Low-Risk and Very-Low-Risk Prostate Cancer: Is There a Role for Focal Therapy in the Era of Active Surveillance? No, Focal Therapy Provides a False Sense of Security and No Proven Benefits

Low-risk and very-low-risk prostate cancers are aptly named. Consider, for example, the recent observation that these cancers have almost no potential for local invasion or metastatic spread. In more than 14,000 fully embedded radical prostatectomy specimens containing Gleason 3+3 cancers, there was not a single associated pelvic lymph node metastasis.[1] The recurrence rate was 0.5% in 2,551 organ-confined Gleason 3+3 cancers after radical prostatectomy, without a single patient developing a metastasis or dying of prostate cancer.[2] Given the repeatedly proven indolent nature of low- and very-low-risk prostate cancer, observation-as opposed to intervention-is quickly becoming the accepted course of initial management. Urologists are abandoning the therapeutic imperative associated with a prostate cancer diagnosis.

Why, then, would one offer focal ablation in this setting? Those advocating this approach have been abetted by the slow progression of low-risk prostate cancer and a lack of long-term data, supporting the illusion of therapeutic durability. Focal ablation also exploits the uncertainty associated with active surveillance and a patient’s anxiety when facing the morbidity of definitive whole-gland treatment. Advocates of focal ablation claim to address this alleged unmet clinical need by offering “treatment” in a kinder and gentler manner. Unfortunately, the solution offered by focal ablation creates a new set of problems: Will this actually delay progression in a meaningful fashion, and if not, will it compromise subsequent treatment? There are biological, technical, and logical reasons that the current forms of focal ablation will fail to earn a foothold in the age of active surveillance.

Biologically, clinical prostate cancer emerges from molecular alterations occurring throughout the prostate gland.[3] This field effect and the resulting multifocality of prostate cancer confound focal approaches because, with time, failure becomes inevitable. Ablation with noncurative intent may be appropriate in clinical situations when cure is not necessary, such as in elderly or frail patients. But the very cancers in which a focal approach could be used are precisely the ones in which it should not be used. In most of those that recur after focal ablation, the next steps are far from clear; the oncologic and functional outcomes of salvage therapy are clearly inferior to those applied as primary treatment.[4] Focal ablation is an unnecessary tampering with the natural history of prostate cancer, burning bridges for a short-term, false sense of security.

Technically, targeted focal ablation is a misnomer. At best, only 25% of prostate cancers are unilateral, and there are no clinical or pathologic features to accurately identify them.[5] In low-risk disease, a dominant tumor cannot be reliably detected using standard transrectal ultrasound–guided biopsy.[6] Despite advances in prostate imaging and biopsy techniques, neither is able to identify every cancer within a prostate; focal ablation remains a shot in the dark. Given this uncertainty, focal ablations currently target much more of the gland than seems necessary. Furthermore, current focal ablative techniques fail to eradicate every targeted cancer. Radiographic change in tissue characteristics, either in real time or after treatment, does not necessarily equate to cancer destruction.

Most troubling of all, there are no prospectively established criteria for success or failure with focal ablation. The current application of radiation-based definitions is inappropriate. Focal therapy can only be considered therapeutic when adequately powered and controlled clinical trials have demonstrated benefits over observation with meaningful endpoints, such as time to local morbidity, development of metastatic disease, or prostate cancer–specific death. Herein lies the real challenge: How does one prove ablation is better than no ablation for an endpoint that almost never occurs? In the absence of a demonstrated clinical benefit, focal ablation will remain in its current position-on the fringes of mainstream prostate cancer care.

As oncologists, we are all confronted by patients with cancers for which the best course of action is no action. Just as one would never give homeopathic doses of cytotoxic chemotherapy in the name of treatment or apply adjuvant therapies “just in case” when there is almost no chance of recurrence, one should not advise a patient with low- or very-low-risk prostate cancer to undergo a focal ablation. The kindest and gentlest approach is to first do no harm.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS) <6 have the potential to metastasize to lymph nodes? Am J Surg Pathol. 2012;36:1346-52.

2. Hernandez DJ, Nielsen M, Han M, et al. Natural history of organ-confined (pT2), Gleason 6 prostate cancer after radical prostatectomy. Urology. 2008;72:172-6.

3. Yu YP, Landsittel D, Jing L et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol. 2004;22:2790-9.

4. Lawrentschuk N, Finelli A, Van der Kwast TH, et al. Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer. J Urol. 2011;185:862-8.

5. Briganti A, Tutolo M, Suardi N, et al. There is no way to identify patients who will harbor small volume, unilateral prostate cancer at final pathology: implications for focal therapies. Prostate. 2012;72:925-30.

6. Washington SL, Bonham M, Whitson JM, et al. Transrectal ultrasonography-guided biopsy does not reliably identify dominant cancer location in men with low-risk prostate cancer. BJU Int. 2012;110:50-5.