According to the European Association of Urology (EAU) guidelines, there are three possible options when biochemical recurrence occurs after surgery when PSA levels are between 0.2-0.5 ng/ml after surgery. The first option is administering “blind” early salvage radiotherapy. Another option is to wait for further PSA increase to perform PET/CT imaging and then decide on appropriate salvage treatment. The last possible option is to wait for a further PSA rise, and not to perform any imaging if the PSA progression is indolent.
The problem with PET PSMA imaging at very low PSA levels is the very low positivity rates of diagnosing a recurrence, ranging between 11.3-58.3% for PSA levels less than 0.2 ng/ml, and ranging between 11-61.5% for PSA levels less than 0.5 ng/ml. 1 The EAU guidelines clearly state that in the selection of candidates for salvage treatment, imaging is only to be performed if the outcome will influence the subsequent treatment decisions. The guidelines have a weak recommendation to perform PET PSMA scan if the PSA level is above one ng/ml. Additionally, the guidelines state that post-surgery patients with a rising PSA should receive radiotherapy. Another option is to offer active surveillance and delayed salvage radiotherapy to patients with biochemical recurrence and favorable prognostic factors (<pT3a, time to biochemical recurrence >three years, PSA doubling time > 12 months, Gleason score <=7, who may not benefit from intervention).
There is evidence supporting early salvage radiotherapy. This early treatment has been shown to be associated with a significant 3-fold increase in cancer-specific survival when compared to those who did not receive salvage treatment. 2 Salvage radiotherapy within two years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a PSA doubling time of fewer than six months. The importance of the PSA value at initial salvage radiotherapy is extremely high. The lower the PSA value, the lower the rate of the cumulative incidence rate of distant metastases, as depicted in Figure 1. Known predictors of cancer-specific mortality include pathological stage >=T3b, and Gleason score >=8. Patients with these risk factors and rising PSA postoperatively should receive early salvage radiotherapy. 3
Figure 1 – The importance of PSA values at initial salvage radiotherapy
Recently, a study was published on the use of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer. This 24-gene predictor was called PORTOS, and patients with a high PORTOS were shown to have lower rates of metastases with postoperative radiotherapy (while no difference was shown in low PORTOS). 4 Due to the lack of randomized controlled trials, there are several ongoing trials that will hopefully help us to answer several important questions. These include the dosage required for salvage radiotherapy (the SAKK 09/10 trial), the field required (RTOG trials), and whether early salvage is equal to adjuvant radiotherapy (the RADICALS, RAVES, and GETUG trials).
Whether androgen deprivation therapy (ADT) should be added to salvage radiotherapy is another important question that needs to be answered. The New England Journal of Medicine published a randomized controlled study by Shipley et al. in 2017 trying to answer this question.5 In this study 761 post-surgery patients with pT3N0 or pT2N0 R0/R1 who had developed elevated PSA levels from 0.2 ng/ml to 0.4 ng/ml (with 50% of the patients having a PSA > 0.7 ng/ml) were randomized to two groups. In one group radiotherapy and placebo were given, and in the second group radiotherapy and 24 months of 150 mg bicalutamide were given. A clear overall survival advantage was seen in the bicalutamide group with 108 vs. deaths, and a hazard ration of 0.77 (95% C.I. 0.59-0.99), p=0.04. Another relevant open-label multicenter phase 3 randomized controlled trial performed in 43 French centers was published in Lancet Oncology. In this trial, post-surgery patients with rising PSA were randomized to either standard salvage radiotherapy or to salvage radiotherapy plus short-term ADT (goserelin) on the first day of radiotherapy and three months later. Again, a clear advantage in progression-free survival was seen in the goserelin group, with a hazard ratio of 0.5 (95% C.I. 0.38-0.66), p=0.0001. 6 A retrospective multicenter study demonstrated that patients with more aggressive disease (pT3/4 and Gleason grade group 4-5 or pT3b/4 and PSA >=0.4 ng/ml) benefitted from concomitant ADT.
However, there is data demonstrating that early postoperative radiotherapy is associated with worse functional outcomes in patients with recurrent prostate cancer. It was shown that time from radical prostatectomy to radiotherapy had an important role in the recovery of erectile function and urinary incontinence. If given earlier, radiotherapy lowers the rate of functional recovery of these patients. 7
The next important topic discussed by Dr. Briganti was the performance of salvage radical prostatectomy after radiotherapy. The EAU guidelines state that the recommendation to treat highly selected patients with localized prostate cancer and a histologically proven local recurrence with radical salvage prostatectomy is weak. This should only be performed in highly experienced centers. Any kind of focal therapy should not be offered in this setting as it is still experimental. There are currently several mainly small retrospective series of radical salvage prostatectomy, making it difficult to appreciate the true benefit of this procedure. According to the EAU guidelines, salvage radical prostatectomy should be offered to patients with a life expectancy of at least ten years, patients with a biopsy grade group of 3 or less, no lymph node involvement or evidence of metastatic disease, and pre-radiotherapy clinical stage of T1-T2. The criteria result in significantly better outcomes for these patients. As can be expected, the side effect profile of this procedure is significantly worse than for that of primary radical prostatectomy. These include rectal injury in 0-15% of cases, anastomotic stricture in 0-41%, erectile dysfunction in 0-90.8% of cases, and urinary incontinence in 20-78.1% of cases. Lastly, Clavien grade 3-5 complications occur in 0-33% of cases. This can be done either with open surgery or with robotic surgery, demonstrating no difference in functional outcomes, but better perioperative outcomes.8 In any case, the EAU guidelines clearly state that the real efficacy of this salvage procedure remains unproven, as its impact on survival.
The last topic discussed was salvage lymph node dissection after radical prostatectomy with evident recurrence in the pelvic lymph nodes. There is currently no long-term data on this procedure, and it is difficult to finalize any conclusions regarding it.
Dr. Briganti summarized his great talk reiterating a few important points. Men that are potentially suitable for salvage curative treatment should not be treated with ADT. When indicated, salvage radiotherapy should be given at the earliest sign of disease recurrence (especially in men with adverse features at radical prostatectomy). When radical salvage prostatectomy is contemplated, it is important to properly counsel the patients regarding functional and oncological outcomes.
Presented by: Alberto Briganti, Milan, Italy
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2nd EAU Update on Prostate Cancer (PCa18)– September 14-15, 2018 – Milan, Italy
References:
1. De Visschere P et al. Eur Urol Oncology , 2018
2. Trock et al, JAMA, 23: 2760-9, 2008
3. Fossati N et al. Eur Urol, in press 2018
4. Zhao et al. Lancet Oncol, 17: 1612-20, 2016
5. Shipley e al. NEJM 2017; 376: 417-428
6. Carrie et al. Lancet Oncol 2016; 17:747-56
7. Zaffuto et al. J Urol 2017; 197:669-75
8. Gontero, et al. EAU 2017