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Adjuvant and Salvage Radiotherapy after Prostatectomy: ASTRO/AUA Guideline (2013, amended 2018 & 2019)

ASTRO/AUA Guideline: Published 2013, Amended in 2018 & 2019

The purpose of this guideline is to provide direction to clinicians and patients regarding the use of radiotherapy after radical prostatectomy in the adjuvant or salvage setting. The strategies and approaches recommended in the guideline were derived from evidence-based and consensus-based processes.  This document constitutes a clinical strategy; therefore, the most effective treatment approach for a particular patient is best determined by the patient, his family, and a multi-disciplinary team of providers using the shared decision-making model.  This guideline amendment incorporates newly-published literature into the original ASTRO/AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guideline and to provide an updated clinical framework for clinicians.

Note to the Reader: This document was amended in October 2018, and again in May 2019 to reflect new Level 1 literature that was released since the original publication of the guideline in April 2013 related to the use of hormone therapy with salvage radiation therapy. In addition, new long-term data from the ARO 96-02 trial of adjuvant radiotherapy was incorporated to update the existing evidence base. The role of genomic classifiers on post-prostatectomy treatment assignment and its potential for predicting therapeutic outcomes is also discussed in this amended guideline.

Unabridged version of this Guideline [pdf]
Amendment Summary [pdf]
Appendices [pdf]
ASCO endorsement

Panel Members

Ian Murchie Thompson*, Richard Valicenti*, Peter C. Albertsen, Brian Davis, S. Larry Goldenberg, Carol A. Hahn, Eric A. Klein, Jeff Michalski, Mack Roach III, Oliver Sartor, J. Stuart Wolf Jr. and Martha Faraday

The Practice Guidelines Committee would like to acknowledge the contributions of Dr. Anthony V. D’Amico and Dr. Thomas M. Pisansky to the 2019 Guideline Amendment.

*Equal author contribution

Executive Summary

Purpose

The purpose of this guideline is to provide direction to clinicians and patients regarding the use of radiotherapy after radical prostatectomy in the adjuvant or salvage setting. The strategies and approaches recommended in the guideline were derived from evidence-based and consensus-based processes.  This document constitutes a clinical strategy; therefore, the most effective treatment approach for a particular patient is best determined by the patient, his family, and a multi-disciplinary team of providers using the shared decision-making model.

Methods

A systematic review of the literature using the PubMed, Embase and Cochrane databases (search dates 1/1/90 to 12/15/12) was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy.  The review yielded an evidence base of 294 articles after the application of inclusion/exclusion criteria.  These publications were used to create the guideline statements.  If sufficient evidence existed, then the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty) or C (low quality evidence; low certainty) and evidence-based statements of Standard, Recommendation or Option were developed.   Additional information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed.  See text for definitions and detailed information. In April 2018, the guideline underwent its first amendment, which incorporated evidence from three randomized controlled trials into the evidence base. A new evidence-based statement was also developed to discuss the use of hormone therapy in the salvage radiotherapy setting. 

Guideline Statements

Guideline Statement 1. Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery. (Clinical Principle)

Guideline Statement 2. Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer. They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of three randomized controlled trials that addressed these outcomes indicated a benefit but the other two trials did not demonstrate a benefit. However, these two trials were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy. (Clinical Principle)

Guideline Statement 3. Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression. (Standard; Evidence Strength: Grade A)

Guideline Statement 4. Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate. (Clinical Principle)

Guideline Statement 5. Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is > 0.2 ng/ml with a second confirmatory level > 0.2 ng/ml. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 6. A restaging evaluation in the patient with a PSA recurrence may be considered. (Option; Evidence Strength: Grade C)

Guideline Statement 7. Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 8. Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA. (Clinical Principle)

Guideline Statement 9. Clinicians should offer hormone therapy to patients treated with salvage radiotherapy (postoperative PSA >0.20 ng/mL) Ongoing research may someday allow personalized selection of hormone or other therapies within patient subsets. (Standard; Evidence Strength: Grade A)

Guideline Statement 10. Patients should be informed of the possible short-term and long-term urinary, bowel, and sexual side effects of radiotherapy as well as of the potential benefits of controlling disease recurrence. (Clinical Principle)

Introduction

This guideline’s purpose is to provide direction to clinicians and patients regarding the use of radiotherapy (RT) after radical prostatectomy (RP) in patients with and without evidence of prostate cancer recurrence. The strategies and approaches recommended in this document were derived from evidence-based and consensus-based processes. This document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by discussions among the multidisciplinary team of physicians, the patient, and his family. As the science relevant to the use of RT after RP evolves and improves, the strategies presented here will require amendment to remain consistent with the highest standards of clinical care.

Methodology

A systematic review was conducted to identify published articles relevant to the use of RT after RP, including its efficacy in patients with detectable and undetectable prostatic specific antigen (PSA) levels, its toxicity and quality of life (QoL) impact and optimal imaging strategies to determine the appropriateness of RT use in patients suspected of recurrence. Literature searches were performed on English-language publications using the PubMed, Embase and Cochrane databases from 1/1/1990 to 12/15/2012. Preclinical studies (e.g., animal models), commentary, and editorials were excluded. Only studies in which PSA data were provided for 75% or more patients were included. Review article references were checked to ensure inclusion of all possibly relevant studies. Multiple reports on the same patient group were carefully examined to ensure inclusion of only nonredundant information. The review yielded an evidence base of 294 articles from which to construct a clinical framework for the use of RT after prostatectomy.

Quality of Individual Studies and Determination of Evidence Strength. Quality of individual studies that were randomized controlled trials (RCTs) or controlled clinical trials was assessed using the Cochrane Risk of Bias tool.1 Case-control studies and comparative observational studies were rated using the Newcastle-Ottawa Quality Assessment Scale.2 Because there is no widely-agreed upon quality assessment tool for single cohort observational studies, the quality of these studies was not assessed except in the case of diagnostic accuracy studies. Diagnostic accuracy studies were rated using the Quality Assessment Tool for Diagnostic Studies.3,4

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes consideration of study design, individual study quality, consistency of findings across studies, adequacy of sample sizes and generalizability of samples, settings, and treatments for the purposes of the guideline. The American Urological Association (AUA) categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings) or Grade C (observational studies that are inconsistent, have small sample sizes or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.5

For some clinical issues, there was little or no evidence from which to construct evidence-based statements. Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.6 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge and judgment for which there is no evidence.

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty and the Panel’s judgment regarding the balance between benefits and risks/burdens.5 Standards are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade A (high level of certainty) or Grade B (moderate level of certainty) evidence. Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade C (low level of certainty) evidence. Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; Options may be supported by Grade A (high certainty), B (moderate certainty), or C (low certainty) evidence.

Limitations of the Literature. The Panel proceeded with full awareness of the limitations of the RT after RP literature. A major limitation of this literature is the lack of a large number of RCTs to guide decision-making in patients with and without evidence of recurrence. Further, a major limitation of all RCTs in localized prostate cancer with long-term follow-up is the change in characteristics of contemporary patients; because of increased prostate cancer screening via PSA testing and consequent detection of disease and initiation of therapy at earlier disease stages, patients recruited into trials decades ago have a greater risk of adverse outcomes than do contemporary patients. However, the Panel is fully aware that these issues will always be present in trials of therapies for localized prostate cancer because disease events (e.g., metastases and death) generally occur one to two decades after treatment.

Additional limitations include the preponderance of non-randomized studies; poorly-defined or heterogeneous patient groups; the lack of group equivalence in terms of pathological risk factors in studies that compared RT administered to patients with and without recurrence; variability in PSA assay sensitivity and in failure criteria across studies and over time; heterogeneity of cumulative radiation dose, dose schedules, methods of administering radiation and treatment planning protocols; the paucity of studies with follow-up duration longer than 60 months; and the overwhelming focus of the literature on biochemical recurrence with less information available regarding metastatic recurrence, cancer-specific survival (CSS) and overall survival (OS). In addition, relatively few studies focused on QoL outcomes that are of critical importance to patients, such as voiding and erectile function.

Process. The Radiotherapy after Prostatectomy Panel was created in 2011 by the AUA and the American Society for Radiation Oncology (ASTRO). The AUA Practice Guidelines Committee and the ASTRO Guidelines Committee selected the Panel Chairs and the additional panel members with specific expertise in this area.

AUA and ASTRO conducted a thorough peer review process. The original version of the draft guidelines document was distributed to 75 peer reviewers, of which 44 reviewers provided comments. The panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA Practice Guidelines Committee and the ASTRO Guidelines Committee. Then it was submitted to the AUA and ASTRO Boards of Directors for final approval. Funding of the panel was provided by the AUA and ASTRO; panel members received no remuneration for their work.

Guideline Amendment.

In October 2018, the guideline was amended to maintain currency through a process in which newly published high quality literature was identified, reviewed, and integrated into the original 2013 guideline. The original search strategy, with two differences, was re-implemented by an experienced medical librarian. It was limited to publication dates from September 2012 to December 2017, and it added the MeSH heading “Radiotherapy, Adjuvant” that was deliberately excluded from the search strategy used during the production of the original guideline. The Panel had also added two new key questions to explore during this timeframe search. The new key questions concerned (a) the use of genomic classifiers to predict treatment outcomes in the radiation after prostatectomy setting, and (b) the treatment of oligo-metastases with radiation post-prostatectomy. A new search strategy was developed to identify literature relevant to the two new key questions. This search was conducted from January 1990 to December 2017 to ensure uniformity with the search period used to explore the questions from the original guideline. These searches yielded a total of 2,516 references of which 2,361 were excluded after de-duplication and title and abstract review. Full texts were retrieved for 155 references for more detailed review. Using methodological criteria employed in the original guideline and the best evidence approach, synthesis of new, relevant evidence was focused on the recent publication of three randomized controlled trials with 60 or more months of follow-up. Two of these trials formed the crux of this amended guideline by providing evidence on the use of hormone therapy among men who received salvage radiotherapy (SRT) after primary RP, a patient population who until now, have lacked Level 1 evidence-based recommendations. In addition, long-term data from the ARO 96-02 trial comparing adjuvant radiotherapy (ART) to wait-and-see was incorporated to update Guideline Statement 2. No relevant studies were found to directly address the two new key questions concerning the predictive ability of genomic classifiers and treatment of oligo-metastases in the radiation after prostatectomy setting.

Table 1: AUA Nomenclature
Linking Statement Type to Level of Certainty and Evidence Strength

Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A (high quality; high certainty) or B (moderate quality; moderate certainty) evidence

Recommendation: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade C (low quality; low certainty) evidence

Non-directive statement that leaves the decision regarding an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears equal or appears uncertain based on Grade A (high quality; high certainty), B (moderate quality; moderate certainty), or C (low quality; low certainty) evidence

Clinical Principle: a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature

Expert Opinion: a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

Background

In 2018, an estimated 174,650 men were diagnosed with prostate cancer.7 The most common primary treatment for localized disease is RP.8 In approximately two-thirds of men, prostatectomy constitutes a cure, but within 10 years, up to one-third of patients will present with recurrent disease.9-12 Recurrence after prostatectomy is thought to result from residual subclinical disease in the operative site that later manifests as a rising PSA level, a local tumor recurrence, metastatic disease or occult metastatic disease that was present at the time of the prostatectomy. The risk of recurrence is greater among men with adverse pathology, such as positive surgical margins, seminal vesicle invasion (SVI), extraprostatic extension (EPE) and higher Gleason scores.13-22

Clinicians, therefore, frequently face two scenarios in the patient for whom RP is the primary prostate cancer treatment. In the high-risk patient, revealed to have adverse pathological features at prostatectomy, clinicians and patients face the question of whether an ART should be considered to prevent possible future recurrence. In the post-RP patient who later presents with a detectable PSA level, appropriate salvage therapies may be considered. This guideline focuses on the evidence for use of RT in the adjuvant and salvage contexts.

Definitions

ART is defined as the administration of RT to post-RP patients at a higher risk of recurrence because of adverse pathological features prior to evidence of disease recurrence (i.e., with an undetectable PSA). There is no evidence that examines the timing of the first PSA test post-RP to determine a patient’s disease status; in the Panel’s clinical experience, the first PSA generally should be obtained two to three months post-RP. ART is usually administered within four to six months following RP. Generally, RT is initiated after the return of acceptable urinary control. As sexual function can require one to two years before a full return of function is observed, return of erections is not a requirement before initiation of adjuvant radiation.

SRT is defined as the administration of RT to the prostatic bed and possibly to the surrounding tissues, including lymph nodes, in the patient with a PSA recurrence after surgery but no evidence of distant metastatic disease.

Biochemical recurrence after surgery is defined as a detectable PSA level > 0.2 ng/mL with a second confirmatory level > 0.2 ng/mL.

The most commonly-reported post-prostatectomy outcome in the peer-reviewed literature is biochemical recurrence and biochemical recurrence-free survival (bRFS). Other reported outcomes include local recurrence and local recurrence-free survival (RFS), metastatic recurrence and metastatic recurrence-free survival (mRFS), clinical progression-free survival (cPFS): defined as no evidence of local or metastatic progression, excluding evidence of biochemical recurrence), CSS and OS. Clinicians generally use regularly-obtained PSA levels over time in post-RP patients to detect recurrence, to trigger the administration of additional therapies and/or to guide further diagnostic evaluations.

Findings

ART. The highest-quality evidence that addresses the use of RT after RP is provided by three RCTs that have examined the effect of RT delivered primarily in an adjuvant context. Findings from the three trials are reviewed below. It is important to note that the three trials were powered for different primary outcomes. The primary outcome for Southwest Oncology Group (SWOG) 8794 was metastases-free survival, defined as time to first evidence of metastatic disease or death due to any cause. The primary outcome for European Organisation for Research and Treatment of Cancer (EORTC) 22911 was initially local control, but changed in March 1995 to cPFS. The primary outcome in ARO 96-02 was biochemical progression-free survival. Further, the majority of patients in the RT arms of these three trials were treated with 60 Gray (Gy), a dose somewhat lower than currently used.

Biochemical recurrence. Three RCTs (SWOG 8794, EORTC 22911 and ARO 96-02), all with more than 10 years of follow-up, documented significant improvements in bRFS among patients with adverse pathological features (i.e., SVI, positive surgical margins and/or EPE) with the use of ART in comparison with observation only post-prostatectomy.23-27 A meta-analysis of biochemical recurrence data performed as part of the literature review yielded a pooled hazard ratio of 0.47 (95% CI=0.40 – 0.56; p<0.001; random effects model; see Appendix A). ARO 96-02 is the only trial in which all participants were required to have undetectable PSA (<0.5 ng/ml) to be included in the study; based on the detection limit of the assay used in the trial, all participants in ARO 96-02 were reported to achieve a PSA of <0.1 ng/ml prior to commencing the ART or the wait-and-see protocol.

Locoregional recurrence. SWOG 8794 and EORTC 22911 demonstrated a reduction in locoregional failure in ART patients compared to RP-only patients; ARO 96-02 did not assess locoregional failure. This difference was statistically significant in EORTC 2291125 at median 10.6 years of follow-up with 8.4% of ART patients having locoregional failure compared to 17.3% of RP-only patients. In SWOG 8794, also at 10.6 years of follow-up, locoregional recurrence was 8% in the ART group, and 22% in the RP only group (p< 0.01).24

Hormonal-therapy free survival. SWOG 8794 also reported a statistically significant improvement in hormone therapy-free survival in ART patients compared to RP-only patients with approximately 84% of ART patients remaining hormone-therapy free compared to approximately 66% of RP only patients at 10 years. EORTC 22911 reported that by year 10, 21.8% of patients in the ART group had started an active salvage treatment (including SRT or hormone therapy) compared to 47.5% of patients in the RP-only group, a statistically significant difference. It should be noted that the use of salvage therapies was at physician discretion and not prescribed by trial protocols.

Clinical progression. SWOG 8794 and EORTC 22911 also both demonstrated improved cPFS (defined as clinical or imaging evidence of recurrence or death but not including biochemical progression) in patients who had ART compared to those who had RP only. This difference was statistically significant in SWOG 8794 at median 10.6 years of follow-up, and borderline significant (p=0.054) in EORTC 22911 at the same follow-up point. The weaker effect in EORTC 22911 may have been the result of the higher rate of non-prostate cancer mortality among the ART group (17.1%) compared to the RP-only group (12.3%) or possibly because salvage treatments in the RP only group were initiated at lower PSA levels than in the ART group.

Metastatic recurrence and OS. Only SWOG 8794 demonstrated significantly improved OS (74% in ART patients compared to 66% for RP only patients) and significantly improved mRFS (defined as evidence of metastases or death from any cause; 71% for ART patients compared to 61% for RP-only patients) with the use of ART compared to RP-only at more than 12 years of follow-up.24,28 These findings did not replicate in EORTC 22911 at median 10.6 years of follow-up.25

There are several differences between the two trials that may be relevant to the disparate findings. The OS rate of the RP-only group in SWOG 8794 was much lower (66.0%) than the RP-only group in EORTC 22911 (80.7%); the reason for the lower survival rate in SWOG 8794 is not clear. The trials used identical patient selection criteria. Patient demographics were reported differently in the two trials, making it somewhat difficult to compare recruited patient characteristics that might be relevant to the disparate findings. The proportion of patients administered preoperative hormone therapies was similar (SWOG 8794: 8% of RP-only group, 9% of ART group; EORTC 22911: 10% of each group). More patients had SVI in EORTC 22911 (approximately 25% of each group) than in SWOG 8794 (10% to 11% of each group). In SWOG 8794, 68% of the RP-only group and 67% of the ART group had EPE or positive margins. EORTC 22911 reported that 78.9% of the RP-only group and 75.1% of the ART group had EPE and 63% of the RP-only group and 62.2% of the ART group had positive margins. The proportion of patients with post-RP PSA values < 0.2 ng/ml also was relatively similar across trials (SWOG 8794: 68% of RP-only group, 65% of ART group; EORTC 22911: 68.6% of RP-only group, 70.3% of ART group). It is noteworthy that the median age of the SWOG 8794 RP only group was 1.7 years older (65.8 years) than the median age of the ART group (64.1 years). Median OS for the RP-only group (13.3 years) was 1.9 years less than for the ART group (15.2 years), raising the possibility that the survival difference between the arms might be the result of the older age at enrollment of the RP only group. In the other two trials, there was no age difference between the two groups. None of these patient-level differences clearly explain the outcome differences. It also is possible that salvage treatments in SWOG 8794 were not used as extensively as in EORTC 22911; the trials had similar rates of salvage treatment despite higher relapse rates in SWOG 8794. An additional possibility has to do with the fact that the number of deaths from prostate cancer in EORTC 22911 was extremely low, making it unlikely that ART would result in a survival advantage. A definitive answer has yet to be identified.

Subgroup Findings

The three RCTs also reported outcomes for various patient subgroups (see Appendix C for table of subgroup findings). The Panel is fully aware of the clinical need for evidence-based risk stratification to inform decision-making regarding the use of ART in patients with specific pathological findings. However, after reviewing the subgroup findings from the best evidence available (the three RCTs) the Panel could not come to definitive conclusions. There are inconsistencies across trials in terms of which subgroups were selected for analysis and inconsistencies in the findings across subgroups. In addition, subgroup analyses were not performed for all outcomes. Further, the Panel notes that the trials did not stratify randomization by subgroups and that these comparisons were unplanned, internal analyses for which the trials did not necessarily have sufficient statistical power. Subgroup analyses, therefore, should be interpreted with caution and their utility is primarily to generate hypotheses and guide new research directions, not to test hypotheses. These analyses are summarized below.

Positive surgical margins. All three trials reported a statistically significant improvement in bRFS among patients with positive surgical margins who received RT compared to patients who did not. In addition, both SWOG 8794 and EORTC 22911 reported a significant improvement in clinical recurrence-free survival (cRFS) among patients who received RT (this outcome was not addressed by ARO 96-02). Only EORTC 22911 reported OS data for this subgroup; there were no differences in OS between patients who did or did not receive RT.

Patients with positive surgical margins comprised the majority in EORTC 22911 (62.2% of the ART group; 63% of the RP-only group) and in ARO 96-02 (68% of the ART group; 61% of the RP only group). SWOG 8794 did not report the number of patients with positive margins separately but reported that 67% of patients in the ART group and 68% in the RP-only group had disease that extended beyond the capsule or had positive margins.

Negative surgical margins. Among patients with negative surgical margins, EORTC 22911 reported that the use of RT did not improve cRFS rates and significantly decreased OS (HR=1.68; 95% CI=1.10-2.56). Although EORTC 22911 reported a significant improvement in bRFS with RT in this subgroup, ARO 96-02 reported no improvement with RT. SWOG 8794 did not address outcomes among patients with negative margins.

SVI. In patients with SVI, SWOG 8794 and EORTC 22911 reported significantly improved bRFS with RT. However, RT did not improve cRFS in either trial, mRFS in SWOG 8794 or OS in EORTC 22911. Further, ARO 96-02 reported no difference in bRFS with RT among patients with SVI.

Absence of SVI. Only EORTC 22911 reported on patients without SVI and the findings are exactly the same as for patients with SVI: improved bRFS but no difference in cRFS or OS.

EPE. EORTC 22911 and ARO 96-02 reported significantly improved bRFS with use of RT among patients with EPE. EORTC 22911 reported no differences, however, in cRFS or OS. SWOG 8794 did not report on this subgroup.

Absence of EPE. Only EORTC 22911 reported on outcomes among patients without EPE. Similar to patients with EPE, use of RT among patients without EPE significantly improved bRFS but not cRFS or OS.

Gleason score subgroups. EORTC 22911 and ARO 96-02 both reported significantly improved bRFS with use of RT among Gleason 2-6 patients. SWOG 8794 reported no differences, however, in mRFS with use of RT in this subgroup.

Gleason 7-10. ARO 96-02 reported significant improvement in bRFS with use of RT among Gleason 7-10 patients. EORTC 22911 reported improved bRFS among Gleason 7 patients that did not reach statistical significance and no difference with RT among Gleason 8-10 patients. SWOG 8794 reported a statistically significant improvement in mRFS with RT, however, among Gleason 7-10 patients.

Patient age. EORTC 22911 reported on outcomes for patients younger than age 65 years, age 65 to 69 years and age 70 years and older. In patients younger than age 65 years, the use of RT resulted in significant improvements in bRFS and cRFS. Among patients aged 65 to 69 years, the use of RT resulted in significant improvements in bRFS but not cRFS. Among patients aged 70 years and older, the use of RT did not improve bRFS or cRFS and, in fact, appeared to worsen OS (HR=2.94; 95% CI=1.75-4.93, p<0.05). Whether worsened OS was the result of an unrecognized detrimental effect of RT in elderly men is not clear.

Observational studies also have evaluated the use of ART; because of the confounds to interpretation and to causal attribution inherent in designs that lack randomization and other controls for bias, the Panel based its judgments regarding ART primarily on the findings from the RCTs.

Interpretation

The Panel interpreted the findings from the RCTs to indicate that ART after prostatectomy may benefit patients with high-risk pathological features. The most consistent findings were an improvement in bRFS across all three trials and improvements in locoregional and cRFS in the two trials that reported these outcomes, with less consistent findings across trials for other outcomes. The most consistent finding for subgroup benefit was for positive margin patients with all three trials reporting improved outcomes with RT.

The Panel is fully aware that the apparent benefits associated with RT are the result, in part, of a subset of patients treated with RT who never would have presented with recurrence. It is the nature of adjuvant therapies to treat high-risk patients with full knowledge that this decision will result in some patients who are over-treated. It should be noted that primary therapy for localized prostate cancer (e.g., RP, primary RT) also is employed for the benefit of an unknown minority of patients with the understanding that this strategy will result in over-treatment of a large number of men who never would have experienced an adverse event from their tumor.

The number needed to treat (NNT) is a helpful statistic to put these issues in context; the lower the NNT, the more effective the treatment or intervention in preventing the designated outcome. For example, the European Randomized Study of Screening for Prostate Cancer followed men randomly assigned to a PSA screening group compared to a control group not offered screening.29 At median 11 years of follow-up the authors reported that 1,055 men would need to be invited for screening and 37 cancers would need to be detected in order to prevent one death from prostate cancer.

With regard to prostatectomy compared to watchful waiting, Bill-Axelson29 reported that at 15 years post-RP, the NNT for overall survival was 15. That is, approximately 15 men would have to undergo prostatectomy in order to prevent one death from any cause compared to watchful waiting. Using data from approximately 45,000 patients from the SEER database, Abdollah30 stratified patients into high-risk (pT2c or Gleason 8-10) vs. low-intermediate risk (all other patients) and reported an NNT at 10 years of follow-up of 13 for death from prostate cancer for high-risk patients and an NNT of 42 for low-intermediate risk patients.

With regard to prostatectomy compared to watchful waiting, Bill-Axelson30 reported that at 15 years post-RP, the NNT for OS was 15. That is, approximately 15 men would have to undergo prostatectomy in order to prevent one death from any cause compared to watchful waiting. Using data from approximately 45,000 patients from the SEER database, Abdollah31 stratified patients into high-risk (pT2c or Gleason 8-10) vs. low-intermediate risk (all other patients) and reported an NNT at 10 years of follow-up of 13 for death from prostate cancer for high-risk patients and an NNT of 42 for low-intermediate risk patients.

With regard to RP plus ART compared to RP-only, SWOG 8794 reported an NNT of 9.1 for OS, indicating that approximately 9 men would need to be treated with RP+ART compared to RP only to prevent one death from any cause at median 12.6 years of follow up.i,24 With regard to preventing metastatic disease, SWOG 8794 reported an NNT of 12.2. EORTC 22911 did not replicate these findings and reported a higher overall death rate among RP+ART patients (25.9%) compared to RP-only patients (22.9%). These data yield a negative NNT, indicating a lack of benefit for the active treatment. With regard to CSS, for which EORTC 22911 also did not document a treatment benefit, the NNT calculated from the raw data provided in Appendix B25 is 55.6, indicating that approximately 56 men would need to be treated with RP+ART to prevent one case of death from prostate cancer at 10.6 years of follow-up compared to RP-only (the other two trials did not report cancer-specific data). As a point of comparison, a pooled NNT for preventing biochemical recurrence derived from combining SWOG 8794, EORTC 22911 and ARO 96-02 is 4.4. Combining local recurrence data from SWOG 8794 and EORTC 22911 yields an NNT of 9.8. Combining clinical progression data from SWOG 8794 and EORTC 22911 yields an NNT of 13.8.

Given the findings from the RCTs, the nature of adjuvant treatments to inevitably result in over-treatment of some patients, and the contextual information provided by NNTs, the Panel emphasizes that ART should be offered to all patients at high risk of recurrence because of adverse pathological features. The offering of ART should occur in the context of a thorough discussion of the potential benefits and risks/burdens associated with ART (see Guideline Statements 2 and 3). Ultimately, whether ART is likely to benefit a particular patient and should be administered is a decision best made by the multidisciplinary treatment team and the patient with full consideration of the patient’s history, values and preferences.

SRT. Evidence regarding the efficacy of SRT in the post-RP patient is available in the form of a large literature composed of observational studies; however, only a few studies compared post-RP patients with PSA or local recurrence who received SRT to patients with PSA or local recurrence post-RP who did not receive further therapy.32,33 Generally, these studies indicate that SRT improves outcomes compared to RP-only patients but the benefits may be specific to certain risk groups (see Discussion under Guideline Statement 7). In addition, two of the three RCTs (SWOG 8794 and EORTC 22911) enrolled patients with detectable PSA levels post-RP salvage patients by definition. These two trials also generally revealed better outcomes among SRT patients compared to RP-only patients with evidence of PSA recurrence (see Discussion under Guideline Statement 7).

ART vs. SRT. One of the most pressing clinical questions regarding the care of the post-RP patient is whether it is better to administer RT before evidence of recurrence (i.e. RT as adjuvant therapy) or to wait until recurrence manifests and then administer RT as salvage therapy. It is acknowledged that the use of ART may involve irradiation of some patients who never would have had recurrent cancer, thus exposing them unnecessarily to the risks, toxicity, and QoL impact of RT. Waiting to administer RT as a salvage therapy limits its use to patients with recurrence but, particularly in patients with high-risk disease, could be less effective and could allow the progression to metastatic disease.

The literature review attempted to address this issue by examining the large number of observational studies that reported outcomes for ART and SRT patients in the PSA era. Study arms were categorized as adjuvant if post-RP patients administered RT had no evidence of recurrence based on the PSA failure threshold used by the authors. Study arms were categorized as salvage if post-RP patients had evidence of PSA or local recurrence at the time of RT administration. A third group of studies in which outcomes for ART and SRT patients were combined also was retrieved. Mixed studies were considered with regard to toxicity and quality of life outcomes (see section below) but not for efficacy outcomes.

The search yielded 48 ART study arms reporting outcomes for 4,043 patients.18,32,34-75 The search yielded 137 SRT study arms reporting outcomes for 13,549 patients.18,32,33,37-40,44-47,51,52,54,56-62,64,66,68-70,73-164

When this literature is examined as a whole, it appears that ART patients generally have better outcomes compared to SRT patients. For example, ART study arms generally report lower rates of biochemical recurrence and metastatic recurrence than do SRT study arms at similar post-RP follow-up durations. Patterns with regard to CSS and OS are less clear because few ART studies reported these outcomes.

Overall, the interpretation that ART leads to superior outcomes is difficult to make with certainty in the absence of randomization and given that SRT studies focus only on patients who have already relapsed, making direct comparisons with ART studies problematic. ART and SRT studies also differ across numerous factors, any of which potentially confound interpretation. These include differences in patient characteristics (e.g., ART patients generally have more adverse pathological profiles), RT protocols (e.g., SRT studies often used higher RT doses than ART studies), failure definitions, follow-up durations, and in other key factors. In addition, most of the published literature reports findings from the use of older RT techniques (e.g., external beam radiation therapy [EBRT] protocols), making it unclear whether newer techniques might result in fewer apparent differences between ART and SRT outcomes.

Given these issues, the Panel concluded that it is not possible from the available evidence to address the question of the superiority of ART vs. SRT. A recent propensity score-matched, multi-institutional analysis has attempted to address this issue, reporting no difference in bRFS rates at 60 months between pT3N0 patients administered RT adjuvantly compared to those observed and treated with early SRT (with PSA ≤ 0.5 ng/ml).37 In this analysis, however, the follow-up duration for the observed group was considerably shorter (median 30 months) than the follow-up duration for the ART group (median 67 months). Currently, the Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial (MRC PR10, NCIC PR13) is actively accruing patients to address this important question. The Radiotherapy - Adjuvant Versus Early Salvage (RAVES) trial (TROG 08.03) closed prematurely because the rate of participant accrual diminished over time; see more detailed discussion in Research Needs and Future Directions.

Radiotherapy techniques and protocols in the post-prostatectomy patient. The Panel’s literature review attempted to address the question of which RT techniques and doses produced optimal outcomes in the adjuvant and salvage context. It was not possible to answer these questions, however, from the available data.

Specifically, approximately one-third of the ART and SRT observational studies treated patients with conventional external beam modalities that have since been replaced by more sophisticated approaches using three-dimensional conformal RT (3D-CRT) or intensity-modulated radiotherapy (IMRT) methods. The published literature has lagged well behind the implementation of these newer methods, with only one-quarter of the reviewed studies reporting use of 3D-CRT techniques and less than 5% reporting use of IMRT techniques. The remaining studies used either a mix of techniques, without separating patient outcomes based on technique or did not report enough information to determine the type of RT used. The lack of studies using newer RT methods made it difficult to definitively address the question of optimal methods in general and whether these might differ in the adjuvant v. salvage contexts.

With regard to the randomized controlled trials of ART, the men treated in SWOG 8794 and EORTC 22911 were administered RT using EBRT techniques;23,165 patients in ARO 96-02 were administered 3D-CRT.26 Although there were no clear differences in toxicity among the RT arms of the three RCTs, a broader literature suggests that patients treated with 3D-CRT and IMRT would be expected to experience less treatment-related toxicity and better biochemical and local control compared to men irradiated with traditional techniques.55,166

Among the observational studies, the RT dosages varied from 50 to 78 Gy with most studies administering doses in the 60 to 70 Gy range and with SRT studies administering somewhat higher radiation dosages than ART studies (median ART dose: 61 Gy; median SRT dose: 65 Gy). Although RT dose-escalation has been shown in multiple randomized trials to improve freedom from biochemical relapse when used as primary treatment for localized prostate cancer, the optimal post-prostatectomy radiation dose is less clear and has never been tested in a prospective fashion. However, the clinical data suggest that doses above 65 Gy can be safely delivered and may lead to improved tumor control as determined by a reduction in biochemical progression.43,108,141,167 In the three RCTs, the majority of patients were treated with radiation doses of 60 Gy, which was lower than the dose used in most observational studies.

Among the observational studies, the RT dosages varied from 50 to 78 Gy with most studies administering doses in the 60 to 70 Gy range and with SRT studies administering somewhat higher radiation dosages than ART studies (median ART dose – 61 Gy; median SRT dose – 65 Gy). Although RT dose-escalation has been shown in multiple randomized trials to improve freedom from biochemical relapse when used as primary treatment for localized prostate cancer, the optimal post-prostatectomy radiation dose is less clear and has never been tested in a prospective fashion. However, the clinical data suggest that doses above 65 Gy can be safely delivered and may lead to improved tumor control as determined by a reduction in biochemical progression.7, 42, 107, 140, 166 In the three RCTs, the majority of patients were treated with radiation doses of 60 Gy, which was lower than the dose used in most observational studies.

In the Panel’s view, 64-65 Gy is the minimum dose that should be delivered in the post-RP setting but decisions regarding dose should always be made by the treating physician who has full knowledge of a particular patient’s functional status, history, and tolerance for toxicity. The Panel is aware that there is controversy in the field regarding appropriate RT targets and field size. This issue was beyond the scope of this guideline; however, guidance can be found in Michalski,168 Sidhom,169 Wiltshire170 and Poortmans.171

Given the difficulties in interpreting findings from the observational studies and the lack of high-quality evidence regarding optimal RT dosing and protocols in the adjuvant and salvage contexts, it is not possible at this time to identify the best RT strategies for these patients.

Use of hormone therapy in conjunction with RT in the post-RP patient. One of the questions faced by the clinician and post-RP patient is whether, when, for how long and in what form hormone therapy should be administered. The original systematic review attempted to address these questions by retrieving literature that focused on the use of hormone therapy in patients who underwent prostatectomy and then ART or SRT. The Panel’s conclusion after reviewing the available evidence (see brief review below) in 2013 was that, given the methodological weaknesses of this literature, it was not possible to provide guidance regarding the use of hormone therapy in conjunction with ART or SRT. These weaknesses include observational, non-randomized study designs; small sample sizes and consequent lack of statistical power to reliably detect differences between RT-only and RT+hormone therapy groups; lack of equivalence of RT and RT+hormone therapy groups on pathological risk factors; large differences in hormone therapy protocols, including when it was administered (e.g., pre-RP, pre-RT, during RT, post-RT) and for how long (e.g., weeks vs. months vs. years); primary focus on biochemical recurrence with relatively few reports that focused on local recurrence, metastatic recurrence, CSS and OS; and, other differences across studies that may be relevant to efficacy such as differences in RT techniques, targets, and total dose administered.

When the original guideline was published, the Radiation Therapy Oncology Group (RTOG) 9601 trial of SRT with or without 24 months of bicalutamide (150 mg daily) had been presented in abstract form only. At median follow-up of 7.1 years, patients who received SRT with bicalutamide had significantly improved freedom from biochemical progression and significantly fewer metastases.172 The Panel viewed these findings as promising, but awaited full publication to provide more detailed guidance regarding bicalutamide use with SRT. During the writing of this amendment, 13-year follow-up data from the trial was published (n=384 bicalutamide and n=376 placebo).173 In addition, 5-year follow up data from the GETUG-AFU 16 trial that examined the effects of SRT with (n=369) or without (n=374) subcutaneous goserelin acetate (10.8 mg given on the first day of RT and again 3 months later) had been published.174 These two randomized controlled trials provide the Level 1 evidence required to properly validate the treatment effect of hormone therapy with SRT.

A third such trial, RTOG 0534, completed recruitment of 1,792 participants in March 2015; it is a 3-arm randomized controlled trial with assignment to prostate bed SRT with or without 4- to 6-month duration hormone therapy, or to the same hormone therapy with pelvic nodal and prostate bed RT in men with rising PSA after prostatectomy. Another trial, RADICALS, is addressing the use of hormone therapy (bicalutamide, goserelin and leuprolide) and its duration (6 months vs. 24 months) in the ART and SRT context.172 Mature results from these trials, once reported, will help answer important additional questions regarding hormone therapy use, its duration, and RT field size requirements.

Hormone therapy in the adjuvant setting. Only five observational studies compared RP patients who received ART to those who received ART in combination with some form of hormone therapy.36,55,56,58,173 Although all four studies reported findings suggesting that patients who received hormone therapy in combination with ART had better outcomes, only one study reported a statistically significant difference between groups. Specifically, Bastide36 reported at median follow-up 60.3 months that the ART+hormone therapy group had significantly higher bRFS rates at five and seven years than did the ART only group (82.8% vs. 44.4%, respectively, at 5 years; 62.1% vs. 28.6%, respectively, at 7 years). bRFS rates for two additional comparison groups (patients who had RP only and patients who had RP+hormone therapy but did not have ART) were similar to rates for the ART only group. All patients in this study had SVI but the distribution of other risk factors (i.e., Gleason scores, positive margins) differed somewhat across groups. The hormone therapy administered was an luteinizing hormone-releasing hormone (LHRH) analog; it was initiated on the first day of RT with median duration 12 months. These findings require replication in a randomized trial such as the ongoing RADICALS trial. Ost173 did not detect a difference in bRFS at seven years (ART only – 86%; ART + hormone therapy – 79%) or cRFS (ART only – 90%; ART + hormone therapy – 83%) on univariate analysis but on multivariate analysis the use of hormone therapy resulted in a significant hazard ratio of 0.4 for bRFS and 0.1 for cRFS. However, the two groups exhibited significant imbalances in pathologic risk factors, emphasizing the need for appropriately stratified randomized studies. Additional information is provided by DaPozza174 which reported that ART+hormone therapy significantly improved bRFS and CSS on multivariate analyses (but not univariate analysis) compared to patients who received hormone therapy-only (all patients in this study had positive nodes); however, there was no ART only comparison group in this study. Without data from RCTs in the adjuvant RT setting, the Panel concluded that the role of hormone therapy in this context remains uncertain until the reporting of the RADICALS trial.

Hormone therapy in the salvage setting. At the time of publication of the original guideline in 2013, there were no RCTs with published data to evaluate the use of hormone therapy in the SRT setting. Based on the evaluation of 23 observational studies evaluating RP patients who received SRT alone compared to those selected to receive SRT in combination with some form of hormone therapy, most studies suggested better outcomes for patients selected for SRT in combination with hormone therapy. 33,56,58,64,75,76,83,92,93,95,100,106,110,116,125,128,130,143,145-148,163 However, these studies included heterogeneous patient groups, various RT and hormone therapy regimens, and varying follow-up durations. The type, sequencing, and duration of hormone therapy was not uniform, and the risk of bias and other confounders was substantial. The Panel concluded at that time that the role of hormone therapy in the SRT setting was unclear, because outcomes from RCTs were lacking.

Results from the RTOG 9601175 and GETUG-AFU 16176 trials had been published at the time of this amendment (see Appendix D). Both trials examined the use of hormone therapy in the SRT setting. However, there are inherent differences of particular note between the trials apart from disparate follow-up durations (13 years versus five years). The type and duration of hormone therapy was different between trials. RTOG 9601 used the oral anti-androgen bicalutamide at high-dose (150 mg daily), while GETUG-AFU 16 used the Gonadotropin Releasing Hormone (GnRH) receptor agonist goserelin subcutaneously. GETUG-AFU 16 specified short-term, six-month duration hormone therapy during SRT compared to long-term, 24-month duration anti-androgen in RTOG 9601. In addition, the trials were designed to examine different primary outcomes; OS in RTOG 9601, and progression-free survival (biochemical or clinical progression, or all-cause mortality) in GETUG-AFU 16. The inclusion criteria and characteristics of the overall study populations were also somewhat different. RTOG 9601 enrolled men with pT2 disease and positive surgical margins or pT3 disease, all of whom had no pathologic evidence of nodal involvement, as every participant had undergone RP and pelvic lymphadenectomy. GETUG-AFU 16 included men with pT2-pT4a disease who may or may not have had nodal involvement, in that 26% had not undergone pelvic lymphadenectomy. Men in GETUG-AFU 16 were required to have undetectable PSA (<0.1 ng/mL) for at least 6 months post-prostatectomy, and 80% had PSA <0.5 ng/mL and 94% had PSA <1.0 ng/mL at trial entry. In contrast, the proportion of participants with undetectable PSA before SRT is not known from the publication of RTOG 9601, although a PSA nadir >0.5 ng/mL after prostatectomy was reported in 12% of patients. Pelvic nodal RT was not given in RTOG 9601, but 61% of participants who did not undergo pelvic nodal lymphadenectomy in the GETUG-AFU 16 trial received elective pelvic RT. Median age was similar in both trials, and men were enrolled only if their life expectancy was more than 10 years. Men in GETUG-AFU 16 had a better risk profile compared to RTOG 9601: pT3 disease: 46% vs. 67%; positive surgical margins: 50% vs. 75%; Gleason score >8 – 11% vs. 17%; persistently elevated PSA post-prostatectomy >0.5 ng/mL: 0% vs. 12%; and median PSA at trial entry: 0.3 ng/mL vs. 0.6 ng/mL.

After a median follow-up of 13 years, RTOG 9601 reported a reduction in the 12-year incidence of biochemical recurrence (HR=0.48; 95% CI=0.40-0.58; p<0.001), distant metastasis (HR=0.63; 95% CI=0.46-0.87; p=0.005) and prostate cancer-specific mortality (HR=0.49; 95% CI=0.32-0.74; p<0.001), and improved OS (HR=0.77; 95% CI=0.59-0.99; p=0.04) with assignment to bicalutamide (compared with placebo) and SRT. Survival was improved with bicalutamide in most reported subgroups, and was statistically significantly so in those with Gleason score 7, trial entry PSA 0.7-4.0 ng/mL, or positive surgical margins.

In the GETUG-AFU 16 trial, improved progression-free survival (biochemical or clinical progression, or all-cause mortality) was reported with addition of goserelin to SRT (HR=0.50; 95% CI=0.38-0.66; p<0.0001) at 5 years follow-up; subgroup analyses favored goserelin use in all age, risk, pre-prostatectomy and pre-SRT PSA, and pre-SRT PSA doubling time (PSADT) groups. There were more local and metastatic progression events in the group assigned SRT alone (tests of significance not done), and also more deaths attributed to prostate cancer and from any cause. Between-group comparison awaits the 10-year pre-specified survival analysis plan.

In general, both trials reported limited data on early adverse events, and had used different reporting tools. However, some similarities are apparent. For example, similar rates of genitourinary (GU) and gastrointestinal (GI) adverse events were reported in both arms of both studies, and these were primarily mild. Most importantly, when discussing hormone therapy, an emphasis on examining its adverse effects becomes relevant. GETUG-AFU 16 reported higher rates of hot flashes (46% vs. <1%) and sweating (13% vs. 0%) with goserelin vs SRT alone, but these were overwhelmingly mild-to-moderate (grade 1-2) in severity. No difference in hot flashes was reported in RTOG 9601, but mild-to-moderate (grade 1-2) gynecomastia was reported in 67% of men assigned to high-dose (150 mg daily) bicalutamide versus 11% who received placebo; 4% of men had severe gynecomastia with bicalutamide. Gynecomastia with six-month duration goserelin was very rare (<1%) in the GETUG-AFU 16 trial.

Given the findings from the RCTs, taking note of the differences between the trials and possible limitations, the Panel concluded that there was sufficiently strong evidence overall to encourage clinicians to inform patients and offer the option to add hormone therapy to SRT. The Panel recognized that neither trial was designed to identify specific patients within the overall targeted population in whom a hormone therapy benefit could be excluded. The offering of hormone therapy therefore should be accompanied by a thorough discussion of the potential benefits and risks/burdens associated with its use in the SRT setting (see Guideline Statement 9). Shared decision-making that considers the patient’s values, preferences, and history is encouraged.

More high quality evidence will be required to identify subgroups that would and would not benefit from the addition of hormone therapy to SRT, and to provide specific recommendations on the type and optimal duration of such.

Toxicity and QoL impact of RT post-prostatectomy. A key concern of clinicians and patients when ART or SRT is contemplated is the toxicity and QoL effects of RT in patients who have already undergone prostatectomy. The Panel’s systematic review retrieved the literature relevant to these issues; findings are reviewed below. In addition to ART and SRT studies, studies that reported on mixed groups of ART and SRT patients were included given the importance of understanding toxicity effects. It was not possible to delineate differences in RT toxicity and QoL effects between ART and SRT studies given the many confounds to interpretation. These included: the absence of pre-RP information regarding GU, GI, and sexual functioning; large differences in the RP to RT interval, with consequent differential recovery from prostatectomy in ART v. SRT patients; the use of somewhat higher radiation doses in SRT studies; and, the paucity of published studies using newer RT delivery modes such as 3D-CRT and IMRT that might minimize toxicity. In particular, among the three RCTs, only ARO 96-02 used newer RT methods. Toxicity overall, therefore, may be somewhat less than the majority of the published literature reports.

Toxicity. The most commonly-used measures to report toxicity information were the RTOG measure for acute effects (through day 90) and the EORTC measure for late RT effects (persisting beyond day 90 or developing after day 90). The second most commonly-used measure was the Common Toxicity Criteria Adverse Event (CTCAE) measure; authors who reported toxicity data using this measure specified the same time frames. Both measures use a rating system of 0 to 5: a score of 0 indicates no change in function; 1 indicates a minor change in function that generally does not require any clinical action; 2 indicates a moderate change in function that may require medication; 3 indicates a major change in function sufficient to require more aggressive medication use or outpatient procedures; 4 indicates severe symptoms requiring hospitalization and surgical procedures; and, 5 indicates death (see Appendix E). A total of 107 study arms reported at least one measure of toxicity; these arms included 13 ART study arms reporting on a total of 1,735 patients, 58 SRT study arms reporting on a total of 5,574 patients and 36 mixed ART-SRT study arms reporting on a total of 4,838 patients.18,26,39,40,42-44,46,47,50,55-57,60,63,65,67,68,72,75,76,79,80,82,83,85,87,88,90-93,97,100,104-106,112-114,122,123,125,128-130,133-136,138,140-143,149,151,152,154,155,158-161,163,165,166,173,177-203

Acute toxicity. Of the 107 study arms that reported any toxicity information, 38 reported at least one measure of acute GU toxicity (5 ART arms, 13 SRT study arms, and 20 mixed study arms) and 34 reported at least one measure of acute GI toxicity (2 ART arms, 13 SRT arms, 19 mixed arms).

The ranges for proportions of patients experiencing grade 1-2 and grade 3-4 acute toxicities are presented in Appendix F; no grade 5 toxicities (deaths) were reported. Grade 1-2 acute toxicities were characterized by extremely wide ranges, with a great deal of variability across studies, and high percentages in many study arms, suggesting that these effects are relatively common. Grade 3-4 toxicities, however, were relatively uncommon.

With regard to acute GU effects, two studies compared patients treated with 3D-CRT to patients treated with IMRT.100,177 Both studies reported that use of 3D-CRT resulted in higher rates of grade 2 or greater toxicities (12.3% and 20.8%, respectively) compared to IMRT (6.6% and 13.4%, respectively). One study compared patients treated with EBRT to patients treated with 3D-CRT.191 Patients treated with EBRT had higher rates of grade 2 or 3 acute GI toxicity (83%) compared to patients treated with 3D-CRT (61%). Rates of grade 2 or 3 acute GU toxicity were statistically similar (EBRT: 22%; 3D-CRT: 30%). There were no grade 4 events in either group. In contrast, Eldredge187 reported that patients treated with EBRT or with cone-beam computed tomography (CT)-guided 3D-CRT had similar rates of acute grade 2 GU (13% in both groups) and GI toxicities (EBRT: 15%; 3D-CRT: 13%).

Additional acute GU toxicity information was reported by Bolla165 one of the three RCTs that evaluated adjuvant RT, using the World Health Organization (WHO) scale for acute effects. The WHO scale breaks down functioning into 0: no change, 1: slight disturbance; 2: greater disturbance but without influence on daily life; 3: toxicities requiring treatment; and 4: severe toxicities requiring vigorous treatment or hospitalization. Grade 1 and 2 frequency symptoms (44.9% and 17.3%, respectively), were the most frequently reported acute GU toxicities. Grade 3 frequency was uncommon (3.3%) and grade 4 frequency was rare (0.4%). Grade 1 and 2 dysuria occurred in 37.9% and 10.3% of patients, respectively, with only 1.1% reporting grade 3 dysuria and no reports of grade 4. Hematuria was uncommon, with 3.7% of patients exhibiting grade 1, 0.9% exhibiting grade 2 and no patients exhibiting the higher grades.

With regard to acute GI effects, Goenka100 reported that 3D-CRT patients had higher levels of grade 2 or greater toxicities (13.2%) compared to IMRT patients (7.6%). Alongi177 divided toxicities into lower and upper GI and reported that patients treated with 3D-CRT had higher lower GI toxicity rates (8.6%) and higher upper GI toxicity rates (22.2%) than did patients treated with IMRT (lower: 3.3%; upper: 6.6%).

Using the WHO scale, Bolla165 reported that rates of diarrhea were grade 1: 38.3%, grade 2: 17.7%, grade 3: 5.3%, and grade 4: 0%. Nausea/vomiting symptoms were uncommon, with grade 1 levels manifested in 4.2% of patients, grade 2 in 0.2%, and no patients exhibiting grade 3 or 4.

Late toxicity. Of the total 107 study arms that reported any toxicity information, 51 reported at least one measure of late GU toxicity (9 ART arms, 26 SRT study arms, and 16 mixed study arms) and 41 reported at least one measure of late GI toxicity (4 ART arms, 22 SRT arms, 15 mixed arms). It is important to note that commonly cumulative rates of late toxicities are reported; these rates do not take into account the fact that many of these patients ultimately have resolution of their symptoms.

The ranges for proportions of patients experiencing grade 1-2 and grade 3-4 late toxicities are presented in Appendix G; no grade 5 toxicities (deaths) were reported. Similar to acute toxicity data, grade 1-2 late toxicities were characterized by extremely wide ranges, with a great deal of variability across studies (except for GI toxicity in ART study arms for which only 4 values were available), and high percentages in many study arms, suggesting that these effects are relatively common. Grade 3-4 toxicities, however, were relatively uncommon.

Late toxicity over time. In contrast to acute toxicities, late toxicities may manifest cumulatively for several years post-RT and persist for many years.

Ost Lumen130 noted that the probability of late grade 2-3 GU toxicity rose from 12% at 24 months post-SRT to 22% at 60 months post-SRT. Pearse195 reported a similar pattern with 13% of patients manifesting grade 2 or higher GU toxicity at 12 months post-SRT, rising to 28% at 48 months post-SRT, and remaining at 28% at 60 months post-SRT. Feng188 reported in a mixed group of patients that grade 2 or higher toxicities occurred in 4% of patients at 12 months post-RT rising to 12% at 60 months post-RT. Goenka100 reported on patients who were administered 3D-CRT or IMRT and noted that the probability of late grade 2 or higher toxicities for 3D-CRT patients ranged from 5% at 24 months post-SRT to 25% at 96 months post-SRT. For IMRT, 9% of patients exhibited grade 2 or higher toxicities at 24 months post-SRT with the proportion rising to 16.8% at 60 months post-SRT and remaining at 16.8% through 120 months of post-SRT follow-up. Iyengar191 reported at median five years follow-up that statistically similar proportions of EBRT (19%) and 3D-CRT (16%) patients had grade 2 or higher late GU toxicities. The most common symptoms were urinary frequency (14.6%) and bleeding (8.6%). Incontinence as the only late GU symptom was almost twice as common among patients treated with EBRT (7.5%) compared to patients treated with 3D-CRT (4%).

Cozzarini185 assessed toxicity rates in an ART cohort (n=556) compared to an SRT cohort (n=186) at median 8 years of follow-up post-RT (either EBRT or 3D-CRT). These authors reported statistically indistinguishable probabilities of late Grade 3 GU effects of 12.2% among ART patients and 10% among SRT patients. The ART and SRT groups had similar rates of urethral stricture requiring dilation (ART: 5%; SRT: 3%), of grade 3 bleeding (ART: 2%; SRT: 1%), and of severe incontinence (ART: 7%; SRT: 6%). Each group had only one case of grade 4 toxicity (necessitating radical cystectomy in both cases).

Late GI toxic effects are less common. Ost Lumen130 also reported that the probability of late grade 2-3 GI toxicity rose from 3% at 24 months post-SRT to 8% at 48 months post-RT and remaining at 8% at 60 months post-SRT. Pearse195 reported a similar pattern with 3% of patients manifesting grade 2 or higher GU toxicity at 12 months post-SRT, rising to 7% at 36 months post-SRT, and remaining at 7% at 60 months post-SRT. Feng188 reported in a mixed group of patients that grade 2 or higher toxicities occurred in 2% of patients at 12 months post-RT rising to 4% at 60 months post-RT. Goenka100 reported on patients who were administered 3D-CRT or IMRT and noted that the probability of late grade 2 or higher toxicities for 3D-CRT patients ranged from 4.5% at 24 months post-SRT to 10.2% at 96 months post-SRT. For IMRT, 1% of patients exhibited grade 2 or higher toxicities at 24 months post-SRT with the proportion rising to 4.0% at 72 months post-SRT and remaining at 4.0% through 120 months of post-SRT follow-up. Iyengar191 reported at median five years follow-up that statistically similar proportions of EBRT (13.7%) and 3D-CRT (14%) patients had grade 2 or higher late GI toxicities. The most common symptoms were rectal bleeding (12%) and frequency (4.3%). Rectal bleeding as the only late GI symptom, however, was twice as likely among 3D-CRT-treated patients (17%) compared to EBRT-treated patients (8.2%).

In addition, both Cozzarini185 and Tramacere67 reported that the presence of acute toxicity was a significant predictor of late toxicities.

Additional late toxicity information is provided by Thompson,23 one of the three RCTs (SWOG 8794). At median 127 months follow-up, urethral stricture was more common among RT patients (17.8%) than among RP-only patients (9.5%). Proctitis also was more common among RT patients (3.3%) than among RP-only patients (0%). Moinpour204 reported on frequency symptoms defined as >8 voids/day among a subset of patients from SWOG 8794. Before RT, rates of frequency were similar between groups (21% of patients who then received RT; 22% of RP-only patients). Frequency rates rose post-RT for RT patients (12 months: 27.5%; 24 months: 23%; 36 months: 26%; 48 months: 28%) but decreased for RP-only patients (12 months: 14%; 24 months: 12%; 36 months: 13%; 48 months: 15%). By 60 months post-RT, however, the two groups had similar frequency rates that were indistinguishable from pre-RT values (RT: 22%; RP only: 19.5%). Rates of bowel movement tenderness, although similar between groups post-RP and pre-RT, became elevated among RT patients post-RT and remained elevated through 60 months of follow up (six months post-RT: 18%; post-RP only: 5%; 60 months post-RT:18.5%; post-RP only: 11%).

Urinary incontinence. To understand the impact of RT on urinary incontinence (UI) post RP, the Panel focused on studies that provided either pre-RT baseline information and/or reported findings for a comparison group.

Five ART studies reported in six papers provided information on UI.23,42,205-208 One study provided pre-RT information (25 of 69 patients with UI) and reported at median 50.4 months follow-up that one additional patient had developed UI.42 Three reports compared ART patients to RP-only patients; at follow-up durations ranging from one to three years, ART and RP-only patients had indistinguishable and low rates of UI and pad use (ART: 12-23%; RP only: 14–19%).205-207 Two reports focused on patients from the RCTs23, 208 (EORTC 22911; SWOG 8794). Van Cangh208 noted that among patients from the Belgian arm of EORTC 22911, there were no statistically significant differences between ART and RP-only patients in grade 2-3 UI (grade 2: use of 1-4 pads soaked; grade 3: more than 4 pads) pre-RP (ART: 8.3%; RP only: 9.6%) or at 24 months post-RP/RT (ART: 8.3%; RP-only: 2%). Thompson23 reported a non-significant difference in total UI between ART patients (6.5%) and RP-only patients (2.8%) at median 127 months follow up.

Seven SRT studies that included pre-RT baseline information and/or a comparison group reported information regarding UI.46,79,85,87,106,186,195 As a group, these studies reported either isolated cases of new onset UI and/or mild worsening of UI in small numbers of patients (usually one or two patients).

QoL. Few studies focused on the QoL impact of urinary and GI symptoms and on overall QoL post-RT. No ART studies, two SRT studies, and one mixed study reported urinary and GI-related QoL information using a validated measure. Using the EPIC (score range 0-100 with higher scores indicating better QoL), Pinkawa198 reported that pre-RT, SRT patients had urinary-related function and bother scores that ranged from 75 to 87. Although urinary function and bother scores worsened immediately after RT, scores returned to pre-RT levels by two months post-RT and remained at those levels at >1 year post-RT. Pre-RT, mean bowel function score was 92 and bowel bother score was 94. Post-RT, there was a significant decrease in function and bother scores (indicating worse QoL) that did not recover to pre-RT levels until one year post-RT. Similar patterns were evident for individual symptoms of rectal urgency, fecal incontinence, painful bowel movements, and having a moderate/big problem from bowel dysfunction. Hu209 reported responses to the UCLA Prostate Cancer Index in SRT patients and noted that urinary and bowel function and bother scores did not change from pre-RT to 12-18 months post-RT. In a group of 78 mixed patients treated with IMRT, Corbin210 reported after administering the EPIC-26 and the International Prostate Symptom Index at 2-, 6-, 12-, 18-, and 24-month intervals post-RT that there were no declines in urinary continence or gastrointestinal QoL outcomes.

One ART study reported overall quality of life data. Moinpour204 (data subset from SWOG 8794) reported that pre-RT, similar proportions of ART patients (47%) and RP-only patients (52%) reported having a normal health-related QoL. These proportions increased over time for the ART group, with 69% of patients reporting a normal quality of life at 60 months post-RT. In contrast, for the RP-only patients, the proportions remained the same, with 51% reporting a normal quality of life at 60 months post-RP. For up to 36 months post-RT, ART patients had higher symptom distress scores than did RP-only patients, but by 48 and 60 months post-RT, ART patients had lower distress scores than RP-only patients. For the RAND Medical Outcomes subscales (Physical Function, Emotional Function, Social Function, and Role Function), the groups were indistinguishable throughout follow-up.

One SRT study reported overall QoL data.209 SRT patient scores on the RAND physical component summary and mental component summary did not change from pre-RT to 12-18 months post-RT. The population mean on these scales is 50; SRT patient mean scores ranged from 46.0 to 54.0.

Erectile Function

ART studies. Five studies reported information in six publications regarding erectile function in ART patients.42,44,50,204-206 Given the limited number of studies, the lack of validated measures, the absence of key data over time (particularly pre-RP baseline data) and potential confounding variables, such as unequal use of hormone therapy across patient groups and lack of full recovery from RP (RP to RT interval < 6 months), it is not possible to determine the impact of RT on erectile function when given for adjuvant purposes to post-RP patients. It is noteworthy that the percentages of patients who had intact erectile function post-RP but pre-RT were low, ranging from 7% to 33.3% with the most rigorous data from SWOG 8794204 indicating that only 7% of men had intact function pre-RT.

SRT studies. The impact of SRT on erectile function also is difficult to determine. Thirteen studies reported erectile function information in SRT patients.44,60,79,82,91,100,160,161,166,179,186,198,209 Nine of these studies reported only proportions of patients with erectile dysfunction (ED) at various time points and provide contradictory information (three studies reported no change post-RT and six reported increased proportions of patients with ED post-RT). In most of these studies sample sizes were extremely small (<50); pre-RP functioning was not reported; the type of RP was not reported or varied (some patients had nerve-sparing procedures and others did not); the RP to RT interval was less than two years, making it unclear whether erectile function had fully recovered post-RP; patients were followed for less than two years; and data were obtained from physician chart notes rather than patient-reported. Four studies used some type of validated measure. Although the sample sizes were larger, many of the same potential confounders remain. Three of these studies reported no changes over time from the post-RP/pre-RT measurement point throughout follow-up; one reported increased ED rates.

In addition, similar to the ART studies, post-RP patients who presented for SRT had very low rates of adequate erectile function (3.8% to 35.7%; most studies reported that <10% patients had full potency post-RP but pre-RT) and low scores on QoL measures of sexual function/bother. The only study that included pre-RP data60 reported that 74 of 110 patients (73%) were fully potent pre-RP, 9 (9%) were partially potent, and 18 (18%) were impotent. Post-RP/Pre-RT, 7 of 74 previously potent patients remained potent (9.5%); 14 of 74 previously potent patients became partially potent (19%); 53 of 74 previously potent patients became impotent (71.6%); in addition, all 9 patients who were partially potent pre-RP became impotent. Post-RT (minimum follow-up 60 months), of the 21 patients who were potent or partially potent post-RP, 9 (43%) became impotent, 10 (47.6%) became or remained partially potent, and 2 (9.4%) retained full potency; 1 of the 9 patients who lost partial potency post-RP regained partial potency during follow-up.

Mixed studies. One mixed study reported poor erectile function in 62% of men post-RP but pre-RT and in 66% of men 24 months post-RT. There were no differences over time in the proportions of men reporting problems with erectile strength or with sexual performance or reporting difficulty with orgasm.210

Overall, given the paucity of available data and the potential confounds to interpretation, the Panel interpreted these data to indicate that the impact of RT on erectile function given in either the adjuvant or salvage context is not currently known.

Secondary malignancies. Findings from studies carried out to investigate the risk of secondary malignancies resulting from the use of RT post-RP are contradictory as pointed out by Guedea.211 Specifically, Bhojani212 estimated that the hazard ratio of developing a rectal tumour at 120 months was 2.2 in patients treated with RT compared with the general population. In contrast, a Canadian study evaluated all prostate cancer cases treated in British Columbia from 1984 to 2000 and found no significant difference between observed and expected secondary cancer rates, regardless of whether treatment included RT.213 In addition, none of the trials that focused on ART or SRT have reported secondary malignancy data. Further, post-RP men may not be an accurate control group for estimating the risk of secondary malignancies post-RT because there is evidence that they have a lower risk of secondary cancers than the general population.214 Finally, the risk of secondary cancers also may be related to co-existing factors such as the presence of past or current smoking.215-217 The Panel concluded that at this time the risk of a secondary malignancy as a result of the administration of RT in the adjuvant or salvage context is not known.

Guidelines

Guideline Statement 1

Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery.  (Clinical Principle)

Discussion


Guideline Statement 2

Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer.  They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of three randomized controlled trials that addressed these outcomes indicated a benefit but the other two trials did not demonstrate a benefit. However, these two trials were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy. (Clinical Principle)

Discussion


Guideline Statement 3

Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence and clinical progression.  (Standard; Evidence Strength: Grade A)

Discussion


Guideline Statement 4

Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease.  Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate.  (Clinical Principle)

Discussion


Guideline Statement 5

Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml.  (Recommendation; Evidence Strength: Grade C)

Discussion


Guideline Statement 6

A restaging evaluation in the patient with a PSA recurrence may be considered.  (Option; Evidence Strength: Grade C)

Discussion


Guideline Statement 7

Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease.  (Recommendation; Evidence Strength: Grade C)

Discussion


Guideline Statement 8

Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA.  (Clinical Principle)

Discussion


Guideline Statement 9

Clinicians should offer hormone therapy to patients treated with salvage radiotherapy (postoperative PSA ≥0.2 ng/mL). Ongoing research may someday allow personalized selection of hormone or other therapies within patient subsets. (Standard; Evidence Strength: Grade A);

Discussion


Guideline Statement 10

Patients should be informed of the possible short-term and long-term urinary, bowel, and sexual side effects of radiotherapy as well as of the potential benefits of controlling disease recurrence. (Clinical Principle)

Discussion


Research Needs and Future Directions

Ongoing Clinical Trials. Several ongoing clinical trials will help to clarify the magnitude and impact of ART or SRT, the relative value of combining RT with hormone and other therapies, and potentially make clear which patients are more likely to benefit from specific therapies, therapy combinations, and therapeutic contexts.

RTOG 0534 is randomizing post-prostatectomy patients (pT2N0/Nx or pT3N0/Nx) with Gleason scores ≤9, with or without positive margins, and with post-RP PSA of ≥ 0.1 ng/mL to < 2.0 ng/mL to prostate bed RT, prostate bed RT plus short-term ADT (four to six months) or pelvic lymph node RT plus prostate bed RT plus short-term ADT. Patients are stratified by SVI status, Gleason score ≤7 or 8-9, pre-RT PSA of ≥0.1 to 1.0 ng/mL or >1.0 to

The RADICALS trial is a 3,000-subject study taking place in the UK, Canada, Denmark and Republic of Ireland recruiting post-prostatectomy patients who are within 22 weeks of RP with post-RP PSA ≤0.2 ng/mL with one or more of the following characteristics: pT3 or pT4 disease; Gleason score 7-10; preoperative PSA ≥ 10 ng/mL; and/or positive margins. This trial is addressing two critical questions in post-RP patients. The first question is the comparative efficacy of the ART vs. SRT approach. Patients are randomized to either immediate adjuvant RT or to regular PSA testing and SRT if PSA becomes detectable. The second, concurrent randomization addresses the question of the role of hormone therapy. Patients receiving radiation (either ART or SRT) are further randomized to three treatment arms: radiation alone, radiation plus six months of hormone therapy or radiation plus two years of hormone therapy. This study will address perhaps the most contentious of issues regarding radiation after surgery: whether SRT when PSA becomes detectable is equivalent to early ART.

The RAVES trial (TROG 08.03) was a phase III multi-center trial taking place in Australia and New Zealand comparing ART with early SRT in patients with positive margins or EPE. The primary trial aim was to determine whether surveillance with early SRT results in equivalent biochemical control and improved QoL when compared with ART. Secondary outcomes include QoL, toxicity, anxiety/depression, bRFS, OS, CSS, time to distant failure, time to local failure, time to initiation of hormone therapy, quality adjusted life years, and cost-utility. The rate of participant accrual diminished over time, and the trial closed prematurely with entry of 333 of the 470 patients planned.

Improved imaging techniques. A major question among patients who are undergoing treatment for localized, higher-risk prostate cancer is the true extent of disease. For example, patients with high-volume, high-grade disease whose staging studies (generally bone and CT scans) are negative are those who are most likely to exhibit an immediate PSA relapse, demonstrating pre-existing disease beyond the prostate at the time of diagnosis and treatment. Another challenging class of patients is those who have locally-extraprostatic (e.g., positive margins or seminal vesicle invasion) disease or microscopic nodal disease. In both groups of patients, improved imaging techniques would help to better define appropriate therapies or modifications to existing therapies. Knowing the true extent of disease could lead to more rational nerve-sparing at the time of surgery or could lead to the extension of radiation to include nodal groups or replacement of local therapy (radiation or surgery) with systemic therapy for patients with occult distant metastases. In the realm of ART or SRT, better imaging could allow confirmation that residual disease is confined to the pelvis before embarking on therapy. A significant challenge will be the design of clinical trials to confirm the sensitivity and specificity of such imaging techniques as these studies are confounded by the very long natural history of the disease and the fact that in almost all cases, histologic confirmation that scans are true positive or true negative is lacking. Advances in this field are most likely to be achieved by study designs with clinically-practical outcomes.

New PET imaging tracers appear more accurate in the assessment of prostate cancer than conventional 18F deoxyglucose PET imaging. Further research in 11C-or 18F-choline or 11C-acetate for assessment of local and regional disease is required to validate their utility in the postoperative setting. Similarly, improved bone metastases imaging with 18F-sodium fluoride will allow clinicians to avoid futile local therapy in men with documented metastatic disease. Improved MRI imaging with DCE or magnetic resonance spectroscopy will define sites of local recurrence and improve SRT targeting and the need to add adjuvant therapies, such as hormone therapy in patients with bulky recurrences not expected to be eradicated with conventional doses of radiation therapy.

Biomarkers of prognosis. A significant need in the arena of adjuvant therapies of prostate cancer are biomarkers of prognosis. To illustrate this point simply requires an examination of SWOG 8794, the only clinical trial finding a survival benefit to adjuvant radiation.24 With a median follow-up of 12.6 years and up to 20 years of follow-up overall, metastases (the primary outcome) were reported in only 37 of 211 patients in the RP-only group and in 20 of 214 patients in the ART group. Although a high-risk population, most men did not develop metastases nor die from their cancer; nonetheless, the number needed to treat with radiation to prevent one case of metastatic disease at a median follow-up of 12.6 years was 12.2.

Ideally, ART or SRT should be given only to the patient who will ultimately develop an adverse outcome (e.g., metastases or death from cancer) and in whom treatment will prevent that outcome. The advantage of patients undergoing prostatectomy is that both blood-based biomarkers as well as tissue biomarkers from the entire prostate are available for analysis. A host of new markers have been identified which may be linked with disease prognosis. It is possible to embed these biomarkers within trials such as RADICALS as secondary objectives to validate their utility in discriminating the patient who is most likely to benefit from ART or SRT.

Genomic classifiers as predictors of treatment effectiveness. Tissue microarray analysis of prostatectomy samples can describe the gene expression profile of the prostate cancer phenotype. The Decipher™ genomics resource information database has been recently used to link genomic findings with clinical outcomes, as have other methods. Development and validation of the Decipher™ genomic classifier uses a cluster of 22 transcriptome signature biomarkers (Decipher™ - POSTOP) as a prognostic risk stratification tool to identify patients with significantly different outcomes following ART or SRT after radical prostatectomy.312,313 At the time of this amendment, six retrospective studies and one Markov decision analysis using the Decipher™ - POSTOP classifier had been published, demonstrating its prognostic association with disease progression, focusing particularly on distant metastases, after radical prostatectomy.314-320 A 24-gene post-operative RT outcomes score (PORTOS) profile has been described also,326 as has a 50-gene (PAM50) molecular subtyping of basal and luminal cell lineage.327 Although prognostic, further study is needed to determine whether genomic classifiers are predictive of outcome in a yet to be treated patient, and whether it is predictive for efficacy of a particular treatment (RT, hormone therapy, or chemotherapy). A genomic classifier as a predictive marker will identify individuals in whom the effectiveness of a controlled treatment method varies as a direct result of the marker, and as it relates to a particular outcome (for example, metastasis-free survival). At present, there is ongoing recruitment to a RCT conducted by NRG Oncology (GU002) that uses Decipher™ - POSTOP as a pre-randomization stratification factor with participants categorized into low/intermediate genomic classifier score and high genomic classifier score. Participants are then randomized to receive either SRT with hormone therapy or the same with chemotherapy. Treatment response by genomically-defined subsets of patients will be used to assess whether the genomic classifier predicted response to chemotherapy. NRG Oncology (GU006) incorporates PAM50 molecular subtyping in a similar manner, seeking to determine whether it is predictive of response to the next-generation anti-androgen apalutamide. The present level of evidence cannot discern whether such genomic classifiers predict the efficacy, or lack thereof, of ART or SRT after prostatectomy. The timing (ART, early SRT, late SRT), type, targeted volume, and dosage of RT, and the use and duration of hormone therapy are confounding variables that limit certainty in the interpretation of the current literature.

Quality of life. A major challenge with all prostate cancer therapies is the impact of therapy on QoL including sexual, urinary and GI systems. The generally unanswered question in high-risk patients who are candidates for ART or SRT is how QoL is modulated by such therapies and how this compares and balances with the impact of therapy on survival outcomes. A major problem in most prostate cancer clinical trials (and clinical trials in general) is that QoL studies are underresourced and often undervalued with the primary focus on disease control. Clinical trials of SRT or ART should be designed in such a fashion so as to monitor disease and therapy-related QoL outcomes and to have a pre-planned analysis that integrates both survival and QoL outcomes to allow future patients and physicians to weigh the outcomes to reach a treatment decision for an individual patient.

Clinical trials are being conducted to evaluate the postoperative rehabilitation of men undergoing RP. Biofeedback, physical nerve stimulation and pharmaceutical intervention with phosphodiesterase inhibitors may lessen the impact of surgery on urinary and sexual dysfunction. Improved RT targeting may also lessen the adverse consequences of treatment for men receiving either ART or SRT.

Combination or systemic therapies. For some patients who undergo ART or SRT, such treatment is not sufficient to control the disease. In SWOG 8794, 20 of 214 patients developed metastatic disease despite early ART.24 In these men, either alternative systemic therapy or combination therapy may have prevented this outcome. The major questions for these highest-risk men are (a) can early identification of men most likely to exhibit disease progression be accomplished (i.e., with prognostic markers), and (b) what are optimal therapies for these men (e.g., other therapies such as hormone therapies in combination with RT or alternate therapies that replace RT)?

Some evidence to suggest that combination/alternative therapy may be beneficial comes from early results of SWOG 9921. This trial randomized high-risk patients post-RP to two years of adjuvant ADT with or without chemotherapy.321 In this study, the surgery plus hormone therapy arm included some patients who had received RT due to pT3 disease and, with early follow-up, higher-than-expected disease-free survival results were encountered. Prospective clinical trials are needed to examine prospectively the utility of systemic therapies in combination with RT and other local therapies for such high risk disease.

Comorbidities. An issue that pervades the management of prostate cancer is how patient comorbidities affect treatment decision-making. Most patients are older and, in many, death due to other causes is far more frequent than death or complications from disease progression. Methods to better predict the chronology of disease relapse and progression as well as life expectancy will enhance the selection of patients most likely to benefit from ART or SRT. Additionally, as radiation does have side effects, the prediction of men more likely to have these complications would help better select patients for treatment. Some comorbidities such as diabetes, hypertension, and vascular disease may increase the risk of radiation-related toxicity. Predictors for such outcomes could be based on functional (e.g., validated measures of erectile, urinary or GI function) or biologic (e.g., DNA repair mutations) measures.

Tools and Resources

Radiation After Prostatectomy – Clinical Problem Solving (CPS) Protocol

References

  1. JDA H: Assessing quality of included studies in Cochrane Reviews. In: The Cochrane Collaboration Methods Group Newsletter, p. 11, 2007
  2. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. 2009; http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
  3. Whiting P, Rutjes AW, Reitsma JB et al: The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3: 25.
  4. Whiting P, Rutjes AW, Dinnes J et al: Development and validation of methods for assessing the quality of diagnostic accuracy studies. Health Technol Assess 2004; 8: iii.
  5. Faraday M, Hubbard H, Kosiak B et al: Staying at the cutting edge: a review and analysis of evidence reporting and grading; the recommendations of the American Urological Association. BJU Int 2009; 104: 294.
  6. CC H and BA S: The Delphi technique: making sense of consensus. Practical Assessment, Research & Evaluation 2007; 12: 1.
  7. American Cancer Society: Key statistics for prostate cancer. 2018; https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html; downloaded 9/25/2018.
  8. Miller DC, Gruber SB, Hollenbeck BK et al: Incidence of initial local therapy among men with lower-risk prostate cancer in the United States. J Natl Cancer Inst 2006; 98: 1134.
  9. Amling CL, Blute ML, Bergstralh EJ et al: Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol 2000; 164: 101.
  10. Chun FK, Graefen M, Zacharias M et al: Anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer. World J Urol 2006; 24: 273.
  11. Han M, Partin AW, Pound CR et al: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001; 28: 555.
  12. Bianco FJ, Jr., Scardino PT and Eastham JA: Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function ("trifecta"). Urology 2005; 66: 83.
  13. Stephenson AJ, Scardino PT, Eastham JA et al: Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006; 98: 715.
  14. Swindle P, Eastham JA, Ohori M et al: Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 2005; 174: 903.
  15. Kupelian PA, Katcher J, Levin HS et al: Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997; 37: 1043.
  16. Epstein JI, Pizov G and Walsh PC: Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993; 71: 3582.
  17. Zietman AL, Edelstein RA, Coen JJ et al: Radical prostatectomy for adenocarcinoma of the prostate: the influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 1994; 43: 828.
  18. Lee HM, Solan MJ, Lupinacci P et al: Long-term outcome of patients with prostate cancer and pathologic seminal vesicle invasion (pT3b): effect of adjuvant radiotherapy. Urology 2004; 64: 84.
  19. Ohori M, Wheeler TM, Kattan MW et al: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995; 154: 1818.
  20. Lowe BA and Lieberman SF: Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: selecting the patient for adjuvant therapy. J Urol 1997; 158: 1452.
  21. Pound CR, Partin AW, Eisenberger MA et al: Natural history of progression after PSA elevation following radical prostatectomy. Jama 1999; 281: 1591.
  22. Catalona WJ and Smith DS: 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152: 1837.
  23. Thompson IM, Jr., Tangen CM, Paradelo J et al: Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296: 2329.
  24. 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: 956.
  25. Bolla M, van Poppel H, Tombal B et al: Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018.
  26. 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: 2924.
  27. 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: 243.
  28. Swanson GP and Thompson IM: Adjuvant radiotherapy for high-risk patients following radical prostatectomy. Urol Oncol 2007; 25: 515.
  29. Schroder FH, Hugosson J, Roobol MJ et al: Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981.
  30. Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708.
  31. Abdollah F, Sun M, Schmitges J et al: Survival benefit of radical prostatectomy in patients with localized prostate cancer: estimations of the number needed to treat according to tumor and patient characteristics. J Urol 2012; 188: 73.
  32. Boorjian SA, Karnes RJ, Crispen PL et al: Radiation therapy after radical prostatectomy: impact on metastasis and survival. J Urol 2009; 182: 2708.
  33. 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: 2760.
  34. Abdollah F, Suardi N, Cozzarini C et al: Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol 2013; 63: 998.
  35. Arcangeli G, Strigari L, Arcangeli S et al: Retrospective comparison of external beam radiotherapy and radical prostatectomy in high-risk, clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009; 75: 975.
  36. Bastide C, Rossi D, Lechevallier E et al: Seminal vesicle invasion: what is the best adjuvant treatment after radical prostatectomy? BJU Int 2012; 109: 525.
  37. 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: 472.
  38. Budiharto T, Perneel C, Haustermans K et al: A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy. Radiother Oncol 2010; 97: 474.
  39. Caraffini B, De Stefani A, Vitali E et al: Postoperative radiotherapy after radical prostatectomy for prostate carcinoma: the experience of the Brescia Radium Institute. Radiol Med 2006; 111: 741.
  40. Catton C, Gospodarowicz M, Warde P et al: Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol 2001; 59: 51.
  41. Cheng WS, Frydenberg M, Bergstralh EJ et al: Radical prostatectomy for pathologic stage C prostate cancer: influence of pathologic variables and adjuvant treatment on disease outcome. Urology 1993; 42: 283.
  42. Choo R, Hruby G, Hong J et al: Positive resection margin and/or pathologic T3 adenocarcinoma of prostate with undetectable postoperative prostate-specific antigen after radical prostatectomy: to irradiate or not? Int J Radiat Oncol Biol Phys 2002; 52: 674.
  43. Cozzarini C, Montorsi F, Fiorino C et al: Need for high radiation dose (>or=70 Gy) in early postoperative irradiation after radical prostatectomy: a single-institution analysis of 334 high-risk, node-negative patients. Int J Radiat Oncol Biol Phys 2009; 75: 966.
  44. Do LV, Do TM, Smith R et al: Postoperative radiotherapy for carcinoma of the prostate: impact on both local control and distant disease-free survival. Am J Clin Oncol 2002; 25: 1.
  45. Eggener SE, Roehl KA, Smith ND et al: Contemporary survival results and the role of radiation therapy in patients with node negative seminal vesicle invasion following radical prostatectomy. J Urol 2005; 173: 1150.
  46. Hagan M, Zlotecki R, Medina C et al: Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59: 329.
  47. Kalapurakal JA, Huang CF, Neriamparampil MM et al: Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy. Int J Radiat Oncol Biol Phys 2002; 54: 1047.
  48. Kamat AM, Babaian K, Cheung MR et al: Identification of factors predicting response to adjuvant radiation therapy in patients with positive margins after radical prostatectomy. J Urol 2003; 170: 1860.
  49. Leibovich BC, Engen DE, Patterson DE et al: Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin. J Urol 2000; 163: 1178.
  50. Macdonald OK, Lee RJ, Snow G et al: Prostate-specific antigen control with low-dose adjuvant radiotherapy for high-risk prostate cancer. Urology 2007; 69: 295.
  51. Mayer R, Pummer K, Quehenberger F et al: Postprostatectomy radiotherapy for high-risk prostate cancer. Urology 2002; 59: 732.
  52. McCarthy JF, Catalona WJ and Hudson MA: Effect of radiation therapy on detectable serum prostate specific antigen levels following radical prostatectomy: early versus delayed treatment. J Urol 1994; 151: 1575.
  53. Neulander EZ, Wajsman Z and Greene GF: Radical prostatectomy and postoperative radiation in patients with adenocarcinoma of prostate of intermediate and high risk for recurrence. J Ark Med Soc 2005; 101: 276.
  54. Nudell DM, Grossfeld GD, Weinberg VK et al: Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology 1999; 54: 1049.
  55. Ost P, Fonteyne V, Villeirs G et al: Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur Urol 2009; 56: 669.
  56. Ost P, De Troyer B, Fonteyne V et al: 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: 1316.
  57. Pacholke HD, Wajsman Z, Algood CB et al: Postoperative adjuvant and salvage radiotherapy for prostate cancer: impact on freedom from biochemical relapse and survival. Urology 2004; 64: 982.
  58. Pai HH, Eldridge B, Bishop D et al: Does neoadjuvant hormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy? Can J Urol 2009; 16: 4541.
  59. Peschel RE, Robnett TJ, Hesse D et al: PSA based review of adjuvant and salvage radiation therapy vs. observation in postoperative prostate cancer patients. Int J Cancer 2000; 90: 29.
  60. Petroski RA, Warlick WB, Herring J et al: External beam radiation therapy after radical prostatectomy: efficacy and impact on urinary continence. Prostate Cancer Prostatic Dis 2004; 7: 170.
  61. Schaefer U, Witt F, Schueller P et al: Prostate-specific antigen (PSA) in the monitoring of prostate cancer after radical prostatectomy and external beam radiation. Anticancer Res 2000; 20: 4989.
  62. Schafer U, Witt F, Micke O et al: Adjuvant radiotherapy in locally confined prostate cancer. Anticancer Res 2003; 23: 983.
  63. Schild SE and Pisansky TM: The role of radiotherapy after radical prostatectomy. Urol Clin North Am 2001; 28: 629.
  64. Taylor N, Kelly JF, Kuban DA et al: Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 2003; 56: 755.
  65. Teh BS, Bastasch MD, Mai WY et al: Long-term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins. J Urol 2006; 175: 2097.
  66. 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: 1298.
  67. Tramacere F, Gianicolo EA, Pignatelli A et al: High-dose 3D-CRT in the radical and postoperative setting for prostate cancer. Analysis of survival and late rectal and urinary toxicity. Tumori 2012; 98: 337.
  68. Tsien C, Griffith KA, Sandler HM et al: Long-term results of three-dimensional conformal adjuvant and salvage radiotherapy after radical prostatectomy. Urology 2003; 62: 93.
  69. Valicenti RK, Gomella LG, Ismail M et al: Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: effect of early adjuvant radiation therapy on biochemical control. Cancer 1998; 82: 1909.
  70. Valicenti RK, Gomella LG, Ismail M et al: Effect of higher radiation dose on biochemical control after radical prostatectomy for PT3N0 prostate cancer. Int J Radiat Oncol Biol Phys 1998; 42: 501.
  71. Valicenti RK, Gomella LG, Ismail M et al: The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys 1999; 45: 53.
  72. Valicenti RK, Chervoneva I and Gomella LG: Importance of margin extent as a predictor of outcome after adjuvant radiotherapy for Gleason score 7 pT3N0 prostate cancer. Int J Radiat Oncol Biol Phys 2004; 58: 1093.
  73. Vargas C, Kestin LL, Weed DW et al: Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys 2005; 61: 714.
  74. Vicini FA, Ziaja EL, Kestin LL et al: Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 1999; 54: 111.
  75. Wadasaki K, Kaneyasu Y, Kenjo M et al: Treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Clin Oncol 2007; 12: 37.
  76. Anscher MS, Clough R and Dodge R: Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 2000; 48: 369.
  77. Bastide C, Savage C, Cronin A et al: Location and number of positive surgical margins as prognostic factors of biochemical recurrence after salvage radiation therapy after radical prostatectomy. BJU Int 2010; 106: 1454.
  78. Bernard JR, Jr., Buskirk SJ, Heckman MG et al: Salvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysis. Int J Radiat Oncol Biol Phys 2010; 76: 735.
  79. Borg M, Sutherland P, Stapleton A et al: Outcome of post-prostatectomy radiotherapy in one institution. Australas Radiol 2006; 50: 475.
  80. Brodak M, Kosina J, Holub L et al: Radical prostatectomy in high-grade prostate cancer, salvage and adjuvant radiotherapy. Urol Int 2011; 86: 146.
  81. Brooks JP, Albert PS, O'Connell J et al: Lymphovascular invasion in prostate cancer: prognostic significance in patients treated with radiotherapy after radical prostatectomy. Cancer 2006; 106: 1521.
  82. Buskirk SJ, Schild SE, Durr ED et al: Evaluation of serum prostate-specific antigen levels after postoperative radiation therapy for pathologic stage T3, N0 prostate cancer. Mayo Clin Proc 1996; 71: 242.
  83. Buskirk SJ, Pisansky TM, Schild SE et al: Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol 2006; 176: 985.
  84. Cadeddu JA, Partin AW, DeWeese TL et al: Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998; 159: 173.
  85. Chawla AK, Thakral HK, Zietman AL et al: Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology 2002; 59: 726.
  86. Cheung R, Kamat AM, de Crevoisier R et al: Outcome of salvage radiotherapy for biochemical failure after radical prostatectomy with or without hormonal therapy. Int J Radiat Oncol Biol Phys 2005; 63: 134.
  87. Choo R, Morton G, Danjoux C et al: Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery. Radiother Oncol 2005; 74: 163.
  88. Choo R, Hruby G, Hong J et al: (IN)-efficacy of salvage radiotherapy for rising PSA or clinically isolated local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2002; 53: 269.
  89. Coetzee LJ, Hars V and Paulson DF: Postoperative prostate-specific antigen as a prognostic indicator in patients with margin-positive prostate cancer, undergoing adjuvant radiotherapy after radical prostatectomy. Urology 1996; 47: 232.
  90. Cozzarini C, Bolognesi A, Ceresoli GL et al: Role of postoperative radiotherapy after pelvic lymphadenectomy and radical retropubic prostatectomy: a single institute experience of 415 patients. Int J Radiat Oncol Biol Phys 2004; 59: 674.
  91. Cremers RG, van Lin EN, Gerrits WL et al: Efficacy and tolerance of salvage radiotherapy after radical prostatectomy, with emphasis on high-risk patients suited for adjuvant radiotherapy. Radiother Oncol 2010; 97: 467.
  92. de la Taille A, Flam TA, Thiounn N et al: Predictive factors of radiation therapy for patients with prostate specific antigen recurrence after radical prostatectomy. BJU Int 2002; 90: 887.
  93. De Meerleer G, Fonteyne V, Meersschout S et al: Salvage intensity-modulated radiotherapy for rising PSA after radical prostatectomy. Radiother Oncol 2008; 89: 205.
  94. Delongchamps NB, Zerbib M, Mejean A et al: Conformal radiotherapy for detectable PSA following radical prostatectomy: efficacy and predictive factors of recurrence. Can J Urol 2009; 16: 4813.
  95. Do T, Parker RG, Do C et al: Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Cancer J Sci Am 1998; 4: 324.
  96. Do T, Dave G, Parker R et al: Serum PSA evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes. Int J Radiat Oncol Biol Phys 2001; 50: 1220.
  97. Forman JD, Meetze K, Pontes E et al: Therapeutic irradiation for patients with an elevated post-prostatectomy prostate specific antigen level. J Urol 1997; 158: 1436.
  98. Garg MK, Tekyi-Mensah S, Bolton S et al: Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology 1998; 51: 998.
  99. Geinitz H, Riegel MG, Thamm R et al: Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Oncol Biol Phys 2012; 82: 1930.
  100. Goenka A, Magsanoc JM, Pei X et al: Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol 2011; 60: 1142.
  101. Haab F, Meulemans A, Boccon-Gibod L et al: Effect of radiation therapy after radical prostatectomy on serum prostate-specific antigen measured by an ultrasensitive assay. Urology 1995; 45: 1022.
  102. Hayashi S, Hayashi K, Yoshimura R et al: Salvage radiotherapy after radical prostatectomy: outcomes and prognostic factors especially focusing on pathological findings. J Radiat Res 2012; 53: 727.
  103. Hugen CM, Polcari AJ, Quek ML et al: Long-term outcomes of salvage radiotherapy for PSA-recurrent prostate cancer: validation of the Stephenson nomogram. World J Urol 2010; 28: 741.
  104. Jacinto AA, Fede AB, Fagundes LA et al: Salvage radiotherapy for biochemical relapse after complete PSA response following radical prostatectomy: outcome and prognostic factors for patients who have never received hormonal therapy. Radiat Oncol 2007; 2: 8.
  105. Jereczek-Fossa BA, Zerini D, Vavassori A et al: Sooner or later? Outcome analysis of 431 prostate cancer patients treated with postoperative or salvage radiotherapy. Int J Radiat Oncol Biol Phys 2009; 74: 115.
  106. Katz MS, Zelefsky MJ, Venkatraman ES et al: Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol 2003; 21: 483.
  107. Kim BS, Lashkari A, Vongtama R et al: Effect of pelvic lymph node irradiation in salvage therapy for patients with prostate cancer with a biochemical relapse following radical prostatectomy. Clin Prostate Cancer 2004; 3: 93.
  108. King CR and Spiotto MT: Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 2008; 71: 23.
  109. King CR, Presti JC, Jr., Gill H et al: Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? Int J Radiat Oncol Biol Phys 2004; 59: 341.
  110. King CR, Presti JC, Brooks JD et al: Postoperative prostate-specific antigen velocity independently predicts for failure of salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 2008; 70: 1472.
  111. Koppie TM, Grossfeld GD, Nudell DM et al: Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol 2001; 166: 111.
  112. Kruser TJ, Jarrard DF, Graf AK et al: Early hypofractionated salvage radiotherapy for postprostatectomy biochemical recurrence. Cancer 2011; 117: 2629.
  113. Kundel Y, Pfeffer R, Lauffer M et al: Salvage prostatic fossa radiation therapy for biochemical failure after radical prostatectomy: the Sheba experience. Isr Med Assoc J 2004; 6: 329.
  114. Lee LW, McBain CA, Swindell R et al: Hypofractionated radiotherapy as salvage for rising prostate-specific antigen after radical prostatectomy. Clin Oncol (R Coll Radiol) 2004; 16: 517.
  115. Leventis AK, Shariat SF, Kattan MW et al: Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001; 19: 1030.
  116. Liauw SL, Weichselbaum RR, Zagaja GP et al: Salvage radiotherapy after postprostatectomy biochemical failure: does pretreatment radioimmunoscintigraphy help select patients with locally confined disease? Int J Radiat Oncol Biol Phys 2008; 71: 1316.
  117. Loeb S, Roehl KA, Viprakasit DP et al: Long-term rates of undetectable PSA with initial observation and delayed salvage radiotherapy after radical prostatectomy. Eur Urol 2008; 54: 88.
  118. Macdonald OK, Schild SE, Vora SA et al: Salvage radiotherapy for palpable, locally recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys 2004; 58: 1530.
  119. Macdonald OK, Schild SE, Vora SA et al: Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol 2003; 170: 1833.
  120. MacDonald OK, Schild SE, Vora S et al: Salvage radiotherapy for men with isolated rising PSA or locally palpable recurrence after radical prostatectomy: do outcomes differ? Urology 2004; 64: 760.
  121. Macdonald OK, D'Amico AV, Sadetsky N et al: Predicting PSA failure following salvage radiotherapy for a rising PSA post-prostatectomy: from the CaPSURE database. Urol Oncol 2008; 26: 271.
  122. Maier J, Forman J, Tekyi-Mensah S et al: Salvage radiation for a rising PSA following radical prostatectomy. Urol Oncol 2004; 22: 50.
  123. Matsui Y, Ichioka K, Terada N et al: Impact of volume weighted mean nuclear volume on outcomes following salvage radiation therapy after radical prostatectomy. J Urol 2004; 171: 687.
  124. Medini E, Medini I, Reddy PK et al: Delayed/salvage radiation therapy in patients with elevated prostate specific antigen levels after radical prostatectomy. A long term follow-up. Cancer 1996; 78: 1254.
  125. Monti CR, Nakamura RA, Ferrigno R et al: Salvage conformal radiotherapy for biochemical recurrent prostate cancer after radical prostatectomy. Int Braz J Urol 2006; 32: 416.
  126. Mosbacher MR, Schiff PB, Otoole KM et al: Postprostatectomy salvage radiation therapy for prostate cancer: impact of pathological and biochemical variables and prostate fossa biopsy. Cancer J 2002; 8: 242.
  127. Nagda SN, Mohideen N, Lo SS et al: Long-term follow-up of 111In-capromab pendetide (ProstaScint) scan as pretreatment assessment in patients who undergo salvage radiotherapy for rising prostate-specific antigen after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 2007; 67: 834.
  128. Neuhof D, Hentschel T, Bischof M et al: Long-term results and predictive factors of three-dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy. Int J Radiat Oncol Biol Phys 2007; 67: 1411.
  129. Numata K, Azuma K, Hashine K et al: Predictor of response to salvage radiotherapy in patients with PSA recurrence after radical prostatectomy: the usefulness of PSA doubling time. Jpn J Clin Oncol 2005; 35: 256.
  130. Ost P, Lumen N, Goessaert AS et al: High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol 2011; 60: 842.
  131. Patel R, Lepor H, Thiel RP et al: Prostate-specific antigen velocity accurately predicts response to salvage radiotherapy in men with biochemical relapse after radical prostatectomy. Urology 2005; 65: 942.
  132. Pazona JF, Han M, Hawkins SA et al: Salvage radiation therapy for prostate specific antigen progression following radical prostatectomy: 10-year outcome estimates. J Urol 2005; 174: 1282.
  133. Perez CA, Michalski JM, Baglan K et al: Radiation therapy for increasing prostate-specific antigen levels after radical prostatectomy. Clin Prostate Cancer 2003; 1: 235.
  134. Peyromaure M, Allouch M, Eschwege F et al: Salvage radiotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients. Urology 2003; 62: 503.
  135. Pisansky TM, Kozelsky TF, Myers RP et al: Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 2000; 163: 845.
  136. Quero L, Mongiat-Artus P, Ravery V et al: Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience. BMC Cancer 2008; 8: 26.
  137. Rogers R, Grossfeld GD, Roach M, 3rd et al: Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 1998; 160: 1748.
  138. Sasaki T, Nakamura K, Shioyama Y et al: Low pre-radiotherapy prostate-specific antigen level is a significant predictor of treatment success for postoperative radiotherapy in patients with prostate cancer. Anticancer Res 2006; 26: 2367.
  139. Schild SE, Buskirk SJ, Robinow JS et al: The results of radiotherapy for isolated elevation of serum PSA levels following radical prostatectomy. Int J Radiat Oncol Biol Phys 1992; 23: 141.
  140. Schwarz R, Krull A, Tribius S et al: Results of three dimensional conformal radiotherapy and hormonal therapy for local recurrence after radical prostatectomy. Strahlenther Onkol 2005; 181: 442.
  141. Siegmann A, Bottke D, Faehndrich J et al: Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival: results of a retrospective study. Strahlenther Onkol 2011; 187: 467.
  142. Siegmann A, Bottke D, Faehndrich J et al: Salvage radiotherapy after prostatectomy - what is the best time to treat? Radiother Oncol 2012; 103: 239.
  143. Song DY, Thompson TL, Ramakrishnan V et al: Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology 2002; 60: 281.
  144. Song C, Kim YS, Hong JH et al: Treatment failure and clinical progression after salvage therapy in men with biochemical recurrence after radical prostatectomy: radiotherapy vs androgen deprivation. BJU Int 2010; 106: 188.
  145. Soto DE, Passarelli MN, Daignault S et al: Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves treatment outcomes in high-risk patients. Int J Radiat Oncol Biol Phys 2012; 82: 1227.
  146. Spiotto MT, Hancock SL and King CR: Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys 2007; 69: 54.
  147. Stephenson AJ, Shariat SF, Zelefsky MJ et al: Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. Jama 2004; 291: 1325.
  148. 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: 2035.
  149. Stockdale AD, Vakkalanka BK, Fahmy A et al: Management of biochemical failure following radical prostatectomy: salvage radiotherapy - a case series. Prostate Cancer Prostatic Dis 2007; 10: 205.
  150. Swanson GP, Du F, Michalek JE et al: Long-term follow-up and risk of cancer death after radiation for post-prostatectomy rising prostate-specific antigen. Int J Radiat Oncol Biol Phys 2011; 80: 62.
  151. Symon Z, Kundel Y, Sadetzki S et al: Radiation rescue for biochemical failure after surgery for prostate cancer: predictive parameters and an assessment of contemporary predictive models. Am J Clin Oncol 2006; 29: 446.
  152. Tefilli MV, Gheiler EL, Tiguert R et al: Quality of life in patients undergoing salvage procedures for locally recurrent prostate cancer. J Surg Oncol 1998; 69: 156.
  153. Terai A, Matsui Y, Yoshimura K et al: Salvage radiotherapy for biochemical recurrence after radical prostatectomy. BJU Int 2005; 96: 1009.
  154. Tomita N, Kodaira T, Furutani K et al: Early salvage radiotherapy for patients with PSA relapse after radical prostatectomy. J Cancer Res Clin Oncol 2009; 135: 1561.
  155. Umezawa R, Ariga H, Ogawa Y et al: Impact of pathological tumor stage for salvage radiotherapy after radical prostatectomy in patients with prostate-specific antigen < 1.0 ng/ml. Radiat Oncol 2011; 6: 150.
  156. Van Der Poel HG, Moonen L and Horenblas S: Sequential treatment for recurrent localized prostate cancer. J Surg Oncol 2008; 97: 377.
  157. Vanuytsel L, Janssens G, Van Poppel H et al: Radiotherapy for PSA recurrence after radical prostatectomy. Eur Urol 2001; 39: 425.
  158. Ward JF, Zincke H, Bergstralh EJ et al: Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy. J Urol 2004; 172: 2244.
  159. Wiegel T, Lohm G, Bottke D et al: Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys 2009; 73: 1009.
  160. Wilder RB, Hsiang JY, Ji M et al: Preliminary results of three-dimensional conformal radiotherapy as salvage treatment for a rising prostate-specific antigen level postprostatectomy. Am J Clin Oncol 2000; 23: 176.
  161. Wu JJ, King SC, Montana GS et al: The efficacy of postprostatectomy radiotherapy in patients with an isolated elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 1995; 32: 317.
  162. Xu Y, Liu R, Zhang Z et al: Variables which might predict the response to salvage radiotherapy in chinese patients with biochemical failure after radical prostatectomy. Urol Int 2006; 77: 205.
  163. Yoshida T, Nakayama M, Suzuki O et al: Salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy for prostate cancer: a single-center experience. Jpn J Clin Oncol 2011; 41: 1031.
  164. Youssef E, Forman JD, Tekyi-Mensah S et al: Therapeutic postprostatectomy irradiation. Clin Prostate Cancer 2002; 1: 31.
  165. Bolla M, van Poppel H, Collette L et al: Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572.
  166. Zelefsky MJ, Leibel SA, Kutcher GJ et al: Three-dimensional conformal radiotherapy and dose escalation: where do we stand? Semin Radiat Oncol 1998; 8: 107.
  167. Ohri N, Dicker AP, Trabulsi EJ et al: Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer 2012; 48: 837.
  168. Michalski JM, Lawton C, El Naqa I et al: Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010; 76: 361.
  169. Sidhom MA, Kneebone AB, Lehman M et al: Post-prostatectomy radiation therapy: consensus guidelines of the Australian and New Zealand Radiation Oncology Genito-Urinary Group. Radiother Oncol 2008; 88: 10.
  170. Wiltshire KL, Brock KK, Haider MA et al: Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy. Int J Radiat Oncol Biol Phys 2007; 69: 1090.
  171. Poortmans P, Bossi A, Vandeputte K et al: Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol 2007; 84: 121.
  172. Parker C, Sydes MR, Catton C et al: Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy. BJU Int 2007; 99: 1376.
  173. Ost P, Cozzarini C, De Meerleer G et al: High-dose adjuvant radiotherapy after radical prostatectomy with or without androgen deprivation therapy. Int J Radiat Oncol Biol Phys 2012; 83: 960.
  174. Da Pozzo LF, Cozzarini C, Briganti A et al: Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009; 55: 1003.
  175. Shipley WU, Seiferheld W, Lukka HR et al: Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med 2017; 376: 417.
  176. Carrie C, Hasbini A, de Laroche G et al: Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 2016; 17: 747.
  177. Alongi F, Fiorino C, Cozzarini C et al: IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomy. Radiother Oncol 2009; 93: 207.
  178. Azelie C, Gauthier M, Mirjolet C et al: Exclusive image guided IMRT vs. radical prostatectomy followed by postoperative IMRT for localized prostate cancer: a matched-pair analysis based on risk-groups. Radiat Oncol 2012; 7: 158.
  179. Bastasch MD, Teh BS, Mai WY et al: Post-nerve-sparing prostatectomy, dose-escalated intensity-modulated radiotherapy: effect on erectile function. Int J Radiat Oncol Biol Phys 2002; 54: 101.
  180. Bellavita R, Massetti M, Abraha I et al: Conformal postoperative radiotherapy in patients with positive resection margins and/or pT3-4 prostate adenocarcinoma. Int J Radiat Oncol Biol Phys 2012; 84: e299.
  181. Brooks JP, Albert PS, Wilder RB et al: Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors. J Urol 2005; 174: 2204.
  182. Cheng JC, Schultheiss TE, Nguyen KH et al: Acute toxicity in definitive versus postprostatectomy image-guided radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2008; 71: 351.
  183. Choo R, Pearse M, Danjoux C et al: Analysis of gastrointestinal and genitourinary morbidity of postoperative radiotherapy for pathologic T3 disease or positive surgical margins after radical prostatectomy using national cancer institute expanded common toxicity criteria. Int J Radiat Oncol Biol Phys 2008; 72: 989.
  184. Cozzarini C, Fiorino C, Ceresoli GL et al: Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6-70.2 Gy). Int J Radiat Oncol Biol Phys 2003; 55: 688.
  185. Cozzarini C, Fiorino C, Da Pozzo LF et al: Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients. Int J Radiat Oncol Biol Phys 2012; 82: 191.
  186. Duchesne GM, Dowling C, Frydenberg M et al: Outcome, morbidity, and prognostic factors in post-prostatectomy radiotherapy: an Australian multicenter study. Urology 2003; 61: 179.
  187. Eldredge HB, Studenski M, Keith SW et al: Post-prostatectomy image-guided radiation therapy: evaluation of toxicity and inter-fraction variation using online cone-beam CT. J Med Imaging Radiat Oncol 2011; 55: 507.
  188. Feng M, Hanlon AL, Pisansky TM et al: Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys 2007; 68: 1417.
  189. Fontaine E, Ben Mouelli S, Thomas L et al: Urinary continence after salvage radiation therapy following radical prostatectomy, assessed by a self-administered questionnaire: a prospective study. BJU Int 2004; 94: 521.
  190. Goldner G and Potter R: Radiotherapy in lymph node-positive prostate cancer patients - a potential cure? Single institutional experience regarding outcome and side effects. Front Radiat Ther Oncol 2008; 41: 68.
  191. Iyengar P, Levy LB, Choi S et al: Toxicity associated with postoperative radiation therapy for prostate cancer. Am J Clin Oncol 2011; 34: 611.
  192. Jung C, Cookson MS, Chang SS et al: Toxicity following high-dose salvage radiotherapy after radical prostatectomy. BJU Int 2007; 99: 529.
  193. Macdonald OK, D'Amico AV, Sadetsky N et al: Adjuvant radiotherapy in prostate cancer: predictors of prostate-specific antigen recurrence from the CaPSURE database. Urology 2007; 70: 106.
  194. Nath SK, Sandhu AP, Rose BS et al: Toxicity analysis of postoperative image-guided intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010; 78: 435.
  195. Pearse M, Choo R, Danjoux C et al: Prospective assessment of gastrointestinal and genitourinary toxicity of salvage radiotherapy for patients with prostate-specific antigen relapse or local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2008; 72: 792.
  196. Perna L, Alongi F, Fiorino C et al: Predictors of acute bowel toxicity in patients treated with IMRT whole pelvis irradiation after prostatectomy. Radiother Oncol 2010; 97: 71.
  197. Peterson JL, Buskirk SJ, Heckman MG et al: Late toxicity after postprostatectomy salvage radiation therapy. Radiother Oncol 2009; 93: 203.
  198. Pinkawa M, Fischedick K, Asadpour B et al: Health-related quality of life after adjuvant and salvage postoperative radiotherapy for prostate cancer - a prospective analysis. Radiother Oncol 2008; 88: 135.
  199. Riou O, Laliberte B, Azria D et al: Implementing intensity modulated radiotherapy to the prostate bed: dosimetric study and early clinical results. Med Dosim 2013; 38: 117.
  200. Schild SE, Buskirk SJ, Wong WW et al: The use of radiotherapy for patients with isolated elevation of serum prostate specific antigen following radical prostatectomy. J Urol 1996; 156: 1725.
  201. Sharma R, Chuba PJ, Duclos M et al: Differences in dosimetry and toxicity between definitive and postprostatectomy radiation therapy. Radiology 1997; 204: 211.
  202. Suzuki K, Nakano K and Morita T: Outcome of adjuvant radiotherapy after radical prostatectomy for prostate cancer patients. Urol Int 2010; 84: 382.
  203. Valicenti RK, Gomella LG, Ismail M et al: Durable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: the importance of radiation dose. Urology 1998; 52: 1034.
  204. Moinpour CM, Hayden KA, Unger JM et al: Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008; 26: 112.
  205. Formenti SC, Lieskovsky G, Simoneau AR et al: Impact of moderate dose of postoperative radiation on urinary continence and potency in patients with prostate cancer treated with nerve sparing prostatectomy. J Urol 1996; 155: 616.
  206. Formenti SC, Lieskovsky G, Skinner D et al: Update on impact of moderate dose of adjuvant radiation on urinary continence and sexual potency in prostate cancer patients treated with nerve-sparing prostatectomy. Urology 2000; 56: 453.
  207. Hofmann T, Gaensheimer S, Buchner A et al: An unrandomized prospective comparison of urinary continence, bowel symptoms and the need for further procedures in patients with and with no adjuvant radiation after radical prostatectomy. BJU Int 2003; 92: 360.
  208. Van Cangh PJ, Richard F, Lorge F et al: Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized study. J Urol 1998; 159: 164.
  209. Hu JC, Elkin EP, Krupski TL et al: The effect of postprostatectomy external beam radiotherapy on quality of life: results from the Cancer of the Prostate Strategic Urologic Research Endeavor. Cancer 2006; 107: 281.
  210. Corbin KS, Kunnavakkam R, Eggener SE et al: Intensity modulated radiation therapy after radical prostatectomy: Early results show no decline in urinary continence, gastrointestinal, or sexual quality of life. Pract Radiat Oncol 2013; 3: 138.
  211. Guedea F, Ramos A, Herruzo I et al: Treatment of localised prostate cancer with radiation therapy: evidence versus opinion. Clin Transl Oncol 2010; 12: 315.
  212. Bhojani N, Capitanio U, Suardi N et al: The rate of secondary malignancies after radical prostatectomy versus external beam radiation therapy for localized prostate cancer: a population-based study on 17,845 patients. Int J Radiat Oncol Biol Phys 2010; 76: 342.
  213. Pickles T and Phillips N: The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000. Radiother Oncol 2002; 65: 145.
  214. Eifler JB, Humphreys EB, Agro M et al: Causes of death after radical prostatectomy at a large tertiary center. J Urol 2012; 188: 798.
  215. van Leeuwen FE, Klokman WJ, Stovall M et al: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 1995; 87: 1530.
  216. Koivisto-Korander R, Scelo G, Ferro G et al: Second primary malignancies among women with uterine sarcoma. Gynecol Oncol 2012; 126: 30.
  217. Zelefsky MJ, Pei X, Teslova T et al: Secondary cancers after intensity-modulated radiotherapy, brachytherapy and radical prostatectomy for the treatment of prostate cancer: incidence and cause-specific survival outcomes according to the initial treatment intervention. BJU Int 2012; 110: 1696.
  218. Zietman AL, Coen JJ, Shipley WU et al: Adjuvant irradiation after radical prostatectomy for adenocarcinoma of prostate: analysis of freedom from PSA failure. Urology 1993; 42: 292.
  219. 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: 1245.
  220. Han M, Partin AW, Zahurak M et al: Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003; 169: 517.
  221. Mullins JK, Feng Z, Trock BJ et al: The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. J Urol 2012; 188: 2219.
  222. Albertsen PC, Hanley JA, Penson DF et al: Validation of increasing prostate specific antigen as a predictor of prostate cancer death after treatment of localized prostate cancer with surgery or radiation. J Urol 2004; 171: 2221.
  223. Amling CL, Bergstralh EJ, Blute ML et al: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001; 165: 1146.
  224. Pruthi RS, Haese A, Huland E et al: Use of serum concentration techniques to enhance early detection of recurrent prostate cancer after radical prostatectomy. Urology 1997; 49: 404.
  225. Malik RD, Goldberg JD, Hochman T et al: Three-year postoperative ultrasensitive prostate-specific antigen following open radical retropubic prostatectomy is a predictor for delayed biochemical recurrence. Eur Urol 2011; 60: 548.
  226. Sarno MJ and Davis CS: Robustness of ProsVue linear slope for prognostic identification of patients at reduced risk for prostate cancer recurrence: Simulation studies on effects of analytical imprecision and sampling time variation. Clin Biochem 2012; 45: 1479.
  227. Moul JW, Lilja H, Semmes OJ et al: NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. Urology 2012; 80: 1319.
  228. Swanson GP, Hussey MA, Tangen CM et al: Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007; 25: 2225.
  229. Shinghal R, Yemoto C, McNeal JE et al: Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy. Prostate-specific antigen. Urology 2003; 61: 380.
  230. Eisenberg ML, Davies BJ, Cooperberg MR et al: Prognostic implications of an undetectable ultrasensitive prostate-specific antigen level after radical prostatectomy. Eur Urol 2010; 57: 622.
  231. Chang SL, Freedland SJ, Terris MK et al: Freedom from a detectable ultrasensitive prostate-specific antigen at two years after radical prostatectomy predicts a favorable clinical outcome: analysis of the SEARCH database. Urology 2010; 75: 439.
  232. Reese AC, Fradet V, Whitson JM et al: Poor agreement of prostate specific antigen doubling times calculated using ultrasensitive versus standard prostate specific antigen values: important impact on risk assessment. J Urol 2011; 186: 2228.
  233. Abi-Aad AS, Macfarlane MT, Stein A et al: Detection of local recurrence after radical prostatectomy by prostate specific antigen and transrectal ultrasound. J Urol 1992; 147: 952.
  234. Casciani E, Polettini E, Carmenini E et al: Endorectal and dynamic contrast-enhanced MRI for detection of local recurrence after radical prostatectomy. AJR Am J Roentgenol 2008; 190: 1187.
  235. Scattoni V, Roscigno M, Raber M et al: Multiple vesico-urethral biopsies following radical prostatectomy: the predictive roles of TRUS, DRE, PSA and the pathological stage. Eur Urol 2003; 44: 407.
  236. Macfarlane MT, Abi-Aad A, Stein A et al: Neoadjuvant hormonal deprivation in patients with locally advanced prostate cancer. J Urol 1993; 150: 132.
  237. Drudi FM, Giovagnorio F, Carbone A et al: Transrectal colour Doppler contrast sonography in the diagnosis of local recurrence after radical prostatectomy--comparison with MRI. Ultraschall Med 2006; 27: 146.
  238. Foster LS, Jajodia P, Fournier G, Jr. et al: The value of prostate specific antigen and transrectal ultrasound guided biopsy in detecting prostatic fossa recurrences following radical prostatectomy. J Urol 1993; 149: 1024.
  239. Kapoor DA, Wasserman NF, Zhang G et al: Value of transrectal ultrasound in identifying local disease after radical prostatectomy. Urology 1993; 41: 594.
  240. Leventis AK, Shariat SF and Slawin KM: Local recurrence after radical prostatectomy: correlation of US features with prostatic fossa biopsy findings. Radiology 2001; 219: 432.
  241. Salomon CG, Flisak ME, Olson MC et al: Radical prostatectomy: transrectal sonographic evaluation to assess for local recurrence. Radiology 1993; 189: 713.
  242. Sudakoff GS, Smith R, Vogelzang NJ et al: Color Doppler imaging and transrectal sonography of the prostatic fossa after radical prostatectomy: early experience. AJR Am J Roentgenol 1996; 167: 883.
  243. Tamsel S, Killi R, Apaydin E et al: The potential value of power Doppler ultrasound imaging compared with grey-scale ultrasound findings in the diagnosis of local recurrence after radical prostatectomy. Clin Radiol 2006; 61: 325.
  244. Huch Boni RA, Meyenberger C, Pok Lundquist J et al: Value of endorectal coil versus body coil MRI for diagnosis of recurrent pelvic malignancies. Abdom Imaging 1996; 21: 345.
  245. Cirillo S, Petracchini M, Scotti L et al: Endorectal magnetic resonance imaging at 1.5 Tesla to assess local recurrence following radical prostatectomy using T2-weighted and contrast-enhanced imaging. Eur Radiol 2009; 19: 761.
  246. Sella T, Schwartz LH, Swindle PW et al: Suspected local recurrence after radical prostatectomy: endorectal coil MR imaging. Radiology 2004; 231: 379.
  247. Silverman JM and Krebs TL: MR imaging evaluation with a transrectal surface coil of local recurrence of prostatic cancer in men who have undergone radical prostatectomy. AJR Am J Roentgenol 1997; 168: 379.
  248. Albrecht S, Buchegger F, Soloviev D et al: (11)C-acetate PET in the early evaluation of prostate cancer recurrence. Eur J Nucl Med Mol Imaging 2007; 34: 185.
  249. Castellucci P, Fuccio C, Rubello D et al: Is there a role for (1)(1)C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml? Eur J Nucl Med Mol Imaging 2011; 38: 55.
  250. Reske SN, Blumstein NM and Glatting G: [11C]choline PET/CT imaging in occult local relapse of prostate cancer after radical prostatectomy. Eur J Nucl Med Mol Imaging 2008; 35: 9.
  251. Reske SN, Moritz S and Kull T: [11C]Choline-PET/CT for outcome prediction of salvage radiotherapy of local relapsing prostate carcinoma. Q J Nucl Med Mol Imaging 2012; 56: 430.
  252. Haseman MK, Reed NL and Rosenthal SA: Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen. Positron emission tomography and biopsy correlation. Clin Nucl Med 1996; 21: 704.
  253. Schoder H, Herrmann K, Gonen M et al: 2-[18F]fluoro-2-deoxyglucose positron emission tomography for the detection of disease in patients with prostate-specific antigen relapse after radical prostatectomy. Clin Cancer Res 2005; 11: 4761.
  254. Panebianco V, Sciarra A, Lisi D et al: Prostate cancer: 1HMRS-DCEMR at 3T versus [(18)F]choline PET/CT in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (RRP). Eur J Radiol 2012; 81: 700.
  255. Schillaci O, Calabria F, Tavolozza M et al: Influence of PSA, PSA velocity and PSA doubling time on contrast-enhanced 18F-choline PET/CT detection rate in patients with rising PSA after radical prostatectomy. Eur J Nucl Med Mol Imaging 2012; 39: 589.
  256. Boonsirikamchai P, Kaur H, Kuban DA et al: Use of maximum slope images generated from dynamic contrast-enhanced MRI to detect locally recurrent prostate carcinoma after prostatectomy: a practical approach. AJR Am J Roentgenol 2012; 198: W228.
  257. Sciarra A, Panebianco V, Salciccia S et al: Role of dynamic contrast-enhanced magnetic resonance (MR) imaging and proton MR spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. Eur Urol 2008; 54: 589.
  258. Rischke HC, Schafer AO, Nestle U et al: Detection of local recurrent prostate cancer after radical prostatectomy in terms of salvage radiotherapy using dynamic contrast enhanced-MRI without endorectal coil. Radiat Oncol 2012; 7: 185.
  259. Giannarini G, Nguyen DP, Thalmann GN et al: Diffusion-weighted magnetic resonance imaging detects local recurrence after radical prostatectomy: initial experience. Eur Urol 2012; 61: 616.
  260. Kramer S, Gorich J, Gottfried HW et al: Sensitivity of computed tomography in detecting local recurrence of prostatic carcinoma following radical prostatectomy. Br J Radiol 1997; 70: 995.
  261. Kahn D, Williams RD, Manyak MJ et al: 111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. The ProstaScint Study Group. J Urol 1998; 159: 2041.
  262. Koontz BF, Mouraviev V, Johnson JL et al: Use of local (111)in-capromab pendetide scan results to predict outcome after salvage radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2008; 71: 358.
  263. Texter JH, Jr. and Neal CE: The role of monoclonal antibody in the management of prostate adenocarcinoma. J Urol 1998; 160: 2393.
  264. Wilkinson S and Chodak G: The role of 111indium-capromab pendetide imaging for assessing biochemical failure after radical prostatectomy. J Urol 2004; 172: 133.
  265. Schettino CJ, Kramer EL, Noz ME et al: Impact of fusion of indium-111 capromab pendetide volume data sets with those from MRI or CT in patients with recurrent prostate cancer. AJR Am J Roentgenol 2004; 183: 519.
  266. Beresford MJ, Gillatt D, Benson RJ et al: A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence. Clin Oncol (R Coll Radiol) 2010; 22: 46.
  267. Martino P, Scattoni V, Galosi AB et al: Role of imaging and biopsy to assess local recurrence after definitive treatment for prostate carcinoma (surgery, radiotherapy, cryotherapy, HIFU). World J Urol 2011; 29: 595.
  268. Rinnab L, Mottaghy FM, Simon J et al: [11C]Choline PET/CT for targeted salvage lymph node dissection in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary results of a prospective study. Urol Int 2008; 81: 191.
  269. Scattoni V, Picchio M, Suardi N et al: Detection of lymph-node metastases with integrated [11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: results confirmed by open pelvic-retroperitoneal lymphadenectomy. Eur Urol 2007; 52: 423.
  270. Schilling D, Schlemmer HP, Wagner PH et al: Histological verification of 11C-choline-positron emission/computed tomography-positive lymph nodes in patients with biochemical failure after treatment for localized prostate cancer. BJU Int 2008; 102: 446.
  271. Winter A, Uphoff J, Henke RP et al: First results of [11C]choline PET/CT-guided secondary lymph node surgery in patients with PSA failure and single lymph node recurrence after radical retropubic prostatectomy. Urol Int 2010; 84: 418.
  272. Chang CH, Wu HC, Tsai JJ et al: Detecting metastatic pelvic lymph nodes by 18F-2-deoxyglucose positron emission tomography in patients with prostate-specific antigen relapse after treatment for localized prostate cancer. Urol Int 2003; 70: 311.
  273. Harisinghani MG, Barentsz J, Hahn PF et al: Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003; 348: 2491.
  274. Ross RW, Zietman AL, Xie W et al: Lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) identifies occult lymph node metastases in prostate cancer patients prior to salvage radiation therapy. Clin Imaging 2009; 33: 301.
  275. Meijer HJ, Debats OA, Roach M, 3rd et al: Magnetic resonance lymphography findings in patients with biochemical recurrence after prostatectomy and the relation with the Stephenson nomogram. Int J Radiat Oncol Biol Phys 2012; 84: 1186.
  276. Fortuin AS, Deserno WM, Meijer HJ et al: Value of PET/CT and MR lymphography in treatment of prostate cancer patients with lymph node metastases. Int J Radiat Oncol Biol Phys 2012; 84: 712.
  277. Even-Sapir E, Metser U, Mishani E et al: The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006; 47: 287.
  278. Kane CJ, Amling CL, Johnstone PA et al: Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 2003; 61: 607.
  279. Fuccio C, Castellucci P, Schiavina R et al: Role of 11C-choline PET/CT in the restaging of prostate cancer patients showing a single lesion on bone scintigraphy. Ann Nucl Med 2010; 24: 485.
  280. Fuccio C, Castellucci P, Schiavina R et al: Role of 11C-choline PET/CT in the re-staging of prostate cancer patients with biochemical relapse and negative results at bone scintigraphy. Eur J Radiol 2012; 81: e893.
  281. Luboldt W, Kufer R, Blumstein N et al: Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases. Radiology 2008; 249: 1017.
  282. Cher ML, Bianco FJ, Jr., Lam JS et al: Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol 1998; 160: 1387.
  283. Choueiri TK, Dreicer R, Paciorek A et al: A model that predicts the probability of positive imaging in prostate cancer cases with biochemical failure after initial definitive local therapy. J Urol 2008; 179: 906.
  284. Dotan ZA, Bianco FJ, Jr., Rabbani F et al: Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy. J Clin Oncol 2005; 23: 1962.
  285. Gomez P, Manoharan M, Kim SS et al: Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int 2004; 94: 299.
  286. Okotie OT, Aronson WJ, Wieder JA et al: Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. J Urol 2004; 171: 2260.
  287. Raj GV, Partin AW and Polascik TJ: Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer 2002; 94: 987.
  288. Jadvar H, Desai B, Ji L et al: Prospective evaluation of 18F-NaF and 18F-FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer. Clin Nucl Med 2012; 37: 637.
  289. Kotzerke J, Volkmer BG, Neumaier B et al: Carbon-11 acetate positron emission tomography can detect local recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2002; 29: 1380.
  290. Kwee SA, Coel MN and Lim J: Detection of recurrent prostate cancer with 18F-fluorocholine PET/CT in relation to PSA level at the time of imaging. Ann Nucl Med 2012; 26: 501.
  291. Sandblom G, Sorensen J, Lundin N et al: Positron emission tomography with C11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomy. Urology 2006; 67: 996.
  292. de Jong IJ, Pruim J, Elsinga PH et al: 11C-choline positron emission tomography for the evaluation after treatment of localized prostate cancer. Eur Urol 2003; 44: 32.
  293. Picchio M, Messa C, Landoni C et al: Value of [11C]choline-positron emission tomography for re-staging prostate cancer: a comparison with [18F]fluorodeoxyglucose-positron emission tomography. J Urol 2003; 169: 1337.
  294. Castellucci P, Fuccio C, Nanni C et al: Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med 2009; 50: 1394.
  295. Garcia JR, Soler M, Blanch MA et al: [PET/CT with (11)C-choline and (18)F-FDG in patients with elevated PSA after radical treatment of a prostate cancer]. Rev Esp Med Nucl 2009; 28: 95.
  296. Giovacchini G, Picchio M, Coradeschi E et al: Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging 2010; 37: 301.
  297. Richter JA, Rodriguez M, Rioja J et al: Dual tracer 11C-choline and FDG-PET in the diagnosis of biochemical prostate cancer relapse after radical treatment. Mol Imaging Biol 2010; 12: 210.
  298. Rinnab L, Mottaghy FM, Blumstein NM et al: Evaluation of [11C]-choline positron-emission/computed tomography in patients with increasing prostate-specific antigen levels after primary treatment for prostate cancer. BJU Int 2007; 100: 786.
  299. Rinnab L, Simon J, Hautmann RE et al: [(11)C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy. World J Urol 2009; 27: 619.
  300. Yoshida S, Nakagomi K, Goto S et al: 11C-choline positron emission tomography in prostate cancer: primary staging and recurrent site staging. Urol Int 2005; 74: 214.
  301. Seltzer MA, Barbaric Z, Belldegrun A et al: Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol 1999; 162: 1322.
  302. Pelosi E, Arena V, Skanjeti A et al: Role of whole-body 18F-choline PET/CT in disease detection in patients with biochemical relapse after radical treatment for prostate cancer. Radiol Med 2008; 113: 895.
  303. Cimitan M, Bortolus R, Morassut S et al: [18F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging 2006; 33: 1387.
  304. Heinisch M, Dirisamer A, Loidl W et al: Positron emission tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients: meaningful at PSA < 5 ng/ml? Mol Imaging Biol 2006; 8: 43.
  305. Husarik DB, Miralbell R, Dubs M et al: Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008; 35: 253.
  306. Proano JM, Sodee DB, Resnick MI et al: The impact of a negative (111)indium-capromab pendetide scan before salvage radiotherapy. J Urol 2006; 175: 1668.
  307. Mitchell CR, Lowe VJ, Rangel LJ et al: Operational characteristics of (11)c-choline positron emission tomography/computerized tomography for prostate cancer with biochemical recurrence after initial treatment. J Urol 2013; 189: 1308.
  308. Krause BJ, Souvatzoglou M, Tuncel M et al: The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008; 35: 18.
  309. Giovacchini G, Picchio M, Scattoni V et al: PSA doubling time for prediction of [(11)C]choline PET/CT findings in prostate cancer patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging 2010; 37: 1106.
  310. Breeuwsma AJ, Rybalov M, Leliveld AM et al: Correlation of [11C]choline PET-CT with time to treatment and disease-specific survival in men with recurrent prostate cancer after radical prostatectomy. Q J Nucl Med Mol Imaging 2012; 56: 440.
  311. King CR: The timing of salvage radiotherapy after radical prostatectomy: a systematic review. Int J Radiat Oncol Biol Phys 2012; 84: 104.
  312. Erho N, Crisan A, Vergara IA et al: Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013; 8: e66855.
  313. Karnes RJ, Bergstralh EJ, Davicioni E et al: Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol 2013; 190: 2047.
  314. Dalela D, Santiago-Jimenez M, Yousefi K et al: Genomic classifier augments the role of pathological features in identifying optimal candidates for adjuvant radiation therapy in patients with prostate cancer: development and internal validation of a multivariable prognostic model. J Clin Oncol 2017; 35: 1982.
  315. Nguyen PL, Haddad Z, Ross AE et al: Ability of a genomic classifier to predict metastasis and prostate cancer-specific mortality after radiation or surgery based on needle biopsy specimens. Eur Urol 2017; 72: 845.
  316. Den RB, Feng FY, Showalter TN et al: Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys 2014; 89: 1038.
  317. Den RB, Yousefi K, Trabulsi EJ et al: Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015; 33: 944.
  318. Ross AE, Den RB, Yousefi K et al: Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk. Prostate Cancer Prostatic Dis 2016; 19: 277.
  319. Freedland SJ, Choeurng V, Howard L et al: Utilization of a genomic classifier for prediction of metastasis following salvage radiation therapy after radical prostatectomy. Eur Urol 2016; 70: 588.
  320. Lobo JM, Stukenborg GJ, Trifiletti DM et al: Reconsidering adjuvant versus salvage radiation therapy for prostate cancer in the genomics era. J Comp Eff Res 2016; 5: 375.
  321. Dorff TB, Flaig TW, Tangen CM et al: Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol 2011; 29: 2040.
  322. Van der Kwast TH, Bolla M, Van Poppel H et al: Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007; 25: 4178.
  323. Ayala AG, Ro JY, Babaian R et al: The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma. Am J Surg Pathol 1989; 13: 21.
  324. Sakr WA, Wheeler TM, Blute M et al: Staging and reporting of prostate cancer--sampling of the radical prostatectomy specimen. Cancer 1996; 78: 366.

Abbreviations

3D-CRTThree-dimensional conformal radiotherapy
ARTAdjuvant radiotherapy
ASTROAmerican Society for Radiation Oncology
AUAAmerican Urological Association
bRFSBiochemical recurrence-free survival
cRFSClinical recurrence-free survival
CIConfidence interval
cPFSClinical progression-free survival
CSSCancer-specific survival
CTComputed tomography
CTCAECommon toxicity criteria adverse event
DCEDynamic contrast-enhanced
DREDigital rectal exam
DWEDiffusion weighted
EBRTExternal beam radiotherapy
EDErectile dysfunction
EORTCEuropean organization for research and treatment of cancer
EPE1Extraprostatic extension
GIGastrointestinal
GUGenitourinary
GyGray
HRHazard ratio
IMRTIntensity-modulated radiotherapy
mRFSMetastatic recurrence-free survival
mlMilliliter
MRIMagnetic resonance imaging
MRSIMagnetic resonance spectroscopic imaging
MRLMR lymphography
ngNonogram
NNTNumber needed to treat
OSOverall survival
PETPositron emission tomography
PSAProstatic specific antigen
PSADTPSA doubling time
QoLQuality of life
RADICALSRadiotherapy and androgen deprivation in combination after local surgery
RAVESRadiotherapy - adjuvant versus early salvage
RCTRandomized controlled trial
RFSRecurrence-free survival
RPRadical prostatectomy
RTRadiotherapy
RTOGRadiation therapy oncology group
SPECTSingle-photon emission computerized tomography
SRTSalvage radiotherapy
STIRShort T1 inversion recovery
SVISeminal vesicle invasion
SWOGSouthwest oncology group
TRUSTransrectal ultrasonography
UIUrinary incontinence
WHOWorld Health Organization

The Panel selected the term “EPE” (meaning extraprostatic extension) instead of “ECE” (meaning extracapsular extension) based on reports that the prostate lacks a true capsule and the term “extraprostatic extension” is more accurate.322-324

Disclaimer

This document was written by the Prostate Guidelines Panel of the America Society of Radiation Oncology and the American Urological Association Education and Research, Inc. Both the Guidelines Committee of ASTRO and the Practice Guidelines Committee (PGC) of the AUA selected the respective committee chair. Panel members were selected by the both panel chairs. Membership of the committee included urologists, radiation oncologists, and a medical oncologist, with specific expertise on this disorder. The mission of the committee was to develop recommendations that are analysis-based or consensus-based, depending on Panel processes and available data, for optimal clinical practices in the diagnosis and treatment of prostate cancer. Funding of the committee was provided by ASTRO and the AUA. Committee members received no remuneration for their work. Each member of the committee provides an ongoing conflict of interest disclosure to ASTRO and the AUA. While these guidelines do not necessarily establish the standard of care, ASTRO/AUA seek to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. As medical knowledge expands and technology advances, the guidelines will change. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. Furthermore, this Guideline should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment and propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient. For all these reasons, the guidelines do not pre-empt physician judgment in individual cases. Treating physicians must take into account variations in resources, and patient tolerances, needs, and preferences. Conformance with any clinical guideline does not guarantee a successful outcome. The guideline text may include information or recommendations about certain drug uses ('off label') that are not approved by the Food and Drug Administration (FDA), or about medications or substances not subject to the FDA approval process. ASTRO/AUA urge strict compliance with all government regulations and protocols for prescription and use of these substances. The physician is encouraged to carefully follow all available prescribing information about indications, contraindications, precautions and warnings. These guidelines and best practice statements are not intended to provide legal advice about use and misuse of these substances. ASTRO/AUA assume no liability for the information, conclusions, and findings contained in the Guideline. Although guidelines are intended to encourage best practices and potentially encompass available technologies with sufficient data as of close of the literature review, they are necessarily time-limited and are prepared on the basis of information available at the time the panel was conducting its research on this topic. Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices. For this reason, ASTRO/AUA does not regard technologies or management which are too new to be addressed by this Guideline as necessarily experimental or investigational. In addition, this Guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment are needed or are being explored. This Guideline presents scientific, health, and safety information and may to some extent reflect scientific or medical opinion. It is made available to ASTRO and AUA members, and to the public, for educational and informational purposes only. Any commercial use of any content in this Guideline without the prior written consent of ASTRO or AUA is strictly prohibited.

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