Focal Therapy: A New Active Surveillance Tool?

In the United States and other developed countries, prostate cancer is the most common cancer diagnosis in men.[1] Since the advent and widespread use of prostate-specific antigen (PSA) screening, downward stage migration has been observed, as the majority of those diagnosed have lower-risk, localized disease. While screening has contributed to a decline in mortality,[2,3] the urologic community has faced great criticism for “overtreatment” of this disease, largely because of the resulting treatment-related morbidity and other costs to which many who are unlikely to die-or experience symptoms-from prostate cancer are subjected. Additionally, men diagnosed today are younger,[4] and thus for many, preservation of quality of life is arguably as great a priority as cancer control.

A possible solution to the overtreatment of localized disease is focal ablative therapy, rather than whole-gland treatment, as these procedures may be less invasive, less costly, and less morbid. A variety of techniques exist, including thermal ablation (cryosurgery, high-intensity focused ultrasound [HIFU]) as well as photothermal (laser) ablation, focal radiation (ie, CyberKnife, brachytherapy), photodynamic therapy (PDT) and radiofrequency interstitial tumor ablation (RITA). Appropriate candidates include those with a single focus with or without few foci of very low grade/volume disease, and it is estimated that as many as 33% of men with low-risk disease are appropriate candidates for this “organ-sparing” approach.[5] Because focal therapy does not ablate all prostate tissue, there are inherent concerns that patients remain at risk for recurrence or development of de novo prostate cancer elsewhere.

Active surveillance (AS) is increasingly advocated for men with lower-risk prostate cancer and, as another prostate-sparing approach, this strategy relies on serial PSA screening, digital rectal exam, and prostate biopsy for monitoring of disease progression. Focal therapy is often referred to as the “middle ground” between AS and other whole-gland therapies, as it provides active treatment of cancer while, it is hoped, maintaining a lower adverse effect profile. Major advancements in diagnostic staging tools, including multiparametric magnetic resonance imaging (MRI) and transperineal template-guided-mapping prostate biopsy, can provide information on disease characterization and extent-crucial information for both of these organ-sparing approaches. Tsivian and colleagues[6] propose that the recent success of focal therapy, in achieving both short-term oncologic control and limited morbidity, has several important implications for our current AS protocols.

In their article in this issue of ONCOLOGY, Dr. Tsivian and coauthors suggest that focal treatment could be used to “downstage” disease in those who, because of multifocality, grade, or volume would not otherwise be candidates for (what are largely) low-risk–only inclusion protocols. Because of the indolent nature of prostate cancer as well as the highly effective treatment of multifocal disease via targeting of the dominant or “index” lesion, it is proposed that focal therapy would augment surveillance candidacy and allow for inclusion of those with higher-risk features. As contemporary, large-institution series reveal very high prostate cancer–specific survival rates (> 97%) when carefully selected patients are monitored closely, including those with higher-risk features,[7,8] one has to question the necessity of focal therapy for these patients. Ironically, providing focal therapy as a form of pre-surveillance treatmentmay subject these men to new or even worsened morbidity beyond that of the very limited side-effect profile that has already been established for AS. This is especially true for some forms of treatment, as persistent erectile dysfunction is a major concern even for patients whose prostate cancer is treated using modern third-generation instruments (eg, cryosurgery).[9,10]

Of men who initially choose AS, up to one-third will ultimately undergo radical treatment, due to either subsequent disease restaging, progression, or anxiety.[7,11] In their article, Dr. Tsivian and coauthors propose that focal therapy may be an appropriate salvage therapy for these men, as these lesions could be actively treated and would then be “re-qualified” for AS. Several studies have found pathologic and biochemical outcomes of patients who undergo delayed prostatectomy or radiation therapy to be comparable to those who undergo immediate treatment.[12-14] Tsivian et al suggest that focal therapy could be used as an alternative to radical therapy in men who seek delayed treatment, noting that with eradication of the dominant disease focus, the cancer’s drive for progression is lessoned. While short-term oncologic outcomes of primary focal cryosurgery and HIFU are comparable to those of whole-gland treatments, the oncologic efficacy of focal therapy and delineation of appropriate candidacy remain to be determined. Comparison of oncologic outcomes is further complicated by the use of varied definitions of PSA failure. Further, the definition of “focal” is inconsistent, as the degree of tissue treated in published series varies from tumor only, to ipsilateral hemisphere with or without partial treatment to the opposite side (“hockey stick” template). Thus, it is rather provocative to suggest that focal cancer ablation is safe for men who experience true advancement of disease, especially if this occurs after several years of surveillance.

The authors emphasize that modern specialized imaging and biopsy techniques will allow for appropriate selection and monitoring of those who undergo focal therapy. Utilization of advanced technology is especially important because transrectal ultrasound (TRUS)-guided prostate biopsy, even with the extended-pattern technique, does not reliably identify the dominant cancer location in up to 45% of men with low-volume, multifocal disease.[15] However, the costs associated with frequent specialized imaging and focal therapy technology may call into question their widespread feasibility, and may limit focal therapies to large, tertiary-care centers. Moreover, the availability of certain focal therapies is limited, as HIFU currently is not approved by the US Food and Drug Administration for treatment of prostate cancer.

In conclusion, focal therapy is an appealing addition to our current AS strategies. As a “lesser evil,” focal therapy is showing promise as a therapy that can provide cancer control, while also avoiding many of the radical treatment–associated morbidities. The average prostate cancer patient today is younger and likely to have lower-risk disease, which adds to the ever-more-difficult task of guiding primary treatment decisions. Support of trials that investigate novel therapies such as AS and focal ablative technology is necessary to determine safety and cancer control of these organ-sparing approaches. As we face harsh criticisms of current practice standards, it is paramount not to dismiss focal therapy technology as a spurious innovation, but rather to consider it as a potentially useful tool and a mainstay of future prostate cancer therapy. However, such therapy needs to be rigorously assessed and should not be used to treat patients who need no treatment at all.

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:

REFERENCES

1. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61:1079-92.

2. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-90.

3. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725-32.

4. Lin DW, Porter M, Montgomery B. Treatment and survival outcomes in young men diagnosed with prostate cancer: a population-based cohort study. Cancer. 2009;115:2863-71.

5. Catto JW, Robinson MC, Albertsen PC, et al. Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study. Brit J Cancer. 2011;105:931-7.

6. Tsivian M, Abern MR, Polascik TJ. Evoluation of the concept of focal therapy for prostate cancer. Oncology (Williston Park). 2012;26:XXX-XXX.

7. Dall’era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol. 2012;62:976-83.

8. Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin Oncol. 2011;29:228-34.

9. Asterling S, Greene DR. Prospective evaluation of sexual function in patients receiving cryosurgery as a primary radical treatment for localized prostate cancer. BJU Int. 2009;103:788-92.

10. Hubosky SG, Fabrizio MD, Schellhammer PF, et al. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol. 2007;21:1521-31.

11. Cooperberg MR, Carroll PR, Klotz L. Active surveillance for prostate cancer: progress and promise. J Clin Oncol. 2011;29:3669-76.

12. Duffield AS, Lee TK, Miyamoto H, et al. Radical prostatectomy findings in patients in whom active surveillance of prostate cancer fails. J Urol. 2009;182:2274-8.

13. Warlick C, Trock BJ, Landis P, et al. Delayed versus immediate surgical intervention and prostate cancer outcome. J Natl Cancer Inst. 2006;98:355-7.

14. Dall’Era MA, Cowan JE, Simko J, et al. Surgical management after active surveillance for low-risk prostate cancer: pathological outcomes compared with men undergoing immediate treatment. BJU Int. 2011;107:1232-7.

15. 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.