ABSTRACT: The landscape of prostate cancer has been rapidly evolving, and technological advances in imaging and biopsy tools offer novel approaches to focal therapy. In this dynamic environment, the role of focal therapy for prostate cancer is being shaped both by advances in technology and by reconsidering the epidemiological and outcomes data for available treatments. Here we focus on the evolution of the concept of focal therapy and its potential roles in the management of prostate cancer.
Introduction
Focal therapy for prostate cancer (PCa) is a management concept whereby active therapy is delivered to malignant portion(s) of the gland, eradicating the known and targeted cancer while sparing unaffected tissue and reducing the morbidity of treatment.[1] Whole-gland therapies such as radical prostatectomy and radiation carry a significant burden of side effects, and a concern regarding active surveillance is that it potentially misses the window of opportunity for active treatment and cure. In contrast, focal therapy—which combines active treatment of the identified clinically significant disease with active surveillance of the remaining unaffected prostate tissue—offers an intermediate means of active management of PCa with potentially better-preserved quality of life for the patient.
The landscape of prostate cancer management has been rapidly evolving, with technological advances in imaging and biopsy techniques offering novel tools for focal therapy approaches.[2,3] In this dynamic environment, the role of focal therapy is still being shaped, both by the rapid introduction of new technology and through reconsideration of the evidence regarding the epidemiology of prostate cancer and available treatment options.
Here we will focus on the recent evolution of the concept of focal therapy and the potential applications of this management approach within an array of options currently available for patients with localized PCa.
Focal Therapy as the Lesser Evil
The contemporary practice of overtreatment of low-risk PCa is well documented.[4,5] Today, most men diagnosed with PCa undergo whole-gland treatment, which in some patients will be associated with significant side effects that reduce their quality of life.[6] Importantly, a recent study could not confirm an overall or cancer-specific mortality benefit for radical prostatectomy over watchful waiting in men with low-risk disease.[4] Undoubtedly, however, active intervention puts the patients at risk for potentially severe complications.
Summary of the Available Outcomes of Focal Therapy in the Published Literature
In this setting, focal therapy, with its favorable side effects profile, may be a lesser evil. Preserving a man’s quality of life by avoiding the side effects of whole-gland treatment[7] is a significant consideration in many patients (especially those with low-risk disease), and focal therapy may be an excellent active-treatment option for prostate cancer. In fact, the morbidity of focal therapy approaches has been demonstrated to be quite favorable in several reports.[8-10] Reported potency rates are excellent, and incontinence and bowel-related side effects are extremely rare, whereas these side effects represent a considerable quality-of-life burden associated with whole-gland therapies.[7] (See the Table for a summary of currently available published outcomes of focal therapy, including oncological outcomes and complications.)
Salvaging Active Surveillance
Typically, men on active surveillance protocols harbor low-risk prostate cancer. Progression of disease on active surveillance, understaging of the disease in the initial evaluation, or simply the psychological difficulty that the surveillance strategy poses for some patients most often leads to eventual whole-gland treatment.[11] This transition from active surveillance to whole-gland therapy takes the least invasive approach and transforms it into the standard-template management of cancer, with its potential treatment-related side effects.
In this setting of preselected patients deemed suitable for the least aggressive approach—ie, active surveillance—focal therapy could be integrated seamlessly into a continuum of minimally invasive management of PCa.[12] In other words, if during active surveillance a clinically significant disease focus is identified (eg, by a Gleason score of 7, increased tumor volume, more positive biopsy cores) that “reclassifies” the patient and thereby deems him unfit for active surveillance, this lesion could be actively treated with focal therapy, eliminating the malignant focus and thus “requalifying” the patient for active surveillance. In fact, focal therapy necessarily includes elements of active surveillance, since the multifocal nature of PCa requires that the untreated portion(s) of the gland be monitored.
This approach is novel for PCa management, since we typically rely on the characteristics of PCa at the time of diagnosis while ignoring the dynamics of PCa’s natural history. Perhaps, however, this dogma should be reconsidered. Are the initial characteristics of the disease on presentation more important than staging after focal treatment? Once the focus of concerning disease (ie, the index lesion with a potentially aggressive natural history) has been eliminated, the cancer’s drive for progression has been effectively mitigated.[13]
Expanding the Indications
The evidence of overtreatment is compelling. While in patients with minimal-volume low-risk disease the benefits of any treatment may not be evident, making the right treatment choice becomes paramount in patients with intermediate- and high-risk disease, for whom the risks of disease progression and PCa-related mortality are significant.[4] Given the long natural history of PCa, even in intermediate- and high-risk patients,[14] preservation of a good quality of life is still an important factor that should be carefully weighed when considering management options.
There are no data to support the inferiority of ablative approaches in eliminating cancer cells, as compared to surgical extirpation or radiation. Moreover, the use of ablative approaches may exploit an additional antineoplastic tool—the immune system—by exposing tumor-specific antigens.[15,16] Thus, if a focal therapy approach is technically feasible, that is, if the lesions are amenable to complete ablation with preservation of healthy tissue, it may need to be considered among the management options for intermediate- and high-risk localized disease. In these patients, multimodality approaches may be required in the same manner as adjuvant treatments are employed in combination with surgery and radiation.
In addition, it has been suggested that the metastatic potential and lethality of prostate cancer may be linked to a specific clone of cancer cells,[13] identified as the index lesion—typically the largest focus of cancer with the most adverse pathological features. The evidence in the literature suggests that the index lesion is driving the natural history of prostate cancer, whereas satellite foci play little to no role in disease progression. Hence, specifically targeting the aggressive index lesion would theoretically enable us to control the malignant potential of the disease without turning to more aggressive and morbid management modalities. Utilization of focal therapy in this setting would not preclude future more aggressive treatments if these became necessary.
There is currently a drive toward expanding the criteria of patient eligibility for focal therapy. To establish focal therapy as an alternative to radical prostatectomy or radiation for select patients, the inclusion criteria need to be expanded, with an aim of recruiting intermediate- and high-risk patients for focal therapy trials to confirm the validity of the focal approach from the oncological standpoint.
Focal Therapy as a Downstaging Approach
Currently, strict criteria apply to candidates for active surveillance.[17] As a result, many men with localized, low-risk disease would not qualify[18] (based on number of positive cores, extent of cancer in a core, or prostate-specific antigen [PSA]-related measures) and would therefore resort to whole-gland treatment. In this scenario, focal therapy potentially could be used to downstage PCa, by eliminating malignant foci and reducing the burden of clinically significant disease, potentially enabling some of these patients to display the disease characteristics that would permit enrollment in active surveillance protocols. Similarly, if a patient did not meet the criteria for active surveillance because of a lesion with a Gleason score of 7 but would otherwise be eligible, this criterion could be addressed with focal therapy, effectively extending eligibility for active surveillance to select men with intermediate-risk PCa.
