Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features

William L Hwang; Rahul D Tendulkar; Andrzej Niemierko; Shree Agrawal; Kevin L Stephans; Daniel E Spratt; Jason W Hearn; Bridget F Koontz; W Robert Lee; Jeff M Michalski; Thomas M Pisansky; Stanley L Liauw; Matthew C Abramowitz; Alan Pollack; Drew Moghanaki; Mitchell S Anscher; Robert B Den; Anthony L Zietman; Andrew J Stephenson; Jason A Efstathiou

doi:10.1001/jamaoncol.2017.5230

. 2018 Jan 25;4(5):e175230. doi: 10.1001/jamaoncol.2017.5230

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features

William L Hwang ¹, Rahul D Tendulkar ², Andrzej Niemierko ¹, Shree Agrawal ³, Kevin L Stephans ², Daniel E Spratt ⁴, Jason W Hearn ⁴, Bridget F Koontz ⁵, W Robert Lee ⁵, Jeff M Michalski ⁶, Thomas M Pisansky ⁷, Stanley L Liauw ⁸, Matthew C Abramowitz ⁹, Alan Pollack ⁹, Drew Moghanaki ¹⁰, Mitchell S Anscher ¹¹, Robert B Den ¹², Anthony L Zietman ¹, Andrew J Stephenson ², Jason A Efstathiou ^1,^✉

¹Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

²Departments of Radiation Oncology and Urology, Cleveland Clinic, Cleveland, Ohio

³Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio

⁴Department of Radiation Oncology, University of Michigan, Ann Arbor

⁵Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina

⁶Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri

⁷Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota

⁸Department of Radiation Oncology, University of Chicago, Chicago, Illinois

⁹Department of Radiation Oncology, University of Miami, Miami, Florida

¹⁰Department of Radiation Oncology, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia

¹¹Department of Radiation Oncology, Virginia Commonwealth University Medical Center, Richmond

¹²Department of Radiation Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania

Accepted for Publication: November 16, 2017.

Correction: This article was corrected on February 22, 2018, to fix a data presentation error in the Results paragraph of the Abstract.

^✉

Corresponding Author: Jason A. Efstathiou, MD, DPhil, Massachusetts General Hospital, Harvard Medical School, 100 Blossom St, Cox Bldg, Third Floor, Boston, MA 02114 (jefstathiou@partners.org).

Published Online: January 25, 2018. doi:10.1001/jamaoncol.2017.5230

Author Contributions: Drs Hwang, Tendulkar, Niemierko, and Efstathiou had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hwang, Tendulkar, Efstathiou.

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

Drafting of the manuscript: Hwang, Niemierko, Efstathiou.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hwang, Niemierko, Efstathiou.

Obtained funding: Efstathiou.

Administrative, technical, or material support: All authors.

Study supervision: Efstathiou.

Conflict of Interest Disclosures: Dr Spratt reported serving on the advisory board of Dendreon and being a member of the NRG Oncology Genitourinary Core Committee. Dr Koontz reported receiving research funding from Janssen Pharmaceuticals and consulting for Blue Earth Diagnostics, GenomeDx Biosciences, Laguna Pharmaceuticals, and ChanRX. Dr Michalski reported receiving travel accommodations and expenses from Varian Medical Systems, Siemens Healthcare Diagnostics, ViewRay, and General Electric Systems. Dr Abramowitz reported receiving research funding from Elekta, consulting for General Electric Corporation, and being employed by Artech. Dr Pollack reported receiving research funding from GenomeDx Biosciences. Dr Moghanaki reported receiving travel accommodations and expenses from Varian Medical Systems and honoraria from Augmenix and Varian Medical Systems. Dr Den reported receiving research funding from Medivation as well as consulting honoraria for GenomeDx Biosciences and Bayer Healthcare. Dr Stephenson reported consulting for Bayer, receiving research funding from Medivation/Astellas Pharma, and receiving travel accommodations and expenses from Blue Earth and Genomic Health. Dr Efstathiou reported receiving research funding from the Prostate Cancer Foundation and consulting for Medivation/Astellas, Genentech, Bayer Healthcare, EMD Serono/Pfizer, Blue Earth Diagnostics, and Taris Biomedical. No other disclosures were reported.

Funding/Support: This work was supported by the Prostate Cancer Foundation.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Daniela Buscariollo, MD, Brigham & Women’s Hospital, Boston, Massachusetts, provided helpful discussions. The following individuals assisted with the data-collection process: Chandana Reddy, MS, Cleveland Clinic, Cleveland, Ohio; Rebecca Clayman, MS, Royal College of Surgeons, Dublin, Ireland; Sigolene Galland, MD, Department of Radiation Oncology, University of Bordeaux, Bordeaux, France; Michael Drumm, BA, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; William Jackson, MD, University of Michigan, Ann Arbor; and Skyler Johnson, MD, Yale School of Medicine, New Haven, Connecticut.

^✉

Corresponding author.

PMCID: PMC5885162 PMID: 29372236

Key Points

Question

What is the optimal timing of postoperative radiotherapy for prostate cancer with adverse pathological features?

Findings

In this multi-institutional cohort study of 1566 consecutive patients with prostate cancer with adverse pathological features, adjuvant radiotherapy after prostatectomy was associated with significantly greater freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival compared with early-salvage radiotherapy.

Meaning

Pending prospective validation, these findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy adjuvant radiotherapy rather than surveillance followed by early-salvage radiotherapy.

Abstract

Importance

Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear.

Objective

To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features.

Design, Setting, and Participants

This multi-institutional, propensity score–matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017.

Main Outcomes and Measures

Freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival. All outcomes were measured from date of surgery to address lead-time bias.

Results

Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram.

Conclusions and Relevance

Adjuvant RT, compared with ESRT, was associated with reduced biochemical recurrence, distant metastases, and death for high-risk patients, pending prospective validation. These findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy ART rather than surveillance followed by ESRT.

This multi-institutional cohort study compares adjuvant radiotherapy with early-salvage radiotherapy used to manage postoperative patients with prostate cancer who have adverse pathological features.

Introduction

The use of radical prostatectomy (RP) as the initial treatment of high-risk and locally advanced prostate cancer has increased in the past 2 decades.¹ However, patients with adverse pathological features, such as positive surgical margins, extraprostatic extension, and seminal vesicle invasion, have a 40% to 70% risk of biochemical recurrence.^2,3,4,5,6 Three randomized clinical trials—European Organization for Research and Treatment of Cancer (EORTC) 22911, Arbeitsgemeinschaft Radiologische Onkologie (ARO) 9602, and Southwest Oncology Group (SWOG) 8794—investigating the role of adjuvant radiotherapy (ART) vs observation in patients with these high-risk features demonstrated a progression-free survival benefit, but only SWOG 8794 found a freedom from distant metastases (FFDM) and overall survival (OS) advantage.^{3,5,6,7,8,9,10} On the basis of these findings, the consensus guidelines of the American Urological Association and American Society for Radiation Oncology and the European Association of Urology recommend physician-initiated, multidisciplinary discussions of the potential benefits and risks of ART for patients with adverse pathological features.^11,12

Despite these recommendations, the use of ART in high-risk patients is under 10% and on the decline,¹³ likely because of overtreatment concerns given that many patients who receive ART would likely have never developed postoperative recurrence. Instead, a more common approach is to monitor high-risk patients after RP until the prostate-specific antigen (PSA) level becomes detectable and offer early-salvage radiotherapy (ESRT) (initiated with PSA level ≤0.5 ng/mL). The ESRT strategy is supported by retrospective data suggesting it is often effective for long-term disease control.^{14,15,16,17,18}

Currently, no prospective randomized data are available comparing ART with ESRT, pending 3 ongoing trials.^19,20,21 Previous retrospective studies comparing ART and salvage RT (SRT) yielded discrepant results regarding whether ART improves post-RT freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy, and FFDM, whereas no studies showed an OS advantage for ART.^{4,22,23,24,25,26} Because the optimal timing of postoperative RT for prostate cancer with adverse pathological features remains controversial, we conducted a large, multi-institutional analysis comparing the FFBF, FFDM, and OS between ART and ESRT.

Methods

Study Design, Data Sources, Study Participants, Exposures, and Outcomes

We pooled individual data from 1566 patients with pT2N0M0/R1 or pT3N0M0/R0-1 prostate adenocarcinoma (American Joint Committee on Cancer’s Cancer Staging Manual, 7th edition) who underwent postprostatectomy ART or ESRT at 10 academic medical centers between January 1, 1987, and December 31, 2013. This study obtained institutional review board approval from Massachusetts General Hospital and Cleveland Clinic. Patient informed consent was waived at these institutions because this is a minimal risk study using data collected for routine clinical practice. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017.

All patients were within a consecutive cohort of eligible patients treated at each of the 10 institutions (Massachusetts General Hospital, Cleveland Clinic, University of Michigan, Duke University Medical Center, Washington University School of Medicine, Mayo Clinic, University of Chicago, University of Miami, Virginia Commonwealth University Medical Center, and Sidney Kimmel Cancer Center at Thomas Jefferson University). Patients who had nodal involvement or received preoperative androgen deprivation therapy (ADT) were excluded. The PSA-level detection limits varied over time and among laboratories. In this study, PSA level was considered undetectable if it was less than 0.1 ng/mL or below the sensitivity limit of the assay. Adjuvant RT was defined as RT delivered at an undetectable PSA level, whereas ESRT was defined as RT delivered at a detectable PSA level between and inclusive of 0.1 to 0.5 ng/mL, including those with a persistently detectable PSA level after surgery. Use of ART or ESRT, RT technique, RT dose, pelvic nodal RT, and postoperative ADT administered before or concurrent with RT were at the discretion of the treating physicians.

The study outcomes were postirradiation FFBF, FFDM, and OS. All outcomes were measured from the date of surgery to address potential lead-time bias. Postirradiation biochemical failure (BF) was defined as PSA level rising to 0.2 ng/mL or higher. For patients in the ESRT group who never achieved a PSA level lower than 0.2 ng/mL after radiation, BF was determined as the first documented rise in PSA level above 0.2 ng/mL. Distant metastases was defined as radiographic evidence of metastases. Overall survival was defined as death from any cause.

Statistical Analysis

Patient and treatment characteristics were compared using Fisher exact test and Wilcoxon rank sum test as appropriate. Propensity score (PS) 1-to-1 matching²⁷ using logistic regression and caliper width 0.01 was used to account for covariates potentially associated with treatment selection: age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. Postirradiation FFBF, FFDM, and OS outcomes after ART vs after ESRT were compared using the Kaplan-Meier method. Multivariate competing-risks regression analysis of FFBF accounting for death as a competing risk was performed to compare the outcomes of ART and ESRT when controlling for potential confounders: age at surgery (continuous), year of surgery (continuous), Gleason score (continuous), T stage (pT2/T3a/T3b), margin status (dichotomous), RT dose (Gy; continuous), pelvic nodal RT (dichotomous), and postoperative ADT (dichotomous). Patients who died before developing BF were censored in an informative manner, whereas patients who were alive without BF at last follow-up were censored in a noninformative manner.

A sensitivity analysis was completed to address the limitation that an unknown proportion of patients in the ART group who did not develop BF may have been cured by surgery alone. Toward this end, we randomly removed from the PS-matched ART cohort an increasing number of patients who did not develop BF by the last follow-up visit to represent the assumption that these patients were cured by surgery alone. Next, we iteratively compared the BF rates between the PS-matched ART and ESRT groups using the log-rank test. To estimate FFBF after surgery alone for comparison to the sensitivity analysis, we applied the dynamic postprostatectomy nomogram developed at Memorial Sloan Kettering Cancer Center (eAppendix in the Supplement).

Statistical analyses were performed using Stata, version 14.1 (StataCorp LLC). A 2-tailed P < .05 was considered statistically significant.

Results

Patient and Treatment Characteristics

Of the 1566 patients, 1195 received ESRT and 371 received ART. The median age (interquartile range [IQR]) was 60 (55-65) years. Baseline patient and treatment characteristics are provided in Table 1. As expected, the median (IQR) time from surgery to RT was longer for the ESRT group compared with the ART group (22.9 [8.5-44.3] months vs 4.4 [3.5-6.4] months; P < .001), which translated into a longer median (IQR) follow-up after surgery (92.3 [55.3-134] months vs 65.4 [40-107] months; P < .001). However, there was no difference in median (IQR) follow-up after RT in the ESRT and ART cohorts (55.9 [26.6-96.1] months vs 58.4 [32.0-101.2] months; P = .08).

Table 1. Summary of Patient and Treatment Characteristics.

Characteristic	Before PS Matching			After PS Matching
Characteristic	ESRT (n = 1195)	ART (n = 371)	P Value	ESRT (n = 366)	ART (n = 366)	P Value
Age at surgery, median (IQR), y	60.0 (55.0-64.7)	60.0 (55.2-65.0)	.44^a	61.0 (54.6-65.3)	60.0 (55.0-65.0)	.90^a
Year of surgery, median (IQR)	2002 (1998-2006)	2006 (2000-2008)	<.001^a	2005 (2001-2007)	2006 (2000-2008)	.29^a
Follow-up since surgery, median (IQR), mo	92.3 (55.3-134)	65.4 (40-107)	<.001^a	73.3 (44.9-106.6)	65.8 (40-107)	.22^a
Pathological T stage, No. (%)^b
T2	553 (46.3)	98 (26.4)	<.001^c	109 (29.8)	98 (26.8)	.63^c
T3a	435 (35.4)	183 (49.3)		170 (46.4)	181 (49.5)
T3b	207 (17.3)	90 (24.3)		87 (23.8)	87 (23.8)
Surgical Gleason score, No. (%)
6	248 (20.8)	50 (13.5)	<.001^c	33 (9.0)	50 (13.7)	.18^c
7	722 (60.4)	214 (57.7)		209 (57.1)	210 (57.4)
8	108 (9.0)	46 (12.4)		54 (14.8)	45 (12.3)
9	116 (9.7)	61 (16.4)		70 (19.1)	61 (16.7)
10	1 (0.1)	0 (0)
Margin status, No. (%)
Positive	721 (60.3)	315 (84.9)	<.001^c	318 (86.9)	313 (85.8)	.67^c
Negative	462 (38.7)	53 (14.3)		48 (13.1)	53 (14.5)
Unknown	12 (1.0)	3 (0.8)
Time from surgery to RT, median (IQR), mo	22.9 (8.5-44.3)	4.4 (3.5-6.4)	<.001^a	14.1 (4.9-31.2)	4.5 (3.5-6.4)	<.001^a
Follow-up since RT, median (IQR), mo	55.9 (26.6-96.1)	58.4 (32.0-101.2)	.08^a	49.2 (22.2-80.0)	59.2 (32.0-101.2)	<.001^a
Pre-RT PSA level, median (IQR), ng/mL	0.3 (0.2-0.4)	<0.1	NA	0.3 (0.2-0.4)	<0.1	NA
RT technique, No. (%)
2-D	245 (20.5)	69 (18.6)	<.001^c	58 (15.8)	69 (18.9)	.16^c
3-D CRT	311 (26.0)	64 (17.3)		70 (19.1)	63 (17.2)
IMRT	436 (36.5)	174 (46.9)		192 (52.5)	171 (46.7)
Unknown	203 (17.0)	64 (17.2)		46 (12.6)	63 (17.2)
RT node coverage, No. (%)
Yes	141 (11.8)	43 (11.6)	>.99^c	47 (12.8)	43 (11.7)	.74^c
No	1054 (88.2)	328 (88.4)	>.99^c	319 (87.2)	323 (88.3)	.74^c
RT dose to prostate fossa, median (IQR), Gy	64.8 (64.8-68.1)	64.8 (61.2-66.0)	<.001^a	66.0 (64.8-70.0)	64.8 (61.2-66.0)	<.001^a
RT duration, median (IQR), d	50 (48-52)	49 (46-50)	<.001^a	50 (48-52)	49 (46-50)	<.001^a
Postoperative ADT, No. (%)
Yes	135 (11.3)	23 (6.2)	.004^c	19 (5.2)	23 (6.3)	.63^c
No	1060 (88.7)	348 (93.8)	.004^c	347 (94.8)	343 (93.7)	.63^c

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Abbreviations: ADT, androgen deprivation therapy; ART, adjuvant radiation therapy; ESRT, early-salvage radiation therapy; IMRT, intensity-modulated radiation therapy; IQR, interquartile range; PS, propensity score; PSA, prostate-specific antigen; RT, radiation therapy; 2-D, 2-dimensional; 3-D CRT, 3-dimensional conformal radiotherapy.

SI conversion factor: To convert PSA to micrograms per liter, multiply by 1.0; to convert gray to rad, multiply by 100.

^{^a}

Calculated using the Wilcoxon rank sum test.

^{^b}

All patients with stage T2 had positive surgical margins.

^{^c}

Calculated using the Fisher exact test.

The ESRT group, compared with the ART cohort, had an earlier median (IQR) year of surgery (2002 vs 2006; P < .001), lower pathological T stage (T3: 642 [52.7%] vs 273 [73.6%]; P < .001), lower Gleason score (8-10: 225 [18.8%] vs 107 [28.8%]; P < .001), lower rate of positive margins (721 [60.3%] vs 315 [84.9%]; P < .001), less use of intensity modulated RT (436 [36.5%] vs 174 [46.9%]; P < .001), and greater use of postoperative ADT (135 [11.3%] vs 23 [6.2%]; P = .004). The median (IQR) pre-ESRT PSA level was 0.3 (0.2-0.4) ng/mL. Use of pelvic nodal RT was similar in the ESRT and ART groups (141 [11.8%] vs 43 [11.6%]; P = >.99).

Propensity Score–Matched Analysis

Propensity score matching yielded 366 matched pairs that were well-balanced (Table 1). The mean standardized bias was reduced from 24.8% to 4.5% after matching (eTable and eFigures 1 and 2 in the Supplement). As expected, the median (IQR) time from surgery to RT remained longer in the ESRT group than the ART group (14.1 [4.9-31.2] months vs 4.5 [3.5-6.4] months; P < .001). However, the median (IQR) follow-up after surgery was similar between the ESRT and ART cohorts (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). The median (IQR) RT dose to the prostate fossa was slightly higher in the ESRT group than in the ART group (66.0 [64.8-70.0] Gy vs 64.8 [61.2-66.0] Gy; P < .001 [to convert gray to rad, mulitply by 100]).

After PS matching, all measured outcomes were significantly better with ART compared with ESRT: FFBF (61 vs 140 events; P < .001), FFDM (14 vs 28 events; P = .03), and OS (20 vs 35 events; P = .01). The crude rate of prostate cancer–specific death was higher in the ESRT than the ART cohort (6 vs 1 events), but the small number of events precluded additional statistical analysis. The 12-year actuarial rates for ART vs ESRT were as follows: FFBF (69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), FFDM (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and OS (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%) (Figure).

Multivariate competing-risks analysis (Table 2) demonstrated that the factors independently associated with risk of BF were ART, pathological T stage, surgical Gleason score, nodal RT, and postoperative ADT. Multivariate analyses for FFDM and OS were not performed because of insufficient events.

Table 2. Multivariate Competing-Risks Regression Analyses of Factors Associated With Biochemical Failure After Radical Prostatectomy and Postoperative Radiotherapy.

Factor	PS-Matched Patient Cohort, SHR (95% CI)^a	P Value
ART vs ESRT	0.34 (0.24-0.48)	<.001
Age at surgery	1.00 (0.98-1.02)	.65
Year of surgery	1.02 (0.99-1.05)	.24
Pathological T stage
T2	1 [Reference]
T3a	1.14 (0.78-1.67)	.51
T3b	1.87 (1.20-2.92)	.005
Surgical Gleason score	2.06 (1.75-2.41)	<.001
Surgical margin (±)	1.29 (0.82-2.04)	.27
Omitting nodal RT	2.27 (1.33-3.87)	.003
RT dose (Gy), prostate fossa	0.96 (0.91-1.01)	.10
Postoperative ADT	0.30 (0.12-0.74)	.009

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Abbreviations: ADT, androgen deprivation therapy; ART, adjuvant radiation therapy; ESRT, early-salvage radiation therapy; PS, propensity score; RT, radiation therapy; SHR, subhazard ratio.

^{^a}

Subhazard ratios are reported for a 1-unit increase in the continuous variables.

Sensitivity Analysis

The sensitivity analysis revealed that the decreased risk of BF associated with ART in the PS-matched analysis only lost statistical significance when more than 205 patients (56%) in the ART cohort were assumed to have been cured by surgery alone. In the ART group, the longest time to BF after surgery was 11.4 years. Because only overall Gleason scores were available, we estimated the 12-year FFBF after surgery alone using the contemporary nomogram by accounting for patients with a Gleason score of 7 in 3 different ways: (1) all Gleason score 3 + 4, (2) all Gleason score 4 + 3, and (3) one-third Gleason score 4 + 3 and two-thirds Gleason score 3 + 4 based on previous population studies of prostate cancer with a Gleason score of 7.^28,29,30 For the ART group, the 12-year FFBF estimates were 52%, 33%, and 46%, respectively. All patients in the ESRT group had disease recurrence by definition, but for comparative purposes we also estimated the 12-year FFBF immediately after surgery for this group, which was 61%, 38%, and 55%, respectively.

Discussion

In men with locally advanced T3N0 prostate adenocarcinoma, the role of immediate postoperative RT after RP was investigated in 3 randomized clinical trials.^3,5,6,7,8,9 All 3 trials demonstrated a progression-free survival outcome for immediate radiotherapy over observation, but only SWOG 8794 demonstrated an FFDM and OS improvement.^3,9 A meta-analysis of these 3 trials found that 10-year FFBF, FFADT, and FFDM were superior with immediate RT than a wait-and-see approach, but there was no difference in OS in this combined analysis.¹⁰ There were several potential limitations in these trials. First, survival was not a primary outcome, and the studies were therefore underpowered for this end point. Second, fewer than half of patients who recurred in the observation arms received SRT, as salvage therapy utilization was not prespecified in the trials.^5,9,31 Third, roughly one-third of patients in the immediate RT arms had low-detectable PSA levels before starting RT and therefore technically received ESRT.^3,7 Approximately 20% to 40% of men in the observational arms of these trials never had disease recurrence, indicating the possibility of overtreatment with ART in this patient population.

Improved FFBF after SRT is observed with a lower PSA level at the time of treatment initiation.^15,32,33,34 This observation was corroborated by a recent multi-institutional analysis, which found a 5-year FFBF of 71% for patients with a pre-RT PSA level of 0.01 to 0.20 ng/mL, 63% for 0.21 to 0.50 ng/mL, 54% for 0.51 to 1.0 ng/mL, 43% for 1.01 to 2.0 ng/mL, and 37% for greater than 2.0 ng/mL.¹⁸ Contemporary studies typically define ESRT as SRT delivered at a PSA level of 0.5 ng/mL or lower.^4,25,26,35 Importantly, the 3 randomized clinical trials of immediate RT vs observation do not inform whether the benefits of ART persist in the context of more consistent use of ESRT, and therefore the optimal timing of postoperative RT remains unclear.

To our knowledge, this report represents the largest multi-institutional study comparing ART to ESRT in the literature to-date. We measured all outcomes from the time of surgery to account for lead-time bias given the inherent difference in the timing of ART and ESRT after surgery. Because treatment selection was at the discretion of the treating physicians, it was not surprising that the ESRT group featured less advanced disease than the ART cohort did with less pathological T3, lower Gleason score, and fewer positive margins. Furthermore, approximately twice as many patients in the ESRT group were treated with salvage ADT compared with patients in the ART group receiving adjuvant ADT. These differences contributing to treatment allocation were normalized with PS matching. We found that ART was superior to ESRT for all outcomes: postirradiation FFBF, FFDM, and OS.

To account for the unknown subset of patients in the ART group who would never have developed recurrence after surgery, we performed a sensitivity analysis that determined the decreased risk of BF associated with ART only lost statistical significance when more than 56% of patients in the ART group were assumed to have been cured by surgery alone. This threshold is greater than the estimated 12-year FFBF of 33% to 52% after RP alone as determined by the contemporary nomogram, indicating that the difference in FFBF cannot be attributed to successful surgery alone. In comparison, the estimated 12-year FFBF after RP for the ESRT cohort is higher at 38% to 61%, suggesting that the improved outcomes seen in the ART group, compared with the ESRT group, cannot be simply ascribed to more favorable clinicopathological features. However, because all patients in the ESRT group had recurrent disease after surgery, there may be other unknown or unmeasured factors in the ESRT group that predisposed these patients to worse clinical outcomes. On multivariate competing-risks regression analysis, ART remained significantly associated with decreased BF. Other independent favorable prognostic features were lower Gleason score, lack of seminal vesicle invasion, pelvic nodal RT, and use of postoperative ADT.

Previous retrospective series comparing ART and SRT generally showed increased FFBF but not OS with ART.^{4,22,23,24,25,26} Potential reasons for this difference include a smaller cohort size, shorter follow-up, disparate end points, and varying PSA thresholds at the time of SRT with inclusion of patients with a PSA level greater than 0.5 ng/mL. Furthermore, positive margins have been correlated with better response to postoperative RT^5,8,15,32; 42% of men before PS matching and 28% after PS matching had pT2/R1 disease in our cohort, which is a greater proportion of margin-positive patients than in previous studies. In addition, the proportion of patients with Gleason scores of 8 to 10 was 21% before PS matching and 31% after PS matching, which is higher than in most previous studies^4,22,23 and similar to a recent study that also showed an FFDM advantage with ART.²⁶ Patients with high Gleason scores benefit from ART,^6,9 but this feature is strongly associated with a higher risk of progression after SRT.^{15,16,22,23,32} Therefore, our study population may have been enriched with patients more likely to benefit from postoperative RT, especially after PS matching, for whom there is increasing evidence that outcomes are improved when treatment is initiated at lower PSA concentrations with no clear lower bound.¹⁸ The median RT dose to the prostate fossa in the ESRT cohort was 66 Gy, with 51% of men receiving less than 66 Gy. An SRT dose of at least 66 Gy is associated with a decreased risk of BF³⁶; hence, the use of higher SRT doses may reduce the advantages with ART observed in this study.

A subset of patients received pelvic nodal RT (12%) and/or postoperative ADT (10%). Both treatment factors were associated with reduced BF on multivariate analysis. Two recent randomized studies reported improved progression-free survival and/or OS with the addition of ADT to SRT.^37,38 However, both studies included a substantial number of patients with a PSA level greater than 0.5 ng/mL at the time of postoperative RT; therefore, it is unknown whether these results translate to the early-salvage and adjuvant settings.

Limitations

The primary limitation of this study is its retrospective design and inherent selection bias associated with treatment as rendered, which we attempted to address by performing PS matching for the factors expected to influence decision making. Nevertheless, PS matching cannot account for unmeasured confounders. The treatment center was deidentified during primary data collection, and thus an imbalance in ART and ESRT cases from each institution is a potential confounder. Another important limitation is that, although all patients in the ESRT group had recurrent disease by definition, an unknown subset of patients in the ART group may never have developed recurrence, which may overestimate the benefit of ART. We addressed this limitation by performing a sensitivity analysis. The median follow-up after surgery was significantly longer in the ESRT group compared with the ART group, which raises the possibility of insufficient time to observe distant metastases and mortality events in the ART cohort. However, this difference in follow-up between the 2 groups was no longer present after PS matching, and the median follow-up after RT was comparable between arms. The downward drifting threshold of detectability for PSA over time led to the classification of some men with a PSA level greater than 0.1 ng/mL as receiving ART; however, this should bias the results against ART and therefore is unlikely to confound the validity of our results. Finally, data were unavailable regarding which patients in the ESRT cohort had a persistently detectable PSA level after RP. Nevertheless, identification of this subpopulation is unlikely to be clinically significant given that (1) the changing sensitivity of PSA assays over time renders the definition of a detectable PSA level a moving target and (2) previous multivariate analyses found that a persistently elevated post-RP PSA level had a minimal association with outcomes after SRT.¹⁵

This study provides important insights into the use of postoperative RT for high-risk patients, but we acknowledge the need for randomized prospective evidence to guide best clinical practices. The Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial assigns patients to either ART or ESRT and secondarily addresses the role of concurrent ADT (none vs short-course or long-course).¹⁹ Similarly, the French Groupe d’Étude des Tumeurs Uro-Génitales (GETUG-17) trial randomizes patients with pT3-4N0/R1 carcinoma to ART vs ESRT, but both arms receive short-course ADT.²⁰ In contrast, the Radiotherapy–Adjuvant Versus Early Salvage (RAVES) trial comparing ART and ESRT for patients with pT3N0/R1 carcinoma does not include ADT.^21,39,40 The Radiation Therapy Oncology Group (RTOG) 0534 trial is evaluating salvage pelvic nodal irradiation and ADT for patients with T2-3N0 prostate adenocarcinoma and a postoperative PSA level of 0.1 to 1.0 ng/mL using a 3-arm randomization: (1) prostate fossa irradiation, (2) prostate fossa irradiation + short-course ADT, and (3) prostate fossa/nodal irradiation + short-course ADT.⁴¹

Conclusions

In this large, multi-institutional study, ART compared with ESRT was associated with reduced biochemical recurrence, DM, and death for patients with prostate cancer with adverse pathological features (T3 disease and/or positive margins). The 12-year number needed to treat with ART vs ESRT to prevent 1 BF was 6 to 12 when accounting for the estimated surgical cure rate based on a contemporary nomogram. The current use of ART in high-risk patients is less than 10%.¹³ Our findings suggest that a greater proportion of such men may benefit from ART, especially those for whom the estimated risk of postprostatectomy recurrence is greater than 50%. Pending prospective validation, contemporary practice patterns regarding postoperative RT should be revisited. Further improvement in risk stratification and patient selection for ART and ESRT may be enabled by genomic biomarkers such as the Decipher (GenomeDx) score.^42,43,44 Moreover, novel imaging techniques, such as fluciclovine (¹⁸F) positron emission tomography, may be useful for optimizing RT target coverage in the early-salvage setting.^45,46

Supplement.

eAppendix. Contemporary Nomogram Developed at Memorial Sloan Kettering Cancer Center

eFigure 1. Standardized Bias Across Covariates Used in Propensity Score Matching

eFigure 2. Propensity Score Histogram

eTable. Propensity Score Matching Results

Click here for additional data file.^{(245.1KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eAppendix. Contemporary Nomogram Developed at Memorial Sloan Kettering Cancer Center

eFigure 1. Standardized Bias Across Covariates Used in Propensity Score Matching

eFigure 2. Propensity Score Histogram

eTable. Propensity Score Matching Results

Click here for additional data file.^{(245.1KB, pdf)}

[coi170095r1] 1.Hager B, Kraywinkel K, Keck B, et al. Increasing use of radical prostatectomy for locally advanced prostate cancer in the USA and Germany: a comparative population-based study. Prostate Cancer Prostatic Dis. 2017;20(1):61-66. [DOI] [PubMed] [Google Scholar]

[coi170095r2] 2.Karakiewicz PI, Eastham JA, Graefen M, et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi-institutional assessment of 5831 patients. Urology. 2005;66(6):1245-1250. [DOI] [PubMed] [Google Scholar]

[coi170095r3] 3.Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006;296(19):2329-2335. [DOI] [PubMed] [Google Scholar]

[coi170095r4] 4.Briganti A, Wiegel T, Joniau S, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62(3):472-487. [DOI] [PubMed] [Google Scholar]

[coi170095r5] 5.Bolla M, van Poppel H, Tombal B, et al. ; European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-Urinary Groups . Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380(9858):2018-2027. [DOI] [PubMed] [Google Scholar]

[coi170095r6] 6.Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66(2):243-250. [DOI] [PubMed] [Google Scholar]

[coi170095r7] 7.Bolla M, van Poppel H, Collette L, et al. ; European Organization for Research and Treatment of Cancer . Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. 2005;366(9485):572-578. [DOI] [PubMed] [Google Scholar]

[coi170095r8] 8.Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. 2009;27(18):2924-2930. [DOI] [PubMed] [Google Scholar]

[coi170095r9] 9.Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181(3):956-962. [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi170095r10] 10.Shaikh MP, Alite F, Wu M-J, Solanki AA, Harkenrider MM. Adjuvant radiotherapy versus wait-and-see strategy for pathologic T3 or margin-positive prostate cancer: a meta-analysis [published online February 20, 2017]. Am J Clin Oncol. 2017. doi: 10.1097/COC.0000000000000358 [DOI] [PubMed] [Google Scholar]

[coi170095r11] 11.Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO guideline. J Urol. 2013;190(2):441-449. [DOI] [PubMed] [Google Scholar]

[coi170095r12] 12.Heidenreich A, Bastian PJ, Bellmunt J, et al. ; European Association of Urology . EAU guidelines on prostate cancer, part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65(1):124-137. [DOI] [PubMed] [Google Scholar]

[coi170095r13] 13.Sineshaw HM, Gray PJ, Efstathiou JA, Jemal A. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the national cancer data base. Eur Urol. 2015;68(5):768-774. [DOI] [PubMed] [Google Scholar]

[coi170095r14] 14.Katz MS, Zelefsky MJ, Venkatraman ES, Fuks Z, Hummer A, Leibel SA. Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol. 2003;21(3):483-489. [DOI] [PubMed] [Google Scholar]

[coi170095r15] 15.Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25(15):2035-2041. [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi170095r16] 16.Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299(23):2760-2769. [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi170095r17] 17.Stephenson AJ, Bolla M, Briganti A, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol. 2012;61(3):443-451. [DOI] [PubMed] [Google Scholar]

[coi170095r18] 18.Tendulkar RD, Agrawal S, Gao T, et al. Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J Clin Oncol. 2016;34(30):3648-3654. [DOI] [PubMed] [Google Scholar]

[coi170095r19] 19.Parker C, Clarke N, Logue J, et al. ; RADICALS Trial Management Group . RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol). 2007;19(3):167-171. [DOI] [PubMed] [Google Scholar]

[coi170095r20] 20.Richaud P, Sargos P, Henriques de Figueiredo B, et al. Radiothérapie postopératoire des cancers de la prostate. Cancer Radiother. 2010;14(6-7):500-503. [DOI] [PubMed] [Google Scholar]

[coi170095r21] 21.Pearse M, Fraser-Browne C, Davis ID, et al. A phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy—Adjuvant Versus Early Salvage (RAVES) trial. BJU Int. 2014;113(suppl 2):7-12. [DOI] [PubMed] [Google Scholar]

[coi170095r22] 22.Trabulsi EJ, Valicenti RK, Hanlon AL, et al. A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer. Urology. 2008;72(6):1298-1302. [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi170095r23] 23.Ost P, De Troyer B, Fonteyne V, Oosterlinck W, De Meerleer G. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2011;80(5):1316-1322. [DOI] [PubMed] [Google Scholar]

[coi170095r24] 24.Mishra MV, Scher ED, Andrel J, et al. Adjuvant versus salvage radiation therapy for prostate cancer patients with adverse pathologic features: comparative analysis of long-term outcomes. Am J Clin Oncol. 2015;38(1):55-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi170095r25] 25.Fossati N, Karnes RJ, Boorjian SA, et al. Long-term impact of adjuvant versus early salvage radiation therapy in pT3N0 prostate cancer patients treated with radical prostatectomy: results from a multi-institutional series. Eur Urol. 2017;71(6):886-893. [DOI] [PubMed] [Google Scholar]

[coi170095r26] 26.Buscariollo DL, Drumm M, Niemierko A, et al. Long-term results of adjuvant versus early salvage postprostatectomy radiation: a large single-institutional experience. Pract Radiat Oncol. 2017;7(2):e125-e133. [DOI] [PubMed] [Google Scholar]

[coi170095r27] 27.Leuven E, Sianesi B. PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing. https://ideas.repec.org/c/boc/bocode/s432001.html. Published April 17, 2003. Accessed December 15, 2015.

[coi170095r28] 28.Lau WK, Blute ML, Bostwick DG, Weaver AL, Sebo TJ, Zincke H. Prognostic factors for survival of patients with pathological Gleason score 7 prostate cancer: differences in outcome between primary Gleason grades 3 and 4. J Urol. 2001;166(5):1692-1697. [PubMed] [Google Scholar]

[coi170095r29] 29.Stark JR, Perner S, Stampfer MJ, et al. Gleason score and lethal prostate cancer: does 3 + 4 = 4 + 3? J Clin Oncol. 2009;27(21):3459-3464. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features

William L Hwang, MD, PhD

Rahul D Tendulkar, MD

Andrzej Niemierko, PhD

Shree Agrawal, BS

Kevin L Stephans, MD

Daniel E Spratt, MD

Jason W Hearn, MD

Bridget F Koontz, MD

W Robert Lee, MD, MEd, MS

Jeff M Michalski, MD

Thomas M Pisansky, MD

Stanley L Liauw, MD

Matthew C Abramowitz, MD

Alan Pollack, MD, PhD

Drew Moghanaki, MD, MPH

Mitchell S Anscher, MD

Robert B Den, MD

Anthony L Zietman, MD

Andrew J Stephenson, MD

Jason A Efstathiou, MD, DPhil

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Design, Data Sources, Study Participants, Exposures, and Outcomes

Statistical Analysis

Results

Patient and Treatment Characteristics

Table 1. Summary of Patient and Treatment Characteristics.

Propensity Score–Matched Analysis

Figure. Kaplan-Meier Curves After Adjuvant Radiotherapy (ART) vs After Early-Salvage Radiotherapy (ESRT) in a Propensity Score–Matched Cohort of Patients With pT2N0M0/R1 or pT3N0M0/R0-1 Prostate Adenocarcinoma.

Table 2. Multivariate Competing-Risks Regression Analyses of Factors Associated With Biochemical Failure After Radical Prostatectomy and Postoperative Radiotherapy.

Sensitivity Analysis

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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