Is Radical Prostatectomy Appropriate for Very-High-Risk Prostate Cancer Patients? No.

It has long been recognized that treatment outcomes for men with high-risk prostate cancer are widely variable. Endpoints, such as biochemical failure–free survival (BFFS), distant metastasis–free survival (DMFS), prostate cancer–specific survival (PCSS), and even overall survival (OS), vary according to the high-risk features present at the time of diagnosis.[1-9] Accordingly, the most recent version of the National Comprehensive Cancer Network guidelines includes a very-high-risk category within the larger high-risk cohort. This population, described in a seminal work by Sundi et al, experiences inferior DMFS, PCSS, and OS, and is comprised of patients with primary Gleason pattern 5 disease, Gleason sum 8–10 in ≥ 5 cores, or multiple high-risk factors.[9] While the original work was derived from a database of patients undergoing radical prostatectomy (RP), preliminary results also support the existence of a very-high-risk group among patients treated with primary external beam radiation therapy (EBRT).[10] Men with a diagnosis of very-high-risk prostate cancer may be presented with a variety of treatment options, including some combination of surgery, EBRT, and androgen deprivation therapy (ADT). For clinicians counseling men with very-high-risk prostate cancer, the two goals of maximizing survival and maximizing quality of life (QOL) must both be central.

There is no consensus on the appropriate management strategy for very-high-risk disease and no randomized data comparing RP with EBRT ± ADT. This fact precludes definitive statements on the best approach. The argument that “more is better” (RP followed by EBRT ± ADT) is cognitively seductive, yet there is a paucity of data to support this claim. The only level 1 evidence in this patient population comes from two prospective randomized controlled trials that clearly establish EBRT + ADT as the standard of care, and this should be the benchmark against which any alternatives are compared.[11,12] Additional support for this treatment approach comes from researchers at Johns Hopkins who have separately reported outcomes for very-high-risk disease treated with RP[9] and with EBRT.[10] Comparisons of 10-year outcomes of men treated with EBRT vs RP show superior DMFS (74% vs 37%), PCSS (82% vs 62%) and OS (64% vs 58%) for the former, despite the fact that those treated with EBRT were older (median age, 65 vs 59 years). It should be noted that the reported surgical outcomes are, in fact, more reflective of a “combined modality” approach, with > 50% of patients treated with RP receiving additional therapy with EBRT and/or ADT. Another recently reported series of > 1,500 patients compared BFFS for treatment with RP vs treatment with EBRT in patients with high-risk disease.[13] With long-term follow-up, 10-year BFFS was superior for EBRT (54% vs 47%), with the benefit confirmed on multivariate analysis. Comparisons of different subgroups showed that the benefit existed in all but the lower-risk population (with Gleason 8 disease and prostate-specific antigen [PSA] levels < 10 ng/mL).

Questions of efficacy aside, it has been well documented that each treatment modality comes with attendant side effects and that these effects are additive. With regard to lasting complications of local therapy with either RP or EBRT, there are three domains that are likely to be affected: urinary function, bowel function, and sexual function. A review of cross-sectional studies shows that men treated with RP are consistently more likely to report urinary problems (leakage, frequency, incontinence, etc)[14-17] and sexual dysfunction.[14-18] Long-term prospectively collected data from the Prostate Cancer Outcomes Study clearly documented higher rates (at 5 years post-treatment) of urinary incontinence (13% vs 4%) and erectile dysfunction (76% vs 72%) in surgically treated patients compared with patients treated with EBRT.[19] More importantly, patient-reported bother was statistically higher for surgically treated patients than for EBRT-treated patients in both the urinary and sexual domains (odds ratios, 7.66 and 1.96, respectively). While bowel urgency was more common in patients treated with EBRT, the corresponding rate of patient-reported bother was low (5.8% at 5 years). Of course, the appropriate QOL comparison is not between EBRT and RP but rather between EBRT and RP + EBRT, as the majority of very-high-risk patients undergoing RP will have indications for further therapy.[20] QOL data from the Southwest Oncology Group randomized trial of adjuvant radiation showed that the addition of EBRT to RP resulted in more frequent urinary and early bowel symptoms compared with RP alone.[21]

Due to the absence of level 1 data to guide management of very-high-risk prostate cancer, clinicians are forced to rely on lower-level evidence when counseling patients regarding the most appropriate therapy. The available data suggest that treatment outcomes in this patient population do not vary significantly by treatment and may potentially be superior with EBRT. Moreover, a strategy of primary EBRT will serve to maximize patient QOL. Therefore, it is our opinion that surgery is inappropriate for very-high-risk prostate cancer and that a combination of EBRT and ADT should be the preferred treatment modality.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Freedland SJ, Partin AW, Humphreys EB, et al. Radical prostatectomy for clinical stage T3a disease. Cancer. 2007;109:1273-8.

2. Lodde M, Harel F, Lacombe L, Fradet Y. Substratification of high-risk localised prostate cancer treated by radical prostatectomy. World J Urol. 2008;26:225-9.

3. Loeb S, Schaeffer EM, Trock BJ, et al. What are the outcomes of radical prostatectomy for high-risk prostate cancer? Urology. 2010;76:710-4.

4. Ploussard G, Masson-Lecomte A, Beauval JB, et al. Radical prostatectomy for high-risk prostate cancer defined by preoperative criteria: oncologic follow-up in national multicenter study in 813 patients and assessment of easy-to-use prognostic substratification. Urology. 2011;78:607-13.

5. Yossepowitch O, Eggener SE, Bianco FJ Jr, et al. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J Urol. 2007;178:493-9; discussion 9.

6. Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol. 2008;26:211-8.

7. Pierorazio PM, Ross AE, Han M, et al. Evolution of the clinical presentation of men undergoing radical prostatectomy for high-risk prostate cancer. BJU Int. 2012;109:988-93.

8. Pierorazio PM, Ross AE, Lin BM, et al. Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy. BJU Int. 2012;110:1122-8.

9. Sundi D, Wang VM, Pierorazio PM, et al. Very-high-risk localized prostate cancer: definition and outcomes. Prostate Cancer Prostat Dis. 2014;17:57-63.

10. Narang A, Robertson SP, Ram AN, et al. Very-high-risk localized prostate cancer-outcomes following definitive radiation. Int J Radiat Oncol Biol Phys. 2014;90(suppl 1):S14-S5.

11. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-8.

12. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378(9809):2104-11.

13. Stephans KL Tendulkar RD, Reddy CA, et al. High-risk prostate cancer: radiation or surgery? Int J Radiat Oncol Biol Phys. 2013;87(suppl 2):S371.

14. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al. Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three Surveillance, Epidemiology, and End Results areas. J Clin Oncol. 1996;14:2258-65.

15. Lim AJ, Brandon AH, Fiedler J, et al. Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. J Urol. 1995;154:1420-5.

16. Shrader-Bogen CL, Kjellberg JL, McPherson CP, Murray CL. Quality of life and treatment outcomes: prostate carcinoma patients' perspectives after prostatectomy or radiation therapy. Cancer. 1997;79:1977-86.

17. Yarbro CH, Ferrans CE. Quality of life of patients with prostate cancer treated with surgery or radiation therapy. Oncol Nurs Forum. 1998;25:685-93.

18. Helgason AR, Adolfsson J, Dickman P, et al. Factors associated with waning sexual function among elderly men and prostate cancer patients. J Urol. 1997;158:155-9.

19. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368:436-45.

20. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190:441-9.

21. Moinpour CM, Hayden KA, Unger JM, et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol. 2008;26:112-20.