Focal Therapy for Localized Prostate Cancer

Commentary Focal Therapy for Localized Prostate Cancer Scott Eggener, MD University of Chicago Medicine, Chicago, IL [Rev Urol. 2018;20(4):143–144 doi: 10.3909/riu0823] ® © 2019 MedReviews , LLC N early every element of prostate cancer screening, diagnosis, and management of nonmetastatic disease is controversial and ripe for thoughtful debate. Perhaps no topic is more contentious than focal therapy for localized prostate cancer. The accompanying article [Rev Urol. 2018; 20(4):145–157] is comprehensive, balanced, and an exceptional overview of a relatively new and often confusing topic. Among the many strategies to counteract the pandemic of unwarranted diagnosis and often unnecessary treatment of prostate cancer, focal therapy is hugely attractive. Like the authors, I believe there is a strong rationale for meticulously evaluating this novel treatment paradigm, which is not the same as wholesale and widespread acceptance as a standard-of-care option. As often the case in any controversial topic, there are very strong opinions and loud voices on both sides of the spectrum, ranging from the vociferous “never-ever focal” crowd to outright charlatan focal therapists with very loose indications and lack of necessary follow-up or thorough data collection. Nearly all the reasons given by the “never-evers” are deconstructed and debunked with available published evidence.1 That is not to say focal therapy should be pervasive, as we remain in the nascent stages of its development. The parallels with the evolution of lumpectomy for breast cancer are eerily similar. Over a 50-year period, initial case reports accompanied by skepticism, ridicule, and accusations of malpractice eventually led to multiple randomized trials showing equivalent metastases-free and cancer-specific survival rates compared with radical mastectomy. The original trials had experimental arms without ipsilateral breast radiation therapy, which led to high local recurrence rates but didn’t impact long-term metastases or cancer-specific survival. Consequently, women contemporarily receive adjuvant radiation. Based on high-quality clinical trials, iconoclastic investigators, and brave women, approximately 65% of current women diagnosed with breast cancer have a lumpectomy. Like prostate cancer, breast cancer is typically a multifocal cancer.2 Men are often fervently attracted to the concept of focal therapy, even when it would be uniformly considered a misguided option. This speaks to the intense search for the tripartite holy grail: minimally invasive, highly effective, and risk free. My perspective is large-scale, preferably randomized, studies are imperative to understand the relative merits, drawbacks, and downstream impact of focal therapy and its ever-expanding range of ablative strategies and delivery mechanisms. However, based on available data, I also think highly select and well-informed patients may elect to proceed with focal therapy outside of formal funded clinical trials. Seemingly like the NYU group, I think the ideal candidate has an MRI lesion (or two) with a concordant biopsy showing prostate cancer [preferably Gleason Grade Group (GGG) 2-3] amenable to ablation without significant concerns for meaningful damage to important functional structures. Additionally, it is important to have a Vol. 20 No. 4 • 2018 • Reviews in Urology • 143 4170018_00_RIU0823_V4_rev03.indd 143 1/11/19 8:02 PM Focal Therapy for Localized Prostate Cancer continued well-characterized prostate outside the intended ablation zone. In my practice, this inclusion criteria ultimately amounts to perhaps 5% to 10% of all men newly diagnosed with prostate cancer. Routine ablation of GGG 1 should be discouraged, given the superb long-term outcomes with active surveillance. The introduction of this potential paradigm shift is both exhilarating and exasperating. There are tremendous opportunities to collect data and determine whether focal therapy has an appropriate role. Considerable credit goes to the patients, innovative scientists, companies, investigators, and funding sources involved in the large randomized trial evaluating vasculartargeted photodynamic therapy (PDT) versus active surveillance.3 Although an important minority of patients continued to have cancer within the ablation zone, PDT significantly reduced the presence of higher-grade cancers, cancer “progression,” and need for radical therapy. These are all unequivocally relevant and worthwhile to an individual man. The landscape of proper regulatory oversight and potential approval by the Food and Drug Administration (FDA) is neither straightforward nor imminent. Designing and funding trials with universally accepted meaningful endpoints in a suitable number of men with an appropriate control arm may sound self-evident; it is strikingly more challenging than it seems. However, it is encouraging the FDA recognizes the critical need for prospectively designed trials, is increasingly engaged, flexible to formulate a pathway to approval, and has held three public meetings with key stakeholders since 2013.4-6 Although there is legitimate reason for enthusiasm of the focal therapy paradigm, many significant hurdles remain. Combining clinical, pathologic, genomic, and imaging data to maximally characterize a prostate is useful but still has limitations. Image-guided ablation targeting a specific MRI lesion (or lesions) may underestimate and undertreat the cancer.7 Current modalities are not particularly precise, although many men presume the exact opposite, and preservation of cavernosal nerves is not particularly easy for peripherally based posterolateral lesions. Based on available data, I am confident focal therapy can be less invasive and, with proper patient selection, is usually associated with a more attractive side-effect profile. My primary remaining concern is appropriate evaluation of the intermediate- and long-term oncologic effectiveness, which will require thoughtful and rigorous investigators, patience, and, ideally, a suitable control arm. References 1. 2. 3. 4. 5. 6. 7. Bass EJ, Ahmed HU. Focal therapy in prostate cancer: a review of seven common controversies. Cancer Treat Rev. 2016;51:27-34. Holland R, Veling SH, Mravunac M, et al. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer. 1985;56:979-990. Jarow JP, Thompson IM, Kluetz PG, et al. Drug and device development for localized prostate cancer: report of a Food and Drug Administration/American Urological Association public workshop. Urology. 2014;83:975-978. Azzouzi AR, Vincendeau S, Barret E, et al. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017;18:181191. Jarow JP, Ahmed HU, Choyke PL, et al. Partial gland ablation for prostate cancer: report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop. Urology. 2016;88:8-13. US Food and Drug Administration. Oncology Center of Excellence Public Workshop: Development of Treatments for Localized Prostate Cancer. https:// tinyurl.com/y8l5wg63. Published July 11, 2018. Accessed October 20, 2018. Le Nobin J Rosenkrantz AB, Villers A. Image guided focal therapy for magnetic resonance imaging visible prostate cancer: defining a 3-dimensional treatment margin based on magnetic resonance imaging histology co-registration analysis. J Urol. 2015;194:364-370. 144 • Vol. 20 No. 4 • 2018 • Reviews in Urology 4170018_00_RIU0823_V4_rev03.indd 144 1/11/19 8:02 PM