Radical prostatectomy in high-risk prostate cancer

Authors


Correspondence: Martin Gleave M.D., F.R.C.S.C., F.A.C.S., Vancouver Prostate Centre, Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre, 6th Floor, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada. Email: m.gleave@ubc.ca

Abstract

One consistent finding in the studies regarding treating men with prostate cancer is that men with high-risk disease have the most to gain from treatment with curative intent. Men with high-risk or locally-advanced prostate cancer require treatment to the primary cancer or risk dying prematurely from their disease. Increasingly, combined androgen deprivation therapy + radiation treatment is seen as the standard treatment as a result of prospective studies in this space, and the perceived increased morbidity of radical prostatectomy in the setting of a “low” cure rate as monotherapy. In the absence of a well-conducted randomized trial, there is no definite evidence that one treatment is superior to the other. The advantages of radical prostatectomy are that it provides excellent local control of the primary tumor without an increase in morbidity, accurately stages the disease to guide further therapy, and removes benign sources of prostate-specific antigen so that failures can be promptly identified and subsequent treatment can be initiated in a timely manner. Although several guidelines recommend radiation treatment over radical prostatectomy as first-line treatment, there is no evidence that surgery is inferior and radical prostatectomy should remain part of any informed discussion regarding treatment options for men with high-risk prostate cancer.

Abbreviations & Acronyms
ADT

androgen deprivation therapy

AUA

American Urological Association

BPFS

biochemical progression free survival

CAPRA

Cancer of the Prostate Risk Assessment

CaPSURE

Cancer of the Prostate Strategic Urologic Research Endeavor

CSS

cancer-specific survival

EBRT

external beam radiation treatment

EAU

European Association of Urology

HIFU

high-intensity focused ultrasound

IMRT

intensity-modulated radiation treatment

OS

overall survival

PIVOT

Prostate Intervention Versus Observation Trial

PLND

pelvic lymph node dissection

PSA

prostate-specific antigen

RP

radical prostatectomy

RT

radiation treatment

SEER

Surveillance, Epidemiology and End Results

SPCG-4

Scandinavian Prostate Cancer Group-4

Introduction

Men with high-risk prostate cancer appear to lack informed discussion regarding the role of surgery as primary treatment for their disease. In the past two decades, the proportion of men diagnosed with cT3 high-risk prostate cancer undergoing RP has halved to less than 10%, whereas the proportion receiving EBRT (combined with ADT) has increased from 40% to 60%.[1] In the CaPSURE database, the proportion of men undergoing RP dropped from 42% for moderate high-risk (CAPRA score 5) to 12% for very high-risk (CAPRA score 8–10), whereas the use of RT increased from 16% to 23%. Most surprisingly, considering strong level 1 evidence that supports optimal local control,[2, 3] a staggering 53.5% of men in the highest risk category receive ADT only.[4] There are no evidence-based data to explain these dramatic shifts.

High-risk disease is understood to be a significant likelihood of progressive, symptomatic disease or death from prostate cancer.[5] The widely accepted definition of high-risk prostate was first proposed by D'Amico based on a pretreatment Gleason sum score of ≥8, or at least T2c clinical stage (or cT3 in some classifications), or a presenting PSA level of ≥20 ng/mL.[6-8] Historically, surgery is not recommended in men with high-risk disease because of the morbidity associated with a high-risk of metastatic disease and a cure rate of just 50%.[6, 9-11] However, looking at it another way, this means that 50% of men will be cured and nearly all of these will have avoided the underappreciated morbidity of 2–3 years of ADT associated with RT. Furthermore, the 10-year outcomes from the CaPSURE database for men with high-risk prostate cancer treated with RP report 90% local recurrence-free, 89% systemic progression-free, 95% CSS and 80% OS.[12] Even in the very highest risk category by CAPRA score, approximately 20% of men will be cured with prostatectomy alone.[4]

RP provides excellent local control of the primary tumor, accurately stages the disease to guide further therapy and removes benign sources of PSA, so that failures can be promptly identified and subsequent treatment can be initiated in a timely manner. However, many guidelines are reluctant to endorse RP as equivalent treatment to EBRT and ADT. The National Comprehensive Cancer Network 2012 guidelines rank RP as the third option behind EBRT and EBRT plus brachytherapy (both combined with ADT), and then should be considered only in low volume, non-fixed tumors.

There is no randomized trial that compares RP with RT in men with high-risk prostate cancer, and therefore the optimal treatment is controversial. Retrospective studies in this space have been carried out,[6, 13-22] but must be interpreted with caution considering the many biases that exist between cohorts, particularly the patient selection (i.e. extra comorbidities of men treated with RT). However, whether this point alone accounts for the majority of studies that favor RP over RT remains unclear. These studies do not provide data that infers surgery is inferior to RT; also, there are several biological reasons (discussed later) that support a role for prostatectomy for local control in advanced disease. At the very least, it should be part of the discussion regarding treatment options for men with high-risk prostate cancer.

What is the optimal treatment for men with high-risk localized prostate cancer?

Current trends suggest that we are undertreating men with high-risk prostate cancer.[23] The risk of dying from high-risk prostate cancer is halved by radical local treatment (whether it is surgery or radiation treatment), as compared with observation or ADT alone,[2, 3, 24-27] but it is unknown which is the best local treatment. This is a controversial question and was identified by the Institute of Medicine as one of the top 25 issues to be resolved by comparative effectiveness research.[28]

Outcomes of radical prostatectomy versus observation

Multiple large studies have shown a survival benefit of radical prostatectomy over observation, especially in men with high-risk disease. Data from the SEER database,[26] the SPCG-4[25] and most recently the PIVOT[24] have all shown the benefits of radical prostatectomy over observation with an absolute risk reduction for 10–12 years prostate cancer-specific survival in the range of 7.6–11.2%, and a number needed to treat of 13.[25, 26] Vickers et al. used data from SPCG-4 to create a statistical model to calculate the decrease in risk of death associated with surgery. For a 65-year-old man with high-risk disease, the absolute 10-year risk reduction in prostate cancer mortality attributable to radical prostatectomy was 17.2%.[29] All these benefits are an order of magnitude greater than for low-risk disease.

High PSA does not exclude RP

A high PSA should not exclude men from radical prostatectomy. Pretreatment PSA can reflect not only cancer, but benign prostatic hyperplasia and chronic inflammation.[30] Furthermore, a Mayo Clinic study found that the 10-year PSA recurrence-free survival, metastasis-free survival and cancer-specific survival was 40%, 83% and 90%, respectively, in men with a serum PSA level of 50–99 ng/mL, and 36%, 74% and 79%, respectively, in those with a PSA level of ≥100 ng/mL.[31] These data further show that surgery can cure a significant proportion of men with very high-risk prostate cancer.

Radiation treatment in high-risk disease

Several well-conducted randomized trials, recently reviewed elsewhere,[32, 33] show that EBRT combined with neoadjuvant and adjuvant ADT is superior to EBRT alone. The converse is also true; men with high-risk localized prostate cancer have improved local control and survival when EBRT is added to ADT compared with ADT monotherapy.[2, 3, 27] These studies show, similar to other solid cancers, that superior local control improves cancer outcomes. Importantly, androgen suppression must be of 2–3 years duration to get the maximal benefit.[34-36] Specifically, in men with high-risk prostate cancer, Bolla et al. reported that the 10-year disease-specific mortality was 30% in men who received EBRT alone, compared with just 10% in men who received EBRT plus 3 years of ADT.[37] There is debate about the optimal period of adjuvant hormones, but the AUA and EAU prostate cancer guidelines support RT with neoadjuvant and adjuvant ADT for at least 2 years.[38, 39] The exemplary effort of the radiation oncology community in this space shows that EBRT combined with ADT is superior to either monotherapy regimen, and has led to RT being recommended as the standard of care in the EAU guidelines, with surgery restricted only for “highly selected” patients.[40] Although these studies show the critical role for local control in improving cancer outcomes, they do not infer, in any way, superiority of radiotherapy over surgery in achieving optimal local control.

Radical prostatectomy versus radiation treatment in men with high-risk prostate cancer

In the absence of a large randomized trial that is required to definitively determine which of these two effective treatment modalities is the best for men with high-risk prostate cancer, we are beholden to the immeasurable flaws and biases of the retrospective analyses. There are retrospective analyses that favor RP,[13-18] some that favor RT[19, 20] and several that found no difference between modalities including the only prospective, albeit small, randomized trial in Japanese men.[6, 21, 22]

Several large retrospective analyses favor RP over RT. Abdollah et al. used the SEER database to identify 68 665 patients with localized prostate cancer treated with radical prostatectomy or radiotherapy between 1992 and 2005. Propensity-score matching was used to minimize potential bias related to treatment assignment. In the subgroup of men with high-risk prostate cancer, the 10-year cancer-specific mortality rate was 6.8% for RP versus 11.5% for RT. Multivariable analyses allowing for age and comorbidities confirmed that RP provided superior cancer-specific mortality.[16] Cooperberg et al. compared the risk-adjusted mortality outcomes of 7538 men treated by RP, EBRT or ADT from the CaPSURE registry where over 10% had high-risk disease. Although the median follow up was less than 5 years, there was a significant survival benefit in men with high-risk prostate cancer treated by RP compared with either EBRT or ADT.[13]

Zelefsky et al. used competing risk regression analysis controlling for patient age, clinical stage, serum PSA level, biopsy Gleason score and year of treatment to show that RP was associated with a nearly 10% lower risk of progression to metastasis, and a lower cancer specific mortality as compared with EBRT in 409 men with high-risk prostate cancer.[15] Tewari et al. showed in 453 men with Gleason 8 disease that after a median follow up of over 4 years that the risk of cancer-specific death was 13.4% in those that had RP, 16.8% for RT and 43% for observation.[14] In another study of 528 men with high-risk disease, Albertsen et al. showed that after adjusting for pretreatment Gleason score, PSA, clinical stage, age at diagnosis and comorbidities, the 10-year cancer-specific survival was 90%, 80%, and 70% for surgery, radiation and observation, respectively.[18]

Boorjian et al. reported a retrospective analysis of RP versus RT on high-risk men from the Mayo Clinic. After a median follow up of 10 years for RP (n = 1238) and 6 years for EBRT plus ADT (n = 609), no difference in 10-year disease progression or CSS rates was observed. However, RP had better OS rates (77%) compared with men treated by EBRT and ADT (62%) or EBRT alone (52%). Whether this effect on OS was a result of patient selection or the effects of ADT is unknown.

In contrast, a study by Grimm et al. using strict criteria for study inclusion, which meant including just 17% of 848 papers identified regarding treatment for prostate cancer, found that combination regimens of ADT, EBRT and brachytherapy had higher PSA progression-free survival than surgery, EBRT or brachytherapy alone for high-risk patients.[20] However, the far more important measures of cancer-specific and overall survival were not assessed.

The only published prospective randomized trial is a multicenter Japanese study in a small number of men (n = 95) with high-risk disease treated with neoadjuvant diethylstilboestrol and then randomized to RP (n = 46) or RT (n = 49). After a median follow up of 8.5 years, there was no significant difference between biochemical relapse, clinical progression or CSS. However, it must be recognized that the RT group received no adjuvant ADT and were treated with 40–50 Gy to the pelvis followed by a 20-Gy boost to the prostate, both of which would be considered suboptimal by today's standards.[22]

All these retrospective analyses have incalculable confounders related to different definitions of high-risk prostate cancer, non-randomized and heterogeneous patient populations, non-uniform outcome measures, limited patient numbers, and different treatment regimens (particularly pertinent to the evolution of EBRT regimes). These studies highlight the need for randomized trials to determine whether men with high-risk prostate cancer are better served with surgery, or conversely, have unfavorable results attributed to RT been a result of selection bias with surgery reserved for men in better health.[12, 23]

Radical prostatectomy as part of combined modality treatment

Just 10–12% of men with cT3 or CAPRA score >7 high-risk prostate cancer receive surgery as their primary treatment, presumably because of concerns for excess morbidity and <50% chance of cure as monotherapy.[1, 4, 6] For too long, surgery has been assessed by its success as monotherapy, whereas combined modality treatments are standard in other specialties, such as breast and colon cancer. Modern surgical techniques have comparable morbidities to that for lower risk disease,[41-43] and the growing acceptance of adjuvant RT and even ADT have improved the outcomes of men with high-risk disease. Half of men with residual local disease can be cured with adjuvant RT.[44, 45] Modern surgical series have 10-year CSS and overall survival of approximately 95% and 80%, respectively.[12, 17, 46]

Surgical technique of the radical prostatectomy for high-risk prostate cancer

In the past 25 years, significant improvements in the surgical technique of radical prostatectomy, coupled with advances in anesthesia and analgesia, have resulted in improved cancer control, reduced morbidity and shortened hospital stay, especially for experienced surgeons and high-volume centers.[47] In high-risk prostate cancer, particular attention is paid to wide local excision of the neurovascular bundles, en bloc removal of both layers of Denonvillier's fascia, precise dissection of the apex and wide resection of the bladder neck with en bloc excision of seminal vesicles, followed by bladder neck reconstruction. An extended PLND with removal of the obturator, external iliac, and hypogastric with or without the presacral and common iliac nodes provides significant improvements in the detection of lymph node metastases.[48] Lymph node status is an important prognostic factor, and men with lymph node metastases might benefit from adjuvant ADT.[49] Although prostatectomy is first and foremost a cancer operation, knowing that one-third of men with high-risk prostate cancer will have organ-confined disease[41] means that often a nerve-sparing procedure can be carried out. New technologies, such as magnetic resonance imaging, might also assist in preoperative planning.[50] There is evidence that robotic-assisted laparoscopic prostatectomy provides comparable biochemical recurrence-free survival with open RP.[51] However, some surgeons still prefer the open approach in high-risk men for the ability to carry out an extended PLND, and the being able to “feel” the extent of the tumor when carrying out the resection.[52]

Adjuvant RT

A key tenet in combined modality treatment of surgery in high-risk prostate cancer is the availability of adjuvant RT for adverse pathological features, such as pT3+ disease or a significant positive margin. Several landmark studies have reported improved BPFS rates of 72–74% for adjuvant RT compared with 44–53% for those treated with initial observation.[53-55] However, many men with pT3a or microfocus positive margins can be treated with initial observation and avoid adjuvant RT. The optimal timing of adjuvant versus early salvage RT and the need for concurrent ADT remains undefined. These issues are being addressed by the Radiotherapy and Androgen Deprivation in Combination After Local Surgery (see NCT00541047 at ClinicalTrials.gov) and Radiotherapy Adjuvant versus Early Salvage following Radical Prostatectomy[56] studies. The main disadvantage of adjuvant treatment remains unnecessary radiotherapy in >50% of men who will never develop biochemical recurrence, yet could suffer adverse effects of radiotherapy after surgery, particularly the risks to continence from fibrosis if RT is given too close to surgery. It is for this reason that observation followed by early salvage RT for PSA recurrence is still an acceptable option in select men.[57]

Neoadjuvant and adjuvant ADT

Neoadjuvant ADT causes significant pathological downstaging and decreases surgical positive margin rates; however, early studies and two meta-analyses found no differences in BPFS, CSS and OS.[58-61] It appears that the duration of ADT is important, with Meyer et al. showing that the only benefit for improvements in BPFS came in a cohort of men who received neoadjuvant ADT for more than 3 months (as compared with no effect for those who received 3 months or less).[62] The longest use of adjuvant ADT was reported in the Southwest Oncology Group S9921 study of 983 men with high-risk prostate cancer randomized to combined androgen blockade with goserelin and bicalutamide with or without mitaxantrone for 2 years. An intermediate report strongly suggests that a prolonged course of ADT significantly reduced the rate of disease recurrence and cancer-specific death after RP.[63] Furthermore, Messing et al. showed the positive effect of prolonged adjuvant ADT in men with node-positive disease, where immediate ADT conferred a significant improvement in BPFS, CSS, and OS as compared with observation and delayed ADT.[49]

The benefit of extended courses of ADT is not surprising considering the data from the radiation trials where ADT + EBRT is clearly superior to EBRT alone in all measures of survival, and recent studies have shown that longer periods of ADT are better than shorter periods; that is, 3 years is better than 6 months.[36] Although some of the benefit of ADT is related to its role in sensitizing the cancer to radiation, the benefit of 3 years of ADT over 6 months suggests that prolonged ADT itself might also have a significant role.

Neoadjuvant and adjuvant chemohormonal therapy

The rationale for neoadjuvant or adjuvant chemotherapy in high-risk prostate cancer is based on its activity in castration-resistant prostate cancer and benefits in other solid cancers. No studies to date have shown convincing evidence that chemotherapy, whether alone or in combination with ADT, improves BPFS.[64-67] The concept of neoadjuvant chemotherapy combined with ADT is in keeping with tumor model data indicating that simultaneous chemotherapy and ADT most effectively suppresses prostate cancer tumors compared with sequential treatments of ADT followed by chemotherapy or vice versa.[68] A phase III study to determine if combined neoadjuvant docetaxel + ADT before RP is beneficial as compared with RP alone in men with high-risk prostate cancer is currently in progress (CALGB 90203, NCT00430183 at ClinicalTrials.gov).[69]

Salvage prostatectomy after failure of other primary therapies

There are few more challenging patients than the man seeking salvage prostatectomy with biochemical recurrence after EBRT, cryotherapy or HIFU. These men present with proven resistant tumors sitting in a previously treated field, and might already have compromised sexual, urinary and physical health. A recent review by Mendenhall et al. on treatment options after failed EBRT concluded that RP provided a better cure rate than other salvage therapies (brachytherapy, cryotherapy or HIFU), but acknowledged that the risk of morbidity is high.[70] While daunting, the principles of surgery in these men are early salvage treatment after a careful search to rule out metastatic disease as the cause of PSA recurrence, with patients being aware of the increased risk of erectile dysfunction, urinary tract infection, transient urine leaks, urinary fistula, bladder neck contractures and rectal injury with recto-urethral fistula.[71-73] The CSS after salvage RP has been reported as 73% at 10 years and 60% at 15 years.[72] Although the cancer outcomes are good after salvage surgery, it is still true that RT is better tolerated after RP than the other way around in men requiring additional treatment for their aggressive prostate cancer.[74-76]

What are the pros and cons of radical prostatectomy in men with high-risk prostate cancer?

While the currently irresolvable debate rages on between the best treatment option for men with high-risk prostate cancer, informed discussions with our patients regarding their management can focus on the following points regarding surgery:

Pros

Definitive histopathological diagnosis

Arguably, the greatest advantage of RP is obtaining the true pathological grade and stage of a patient's primary cancer to determine who will benefit most from adjuvant treatments. This includes an accurate assessment of lymph node involvement with a PLND.[49] Preoperative clinical stage is often inaccurate in localized prostate cancer. In a review of the CaPSURE database, an inaccurate clinical stage was assigned to 35.4% of the patients.[77] More specifically, up to 50% of patients with preoperative clinical high-risk prostate cancer will have more favorable prostate cancer on their final pathological specimen.[10, 78] This includes 31–45% of patients who have a biopsy Gleason score of ≥8, but a final RP pathological specimen of ≤7,[79, 80] and 9–44% of patients with cT3 stage will in fact have organ-confined tumors.[9, 41, 43, 81, 82] Importantly, patients who are downgraded have better outcomes than those who are not.[79] Furthermore, many men will be cured with RP alone without a higher rate of complications, and enjoy the benefits of avoiding adjuvant treatments.[41-43]

Excellent local control

There are important biological and psychological benefits of debulking the tumor and removing the prostate as a future source of metastatic cells. Local pelvic control is extremely important, even if there is a risk of micrometastatic disease. Inman et al. reported a local recurrence rate of just 13% after RP in men with high-risk prostate cancer.[31] Furthermore, adjuvant or salvage RT cures another 50% of recurrences, which represents a threefold reduction of death from prostate cancer after surgery with minimal additional morbidity.[44, 45] Conversely, salvage RP is more difficult after RT and less well tolerated by patients.[74] Zelefsky et al. showed that the positive biopsy rate at 2 years after RT in men with high-risk disease is 33% and 16% for those who received 75.6 Gy or 81 Gy, respectively.[83] Although RT techniques are evolving and some of these positive biopsies will not progress to recurrent disease, there is still a concern that RT might lead to a late wave of metastatic seeding from a biologically altered post-irradiated prostate cancer.[84]

Early detection of treatment failure when the PSA level fails to become undetectable or starts to rise

The definition of failure after RP is PSA ≥0.2 ng/mL,[85] whereas, the definition after radiation therapy is a rise of ≥2 ng/mL or more above the nadir.[86] Furthermore, with the removal of all benign causes of PSA, any PSA recurrence after surgery can be more promptly identified and, therefore, treated with salvage therapy with less delay. A large retrospective study of 1540 patients with biochemical recurrence after radical prostatectomy found that salvage RT was most effective in patients with a lower PSA.[45] The 10-year biochemical-free survival was approximately 50% for those with PSA less than 0.5 ng/mL and just 15% in patients whose PSA was more than 1.5 ng/mL at the time of treatment. This is likely because of the risk of local and metastatic progression of the cancer during the delay.

This is a major point that is often overlooked with the definition of PSA failure after RT. Although it is important to reduce the number of false positives as a result of the normal fluctuations in the PSA (including the bounce phenomenon), those that do go on to have a true positive PSA recurrence have missed a substantial window of cure while waiting for the PSA to rise, similar to waiting for a post-RP PSA to climb from 0.5 to 1.5 ng/mL with its associated decrease in biochemical-free survival.

Surgery as part of combined modality treatment

Surgery plays a crucial role in debulking the tumor and providing excellent local control in the combined modality treatment of men with high-risk prostate cancer. It is no longer true that surgery should be avoided if it cannot cure as monotherapy. Combined modality treatment utilizing surgery, radiation treatment and systemic therapy is the standard of care in other cancers, such as colon and breast. Furthermore, the safety of RP followed by RT rather than the other way around has been previously emphasized.[74]

High cure rate and most men can avoid or at least delay ADT

Men receiving RT for high-risk prostate cancer receive at least 2 years of adjuvant ADT with its risk of metabolic syndrome, depression, loss of libido, sexual dysfunction, hot flashes, diabetes, potential cardiovascular morbidity and mortality, osteoporosis and bone fracture.[36-39] Using the CaPSURE data, Meng et al. showed that men with high-risk prostate cancer treated with primary RT were 3.5-fold more likely to receive ADT than patients treated with RRP.[12] The morbidity associated with ADT should not be underestimated, and modern validated quality of life surveys reveal that most men suffer considerably from ADT and benefit from time off ADT.[87]

Approximately half of men with high-risk disease will be cured with RP monotherapy and avoid any further treatment.[9, 10, 42, 43, 88-90] These men will avoid ADT and not be subjected to its inherent morbidity. In the 50% who recur, a shorter course of combined hormone therapy with RT is well tolerated.[87, 91] In a study by the Mayo Clinic on patients with cT3 disease, the average duration of freedom from ADT after RP monotherapy was 4.0 years.[43] Recently, Joniau et al. reported on a cohort of 51 men with very high-risk prostate cancer (cT3b–T4), where 31.4% avoided ADT, and after a median follow up of 9 years the 10 years BPFS rate was 45.8%.[92]

Reduced cost of surgery versus radiation treatment

Although not a direct concern of the patient, there are numerous stakeholders who appreciate that surgery is a cheaper treatment option for local control than modern radiation treatment. According to the Institute for Clinical and Economic Review at Massachusetts General Hospital, the cost of initial definitive local treatment for prostate cancer was $13 553 for surgery and $23 853 for IMRT.[93] In another study that used the SEER database to estimate costs of the first 12 months of treatment after a diagnosis of prostate cancer, surgery (including any adjuvant RT) cost Medicare $15 467 compared with $17 795 for older generation (and less expensive compared with IMRT) 3-D conformal EBRT.[94] Furthermore, the compulsory additional 1–2 years of ADT required by modern RT protocols (contrasted with the 50% of surgical patients who are cured), further adds to the cost of RT over surgery.

Is there a role for “cytoreductive prostatectomy”?

Data from well-matched retrospective studies show that removing the prostate in patients with limited metastases improves overall survival. Two large studies in men with node-positive disease have shown that the 10-year OS for those treated with RP for primary tumor debulking and then ADT was 65% compared with 30% for those in whom the surgery was aborted and treated with ADT alone.[95, 96] Reviewing the two prospective trials in men with lymph node-positive disease suitable for RP, Studer et al.[97] noted that the 10-year overall survival of patients in the Messing trial who had a RP was again approximately 65%,[49] whereas in the European Organization for Research and Treatment of Cancer trial, the men in the arm who received ADT, but did not have a RP, had a 30% OS.[98] Similar results for improved survival in these men have been shown in a RT trial.[3] A systematic review by Verhagen et al. concluded that there was a clinically important survival benefit in men with node-positive disease receiving ADT when local control is achieved of the primary tumor (HR for OS: 0.69; 95% CI 0.61–0.79).[99] Therefore, RP in these men with systemic disease not only provides better local control, but also suggests that the primary cancer plays a significant role in shedding metastatic disease or releasing growth factors that work in an endocrine fashion to assist the growth of metastases.[100]

There is emerging evidence that primary tumors release cytokines and other factors that manipulate distant tissues and the immune system to facilitate metastatic deposits (creating a premetastatic niche) and survival of cancer cells; a function not necessarily carried out by metastases.[101, 102] In urology, you have to look no further than the improved survival associated with cytoreductive nephrectomy in the era of immunotherapy.[103, 104] The importance of the immune system in prostate cancer is highlighted by the efficacy of the first tailored vaccine therapy (Sipuleucel-T) to improve overall survival.[105] Therefore, the role of cytoreductive prostatectomy in men with minimally-metastatic prostate cancer is a rational question that needs to be addressed in the setting of a randomized trial.

Cons

Morbidity

Some argue prostatectomy in men with high-risk disease increases morbidity as a result of locally-advanced disease. However, modern surgical technique for RP in high-risk men is well established, and in experienced hands there is no increase in the risk of complications, such as incontinence or rectal injury.[41-43] Of course, virtually no men are potent after a wide excision of the neurovascular bundles, but most men are also impotent after RT + long-term ADT. Furthermore, if there is no evidence of extensive local spread and armed with the knowledge that one-third of men will have organ-confined disease, a significant proportion of men with high-risk disease are suitable for nerve-sparing RP.[41]

Operating on a man with a terminal disease

Another argument against surgery in these men is that they might already have metastatic disease, and the risks of an operation outweigh the benefits in survival. This can be argued on many fronts. The first is that modern anesthesia and perioperative care reduces the risk of venous thromboembolism and other perioperative complications; indeed, most men are discharged on day 1. Second, pathological downstaging of the final specimen also means that men should not be excluded from attempted local cure. And finally, it has been discussed previously that men with high-risk disease have the most to gain from aggressive local control, and surgery leads to improvements in survival even with metastatic disease.

Asides from comorbidities that preclude surgery, we can think of no reason why men with high-risk locally-advanced disease (and possibly in the future minimally-metastatic disease), should not consider surgery, alongside combined ADT + RT, as a treatment option. Clearly, RP is not suitable in certain cases, but the evidence suggests that the role for surgery should be increasing in high-risk men rather than decreasing as it is now.[1, 12, 46]

Conclusion

Men with high-risk or locally-advanced prostate cancer require treatment for the primary cancer or risk dying prematurely from their disease. Historically, combined ADT + RT has been seen as the standard treatment because of prospective studies in this space and the perceived increased morbidity of surgery in the setting of a “low” cure rate as monotherapy. In the absence of a well-conducted randomized trial, there is no definite evidence that one treatment is superior to the other. With modern surgical techniques in experienced hands, there is no increase in morbidity associated with RP in men with high-risk compared with low-risk prostate cancer.[41-43, 106] In our institution, men go home the next day after an open radical prostatectomy with the usual 4 weeks convalescence. Surgery as monotherapy in high-risk disease (while effective in approximately 40–50% of men) is an antiquated idea and surgery should be considered part of a combined modality approach (where the extra modalities can sometimes be avoided). The advent of new treatments (especially abiraterone and enzalutamide) and those in the pipeline are changing the landscape of advanced prostate cancer with the goal of making it a chronic rather than a terminal disease. Most evidence indicates equivalent, or sometimes superior outcomes of RP over RT. Most importantly, these men should receive informed discussion and allow them to select between options that include either combined ADT + RT or RP with selected layering of additional therapies guided by pathology and early rises in PSA.

Conflict of interest

None declared.

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