Christopher P. Evans, MD

PSA screening has enabled urologists to diagnose prostate cancer at an earlier stage. However, depending on the risk stratification used, up to one-third of newly diagnosed prostate cancer will be classified as high risk based on clinical and pathologic parameters, and are considered to be at higher risk for PSA failure, need for secondary therapy, metastatic progression, and death from systemic disease 

High-risk prostate Ca: Definitions, treatment guidelines

D’Amico et al listed the parameters for which different risk stratifications have been based, with high-risk prostate cancer having any of the following three parameters: PSA value >20 ng/mL, biopsy Gleason score 8–10, or clinical stage >T2c 

 Definitions for high-risk prostate cancer tend to vary depending on the consortium, and each consortium also indicates some differences in management guidelines (table 1).

Once a patient is classified with localized, high-risk disease, one may consider performing germline genetic testing and genetic counselling, given the 6% prevalence of inherited homologous recombination gene mutations in this subset of patients 

 Such information can help in considering cancer risk syndromes, assessing for personal risk of second cancers, primary and secondary treatment selection, and predicting risk of progression after local therapy and decreased overall survival.

Apalutamide prolongs time to mets in nmCRPC

The issue of radical prostatectomy (RP) versus radiation therapy (RT) for high-risk prostate cancer remains a matter of intense debate. The majority of men with high-risk prostate cancer tend to receive external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT), which is in fact the only Category 1 treatment recommendation by the National Comprehensive Cancer Network for this setting (

NCCN Clinical Practice Guidelines in Oncology/Prostate Cancer 

The guideline does note that RP with pelvic lymph node dissection (PLND) may be considered in young, healthier patients without tumor fixation to pelvic sidewall. Likewise, The United Kingdom National Institute for Health and Care Excellence (UK NICE) guidance indicates that men with high-risk localized prostate cancer should be offered a combination of radical radiotherapy and androgen deprivation therapy 

Both the American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology (AUA/ASTRO/SUO) and European Association of Urology-European Society for Radiotherapy & Oncology-International Society of Geriatric Oncology-EAU Section of Urological Research (EAU-ESTRO-SIOG-ESUR) guidelines list RP with PLND and EBRT with ADT as standard treatment options for high-risk prostate cancer 

RP as primary treatment for high-risk prostate Ca

The discrepancies in definitions for high-risk prostate cancer mirror the fact that it is a heterogeneous classification. A significant number will have a more aggressive course that will necessitate close follow-up and prompt administration of additional treatment, but a subset will also be potentially cured by surgery alone. Hence, each patient with high-risk prostate cancer should be apprised of the potential need for multimodal treatment.

T therapy safe in large prostate Ca series

The risk of clinical over-staging is constantly present, and men with high-risk disease tend to be triaged toward systemic treatment rather than surgery. It must be noted that the staging parameters used in prostate cancer are far from perfect, in that the digital rectal exam is fraught with inaccuracy, PSA is determined not only by cancer but by benign tissue and inflammation, among other causes, and pathologic downgrading in RP specimens occurs. Furthermore, the proportion of patients with extracapsular extension, seminal vesicle invasion, and lymph node metastasis among men with high-risk cancer was 35% to 71%, 10% to 33%, and 7% to 23%, respectively 

 This means that a significant number of men deemed not to be candidates for RP actually have organ-confined disease and therefore miss out on a potentially curative surgery.

Given the lack of large, randomized controlled trials to define the optimal treatment for high-risk prostate cancer, the best available information comes from a series of independent studies comparing RP and RT that corrected for selection bias and confounders using propensity score matching 

 Current available data utilized prostate cancer-specific mortality (CSM) and overall survival (OS) outcomes of surgery and RT, in cohorts ranging from 453 to 68,655 (table 2). After adjustment for known covariates, every study demonstrated improvement with surgery as primary therapy in CSM (HR: 0.64-3.2) and OS (HR: 1.5-1.71).

Other than the aforementioned OS and PCM superiority, the use of RP as primary treatment offers several other advantages. Surgery provides a specimen for more accurate pathologic scrutiny and staging, and can therefore be a driver in determining the need for additional treatment (ie, adjuvant radiation plus ADT). Up to 70% of patients can avoid ADT after surgery as primary treatment for high-risk prostate cancer, sparing patients of metabolic (diabetes, osteoporosis) and cardiovascular (arrhythmias, myocardial infarction) morbidities associated with exposure to hormonal therapy 

 In contrast, primary treatment with RT allows for fewer subsequent therapy options, usually limited to ADT as an adjuvant or salvage option.

Patients who received RT are also known to be at risk for urinary complications, including incontinence, urethral strictures, hematuria, and bladder irritative symptoms. They also have higher incidence of rectal morbidity, rectal or anal procedures, hospital admissions, and open surgical procedures 

 The well-established risk of second malignancies in the radiated field and the ill effects toward a person’s immunity and overall health are additional points against RT.

Finally, surgery can also improve the quality of life and provide symptom control in those with LUTS secondary to bladder outlet obstruction, gross hematuria, and renal function deterioration due to ureteral obstruction, among others.

While there is a trend for robotic surgery to be the preferred surgical approach for localized prostate cancer, some are reluctant to perform minimally invasive approaches for high-risk prostate cancer. With increasing experience with the da Vinci robot, more recent data are showing similar oncologic outcomes between open and robot-assisted laparoscopic radical prostatectomy (RALP) for high-risk disease, as well as comparable results in functional outcomes (potency and continence) and complication rates 

 The surgeon’s capability definitely is an important factor in eventual outcomes, and surgery (open or RALP) for high-risk prostate cancer may be better off done in high-volume centers.

The therapeutic benefit of lymph node dissection (LND) in prostate cancer is debatable, but for high-risk disease, a potential cancer-specific survival benefit has been shown, particularly when combined with ADT and RT for those with node-positive disease 

 Extended LND, which allows for removal of a higher number of lymph nodes for high-risk prostate cancer, is advised, with removal of obturator, external, and internal iliac nodes. However, patients must be informed of the risks, including increased blood loss, longer operative time, and risk of lymphocele formation, among others. 

One may consider performing nerve sparing even in high-risk prostate cancer, particularly in patients with organ-confined disease. The judicious use of frozen sections intraoperatively to aid in determining need for wider resections might be worthwhile. Sievert et al have provided insight that the neurovascular bundle in fact composed of several tracks in addition to the main posterolateral band 

 This therefore allows the possibility of “partial nerve sparing.” If one side has high suspicion for extraprostatic disease, unilateral nerve sparing is also feasible and might allow for better recovery of potency compared to non-nerve sparing.

Biomarker assay/mpMRI predict grade reclassification

Overall relapse rates, even with adjuvant and salvage therapies, are still considerable, probably due to occult systemic disease, radiation, and/or hormonal resistance. Neoadjuvant treatment is an attractive concept and has been a subject of research using chemotherapy or ADT, but none has so far translated to survival benefit, and therefore currently is not part of the management for high-risk prostate cancer. The RCT evaluating the benefit of docetaxel and leuprolide or goserelin in high-risk prostate cancer patients before RP (NCT00430183) is the only phase III trial available, although results at this point are not yet mature.

RT for high-risk prostate cancer is a viable option, particularly for older patients and those with significant comorbidities. However, the opportunity for complete pathologic analysis in surgical treatment allows for more precise staging and accurately directs those who will need adjuvant RT with ADT while sparing other patients from treatment-related morbidities in those not indicated to have such therapies. Tumor-related symptoms can also be addressed by surgery. Most importantly, the best evidence available at present indicates RP can provide superior CSM and OS over RT, and thus should be the primary treatment for high-risk prostate cancer, especially in young and healthy patients.

 is professor and chairman, department of urologic surgery, University of California, Davis.

Section Editor Christopher M. Gonzalez, MD, MBA,

 is professor and chair of the department of urology at Loyola University Chicago Stritch School of Medicine, Maywood, IL.

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