For this Crossfire, let’s imagine a 62-year-old man with T2bN1M0 prostate cancer. He has 6/12 cores involved with Grade Group 4 prostate cancer and his PSA is 18 ng/mL. His 2 potentially metastatic right internal iliac lymph nodes on clinical staging were detected by G-68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/CT imaging. He is in excellent health and asymptomatic. The National Comprehensive Cancer Network guidelines (see Figure) state that multimodal therapy with external beam radiotherapy, androgen deprivation therapy (ADT) and abiraterone with prednisone is preferred. However, radical prostatectomy with pelvic lymphadenectomy is also an option in select patients. This approach would likely be an initial step in sequential, multimodal therapy.

In this Crossfire session, Drs Mack Roach and Jeffrey Michalski will address the role of radiotherapy as part of initial therapy in the face of stage cN1 prostate cancer. Randomized prospective data from STAMPEDE arm H show a benefit from the addition of radiation therapy (RT) to standard of care metastatic treatment in the setting of low-volume and cN+ prostate cancer for both progression-free survival and overall survival. This benefit was durable with longer, 5-year follow up subsequently reported.² They will argue that if this patient has a radical prostatectomy, he will require RT afterwards, with no evidence that both are required for the optimal outcome. In their view, there are other lymph nodes potentially harboring metastatic disease that is not appreciated on PSMA PET, but easily and comprehensively covered with intensity modulated RT. There is level I evidence that prophylactic pelvic RT improves PSA control when combined with hormonal therapy (RTOG 9413, POP-RT Trial, RTOG 5034) with low to modest impact on quality of life. Tangential to the role of RT to the primary is the effectiveness of stereotactic body radiation therapy for oligometastases demonstrated in multiple randomized controlled trials (ORIOLE; STAMPEDE; SABR-COMET). Our radiation oncology experts will argue that surgery as initial treatment provides pathology, but really that’s all.

Drs Pow-Sang and Chapin will represent the position for radical prostatectomy as initial treatment. They acknowledge that this case presents both diagnostic and decision making challenges. The incorporation of PSMA PET/CT into clinical practice has led to a newer definition of clinical lymph node–positive disease and resulted in stage migration.³ While this imaging modality has improved staging accuracy in prostate cancer, there are several challenges with differences in tracers used, technique, and expert interpretation. Nevertheless, expert interpretation yields high positive and negative predictive values with positive predictive value ranges of 78.1%-90.5% and negative predictive value ranges of 81.4%-83%.⁴

Prior to the advent of PSMA PET imaging the available, albeit retrospective data, supported completion radical prostatectomy (or RT) in the setting of pathologic nodes, whether on frozen section or final pathology.⁵ The inherent selection bias makes interpretation of those data challenging; however the recommendation has been not to abort surgery in the pathologic node positive setting due to the associated improved survival in patients completing their radical therapy.⁶ A recent Phase II randomized study by Dai and colleagues compared ADT alone to ADT plus surgery or RT in men with oligometastatic prostate cancer defined as 5 or fewer bone or extrapelvic lymph node metastases and no visceral metastases.⁷ There were 100 patients in each group, and in the study group 85 men received surgery and 11 received RT. After a median follow-up of 48 months, the median radiographic progression-free survival was not reached in the study group and was 40 months in the control group (hazard ratio 0.43, 95% confidence interval 0.27-0.70; P = .001). The 3-year overall survival rate was 88% for the study group and 70% for the control group (HR 0.44, 95% CI 0.24-0.81; P = .008). This small trial with surgery as the predominant local therapy is suggestive of a radiographic progression-free survival and overall survival benefit.

It is postulated that men who may benefit the most from surgery are the ones with low-volume primary tumor and with no more than 2 positive lymph nodes on pathologic evaluation, with a life expectancy greater than 10 years and in excellent health without a contraindication for surgery. Benefits of surgery include more precise staging with better determination of lymph node status and an excellent prevention of local symptomatic progression. In addition, the definitive pathology information from the prostatectomy regarding surgical margins, seminal vesicle, and lymph node status, as well as the postoperative PSA nadir, allows for better prognostication and a more personalized approach in patients who might benefit with treatment intensification with RT +/− hormones. Current commercial genomic profiling, while inadequate for prediction of therapy response, may be of more use with subsequent generations. Hormonal therapy might be selectively added after surgery based on the definitive pathology findings and subsequent PSA kinetics.

In the absence of randomized trials comparing surgery with RT, decision-making should include discussion of specific cases in a multidisciplinary tumor board and shared decision-making with the patient, understanding the available evidence, oncologic benefits, and potential side effect/risks attributed to either treatment.