Adjuvant and Salvage Radiotherapy After Prostatectomy: AUA/ASTRO Guideline

You have accessJournal of UrologyAUA Guideline1 Aug 2013Adjuvant and Salvage Radiotherapy After Prostatectomy: AUA/ASTRO Guidelineis companion ofAdjuvant Versus Salvage Post-Prostatectomy Radiation Therapy: A Critical Review of the Evidence Ian M. Thompson, Richard K. Valicenti, Peter Albertsen, Brian J. Davis, S. Larry Goldenberg, Carol Hahn, Eric Klein, Jeff Michalski, Mack Roach, Oliver Sartor, J. Stuart Wolf, and Martha M. Faraday Ian M. ThompsonIan M. Thompson , Richard K. ValicentiRichard K. Valicenti , Peter AlbertsenPeter Albertsen , Brian J. DavisBrian J. Davis , S. Larry GoldenbergS. Larry Goldenberg , Carol HahnCarol Hahn , Eric KleinEric Klein , Jeff MichalskiJeff Michalski , Mack RoachMack Roach , Oliver SartorOliver Sartor , J. Stuart WolfJ. Stuart Wolf , and Martha M. FaradayMartha M. Faraday View All Author Informationhttps://doi.org/10.1016/j.juro.2013.05.032AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: The purpose of this guideline is to provide a clinical framework for the use of radiotherapy after radical prostatectomy as adjuvant or salvage therapy. Materials and Methods: A systematic literature review using the PubMed®, Embase, and Cochrane databases was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. Results: Guideline statements are provided for patient counseling, the use of radiotherapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a re-staging evaluation. Conclusions: Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiotherapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiotherapy as well as the potential benefits of preventing recurrence. The decision to administer radiotherapy should be made by the patient and the multi-disciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. Please visit the ASTRO and AUA websites ( http://www.redjournal.org/webfiles/images/journals/rob/RAP%20Guideline.pdf and http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm) to view this guideline in its entirety, including the full literature review. Introduction The purpose of this guideline is to provide direction to clinicians and patients regarding the use of radiotherapy after prostatectomy as adjuvant or salvage therapy. Methodology A systematic review identified articles relevant to the use of RT after prostatectomy as adjuvant or salvage therapy. Literature searches were performed using the PubMed, Embase and Cochrane databases from 1/1/1990 to 12/15/2012. The review yielded an evidence base of 294 articles. The AUA nomenclature system links statement type to body of evidence strength and the Panel's judgment regarding the balance between benefits and risks/burdens. For discussion of this system, see the unabridged guideline. Limitations of the Literature Limitations of the literature included few randomized controlled trials; lack of group equivalence in pathological risk factors in observational studies; variability in PSA assay sensitivity and failure criteria; heterogeneity of radiation dose and methods; 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 and overall survival. In addition, few studies focused on important quality of life outcomes such as voiding and erectile function. Background Prevalence In 2012, an estimated 241,740 men were diagnosed with prostate cancer.1 In approximately two-thirds of men, radical prostatectomy constitutes a cure but within 10 years up to one-third of patients manifest recurrent disease.2–5 Recurrence risk is greater among men with adverse pathology such as positive surgical margins, seminal vesicle invasion, extraprostatic extension and higher Gleason scores.6–12 Definitions Adjuvant radiotherapy is the administration of radiotherapy post-prostatectomy to patients at a higher risk of recurrence because of adverse pathological features prior to evidence of disease recurrence (i.e., with an undetectable PSA). Salvage radiotherapy is the administration of radiotherapy 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 (PSA) recurrence after surgery is defined as a detectable PSA level >0.2 ng/ml with a second confirmatory level >0.2 ng/ml. Adjuvant radiotherapy The highest quality evidence that addresses the use of radiotherapy after prostatectomy is provided by three RCTs that examined the effect of radiotherapy delivered primarily as ART. A pressing clinical question is whether it is better post-RP to administer RT adjuvantly (before recurrence) or as a salvage therapy (after recurrence). The use of ART involves irradiation of some patients who never would have had recurrent cancer, exposing them unnecessarily to RT side effects. Administering RT as a salvage therapy limits its use to patients with recurrence but, particularly in patients with high-risk disease, could allow progression to metastatic disease. The Panel attempted to address this issue by examining the observational studies that reported outcomes for ART and SRT patients. These studies lack randomization and differ in patient characteristics, RT protocols, failure definitions, and follow-up durations. In addition, most of the published literature reports findings from the use of older RT techniques (e.g., EBRT), making it unclear whether newer techniques might result in fewer apparent differences between ART and SRT outcomes. Overall, the existing literature cannot answer this question. Radiotherapy techniques The Panel attempted to determine which radiotherapy techniques and doses produced optimal outcomes in the adjuvant and salvage contexts. It was not possible to answer these questions from the available data. Specifically, approximately one-third of the ART and SRT observational studies treated patients with conventional external beam modalities which have since been replaced by three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. The published literature does not reflect implementation of these newer methods, with only one-quarter of the reviewed studies reporting use of 3D-CRT techniques and less than five percent reporting use of IMRT techniques. With regard to the RCTs of ART, SWOG 8794 and EORTC 22911 administered RT using EBRT techniques,13,14 and ARO 96-02 administered RT using 3D-CRT.15 The lack of studies using newer RT methods made it difficult to definitively address the question of optimal methods and whether these might differ in the adjuvant vs. salvage contexts. Among observational studies, RT doses ranged from 50–78 Gy; SRT studies administered somewhat higher dosages than ART studies. Although RT dose-escalation improves freedom from biochemical relapse when used as primary treatment for localized prostate cancer, the optimal post-prostatectomy radiation dose has never been tested. Clinical data suggest that doses above 65 Gy can be safely delivered and may lead to improved tumor control.16–20 In the three RCTs, the majority of patients were treated with 60 Gy. In the Panel's view, 64–65 Gy is the minimum dose that should be delivered post-RP but decisions regarding dose should be made by the treating physician who has full knowledge of the patient's functional status, history and toxicity tolerance. The Panel notes that there is controversy regarding RT targets and field size.21–24 A key question is whether, when, for how long and in what form androgen-deprivation therapy (ADT) should be administered. The literature review attempted to address these questions by examining studies that focused on the use of ADT in patients who underwent prostatectomy and then ART or SRT. The Panel's conclusion was that, given the methodological weaknesses of this literature, it is not possible to provide guidance regarding the use of ADT in conjunction with RT. These weaknesses include non-randomized study designs; small sample sizes and lack of statistical power; lack of group equivalence on pathological risk factors; large differences in ADT protocols, including when it was administered and for how long; primary focus on biochemical recurrence; and other differences relevant to efficacy such as differences in RT techniques, targets and total Gy administered. Randomized controlled trials are needed to provide definitive evidence. Guidelines Statements 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) Patients should be counseled before RP that certain pathology findings are associated with higher risks for cancer recurrence. These findings include positive surgical margins, SVI and EPE. Recurrence rates in post-RP patients with adverse pathology may be greater than 60% at 5 years. Two RCTs with more than 10 years of follow-up reported recurrence rates of >60% in high-risk patients who had RP only.25,26 Patients also should be informed that if adverse pathology is detected, then additional therapy after surgery, such as radiotherapy, may be beneficial. 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 (PSA) 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 two randomized controlled trials that addressed these outcomes indicated a benefit but the other trial did not demonstrate a benefit. (Clinical Principle) Patients should be counseled that high-quality evidence indicates that use of ART in patients with adverse pathology reduces the risk of biochemical recurrence, local recurrence, and clinical cancer progression. Patients should be informed that the impact of ART on metastases and overall survival is less clear, with benefits reported in one of two trials with long-term data on these outcomes. 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) The Panel notes that the apparent benefits associated with ART are partially the result of a patient subset treated who never would have presented with recurrence. The Panel emphasizes that ART should be offered to all patients at high recurrence risk because of adverse pathology. By “offered”, the Panel means that the patient, his family and the multi-disciplinary treatment team should engage in a shared decision-making process in which the patient is advised to consider the possibility of additional treatment (i.e. radiotherapy). Whether ART should be administered is a decision best made by the multidisciplinary treatment team and the patient with consideration of the patient's history, functional status, values, preferences and tolerance for the potential toxicities and QoL effects of radiotherapy. Three RCTs (SWOG 8794, EORTC 22911 and ARO 96-02), two with more than 10 years of follow-up, evaluated the effects of ART among patients with adverse pathology13,15,25,26 All trials documented significant improvements in biochemical recurrence-free survival with use of ART compared to RP only (see figure). Two RCTs evaluated locoregional failure (SWOG 8794, EORTC 22911) and reported failure reductions in ART compared to RP only patients (EORTC 22911: ART 8.4%, RP only 17.3%, p <0.05; SWOG 8794: ART 8%, RP only 22%, no p value reported). Meta-analysis of biochemical recurrence data from SWOG 8794,26 EORTC 2291125 and ARO 96–0215 SWOG 8794 and EORTC 22911 also reported statistically significant reductions in salvage therapy use with ART compared to RP only. SWOG 8794 reported improvement in hormonal therapy-free survival in ART patients (84%) compared to RP only patients (66%). EORTC 22911 reported that fewer ART patients (21.8%) had started an active salvage treatment (including salvage radiotherapy or ADT) compared to RP only patients (47.5%). SWOG 8794 and EORTC 22911 also demonstrated improved clinical progression-free survival (defined as clinical or imaging evidence of recurrence or death but not including biochemical progression) in ART compared to RP only patients. This difference was statistically significant in SWOG 8794 and borderline significant (p = 0.054) in EORTC 22911. Prevention of biochemical progression and prevention of locoregional recurrence are important clinical endpoints because these events may trigger salvage therapy with associated toxicities and quality of life impact, and are predictive of metastatic progression. Improved clinical progression-free survival is an important endpoint because it reflects lower rates of local and distant failure and lower death rates. Reduction in salvage therapy initiation is another important clinical endpoint because of the avoidance of the negative consequences of these therapies. SWOG 8794 and EORTC 22911 assessed metastatic recurrence and overall survival. SWOG 8794, but not EORTC 22911, demonstrated significantly improved metastatic recurrence-free survival (43.5% for ART patients, 54% for RP only patients) and overall survival (74% in ART patients, 66% in RP only patients) at more than 12 years of follow-up.26 Only SWOG 8794, however, was designed and powered to test these outcomes. Therefore, it should be emphasized to patients that there is less certainty regarding benefits of ART to prevent metastatic recurrence and improve overall survival. The Panel also notes that RT should be offered to patients with adverse pathology with a persistent detectable post-prostatectomy PSA level. This is a salvage context for RT; SWOG 8794 and EORTC 22911 enrolled some patients with detectable PSA in the early post-RP period (<8 weeks). EORTC 22911 reported that RT improved biochemical recurrence-free point estimates similarly in patients with undetectable post-RP PSA levels (<0.2 ng/ml) and with detectable post-RP PSA levels (≥0.2 ng/ml).25 SWOG 8794 reported that RT improved metastases-free survival point estimates similarly in patients with undetectable (<0.2 ng/ml) and detectable (≥0.2 ng/ml) post-RP PSA.26 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) Prostate specific antigen levels post-RP should be undetectable. An increasing PSA level suggests the presence of residual disease and frequently heralds metastases development and death from prostate cancer. This risk is particularly high among men with rapid PSA doubling times. Half of all men with PSA values doubling faster than every 10 to 12 months after surgery are dead from their disease within 10 to 13 years.12,27 Patients should be informed of the relationship between PSA recurrence and the probability of metastatic recurrence and death from prostate cancer. 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) Most studies assessing the efficacy of RP used a PSA threshold of 0.2 ng/ml to define recurrence. Many ART and SRT studies, including the three RCTs, also used a PSA threshold of 0.2 ng/ml to define recurrence. This definition is consistent with the Prostate-Specific Antigen Best Practice Statement: 2009 Update of the AUA ( http://www.auanet.org/content/media/psa09.pdf). Patients who have had a prostatectomy should be informed that a PSA value ≥0.2 ng/ml that has been confirmed by a second elevated PSA value constitutes evidence of a recurrence. Detection of biochemical recurrence necessitates a thorough discussion of salvage therapies and is sufficient to trigger salvage therapy administration. Data suggest that more favorable biochemical outcomes are associated with very low PSA values at the time radiotherapy is offered.28 The salvage literature also generally reports that patients who receive radiotherapy at lower PSA levels have better outcomes than do patients who receive radiotherapy at higher PSA levels. However, a small percentage of patients (8.8% of patients with biochemical recurrence) may have detectable but stable PSAs for 10 years or more without evidence of clinical failure.29 Therefore, the decision to initiate salvage therapies is best made by the clinician who has full knowledge of the patient's pathology findings, risk factors, family history, preferences and values in consultation with that patient and with full discussion of potential treatment benefits and risks. In the era of ultrasensitive PSA assays, a detectable PSA that is confirmed and rising may be an appropriate trigger for salvage therapy, particularly in patients who are at high risk for recurrence and/or who have other evidence of potential progression. 6. A re-staging evaluation in the patient with a PSA recurrence may be considered. (Option; Evidence Strength: Grade C) In the patient with evidence of PSA recurrence, determining the site of recurrence (local vs. metastatic) may be relevant to select an appropriate salvage strategy. Clinicians should be aware that the yield of some modalities (e.g. bone scan) is extremely low in patients with PSA values below 10 ng/ml.30 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) Two of the RCTs included a patient subgroup that had detectable PSA levels post-RP, i.e. salvage patients. In SWOG 8794, RT significantly reduced metastatic recurrence rates among patients with detectable PSA post-RP.26 In EORTC 22911, RT significantly reduced rates of biochemical failure among patients with detectable PSA post-RP; rates of clinical progression were lower among this group than among patients with detectable PSA post-RP who were observed but the difference was not significant (HR = 0.75, 95% CI 0.52–1.08).25 Two observational studies reported outcomes for SRT patients vs. RP-only patients with detectable PSA or local recurrence. At median 11.5 years post-RP, SRT significantly reduced local recurrence risk (by almost 90%) and systemic progression (by 75%), and delayed the need for ADT administration; these differences were present even after controlling for group differences in clinical and pathological features.31 No overall survival difference was documented, however. At median 9 years post-RP, 22% of men who received no salvage therapy had died of prostate cancer, a significantly higher rate than men who had SRT (11% deaths from prostate cancer).32 This survival advantage was most marked in certain clinical subgroups (see complete guideline). In the context of administering SRT, many observational studies have reported that patients in certain high-risk groups have poorer outcomes than patients without these risk factors or in lower risk groups. These studies focused primarily on bRFS. Generally, although all comparisons were not statistically significant, studies indicate that poorer bRFS is present in patients with higher Gleason scores, higher pT stages, with SVI and with EPE compared to lower risk subgroups. Many considerations are important in the decision to administer SRT. As PSA recurrence may be noted years after RP, patients with limited life expectancy and a low or slowly increasing PSA may have limited benefit from SRT. Other considerations may include sexual, gastrointestinal or urinary function at the time of biochemical recurrence. 8. Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA. (Clinical Principle) The overwhelming majority of observational studies that compared bRFS for SRT patients at lower vs. higher pre-RT PSA levels reported that patients with lower pre-RT PSA levels had higher bRFS rates compared to patients with higher pre-RT PSA levels (differences not always statistically significant). The relevance of pre-SRT PSA level was confirmed by a recent systematic review.33 These authors reported that PSA level before SRT was significantly associated with relapse-free survival with an average 2.6% loss of relapse-free survival for each 0.1 ng/ml PSA increment at the time of SRT. In addition, a meta-regression performed on a selected group of SRT studies indicated that pre-RT PSA levels were significantly associated with 5-year progression-free survival levels such that progression-free survival rates dropped by 18.1% for every 1 ng/ml increase in pre-RT PSA.34 Confirmatory subgroup analyses from SWOG 8794 indicate that among patients with detectable PSA at the time of radiotherapy, those with PSA values ≤1.0 ng/ml had higher 5 and 10-year bRFS rates than those with pre-RT PSA values >1.0 ng/ml.28 Therefore, patients should be advised that if recurrence is detected without evidence of distant metastases, then radiotherapy should be administered at the earliest sign of PSA recurrence. 9. 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) Patient counseling regarding the potential toxicity and quality of life impact of radiotherapy is important to ensure that patients make informed treatment decisions and have appropriate expectations regarding the course and consequences of radiotherapy. Counseling should note that the evidence base for RT toxicity and QoL effects is based mostly on reports using older RT techniques; newer techniques appear to have lower toxicity. The most commonly used measures to report toxicity information were the Radiation Therapy Oncology Group measure for acute effects (through day 90), the RTOG/European Organization for Research and Treatment of Cancer measure for late RT effects (persisting beyond day 90 or developing after day 90) and the Common Toxicity Criteria Adverse Event measure using the same time frames. These measures use a rating system of 0 to 5: 0—no change in function, 1—minor change in function, 2—moderate change in function that may require medication, 3—major change in function sufficient to require more aggressive medication use or outpatient procedures, 4—severe symptoms requiring hospitalization and surgical procedures, and 5—death. Acute Toxicity (table 1) Patients should be informed that during radiotherapy and in the immediate post-RT period of 2–3 months, mild to moderate genitourinary and gastrointestinal effects that may require the use of medication for management have been frequently reported, with over 90% of patients experiencing these effects in some studies. Serious toxicity effects of radiotherapy, including those requiring aggressive medication management, outpatient procedures, or hospitalization, however, are uncommon or rare, with most studies reporting rates of <5%. The lowest acute toxicity rates have been reported with use of IMRT radiotherapy techniques.35,36 Table 1. Acute toxicity effects of radiotherapy after prostatectomy Study arm type % Genitourinary % Gastrointestinal Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Adjuvant 10.5–26 2.0–8.0 22.0–25.0 0.0–2.0 Salvage 3.0–82.0 0.0–6.0 2.9–96.0 0.0–2.2 Mixed 5.0–92.0 0.0–3.0 4.3–87.0 0.0–1.3 Ranges based on RTOG or CTCAE grading systems. Late Toxicity (table 2) Patients should be informed that mild to moderate late toxicities occurring more than 90 days post-RT are commonly reported with some studies reporting rates as high as 79%. Serious late toxicities, however, are relatively uncommon, with most studies reporting rates of 10% or less. Patients also should be told that in a small proportion of patients, late toxicities that are moderate to major may emerge for four to five years post-RT and may persist beyond that point. These toxicities are more likely to include GU symptoms (up to 28% of patients)37 than to include GI symptoms (up to 10.2% of patients).36 The use of newer RT techniques such as IMRT, however, is associated with lower cumulative rates of late GU (up to 16.8% of patients) and GI (4.0% of patients) toxicities.36 Table 2. Late toxicity effects of radiotherapy after prostatectomy Study arm type % Genitourinary % Gastrointestinal Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Adjuvant 2.0–22.0 0.0–10.6 1.0–12.7 0.0–6.7 Salvage 1.0–49.0 0.0–6.0 0.0–66.0 0.0–18.0 Mixed 1.3–79.0 0.0–17.0 2.0–59.0 0.0–4.3 Ranges based on RTOG/EORTC or CTCAE grading systems. Urinary Incontinence Patients should be informed that rates and severity of urinary incontinence in patients who have had RP and then adjuvant RT are generally similar to rates for patients who have had RP only. Sexual Function Patients with intact erectile function post-RP should be informed that the impact of RT on erectile function in men who are post-RP is not clear; studies indicate that the majority of men who present for RT post-RP already have compromised erectile function. Adjuvant RT may reduce the need for salvage therapies. Patients should be informed that the use of ART, because it is associated with improved bRFS compared to RP only, is likely to reduce the need for subsequent salvage therapies. Secondary Malignancies Clinicians should advise patients that the potential for developing secondary malignancies exists when radiotherapy is given, but that studies investigating the risk of developing secondary malignancies in post-RP men undergoing prostate cancer radiotherapy are inconclusive. Future Directions Ongoing Clinical Trials Ongoing clinical trials (e.g. RTOG 0534, RTOG 9601, RADICALS, RAVES) will help to clarify the role of ART or SRT and the value of combining RT with other therapies, and potentially make clear which patients are more likely to benefit from specific therapeutic approaches. Improved Imaging Techniques Patients with high-volume, high-grade disease with negative staging studies are most likely to exhibit an immediate PSA relapse, demonstrating preexisting extraprostatic disease at the time of treatment. Another challenging class of patients is those who have locally extraprostatic disease or microscopic nodal disease. Improved imaging techniques would help to better define appropriate therapies. Prognostic Biomarkers Prognostic biomarkers are greatly needed. In SWOG 8794, the only RCT finding a survival benefit to ART