FOCAL THERAPY The Case for Focal Therapy in Intermediate-risk Prostate Cancer
By: Herbert Lepor, MD, New York University Grossman School of Medicine, New York | Posted on: 09 Jun 2023
In 2023, the management options for intermediate-risk prostate cancer include active surveillance (AS), radical prostatectomy (RP), radiation therapy (RT), and focal therapy (FT). The goals of treatment are to prevent metastasis and mortality from prostate cancer while minimizing short- and long-term treatment-related adverse events. The shared decision process balances oncologic and functional outcomes.
In the 1970s, Willard Whitmore, one of the fathers of urologic oncology, queried, “If treatment for cure is necessary, is it possible? If possible, is it necessary?,” implying the limited benefits of RP or RT. The most recent survival analysis of SPCG-4 (Scandinavian Prostate Cancer Group Trial Number 4), which randomized men with prostate cancer to RP or watchful waiting, reported that 9 and 6 RPs were required to cure or prevent a metastasis, respectively.1 The baseline characteristics of many of the subjects randomized to SPCG-4 were similar to men who are appropriate candidates for both RP and FT. While the study reported a statistically significant benefit of RP for survival and prevention of metastasis, the majority of men, if untreated, would not have died or developed metastasis. Another less relevant oncologic outcome is disease recurrence following RP. In a contemporary multicenter cohort of RP, approximately 20% and 40% of men with intermediate-risk disease will develop a biochemical failure at 2 and 8 years, respectively.2
I was very fortunate as a Hopkins resident to contribute in a small way to the development of the anatomical nerve-sparing RP,3 and have since performed almost 5,000 of these procedures during my 38 years as an academic urologist. My perspective right out of training was to “cure” every prostate cancer until embracing AS for many cases with only low-risk disease. Despite prostate cancer being a multifocal disease, the pretreatment challenge for FT is to detect “unifocal” clinically significant disease (CSD), which is often defined by Gleason pattern (GP) 4 disease. In 2008, NYU Langone Health was one of the early academic centers embracing multiparametric magnetic resonance imaging (mpMRI) and magnetic resonance fusion target biopsy, which enabled “reliable” localization of CSD. In order to validate the ability of mpMRI and targeted/systematic biopsy to identify all sites of CSD in candidates for FT, whole-mount surgical specimens were examined from 57 RP specimens obtained from men who were candidates for FT.4 Assuming the ability to ablate the focal “in-field” disease, untreated out-of-field GP4 disease was observed in 23%. The amount of undetected out-of-field GP4 was consistently <1 mm, which explained why it was undetected by mpMRI and targeted + standard biopsy. AS of very low volume GP4 is an option based on the AUA/European Association of Urology guidelines. Despite the fact GP4 is detected in 50% of men with biopsy Gleason Grade Group 1 undergoing RP,5 AS is often the preferred management for these men. Therefore, if we can effectively ablate the index lesion in men with intermediate-risk disease, then AS of the untreated prostate would be even more appropriate than AS for Gleason Grade Group 1 disease based on lower unrecognized volume of GP4.
Our protocol for men with intermediate-risk disease undergoing primary partial gland cryoablation (PPGCA) has been to undergo a reflex MRI and biopsy between 2-3 years independent of PSA levels or MRI findings. Our oncologic outcomes at 3 years for men with intermediate-risk disease is encouraging. Using this rigorous oncologic follow-up, our reported risk of in-field and out-of-field CSD is only 3% and 14%, respectively (J. S. Wysock, unpublished data, 2023). One-third of out-of-field CSD cases were <0.1 mm and are on AS, one-third have undergone a salvage partial gland ablation, and one-third have been advised or undergone a salvage RP. The 14% risk of biopsy-recurrent disease at 3 years is comparable to the 20% risk of biochemical recurrence after RP for intermediate-risk disease.2
The functional limitations of RP include urinary incontinence, erectile dysfunction, climacturia, penile shortening, and penile curvature. Multicenter studies report rates of incontinence and erectile dysfunction (ED) of 20% and 80%, respectively.6 A high-volume academic center (Memorial Sloan Kettering Cancer Center) reported return to baseline erectile function in men with no baseline ED undergoing bilateral nerve sparing 2 years following RP of only 30%, allowing use of phosphodiesterase type 5 inhibitors with no advantage of the robotic approach.7
The very favorable functional outcomes of FT are what typically drive men to pursue this option over whole-gland treatments. We have published no incontinence or pad use at any time following PPGCA.8 Of men with moderate to severe lower urinary tract symptoms at baseline, the International Prostate Symptom Score improvement is 7 and 11 points, respectively. In men with no ED at baseline, 94% of men have functional erections and in 80% erectile function returns to baseline by 2 years.9 We have reached a very favorable balance between oncologic and functional outcomes following PPGCA.
All men in our prospective longitudinal outcomes study are now encouraged to undergo a protocol MRI and biopsy at 5 years. We look forward to presenting these oncologic outcomes in the next few years.
In 2023, how do I counsel men with intermediate-risk prostate cancers who are candidates for FT using PPGCA?
- Outpatient procedure with expedited recovery and return to work
- No incontinence and improvement of lower urinary tract symptoms
- Significant reduction in semen volume
- Men with moderate baseline ED have greatest risk for early loss of potency with improvement over time
- Extremely low probability for in-field recurrence
- Approximately 10% risk for clinically significant prostate cancer recurrence at 3 years requiring salvage treatment
- For-cause biopsy performed for progressive rising PSA or MRI-suspected disease recurrence
- Protocol biopsy at 5 years
After a shared decision process presenting my published oncologic and functional outcomes following RP and PPGCA, approximately 70% of men will choose FT. The driver of their decision is total avoidance of incontinence, no neoadjuvant androgen deprivation therapy, improved sexual function outcomes, and the opportunity for salvage RP, RT, or FT.
- Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in prostate cancer 29-year follow-up. N Engl J Med. 2018;379(24):2319-2329.
- Epstein JI, Zelefsky MJ, Sjoberg DD, Klein EA. Contemporary prostate cancer grading system: validated alternative to the Gleason score. Eur Urol. 2016;69(3):428-435.
- Walsh PC, Lepor H, Joseph C, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate. 1983;4:473-485.
- Kenigsberg AP, Llukani E, Deng FM, Melamed J, Zhou M, Lepor H. The use of magnetic resonance imaging to predict oncological control among candidates for focal ablation of prostate cancer. Urology. 2018;112:121-125.
- Mufarrij P, Sankin S, Godoy G, Lepor H. Pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy. Urology. 2010;76:689-694.
- Haglind E, Carlsson S, Stranne J, et al. Urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. Eur Urol. 2015;68(2):216-225.
- Capogrosso P, Vertosick EA, Benfante NE, et al. Are we improving erectile function recovery after radical prostatectomy? Analysis of patients treated over the last decade. Eur Urol. 2019;75(2):221-228.
- Thakker S, Wysock J, Matulewicz R, Gogaj R, Lepor H. Early functional outcomes following partial gland cryo-ablation. Can J Urol. 2022;29(3):11128-11135.
- Wysock J, Thakker S, Rapoport E, Gogaj R, Lepor H. Two-year functional outcomes stratified according to baseline erectile function following partial gland. Urology. 2023;171:158-163.