Editing Adjuvant and Salvage Radiotherapy After Prostatectomy (2019)

'''See [https://www.auanet.org/guidelines/guidelines/prostate-cancer-adjuvant-and-salvage-radiotherapy-guideline Original Guideline]'''

== Definitions ==

* '''<span style="color:#ff0000">Adjuvant radiotherapy (ART): administration of radiotherapy (RT) to post-radical prostatectomy (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)</span>'''
* '''<span style="color:#ff0000">Salvage radiotherapy (SRT): administration of RT to post-RP patients with PSA recurrence after surgery but no evidence of distant metastatic disease</span>'''
** '''<span style="color:#ff0000">Biochemical recurrence after surgery is defined as a detectable PSA level > 0.2 ng/mL with a second confirmatory level > 0.2 ng/mL.</span>'''
**'''<span style="color:#ff0000">Radiation for persistent post-prostatectomy PSA after RP is considered salvage[https://uroweb.org/guidelines/prostate-cancer/chapter/treatment], not adjuvant</span>'''
***'''<span style="color:#ff0000">Patients with adverse pathology detected at prostatectomy who have a persistent post-prostatectomy PSA level should be offered post-RP SRT</span>'''

== Advantages vs. Disadvantages ==

* '''ART'''
**'''Disadvantage'''
*** '''Overtreatment with ART:''' 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. SRT avoids overtreatment.
* '''SRT'''
**'''Disadvantage'''
***'''Delayed treatment with SRT:''' waiting to administer RT as a salvage therapy could be less effective, particularly in patients with high-risk disease, and could allow the progression to metastatic disease.
* '''At the time of guideline publication, no published trials comparing ART vs. SRT'''
**Observational studies suggest that ART patients generally have better outcomes compared to SRT patients. However, this is difficult to compare these groups that SRT studies focus only on patients who have already relapsed and the ART group has patients that were never destined to recur

== Pre-operative Counseling ==

* '''Patients who undergo RP for localized prostate cancer should be informed of the potential for adverse pathologic findings that increase risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery.'''
** '''The first PSA generally should be obtained 2-3 months post-RP'''
** Recurrence after RP is thought to result from residual subclinical disease in the operative site 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, extraprostatic extension, and higher Gleason scores'''
** Rates of recurrence in post-RP patients with adverse pathological features may be > 60% at 5 years post-RP

== Adjuvant Radiotherapy ==

=== Evidence ===

*'''3 RCTs (SWOG 8794, EORTC 22911, and ARO 96-02) randomized patients with adverse pathological features at prostatectomy to ART vs. observation'''
** '''See [[Prostate Cancer: Management of Locally Advanced Prostate Cancer|Management of Locally Advanced Prostate Cancer Notes]]'''
** '''All 3 trials have > 10 years follow-up'''
** '''All 3 trials documented significant improvements in biochemical RFS with use of ART.'''
*** The Panel notes that prevention of biochemical progression is an important clinical endpoint because biochemical progression may trigger salvage therapy (i.e., hormone therapy), with its associated toxicities (increased risks for osteoporosis, cardiovascular disease and other health problems with ADT) and QoL impact. In addition, patients with biochemical recurrence are more likely to manifest metastatic recurrence. Therapies for metastatic recurrence, such as hormone therapies, can also have profound QoL impact.
** The 2 RCTs that evaluated locoregional failure (SWOG 8794; EORTC 22911) demonstrated a reduction in locoregional failure with ART
** Both SWOG 8794 and EORTC 22911 reported statistically significant reductions in the use of subsequent salvage therapies with ART
** SWOG 8794 and EORTC 22911 demonstrated improved cPFS (defined as clinical or imaging evidence of recurrence or death but not including biochemical progression) with ART
** '''2 of the trials, SWOG 8794 and EORTC 22911, assessed metastatic recurrence and OS'''. '''Only SWOG 8794 demonstrated significantly improved metastatic recurrence-free survival and overall survival;''' ARO-96-02 and EORTC were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy
* '''Given the consistency of findings across trials regarding other clinically-important endpoints of reduced biochemical and locoregional failure, clinical progression, and the reduction in the need for initiation of salvage therapies in patients administered ART, the Panel concluded that patients with high-risk pathological features should be offered ART.'''

=== Benefits ===

* '''Patients with adverse pathologic findings should be informed that compared to RP only, ART:'''
** '''Reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer'''
** '''Impact on subsequent metastases and overall survival is less clear'''

=== Indications ===
*'''<span style="color:#ff0000">Should be offered to patients with adverse pathologic findings at prostatectomy (3):'''
*#'''<span style="color:#ff0000">Extraprostatic extension'''
*#'''<span style="color:#ff0000">Seminal vesicle invasion'''
*#'''<span style="color:#ff0000">Positive surgical margins'''
*'''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. RT).'''

=== Timing ===
*'''<span style="color:#ff0000">ART is usually administered within 4-6 months following RP, generally after the return of acceptable urinary control'''
** As sexual function can require 1-2 years before a full return of function is observed, '''return of erections is not a requirement before initiation of adjuvant radiation.'''

=== ADT ===
*'''The role of hormone therapy in addition to ART remains uncertain'''
** This will be addressed in the RADICALS trial

== Salvage Radiotherapy ==

* '''At the time of guideline publication, no RCTs directly comparing SRT to ART; evidence limited to observational studies'''
* '''Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastasis or death from prostate cancer. PSA monitoring after radical prostatectomy should be done regularly to enable early administration of salvage therapies if appropriate.'''
** Pound et al. were among the first to describe the time course of disease progression. They followed 1997 consecutive men undergoing RP at the Johns Hopkins Hospital and demonstrated that no man experienced either distant or local recurrence without also demonstrating a rising PSA level. Among 304 men who developed detectable PSA values following surgery, the median time to the development of metastases was 8 years. Men who developed metastatic disease usually died at median 5 years later. The median PSADT provided the most statistically significant prediction of time to distant progression. Men with a PSADT < 10 months usually developed metastases within 5 years of surgery, while men with a PSADT > 10 months developed metastases much later.
** '''Men with an increasing PSA after surgery are at risk for developing metastases and subsequently dying from their disease; this risk is particularly high among men with rapid PSADT.'''
* '''Biochemical recurrence is defined as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml.'''
** '''No evidence to suggest a threshold above which RT is ineffective'''
** Data from retrospective and prospective trials suggest that '''more favorable biochemical outcomes are associated with very low PSA values at the time RT is offered'''.
** A small percentage of patients may have detectable but stable PSAs for ≥10 years without evidence of clinical failure, which may reflect the presence of benign prostate glands in the surgical bed.
** Calculation of PSADT using data derived from ultra-sensitive assays may yield markedly different PSADT values compared to using data derived from higher-threshold assays; how these differences should be interpreted is unclear. Given the lack of evidence regarding the use of ultrasensitive PSA assays to guide care, the Panel judged that the use of the 0.2 ng/ml threshold value with a second confirmatory value to document recurrence is the optimal strategy currently.
* '''A restaging evaluation in the patient with a PSA recurrence may be considered'''
** '''In the patient with evidence of recurrence manifested as a detectable or rising PSA, determining the site of recurrence (local v. metastatic) may be relevant to select an appropriate salvage strategy.'''
** '''Local recurrence'''
*** '''Overall, MRI yielded the highest and most consistent sensitivities and specificities for the detection of local recurrence.'''
*** Other modalities (TRUS, DRE, PET/CT) exhibited excellent sensitivity but poor or variable specificity or vice versa.
** Recurrence in nodes
*** Insufficient data are available to recommend a specific technique
** '''Recurrence in bone'''
*** '''Yield of bone scan is extremely low in patients with PSA < 10 ng/ml;''' at PSA levels < 10 ng/ml, less than 5% of patients had a positive bone scan; given that most patients manifest biochemical failure at PSA values <1.0 ng/ml, the yield of bone scans will be low.
** Metastatic recurrence.
*** Definitive conclusions regarding the best imaging strategy to detect metastatic recurrence are not possible, but data suggest that 11C-choline PET/CT, 18FDG PET and 18FCH PET/CT are promising.
** Recurrence at all sites
*** 11C-choline PET/CT appears promising; the probability of a positive scan, however, may depend on PSA level and PSA dynamics
* '''SRT should be offered to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease'''
** SWOG 8794 and EORTC 22911 included a subgroup of patients who had detectable PSA levels post-RP patients that could be categorized as salvage patients. Salvage RT in these patients was associated with reduced metastatic recurrence and biochemical failure
** Some observational studies suggest a cancer-specific and overall survival benefit
* '''The effectiveness of SRT for PSA recurrence is greatest when given at lower levels of PSA'''
** '''No evidence to suggest a threshold above which RT is ineffective'''
** If recurrence is detected without evidence of distant metastases, SRT should be administered at the earliest sign of PSA recurrence and, ideally, before PSA rises to 1.0 ng/ml.
* '''Clinicians should offer hormone therapy to patients treated with SRT (postoperative PSA ≥0.2 ng/mL).''' Ongoing research may someday allow personalized selection of hormone or other therapies within patient subsets
** 2 RCTs (RTOG 9601175 and GETUG-AFU 16176) evaluated the effects of hormone therapy on OS, and on biochemical and clinical progression among patients who received SRT after prostatectomy. The type and duration of hormone therapy was different between trials. Both trials demonstrated improved PFS while RTOG 9601 also found improved OS.
** Based on findings from these 2 RCTs, the Panel recommends that clinicians offer hormone therapy to candidates for SRT, namely patients with postoperative PSA ≥0.2 ng/mL and no distant metastasis. There is insufficient evidence for such in patients with lower (<0.2 ng/mL) PSA levels. When offered, the clinician must provide information about potential benefits and harms
** Upcoming trials evaluating hormonal therapy: RTOG 0534 (SRT), RADICALS (ART and SRT)

== General ==

=== Adverse Events ===

*'''<span style="color:#ff0000">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.'''
** '''<span style="color:#ff0000">Acute toxicity'''
*** '''In the immediate post-RT period of 2-3 months, mild to moderate GU and GI effects that may require the use of medication for management have been frequently reported'''
*** '''Serious toxicity effects of RT, including those requiring aggressive medication management, outpatient procedures, or hospitalization, however, are uncommon or rare,''' with most studies reporting rates of ≤5% or less.
*** The lowest acute toxicity rates have been reported with use of IMRT RT techniques.
** '''<span style="color:#ff0000">Late toxicity'''
*** '''In contrast to acute toxicities, late toxicities may manifest cumulatively for several years post-RT and persist for many years.'''
*** Patients should be informed that, similar to acute toxicities, mild to moderate late toxicities occurring > 90 days post-RT are commonly reported. Serious late toxicities, however, are relatively uncommon
*** The most common symptoms are urinary frequency (14.6%) and bleeding (8.6%). Late GI toxic effects are less common
*** '''In a small proportion of patients, late toxicities that are moderate to major may emerge for up to 4-5 years post-RT and may persist beyond that point.''' '''These toxicities are more likely to include GU symptoms than to include GI symptoms'''
** '''<span style="color:#ff0000">Urinary incontinence'''
*** '''RT is unlikely to have a major impact on UI.'''
** '''<span style="color:#ff0000">Sexual function'''
*** '''The impact of RT on erectile function in men who have already had a prostatectomy is not clear'''
** '''<span style="color:#ff0000">Other complications include urethral stricture, proctitis, and bowel movement tenderness'''
** '''<span style="color:#ff0000">Secondary malignancies'''
*** The potential for developing secondary malignancies exists when postoperative RT is given, but that studies investigating the risk of developing secondary malignancies in men undergoing prostate cancer RT are conflicting.

=== Radiation Dose ===

*'''<span style="color:#ff0000">There is insufficient evidence to recommend which RT techniques and doses produce optimal outcomes in the adjuvant and salvage context'''
** '''<span style="color:#ff0000">64-65 Gy [recall, 76-80 Gy for localized prostate cancer) 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.

== Future trials ==

* '''RTOG 0534'''
** Objective: compare prostate bed +/- ADT +/- pelvic lymph node RT
** Population: 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
** Randomized to 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.
* '''RADICALS'''
** Addressing two critical questions in post-RP patients:
*** Comparative efficacy of the ART vs. SRT approach
*** Concurrent randomization addresses the question of the role of hormone therapy

== 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
* The present level of evidence cannot discern whether such genomic classifiers predict the efficacy, or lack thereof, of ART or SRT after prostatectomy.

== Questions ==

# What is the difference in timing between salvage and adjuvant radiation after radical prostatectomy?
# What is the definition of biochemical failure after radical prostatectomy?
# Which adverse pathological features on radical prostatectomy specimen would warrant consideration of adjuvant radiation? When should adjuvant radiation be offered, if used?
# As per the 2017 AUA Guidelines on Adjuvant and Salvage Radiotherapy after Prostatectomy, patients should be informed that which outcomes are improved after adjuvant radiation therapy?
# Who should be offered salvage radiotherapy following radical prostatectomy?
# What PSA threshold is considered ideal for consideration of salvage RT after radical prostatectomy?
# What is the minimum dose of radiation that should be administered in the post-radical prostatectomy setting?

== Answers ==

# What is the difference in timing between salvage and adjuvant radiation after radical prostatectomy?
#* Adjuvant: radiation given after prostatectomy when PSA is undetectable i.e. no evidence of recurrence
#* Salvage: radiation given after prostatectomy when PSA is detectable i.e. has evidence of recurrence
# What is the definition of biochemical failure after radical prostatectomy?
#* PSA ≥ 0.2ng/mL and confirmed on repeat testing
# Which adverse pathological features on radical prostatectomy specimen would warrant consideration of adjuvant radiation? When should adjuvant radiation be offered, if used?
#* Adverse features: extraprostatic extension, seminal vesicle invasion, positive margins
#* Adjuvant radiation should be offered after the patient has achieved continence, typically 4-6 months after RP
# As per the 2017 AUA Guidelines on Adjuvant and Salvage Radiotherapy after Prostatectomy, patients should be informed that which outcomes are improved after adjuvant radiation therapy?
## Biochemical-free survival
## Local recurrence
## Clinical progression
# Who should be offered salvage radiotherapy following radical prostatectomy?
#* Patients with PSA or local recurrence in the absence of distant metastasis should be offered salvage radiotherapy with ADT
# What PSA threshold is considered ideal for consideration of salvage RT after radical prostatectomy?
#* 0.2ng/mL
# What is the minimum dose of radiation that should be administered in the post-radical prostatectomy setting?
#* 64-65Gy