Focal Therapy as Alternative for Whole-Gland Therapy for Intermediate-Risk Prostate Cancer

The role of focal therapy in the treatment of localized prostate cancer was reviewed at the 2021 ASTRO annual meeting by Andrew J. Stephenson, MD, Director of Urologic Oncology and Professor of Surgery at Rush University Medical Center, Chicago, IL. Focal therapy has been under discussion for close to 20 years but has not yet been widely adopted for patients outside very specialized practices, Dr Stephenson acknowledged. Now, however, it is almost ready for “prime time” as a consideration for the treatment of patients with intermediate-risk disease, he declared.

Dr Stephenson acknowledged that most of what is known about the lethality associated with intermediate-risk prostate cancer comes from older case series that showed high mortality. One study carried out in the “pre- PSA era” reported mortality rates of ≥50% within 10-15 years of diagnosis among patients with Gleason score 7 disease who had not undergone any definitive treatment.1 However more recent data from the PIVOT randomized trial of surgery versus watchful waiting in men with localized prostate cancer detected by PSA found that for intermediate-risk patients on watchful waiting, the 12- year rate of bone metastases was 9% and prostate cancer-specific mortality 4%, similar to that in patients who had received definitive therapy.2

All the treatments currently available, including surgery and radiation therapy, have significant impacts on quality of life, Dr Stephenson pointed out. Radiation, surgery, or brachytherapy have significant consequences for urinary, bowel, and sexual function, and few patients return to their baseline, pre-treatment level of function.3 The ProtecT trial showed that quality of life outcomes were almost the same whether patients received surgery, radiation therapy, or active surveillance.4 “So we think that active surveillance is going to preserve quality of life in these patients, but the long-term data from ProtecT would argue otherwise,” Dr Stephenson stated, pointing out that 60% of the patients on the active surveillance arm of the trial went on to receive some form of radical therapy.

Organ-sparing (focal) therapy is used in many areas of oncology such as kidney cancer, where it is standard of care for patients with small renal masses, to preserve long-term renal function, Dr Stephenson noted. For prostate cancer, “the key is to achieve similar success rates of oncologic control, while hopefully giving patients benefits in terms of preserving potency and urinary function while reducing rectal toxicity,” he said. Many of the questions raised about focal therapy 10 years ago are still relevant today, he noted. These are: Can unilateral cancers be identified? Can focal therapy be instituted safely and effectively? Will focal therapy improve quality of life while producing acceptable oncologic outcomes? Can treatment failures be identified, retreated, or treated by radical therapies successfully? “In the past 10 years there has been substantial progress in each of these areas,” Dr Stephenson stressed.

An answer to the question of whether unilateral prostate cancers are common was provided by a study in whole-mount specimens from radical prostatectomy patients, which showed that there are typically 2-3 separate cancer foci within the prostate.5 Pathologically, up to 38% of patients will have unilateral cancers (28% for low-risk patients and slightly higher for intermediate-risk patients). Dr Stephenson added that in focal therapy, it may be appropriate to target the larger index tumor, because many studies have shown that the index tumor is the source of progressive disease in almost all patients, with only 3% of index tumors containing Gleason grade tumors lower than the overall Gleason score.6

Image-guided biopsy and staging of prostate cancer have constituted a major step forward in developing focal therapy, Dr Stephenson pointed out. “Prior to the development of high-quality multi-parametric MRI (mpMRI), we relied heavily on 3-dimensional template mapping biopsy using the brachytherapy template and sticking 50-60 needles in the prostate to aggregately assess the extent of disease prior to treatment,” he recalled. A study from Germany illustrated how MRI-guided biopsy could be as effective as a template mapping biopsy in identifying areas of clinically significant prostate cancer.7 For this study, clinically significant prostate cancer was defined as patients with Gleason ≥3+4 disease. So avoiding template mapping biopsy would be beneficial in the acceptance of focal therapy and instituting it in practice, Dr Stephenson suggested.

A recent study that compared MRI-guided biopsy and standard biopsy in men with MRI-visible prostate lesions showed that combining targeted biopsy with standard biopsy gives a very accurate assessment of extent of disease and Gleason grade.8 In addition, combined MRI-guided biopsy and standard biopsy resulted in cancer stage upgrading in only 14% of patients overall. Dr Stephenson added that these data suggest that combining high-quality MRI-guided biopsy with extended 10-12 core standard biopsy will be effective in up to 85% of patients in accurately assessing the disease extent.

The question of whether prostate cancer can be identified as just unilateral has been answered in the affirmative, Dr Stephenson asserted. Conventional transrectal approaches and saturation biopsy approaches are unreliable and there are significant limitations to 3-dimensional transperineal mapping biopsy (patient acceptance, added cost, may compromise downstream treatments). With combined MRI-guided biopsy with standard biopsy, the negative predictive value for clinically significant prostate cancer is up to 85%, so localized disease can be adequately identified.

Information about the status of focal therapy is available from only a few retrospective series. The safety and benefits are unproven and there are many controversies, Dr Stephenson admitted. There are different ways to institute focal therapy, including thermal ablative techniques (cryotherapy, high intensity focused ultrasound [HIFU], radiofrequency ablation), brachytherapy, or other technologies such as irreversible electroporation (NanoKnife, AngioDynamics) or photodynamic therapy.9 Tumor target volume for focal therapy is still under investigation, whether hemiablation, subtotal ablation, or true focal therapy treating the targeted lesion with a small margin.

Addressing patient selection for focal therapy, Dr Stephenson noted that an international consensus formed to identify patient selection for focal therapy trials recommended including patients with T1c-T2a, Gleason score ≤3+4 , and PSA <15 ng/mL.10 mpMRI plus MR-guided biopsy should be performed in addition to systematic transrectal ultrasound (TRUS) guided biopsy. It is acceptable to not treat small areas of Gleason 6 lesions (core length <5 mm). Follow-up should include MRI-guided biopsy. In-field treatment failure is defined as cancer of higher grade, persistent cancer of similar or lower grade after repeat focal therapy to the same area, or the need for additional prostate cancer other than focal therapy. Dr Stephenson noted that PSA level is not considered a reliable marker for treatment success with focal therapy.

For focal cryotherapy, 11 series in 1950 patients with a median (“relatively short”) follow-up of 26 months have been reported, showing “fairly acceptable success rates oncologically,” with significant or insignificant cancer identified in only 5.4% of patients after treatment, Dr Stephenson noted. Secondary treatments were required in fewer than 10% of patients. There were high rates of pad-free continence (100%) and potency (89%). Similar results were seen in the focal HIFU series with a smaller number of patients, with “very acceptable” rates of cancer control and a low percentage (7.8%) of patients needing a secondary treatment either via re-ablation or more radical therapy.9 UK data on a single-center experience with index lesion ablation using HIFU showed very high rates of continence, good rates of potency, and 85% success rate of cancer control at 12 months.11 The trifecta outcome of absence of cancer at 12 months, potency, and continence was achieved in up to 60% of patients, comparing very favorably with radical prostatectomy and radiation series at centers of excellence around the world, Dr Stephenson commented.

Comparison studies of HIFU and irreversible electroporation have mostly shown low rates of in-field recurrence and low rates of out-of-field recurrence, which relates to patient selection, and freedom from radical therapy was achieved in nearly all patients (97%).12 Rates of continence and lack of erectile dysfunction were “very acceptable,” and ≤10% patients had serious morbidities such as fistulas, retention, or hematuria.

Dr Stephenson concluded that although focal therapy for the treatment of intermediate-risk prostate cancer is not yet ready for prime time, it is on its way. “I think most of the treatments should be done on protocol,” he cautioned. “It’s not without toxicity,” he acknowledged, but preliminary data suggest very low rates of sexual dysfunction (<10%) and incontinence (0-7%), with an acceptable rate of complications such as UTI, retention, fistula, and follow-on to TURP. Outcomes in prostate cancer are similar to those with percutaneous ablation in kidney cancer, he noted. In-field treatment failures are about 10-15% in most series. Focal therapy has the additional advantage that it can be done as an office-based procedure under intravenous sedation, which increases its potential for patient acceptance.

“I think of focal therapy as disruptive technology,” Dr Stephenson declared. “A lot of it relies heavily on technical innovations, and I think with improvements in the staging and molecular and biological assessment of prostate cancer and delivery methods, focal therapy is going to be a reality for the careers of most urologic cancer specialists practicing today,” he predicted.