Adjuvant and Salvage Radiotherapy After Prostatectomy (2019)

See Original Guideline

Definitions

• Adjuvant radiotherapy (ART): administration of 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)
• Salvage radiotherapy (SRT): administration of RT to the prostatic bed and possibly to the surrounding tissues, including lymph nodes, in the patient with 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.

• Patients with adverse pathology detected at prostatectomy who have a persistent post-prostatectomy PSA level should be offered post-RP SRT (not technically adjuvant since no period without disease) [source?]

ART vs. SRT

• Advantages/disadvantages
  • 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.
  • 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.
    • 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
    • No published trials comparing ART to SRT
      • Pending publication: RADICALS
• [At the time of guideline publication,] insufficient evidence to determine superiority of ART vs. SRT

ART

• 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
• ART should be offered to patients with adverse pathologic findings (seminal vesicle invasion, positive surgical margins, or extraprostatic extension) at prostatectomy
  • 3 RCTs (SWOG 8794, EORTC 22911, and ARO 96-02) randomized patients with adverse pathological features at prostatectomy to ART vs. observation
    • See 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.
    • 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).
  • 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
  • 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.
  • The role of hormone therapy in addition to ART remains uncertain
    • This will be addressed in the RADICALS trial

SRT

• No RCTs directly comparing SRT to ART; evidence limited 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)