patients were eligible; those with Gleason sum (GS) ≥8 or

pretreatment PSA (iPSA) >20 ng/mL required a bone scan and a computed tomography
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(CT) scan of the abdomen and pelvis to confirm image-based N0M0 status. Men with
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iPSA >40 ng/mL, T-stage ≥T3b, previous transurethral prostatic resection (TUPR), pre-

ADT prostate volume >75 cm3 and those not fit for anesthetic were ineligible (for details

on eligibility see item 2, supplemental on-line material)

Eligible men who provided signed consent were centrally registered, stratified by NCCN
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risk group and randomly assigned to the treatment arms (1:1) using a computer-

generated block randomization (N=4) with allocation concealed in opaque, sequentially

numbered and sealed envelopes prior to commencing therapy. Randomization took

place upon establishing eligibility and obtaining consent; subjects were informed of the

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treatment arm to which they were assigned.

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The trial had two stages: a feasibility phase, open to accrual from 11/2002 to 08/2003,

and a completion phase, open from 08/2004 to 12/2011. In total, 398 men were accrued

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by 29 investigators at 6 centers (listed in item 1, supplemental on-line material).

XXX designed and led the trial. XX chaired an independent Data Monitoring and Safety

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Committee with authority to suspend accrual; XXX, XX, XX and XX preformed data
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analysis.
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The primary endpoint and trial design

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The primary endpoint was biochemical progression free survival (b-PFS) based on the
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nadir + 2ng/mL PSA threshold. Target accrual was 400; the a priori statistical model

assumed a 6.5-year b-PFS of 60% in the worse arm, such that a ≥15% difference
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between the arms should be detectable when the number of biochemical failure events

reached 130 (2-tailed, beta 0.8, alpha 0.05). However, the primary end point was
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defined as b-PFS at 6.5 years median follow-up regardless of the number of events
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recorded. The figure of 6.5 years was based on previous institutional experience using

12 months of ADT and was regarded as equivalent to 5 years from the average time

required for testosterone recovery sufficient to stimulate any residual, hormone sensitive

cancer cells. Specifying analysis at 6.5 years satisfied a practical consideration; namely,
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if a brachytherapy boost did not significantly improve b-PFS by 6.5 years, then adopting

a LDR-PB boost as standard of care would be logically excluded by added complexity

and potential morbidity. At data lockdown (09/30/2014), only the median length of follow

up and the total number of biochemical relapse events (N =76) were known to the trial

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investigators.

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Secondary endpoints

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Secondary endpoints included overall survival (OS), metastasis-free survival (MFS),

and prostate cancer specific survival (PCSS). The incidence and prevalence of

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treatment related adverse effects are reported in a companion paper (ref). The trial also
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included a longitudinal health related quality of life (HR-QoL) study, which is in the final

stages of preparation.
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Patient monitoring:
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PSA, testosterone (TTT) and a complete blood count (CBC) were recorded at baseline

(t0) and at t+2, t+4, t+8, t+12, t+15 and t+18 months, then 6 monthly thereafter. Clinic
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visits occurred at t+4, t+8, t+12 and t+18 months, every 6 months for 5 years and yearly

thereafter.
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Defining prostate cancer death

Two investigators (XXX and XX) independently reviewed the medical records of all

deceased patients. Men treated with systemic agents for metastatic prostate cancer at
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or before their death date were scored as prostate cancer deaths, regardless of the

proximate cause.

Statistical analysis

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This is an intent-to-treat analysis of the primary and secondary survival endpoints. A

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parallel analysis of these endpoints according to the treatment actually received is also

provided (see Table 2). Descriptive statistics were used to compare prognostic factors.

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Actuarial endpoints were calculated by the Kaplan-Meier (K-M) method. Cox regression

was used for univariate (UVA) and multivariable (MVA) analyses. For the b-PFS

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endpoint, UVA included: age; randomization arm; T-stage; GS; iPSA; percent positive
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cores (PPC); NCCN risk stratum; and the number of high-risk features (HRF). For OS,

biochemical failure status was added as a time-dependent variable. Variables with p-

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values ≤0.3 in UVA were included in MVA (backwards:conditional). NCCN risk strata
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and the number of HRF were excluded from MVA models since they are composites of
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other variables. Statistical analyses were done with SPSS version 22 (SPSS, IBM Corp,

Armonk, NY, USA) and SAS, Version 9.3 (SAS Institute Inc., Cary, NC, USA).
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RESULTS
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Patient accrual and protocol violations

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This is an intent-to-treat analysis; 200 men were randomized to the DE-EBRT arm and

198 to the LDR-PB arm. The median follow up for the primary endpoint at the time of

data lock down (08/30/2014) was 6.5 years. Of 29 major protocol violations, 14 were

crossover events; 6 men assigned to DE-EBRT received LDR-PB and 8 crossed the
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opposite way. The remaining 15 violations (7 assigned to DE-EBRT and 8 to LDR-PB)

received neither protocol treatment (items 8 and 9, supplemental on-line material).

Prognostic features

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As shown in Table 1, the prognostic features did not differ significantly between arms;

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276 (69%) met NCCN high-risk criteria, 41% had GS 8-10, 19% had an iPSA >20

ng/mL, 29% had T3a tumors, and, in 68%, cancer was found in ≥50% of cores. Nearly

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half (48%) at least 2 high risk features.

Testosterone Recovery
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Baseline TTT was available for 334 trial subjects. The median baseline TTT was 13.8

nmol/L and 99% (N =330) had baseline TTT >5 nmol/L; 96% of these men recovered to
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>5 nmol/L. The median interval between the first LHRH injection and TTT recovery to >
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5 nmol/L was 21.4 months. The arms did not differ in either the rate or the extent of TTT
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recovery.
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Primary endpoint (b-PFS)

Table 2 details the disease status of all trial subjects as of data lockdown (09/30/2014).
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Table 2 also lists the 5-, 7-, and 9-year K-M estimates (and their 95% confidence
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intervals) for b-PFS, OS, MFS, and PCSS. Table 3a summarizes the UVA and MVA

results for the primary endpoint (b-PFS). Compared to men randomized to LDR-PB,

those randomized to DE-EBRT were twice as likely to experience biochemical failure

(MVA hazard ratio =2.04, p =0.004). Clinical T-stage (p =0.004), iPSA (p =0.01), and
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PPC (p =0.006) were also independent predictors of b-PFS. The 5-, 7- and 9-year K-M

b-PFS estimates were 89%, 86% and 83% for those randomized to LDR-PB versus

84%, 75% and 62% for men randomized to the DE-EBRT (log rank p <0.001, Figure

2a). LDR-PB improved b-PFS in the both the intermediate-risk (p =0.003, Figure 2b)

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and the high-risk (p =0.048, Figure 2c) subsets.

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Post treatment PSA values in non-relapsed subjects

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Among the non-relapsed LDR-PB subjects with at least 4 years follow up (N =137), the

median PSA was 0.01 ng/mL (mean: 0.08, SD: 0.23) and 54% had undetectable PSA

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levels using ultrasensitive assays. In contrast, the median PSA for the equivalent DE-
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EBRT subjects (N =114) was 0.25 ng/mL (mean: 0.35, SD: 0.37) and 8% had an

undetectable PSA.
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Overall survival (OS)

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There have been 68 deaths with no significant difference in OS between the treatment

arms (p =0.293, Figure 2d). Table 3b shows the UVA and MVA for OS in which
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biochemical failure (MVA HR 6.30, p <0.001) and age (MVA HR 1.06/year, p =0.004)

were the only significant predictors of OS. The 5-, 7- and 9-year K-M OS estimates were
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91%, 86% and 78% for those randomized to LDR-PB and 89%, 82% and 74% for those
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randomized to DE-EBRT (Table 2). The median OS has not been reached and is

estimated at 13 years on Cox regression. (For details on causes of death see item 10,

supplemental on-line material.)

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Metastasis free survival (MFS)

Of the 76 trial subjects with biochemical failure, 35 (46%) have developed metastatic

disease; 17 were randomized to LDR-PB and 18 to DE-EBRT (Table 2). The 5-, 7- and

9-year K-M MFS estimates were 93%, 91% and 89% for those randomized to LDR-PB

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and 93%, 93%, and 85% for DE-EBRT (Table 2). On MVA, PPC (p =0.02), T-stage, (p

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=0.02) and GS (p =0.03) were predictive of MFS (the MVA of MFS is shown in item 11,

supplemental on-line material). Twelve of the 35 metastatic events (34%) were in

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subjects with ≥3 high-risk features, a subgroup which constituted only 13% of subjects

(p =0.002).

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Thirty of the 35 metastatic events (86%) occurred within 2 years of biochemical failure
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and the median interval, for this subset, was just 4 months. These 30 men with early

metastatic relapse were distributed evenly between the two arms. In contrast, 37 of the
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remaining 46 men (80%) with biochemical failure that was not associated with early
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metastatic relapse occurred in subjects randomized to DE-EBRT.

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Prostate cancer specific survival (PCSS)

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Death from metastatic prostate cancer was the most common cause of death in the

entire cohort (18 of 68) (item 10, supplemental on-line material). There was no
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difference in PCSS between arms (the MVA of PCSS is shown in item 12, supplemental
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on-line material). There have been 7 prostate cancer deaths among subjects

randomized to LDR-PB and 11 for DE-EBRT resulting in 5-, 7- and 9-year K-M PCSS

estimates of 97%, 96% and 95% for LDR-PB versus 98%, 94% and 92% for DE-EBRT

(Table 2).
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DISCUSSION

Primary endpoint (b-PFS)

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The two previous randomized trials comparing EBRT plus brachytherapy with EBRT

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alone (6,7) differ from this trial in two key features. First, neither employed LDR-PB.

Instead, the experimental arm in Sathya et al. was a 35 Gy boost using a traditional

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temporary Iridium-192 implant, while that of Hoskin et al. used two high-dose-rate

(HDR) Iridium-192 implants of 8.5 Gy each. Secondly, neither used dose escalation for

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comparison. In the Saytha trial, the standard arm was 66 Gy/33 fractions while the
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Hoskin study used a hypo-fractionated regimen of 55 Gy/20 fractions (approximately

equivalent to 64-66 Gy at 2 Gy per fraction). Despite these differences, the three trials
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share a common outcome. In Sathya et al. (N =104), the brachytherapy arm improved
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the 5-year b-PFS by 32% (71% versus 39%). In the larger Hoskin study (N =215), HDR-
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PB boost improved the 7-year b-PFS by 18% (66% versus 48%). In this trial, (N =398)

the LDR-PB boost improved the 7-year b-PFS by 11% (86% versus 75%) and an
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estimated 21% by 9 years follow up (83% versus 62%, see Table 2).

Importantly, the 7-year b-PFS in the DE-EBRT arm of this trial (75%) is consistent with
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the b-PFS outcomes for the dose-escalation arms comparing standard and dose-
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escalated EBRT regimens (1-5). Therefore, in this trial, the LDR-PB boost resulted a b-

PFS gain similar in magnitude to that seen when DE-EBRT is compared to standard

dose EBRT. Assuming the diverging K-M trajectories shown in Figure 2a are
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maintained, the relative advantage in b-PFS associated with the LDR-PB boost will

increase with longer follow up.

Overall survival (OS)

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This trial aligns with other dose escalation studies in showing improved b-PFS, but no

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difference in OS. In this context, note that this trial demonstrated a statistical correlation

between biochemical failure and increased all-cause mortality (MVR HR 6.30, p <0.001;

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Table 3b) and a major reduction in biochemical failure with a LDR-PB boost (MVR HR

=2.04, p 0.004; Table 3a), yet no statistical correlation is seen linking LDR-PB to

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improved OS (MVR HR 1.13, p =0.62; Table 3b). Despite appearances, this is logically
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consistent because the 35 subjects with known metastatic disease are largely

responsible for the correlation between biochemical failure and diminished OS. The
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observed correlation probably reflects diminished survival in a small subset of trial

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subjects with pre-existing, but occult, metastatic disease because in 86% of metastatic
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events (30 of 35) evidence of metastatic disease was identified at or shortly after

biochemical failure. The members of this subset were distributed evenly between arms,
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presumably by the randomization process.

In contrast, 37 of remaining 46 men (80%) with biochemical failure that was not
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accompanied by early metastatic relapse were randomized to DE-EBRT, an observation

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consistent with the hypothesis that LDR-PB improved the b-PFS by improving local

control. Although ‘second wave metastases’ can seed from local failure, multi-year

intervals often separate the two events and the practice of prescribing systemic

therapies for biochemical failure probably expands the interval further.

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Thus, while longer follow up may show an OS benefit with LDR-PB, it is far from certain.

This trial enrolled only 398 subjects with a median age of 68 years. The small sample

size of (now) elderly subjects, combined with the long interval from local recurrence to

life-threatening disease, means that competing causes of mortality will erode any

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potential survival benefit associated with improved local control.

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On the incidence of occult metastatic disease prior to treatment

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Metastatic relapse has occurred in <10% of subjects (35 of 398) (Table 2). This fact

suggests that the incidence of occult metastatic disease was probably <15% at the time

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of registration. This observation implies that for a majority of prostate cancer patients,
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including many with multiple unfavorable prognostic features, sufficient local treatment

can result in long-term biochemical and clinical remission.

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Alternate treatments
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Opinions vary regarding the best initial management for localized prostate cancer with

unfavorable prognostic features. Some expert opinion urges the use of surgical
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prostatectomy (11-13) notwithstanding the absence of randomized data supporting this

as a preferred approach, and the common indications for adjuvant and salvage radiation
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because of adverse pathologic features and biochemical recurrence respectively (14).

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With respect to radiotherapy, randomized data have demonstrated the advantage of

DE-BBRT (1-5) over conventional doses and have shown that combining EBRT with

ADT is superior to either modality alone (15,16). Hypo-fractionated DE-EBRT has been

subjected to randomized comparisons with conventionally fractionated DE-EBRT with

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no consistent trends in b-PFS identified (17-19), although the most definitive study (19)

has demonstrated similar efficacy between 60 Gy in 20 fractions and 74 Gy in 37

fractions. Other investigators are exploring extreme hypo-fractionated EBRT (20) to take

advantage of a purported low α:β ratio.

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Three randomized trials, each incorporating a distinct brachytherapy boost regimen,

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have now demonstrated improved b-PFS compared to EBRT alone. In the case of this

trial, an LDR-PB resulted in K-M b-PFS benchmarks of 83% for high- and 94% for

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intermediate-risk disease at 6.5-year median follow-up (Figures 2b and 2c).

However, these 3 trials have only begun to explore the diversity of brachytherapy, with

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its pallet of isotopes, dose-rates, and techniques. This diversity may prove problematic.
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For example, numerous dose/fractionation schemes have been used for HDR boosts,

making it difficult to define an optimal regimen. And there are several less easily
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quantified, but potentially critical, differences in treatment planning and delivery for both
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HDR-PB and LDR-PB across institutions (21).

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Residual PSA as a surrogate for BED

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In this trial, the median PSA after LDR-PB was ~20 times lower than after a DE-EBRT

(RESULTS), and their respective K-M curves diverge sharply (see Figure 2a)
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suggesting that the long-term b-PFS after LDR-PB boost will be markedly superior to
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DE-EBRT. This observation is consistent with other studies demonstrating a strong

inverse correlation between the probability of long-term biochemical control and the

residual PSA value in non-relapsed subjects at 4 or 5 years post-radiation therapy (22-

24). Because radiation is a local therapy, this phenomenon is best explained if residual
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PSA is proportional to the effect of the radiation on normal prostate glands and the

PSA-secreting cancers that arise from them, which constitutes a practical definition of

Biological Effective Dose (BED).

Although a dose-response must link BED and residual PSA, researchers have not yet

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derived a quantitative model describing it. However, there exist multiple databases

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which contain pre-treatment prognostic information, long-term b-PFS data, and serial

PSA values that are probably suitable for such an effort. If these datasets collectively

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span a sufficient range of radiation dose and fractionation, they could be used to derive

and validate a quantitative dose-response, construct an isoeffect curve, and derive the

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alpha-beta ratio. In this way, residual PSA might become an objective surrogate for
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BED. Using BED to rank radiation prescriptions could help researchers evaluate novel

regimens against known standards and permit comparisons of LDR-PB and HDR-PB
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protocols without recourse to mathematical formulae that contain multiple variables that
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are weakly constrained by empiric observations.

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Study limitations
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Centralized quality assurance procedures including real-time review of EBRT and post

implant dose metrics were not included in this trial. The optimal duration of ADT and the
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role of elective nodal irradiation are still not clearly defined (25-27), and may differ for
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intermediate- and high-risk patients (26,27). Although placed in 40% of DE-EBRT boost

subjects, fiducial markers for image-guidance were not required. Notwithstanding the

small number of patients available for the comparison, we did not observe a difference

in biochemical failure in the DE-EBRT between those with or without use of image-
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guidance. Intensity modulated radiation therapy (IMRT) was not used (28), and although

IMRT may alter toxicity and facilitate safer dose escalation, its use is unlikely to alter

tumor control in a manner independent of the prescribed dose. Of concern, 93% of trial

subjects were accrued from four centers that share a single LDR-PB planning/treatment

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algorithm which differs in some potentially relevant details from those used by other

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high volume LDR-PB programs, implying that the gain in b-PFS observed for the LDR-

PB may not generalize (29,30).

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CONCLUSIONS

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The initial management for high- and intermediate-risk prostate cancer usually involves
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surgery or some form of radiation therapy. At the very least, this trial provides

benchmarks for future comparisons; the 6.5-year K-M b-PFS estimate is 83% for NCCN
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high-risk and 94% for NCCN intermediate-risk subjects who were randomly assigned to
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an LDR-PB boost. Importantly, the results of this trial indicate that most men with
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adverse prognostic features lack occult metastatic spread at presentation and can be

cured by local tumor eradication. In marked contrast to those randomized to DE-EBRT,

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the majority of non-relapsed men assigned to the LDR-PB had undetectable PSA

values when using ultrasensitive assays, implying that LDR-PB frequently provides
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gland-ablative doses of ionizing radiation, while DE-EBRT rarely does.

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However, as detailed in a companion paper, the men who received an LDR-PB also had

a significantly higher incidence of treatment-related genitourinary (GU) morbidity

compared to DE-EBRT. Thus, the LDR-PB boost provided gland-ablative doses, but

produced more adverse events related to normal tissue effects. It is logical to connect
 ACCEPTED MANUSCRIPT

these two facts through the common mechanism of an increased biological effective

dose. Current efforts are directed at reducing toxicity by exploiting better image

guidance and more accurate treatment delivery, and it is possible that technological

solutions might provide the benefits of dose escalation without its liabilities. It is also

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possible that major improvements in the therapeutic ratio may take more than image

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guidance, altered fractionation and HDR-PB (collectively) have to offer, and arguments

derived from radiobiological modeling are no substitute for phase 3 trials and data from

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large prospective cohorts. Until such data are available, incorporating an LDR-PB boost,

or any means of dose escalation that can achieve gland-ablative doses, should be

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individualized and requires careful consideration of the potential risks and benefits.
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REFERENCES

1. Shipley WU, Verhey LJ, Munzenrider JE et al. Advanced prostate cancer: The

results of a randomized comparative trial of high dose irradiation boosting

with conformal protons compared with conventional dose irradiation using

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photons alone. Int J Radiat Oncol Biol Phys 1995;32(1):3-12.

RI
2. Heemsbergen WD, Al-Mamgani, Slot A et al. Long-term results of the Dutch

randomized prostate cancer trial: Impact of dose-escalation on local,

SC
biochemical, clinical failure, and survival. Radiother Oncol 2014;110:104-9.

3. Beckendorf V, Guerif S, Le Prise E et al. 70 Gy versus 80 Gy in localized

U
prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat
AN
Oncol Biol Phys 2011;80(4):1056-63.

4. Dearnaley DP, Jovic G, Syndikus I et al. Escalated-dose versus control-dose

M

conformal radiotherapy for prostate cancer: long-term results form the MRC
D

RT01 randomised controlled trial. Lancet Oncol 2014;15(4):464-73.

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5. Kuban DA, Levy LB, Cheung MR et al. Long-term failure patterns and survival

in a randomized dose-escalation trial for prostate cancer. Who dies of

EP

disease? Int J Radiat Oncol Biol Phys 2011;79(5):1310-17.

6. Sathya JR, Davis IR, Julian JA et al. Randomized trial comparing iridium
C

implants plus external-beam radiation therapy with external-beam radiation

AC

therapy alone in node-negative locally advanced cancer of the prostate. J Clin

Onc 2005;23(6): 1192-9.

7. Hoskin PJ, Rojas AM, Bownes PJ et al. Randomised trial of external beam

radiotherapy alone or combined with high-dose-rate brachytherapy boost for

localized prostate cancer. Radiother Oncol 2012;103(2):217-22.

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8. Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific

antigen free survival outcomes for patients with low intermediate and high risk

prostate cancer treatment by radical therapy. Results of the Prostate Cancer

Results Study Group. BJU Int 2012;109(Supp. 1):22-9.

PT
9. Bittner N, Merrick GS, Galbreath RW, et al. Treatment outcomes with

RI
permanent brachytherapy in high-risk prostate cancer patients stratified into

prognostic categories. Brachytherapy 2015;14:766-772

SC
10. Carpenter TJ, Forsythe K, Kao J, et al. Outcomes for patients with

extraprostatic prostate cancer treated with trimodality therapy, including

U
bracytherapy, external beam radiotherapy and hormone therapy.
AN
Brachytherapy 2011;10:261-8.

11. Eastham JA, Evans CP, Zietman A. What is the optimal management of high
M

risk, clinically localized prostate cancer? Urol Oncol: Sem Orig Invest.
D

2010;28: 557-67
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12. Zelefsky MJ, Eastham JA, Cronin AM et al. Metastasis after radical

prostatectomy or external beam radiotherapy for patients with clinically

EP

localized prostate cancer: A comparison of clinical cohorts adjusted for case

mix. J Clin Oncol 2010;28:1508-13.

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13. Fradet Y. Radical prostatectomy is the most cost-effective primary treatment

AC

modality for men diagnosed with high-risk prostate cancer. Can Urol Assoc J

2012;6(5):396-8.
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14. Tyldesley S, Peacock M, Morris WJ et al. The need for, and utilization of

prostate-bed radiotherapy after radical prostatectomy for patients with

prostate cancer in British Columbia. Can Urol Assoc J 2012;6(2):89-94.

15. Bolla M, Van Tienhoven G, Warde P et al. External irradiation with or without

PT
long-term androgen suppression for prostate cancer with high metastatic risk:

RI
10 year-results of an EORTC randomized study. Lancet Oncol

2010;11(11):1066-73.

SC
16. Mason MD, Parulekar WR, Sydes MR et al. Final report of the Intergroup

randomized study of combined androgen-deprivation therapy plus

U
radiotherapy versus androgen-deprivation therapy alone in locally advanced
AN
prostate cancer. J Clin Oncol. 2015;33(19):2143-50.

17. Pollock A, Walker G, Horwitz EM et al. Randomized trial of hypofractionated

M

external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31:3860-8.

D

18. Arcangeli S, Strigari L, Gomellini S et al. Updated results and patterns of

TE

failure in a randomized hypofractionated trial for high-risk prostate cancer. In J

Radiat Oncol Biol Phys 2012;84(5):1172-8.

EP

19. Dearnaley D, Sydikus I, Mossop H et al. Conventional versus hypofractionated

high-dose intensity-modulated radiotherapy for prostate cancer: 5-year

C

outcomes of the randomized, non-inferiority, phase 3 CHHiP trial. Lancet

AC

Oncol 2016;http:// dx.doi.org/10.1016/S1470-2045(16)30102-4.

20. Musunuru HB, Cheung P, Loblaw A. Evolution of hypofractionated accelerated

radiotherapy for prostate cancer- The Sunnybrook experience. Front Oncol

2014:4:313.
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21. Morton GC. High-dose-rate bracytherapy boost for prostate cancer: rationale

and technique. J Contemp Brachytherapy 2014;6:323-30

22. Lo AC, Morris WJ, Lapointe, V. Prostate specific antigen at 4to 5 years after

low-dose-rate prostate brachytherapy is a strong predictor of disease free

PT
survival. Int J Radiat Oncol Biol Phys 2014;88:87-91

RI
23. Ko EC, Stone NN, Stock RG. PSA nadir of <0.5 ng/mL following

brachytherapy for early-stage prostate adenocarcinoma is associated with

SC
freedom from prostate-specific antigen failure. Int J Radiat Oncol Biol Phys

2012;83:600-7.

U
24. Yock TI, Zietman AL, Shipley WU, et al. Long-term durability of PSA failure-
AN
free survival after radiotherapy for localized prostate cancer. Int J Radiat

Oncol Biol Phys 2002;54:420-6.

M

25. RTOG 0924 - Androgen deprivation therapy and high dose radiotherapy with
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or without whole-pelvic radiotherapy in unfavorable intermediate or favorable

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high risk prostate cancer: A phase III randomized trial. Disease Site Tables:

RTOG Genitourinary Cancer Studies.

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http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Accessed Feb 18,

2015.
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26. RTOG 0815 – A phase III prospective randomized trail of dose-escalated

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radiotherapy with and without short-term androgen deprivation therapy for

patients with intermediate risk prostate cancer. Disease Site Tables: RTOG

Genitourinary Cancer Studies.

http://www.rtog.org/ClinicalTrials/ProtocolTable.asp. Accessed Feb 18, 2015.

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27. Nabid A, Carrier N, Martin A et al. High-risk prostate cancer treated with

pelvic radiotherapy and 36 versus 18 months of androgen blockade: Results

of a phase III randomized study. J Clin Onc 2013;31(suppl 6):abstr 3

28. Al-Mamgani A, Heemsbergen WD, Peeters STH et al. Role of intensity-

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modulated radiotherapy in reducing toxicity in dose escalation for localized

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prostate cancer. Int J Radiat Oncol Biol Phys. 2009;73(3): 685-91.

29. Reference removed to blind reviewers.

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30. Reference removed to blind reviewers.

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FIGURE LEGENDS

Figure 1: Consort diagram. Note that no attempt was made to track screened cases.

Figure 2: Kaplan-Meier plots showing an Intent-to-treat analyses by randomization arm.

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Black line and censor marks = DE-EBRT arm; Red line and censor marks = LDR-PB

arm.

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2a: Biochemical progression free survival (b-PFS) for all trial subjects by

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randomization arm (N =398, log rank p =0.001)

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2b: b-PFS for the NCCN intermediate-risk subset (N =122; log rank p =0.003)
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2c: b-PFS for the NCCN high-risk subset (N =276; log rank p =0.048)
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2d: Overall survival for all trial subjects by randomization arm (N =398; log rank p

= 0.293)
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Table 1: Prognostic features including age, pre-treatment tumor factors, and post

implant dose metrics (for LDR boost patients only) are listed. Numbers in parentheses

are percentages unless otherwise noted. *None of the comparisons demonstrated a

statistically significant difference between the arms.

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By randomization By actual treatment received
All

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Factor patients DE- DE-
LDR-PB LDR-PB Neither
N=398 EBRT EBRT
N=198 N=188 N=15
N=200 N=195

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Median 68 69 67 69 67 67
Age 67.6 67.9 67.4 67.9 67.4 66.4
Mean (SD)
(years) (7.5) (7.5) (7.4) (7.5) (7.5) (8.1)
Range 45-86
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45-86 49-84 45-86 50-85 49-78
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122 63 59 64 54 4
Intermediate
NCCN risk (30.7) (31.5) (29.8) (32.8) (28.7) (26.7)
stratum 276 137 139 131 134 11
High
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(69.3) (68.5) (70.2) (67.2) (71.3) (73.3)

282 143 139 137 135 10
T1c-T2c
Clinical T- (70.9) (71.5) (70.2) (70.3) (71.8) (66.7)
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stage 116 57 59 58 53 5
T3a
(29.1) (28.5) (29.8) (29.7) (28.2) (33.3)
35 18 17 17 17 1
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<5
(8.8) (9.0) (8.6) (8.7) (9.0) (6.7)
156 76 80 74 72 10
5-10
(39.2) (38.0) (40.4) (37.9) (38.3) (66.7)
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132 66 66 66 63 3
10-20
(33.2) (33.0) (33.3) (33.8) (33.5) (20.0)
iPSA 75 40 35 38 36 1
>20
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(ng/mL) (18.8) (20.0) (17.7) (19.5) (19.1) (6.7)

Median 10.7 11.0 10.1 11.0 10.8 8.5
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13.3 13.4 13.2 13.4 13.5 9.9

Mean (SD)
(8.2) (8.3) (8.1) (8.3) (8.3) (4.6)
4.8-
Range 2.4-40.0 2.7-39.1 2.4-40.0 2.7-39.1 2.4-40.0
21.0
22 10 12 11 10 1
6
Gleason (5.5) (5.0) (6.1) (5.6) (5.3) (6.7)
sum (GS) 214 110 104 109 97 8
7
(53.8) (55.0) (52.5) (55.9) (51.6) (53.3)
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162 80 82 75 81 6
8-10
(40.7) (40.0) (41.4) (38.5) (43.1) (40.0)
57 23 34 22 31 4
≤25%
(14.3) (11.5) (17.2) (11.3) (16.5) (26.7)
142 79 63 77 61
25-50% 4 (26.7)
(35.7) (39.5) (31.8) (39.5) (32.4)
84 36 48 34 48

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50-75% 2 (13.3)
(21.1) (18.0) (24.2) (17.4) (25.5)
Percent 113 60 53 60 48
≥ 75% 5 (33.3)
positive (28.4) (30.0) (26.8) (31.3) (25.5)

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cores Data 2 2 2
0 0 0
(PPC) missing (0.5) (1.0) (1.0)

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Median 50 50 61 50 60 50
59.3 60.2 58.3 60.1 58.1 57.6
Mean (SD)
(26.9) (26.9) (26.8) (26.9) (26.4) (28.4)

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Range 7-100 9-100 7-100 9-100 7-100 17-100
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205 101 104 100 98 7
≤1
**Number (51.5) (50.5) (50.5) (51.3) (52.1) (46.7)
of high 140 72 68 66 66 8
2
risk (35.2) (36.0) (34.3) (33.8) (35.1) (53.3)
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features 53 27 26 29 24
≥3 0
(13.3) (13.5) (13.1) (14.9) (12.8)
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Median N/A N/A N/A N/A 108.7 N/A

109.6
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†D90% Mean (SD) N/A N/A N/A N/A N/A

(12.8)
81-
Range N/A N/A N/A N/A N/A
154.3
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Median N/A N/A N/A N/A 94.4 N/A

93.1
‡V100 Mean (SD) N/A N/A N/A N/A N/A
(5.2)
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69.9-
Range N/A N/A N/A N/A N/A
100
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*Chi-square test was performed on categorical variables. Mann-Whitney-Wilcoxon test

was performed on age variable to examine difference between the median values. T-

tests were performed on iPSA and PPC.

**High risk factors include: clinical T-stage =T3a, iPSA >20 ng/mL, GS ≥8, and PPC

≥50%.
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†D90 is minimum dose in Gy received by 90% of the post-implant, CT-based prostate

volume

‡V100 is the percentage of the post-implant, CT-based prostate volume that received

the prescription dose of 115 Gy or higher.

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Table 2: Disease status at data lockdown (09/30/2014) by randomization (intent-to-treat) and by actual treatment arm

received. The median follow up was 6.5 years from the date of the first LHRH injection. (Abbreviations: ANED = alive with

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no evidence of disease recurrence; DNED = deceased with no evidence of disease recurrence at or before date of death;

AWD = alive with disease recurrence; DOWD = dead of disease or with disease recurrence at time of death)

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All By randomization By actual treatment arm received
Analysis Status patients

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N=398 DE-EBRT LDR-PB DE-EBRT LDR-PB Neither

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N=200 N=198 N=195 N=188 N=15
76 51 25 48 21 7
*Relapsed
(19.1) (25.5) (12.6) (24.6) (11.2) (46.7)

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322 149 173 147 167 8
Non-relapsed
(80.9) (74.5) (87.4) (75.4) (88.8) (53.3)

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Metastatic disease 35 18 17 18 14 3

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present (8.8) (9.0) (8.6) (9.2) (7.4) (20.0)
Events: 330 162 168 155 163 12
Alive
(82.9) (81.0) (84.8) (79.5) (86.7) (80.0)
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number of
patients 68 38 30 40 25 3
(%) Deceased
(17.1) (19.0) (15.2) (20.5) (13.3) (20.0)
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274 124 150 120 148 6

ANED
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(68.8) (62.0) (75.8) (61.5) (78.7) (40.0)

48 25 23 27 19 2
DNED
(12.1) (12.5) (11.6) (13.8) (10.1) (13.3)
56 38 18 35 15 6
AWD
(14.1) (19.0) (9.1) (17.9) (8.0) (40.0)
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20 13 7 13 6 1
DOWD
(5.0) (6.5) (3.5) (6.7) (3.2) (6.7)
**Died of prostate 18 11 7 11 6 1
cancer (4.5) (5.5) (3.5) (5.6) (3.2) (6.7)

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86.2 83.8 88.7 84.9 89.7
5 yr

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Biochemical (±3.8) (±5.6) (±4.8) (±5.6) (±4.8)
progression 80.7 75.0 86.2 76.3 88.0
7 yr

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free survival (±4.6) (±7.2) (±5.4) (±7.0) (±5.2)
(b-PFS) 72.7 62.4 83.3 65.0 84.9
9 yr
(±6.2) (±9.8) (±6.6) (±9.6) (±6.6)

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90.0 88.7 91.3 87.4 92.4
5 yr

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(±3.2) (±4.8) (±4.4) (±5.0) (±4.2)
Overall
83.6 81.5 85.7 81.1 87.0
survival 7 yr

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(±4.4) (±6.4) (±5.8) (±6.2) (±5.8)
(OS)
Kaplan- 75.8 73.6 77.9 73.4 79.5
9 yr
(±5.8) (±8.4) (±8.2) (±8.2) (±8.4)

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Meier
N/A†
estimates 92.9 92.5 93.3 92.6 94.1

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(95% CI) 5 yr
(±2.8) (±4.0) (±3.8) (±4.0) (±3.6)
Metastasis
91.7 92.5 91.0 92.6 91.6
free survival 7 yr
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(±3.0) (±4.0) (±4.6) (±4.0) (±4.6)
(MFS)
86.8 84.8 88.6 85.2 90.1
9 yr
(±4.6) (±7.6) (±5.6) (±7.4) (±5.4)
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97.1 97.5 96.8 97.0 97.1

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Prostate 5 yr
(±1.8) (±2.4) (±2.8) (±2.6) (±2.8)
cancer
95.1 94.1 96.0 94.4 96.2
specific 7 yr
(±2.6) (±4.2) (±3.2) (±4.0) (±3.4)
survival
(PCSS) 93.5 92.1 94.8 92.5 95.0
9 yr
(±3.4) (±5.6) (±4.0) (±5.4) (±4.2)
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*Progression free survival is defined as the absence of any biochemical (nadir PSA+2 ng/mL threshold), imaging, or

clinical recurrence of prostate cancer and never having received any form of secondary treatment for prostate cancer after

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completion of the protocol interventions.

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**Patients undergoing systemic treatment for metastatic prostate cancer at the time of death were considered prostate

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cancer specific deaths regardless of the proximal cause of death.

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†NA- not applicable, as there were insufficient cases in the protocol violation group for meaningful actuarial analysis.

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Table 3a: Univariate and multivariable analyses (Cox model; backwards:conditional) for biochemical failure.

Univariate analysis Multivariable Cox model

Variable

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HR 95% CI P value HR 95% CI P value
*†Randomization arm

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2.17 1.33 – 3.45 0.002 2.04 1.25-3.33 0.004
(DE-EBRT vs LDR-PB)
*Percent positive cores

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1.01 1.01 – 1.02 0.001 1.01 1.00-1.02 0.006
(unit = 1%)
*†Clinical T-stage
1.89 1.20 – 3.00 0.006 1.97 1.24-3.13 0.004
(T3a vs T1-T2b)

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*Log iPSA
1.60 1.10 – 2.34 0.014 1.62 1.11-2.36 0.01

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(unit = 1 log)
**†Risk Code
1.66 0.99 – 2.80 0.0557 N/A
(high risk vs intermediate risk)

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**†Number of high risk features
2.60 1.60 – 4.33 <0.001 N/A
(≥ 3 vs ≤ 2)

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*†Gleason Sum
1.28 0.81 – 2.02 0.29 1.38 0.87-2.19 0.17
(8-10 vs ≤ 7)

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Age
1.00 0.97 – 1.03 0.99 N/A
(unit = I year)
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*entered into the MVA model if univariate p <0.3
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**composite variables not entered into the MVA

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†categorical variables
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Table 3b: Univariate and multivariable analysis (Cox model; backwards:conditional) for all-cause mortality

Univariate analysis Multivariable Cox model

Variable

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HR 95% CI P-value HR 95% CI P-value
*†Randomization arm

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1.29 0.80 – 2.08 0.30 1.13 0.69 – 1.84 0.62
(DE-EBRT vs LDR-PB)
Percent positive cores

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1.00 0.99 – 1.01 0.61 N/A
(unit = 1%)
†Clinical T stage
1.04 0.62 – 1.74 0.89 N/A
(T3a vs T1-T2)

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*Log iPSA
1.28 0.86 – 1.89 0.23 1.18 0.80 – 1.73 0.42

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(unit = 1 log)
**†Risk Code
1.13 0.68 – 1.87 0.64 N/A
(high risk vs intermediate risk)

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**†Number of high risk features
1.30 0.68 – 2.49 0.42 N/A
(≥ 3 vs ≤ 2)

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†Gleason Sum
1.23 0.76 – 2.01 0.40 N/A
(8-10 vs ≤ 7)

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*Age (unit = I year) 1.05 1.02 – 1.09 0.004 1.05 1.02 – 1.09 0.006
‡*Disease status (relapse vs no
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6.60 3.80 – 11.4 <0.001 6.30 3.62 – 10.9 <0.001
relapse)
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*entered into the MVA model if univariate p <0.3

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**composite variables not entered into the MVA

†categorical variables; ‡time-dependent variable

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Figure 1: Consort Diagram Randomization (N =398)

Allocation

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Allocated to DE-EBRT arm (N =200) Allocated to LDR-PB arm (N = 198)
• Received allocated intervention (N • Received allocated intervention (N

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=187) =182)
• Did not receive allocated intervention • Did not receive allocated intervention

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(N =13) (N =16)
o 6 received LDR-PB arm o 8 received DE-EBRT arm
(patient decision) (patient decision)
o 7 received neither protocol o 8 received neither protocol

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intervention (patient decision) intervention (patient decision)

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Follow up
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Lost to follow-up (N =1) Lost to follow-up (N =0)

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Cases were censored at last follow-up Cases were censored at last follow-up
and analyzed actuarially and analyzed actuarially
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Analysis
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Analyzed for disease control endpoints Analyzed for disease control endpoints
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(N =200) (N =198)
• Excluded from analysis (N =0) • Excluded from analysis (N =0)

Analyzed for toxicity endpoints (N =195)
• Excluded from analysis (N =13)
o 6 received LDR-PB
intervention and 7 received
neither intervention
• Crossover from LDR-PB arm
included in toxicity analysis (N =8)
Analyzed for toxicity endpoints (N=188)
• Excluded from analysis (N =16)
o 8 received DE-EBRT
intervention and 8 received
neither intervention
• Crossover form DE-EBRT arm
included in toxicity analysis (N =6)
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Figure 2a:
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Numbers at risk:
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Time (yrs) 0 2 3 4 5 6 7 8 9 10

DE-EBRT 200 186 168 145 119 93 74 52 27 11

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LDR-PB 198 184 168 147 127 106 86 59 38 14

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Figure 2b:
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Numbers at risk:
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Time (yrs) 0 2 3 4 5 6 7 8 9 10
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DE-EBRT 63 57 54 49 43 38 30 25 12 4

LDR-PB 59 55 54 50 47 42 35 26 7 6
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Figure 2c:
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Numbers at risk:
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Time (yrs) 0 2 3 4 5 6 7 8 9 10

DE-EBRT 137 129 114 96 76 55 44 27 15 7

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LDR-PB 139 128 114 97 80 64 51 33 21 8

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Figure 2d:
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Numbers at risk:
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Time (yrs) 0 2 3 4 5 6 7 8 9 10

DE-EBRT 200 192 184 161 134 109 85 66 40 16

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LDR-PB 198 191 182 160 137 116 94 65 41 15

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XXXXXX is a randomized trial investigating two methods of dose escalation in the

context of combined modality therapy for NCCN high- and intermediate-risk prostate

cancer that included 12 months of androgen deprivation therapy and whole pelvic

irradiation to 46 Gy. Compared to a 125-Iodine brachytherapy boost, men randomized

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to an external beam boost to a total of 78 Gy were twice as likely to have experienced

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biochemical failure at a median follow up of 6.5 years.

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