MRI-guided focused ultrasound focal therapy produced “a high degree of success” and “a low rate of genitourinary adverse events” when used to treat select patients with intermediate-grade prostate cancer, Behfar Ehdaie, MD, MPH, and colleagues reported in The Lancet Oncology.¹ Dr. Ehdaie is Associate Professor, Urology Service, Department of Surgery at Memorial Sloan Kettering Cancer Center, New York.

Behfar Ehdaie, MD, MPH

In a phase IIb multicenter study among 101 men with grade group 2 or 3 prostate cancer (Gleason score 3 + 4 = 7 or Gleason score 4 + 3 = 7) treated with MRI-guided focused ultrasound focal therapy, biopsies performed at 6 months showed that 96 patients (95%) had no evidence of grade group 2 or higher cancer in the treated area, and 77 patients (76%) had no evidence of grade group 2 or higher cancer in the entire prostate gland. At 24 months, 78 patients (88% of the 89 patients) had no evidence of grade group 2 or higher cancer in the targeted area, and 59 patients (60%) had no evidence of grade group 2 or higher cancer in the entire prostate gland. Serum prostate-specific antigen (PSA) levels decreased after treatment (mean decrease, –3·0 ng/mL), then stabilized at 6 months, and rose slightly at 24 months.

“No grade 4 or 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths,” the authors noted. Scores for erectile, mean intercourse satisfaction, and overall satisfaction were slightly worse at 24 months than at baseline. “These functional outcomes compare very favorably to patient-reported outcomes after whole-gland treatments, such as radical prostatectomy and radiotherapy, which, although effective, are associated with substantial and persistent side effects that impact quality of life,” the authors wrote.

Durability of Results Unknown

The study results “support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term,” the investigators concluded.

“What is unknown is the durability of the trial results compared with active surveillance,” Dr. Eidaie said in an interview with The ASCO Post. “Would MRI-guided focused ultrasound focal therapy demonstrate a clinical benefit long term for avoiding radical treatment with surgery or radiation therapy? The comparative studies would enable us to answer that question.” 

“For now, we believe the data suggest safety for men with intermediate-risk prostate cancer with a focal lesion,” Dr. Ehdaie stated. “We must be mindful that our current preferred treatment option for men with low-risk cancer is active surveillance. We believe the clinical benefit of focal therapy and active surveillance is to avoid radical therapy, including surgery and radiation treatment. So, therefore, the goal would be to determine whether focal therapy provides a paradigm to avoid radical treatment compared with active surveillance.”

“It is important to note,” Dr. Ehdaie added, “that we worked closely with the FDA to determine a trial and outcome that would present an opportunity to achieve a cancer indication for a focal therapy device.”

We believe the clinical benefit of focal therapy and active surveillance is to avoid radical therapy, including surgery and radiation treatment.

— Behfar Ehdaie, MD, MPH

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Select Patients

“Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy,” the authors noted. To “investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localized grade group 2 or 3 intermediate-risk prostate cancer,” the single-arm study, conducted at eight centers, enrolled patients who were diagnosed with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma, with a PSA value of up to 20 ng/mL (median concentration, 5.7 ng/mL). All had grade group 2 or 3 tumor classification confirmed by combined MRI-targeted and systematic biopsies. The men were aged 50 or older, with a median age of 63, and there was no upper age limit or minimum life expectancy requirement.

A total of 53 patients had treatment in the apex, 81 had treatment in the mid-gland, 44 had treatment in the base of the gland, and 26 had treatment directed anteriorly in the transition zone. “The purpose of those data,” Dr. Ehdaie explained, “was to determine where the index tumor was located in our patient population and to demonstrate that not only were we selecting a broad cohort of intermediate-risk prostate cancer patients, including grade group 2 and grade group 3, but also a broad cohort of patients in regard to tumor location.”

The study report described: “MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60–70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring.”

“The advantages of our study,” Dr. Ehdaie explained, “include following all the men in the study with 6-month and 24-month biopsies. We did not rely on imaging or PSA kinetics to determine recurrence.” Another strength “was that it was a multicenter study and included centers both in urban and rural areas and in private practice,” he added. “Therefore, that provides data that this treatment is feasible and acceptable to patients.”

"Although the study is closed,” Dr. Ehdaie noted, “many of those patients continue to be in our practice. Others are also enrolled in centers in which patients are monitored with routine patient-reported outcomes and are centers of excellence regarding reporting retrospective studies.”

Over time, we will see more men treated with focal therapy achieve benefits by delaying or avoiding radical treatment as compared with active surveillance, specifically men with intermediate-risk disease.

— Behfar Ehdaie, MD, MPH

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Avoiding Whole-Gland Treatment

In contrast to therapeutic strategies “directed at the whole gland, despite substantial variation in cancer volume, location, and other risk factors within this category,” the strategy used in the current study, the researchers reported “is to reduce the risk of metastases and preserve quality of life by treating the index tumor alone—that is the highest-grade tumor with the highest risk of metastasis. The emergence of multiparametric MRI and the introduction of ultrasound/magnetic resonance fusion devices to perform MRI-targeted prostate biopsies have raised the possibility of an organ-sparing focal therapy approach,” the authors noted.

“Our results compare favorably with other prospective focal therapy trials; 88% of our patients had no clinically significant cancer (grade group 2 or higher) after treatment in the targeted area, and 60% overall were observed to have no clinically significant prostate cancer detected anywhere within the prostate gland, thereby avoiding whole-gland treatment for at least 24 months after MRI-guided focused ultrasound treatment,” the researchers wrote.

The study data “support the efficacy of MRI-guided focused ultrasound focal therapy for targeting prostate cancer tissue in adequately selected patients with intermediate-risk prostate cancer seeking to avoid radical whole-gland treatment,” the authors wrote.

Increase in Active Surveillance

An increasing number of patients are seeking to avoid whole-gland treatment, Dr. Ehdaie added. “In the past 10 years,” he said, “we have seen a shift in patients seeking treatment for prostate cancer with the emergence of active surveillance. Patients are more accepting and seeking treatment that would avoid radical treatment including surgery or radiation.”

Evidence of the increasing acceptance of active surveillance was seen in a study presented at the 2022 American Urological Association Annual Meeting and reported in The ASCO Post.^2,3 A retrospective analysis among more than 20,000 men with low-risk prostate cancer found that nearly 60% opted for active surveillance in 2021 compared with 27% in 2014.

Comfort with active surveillance “is predominantly based on the communication and trust between the patient and the physician,” Dr. Ehdaie commented. “If a patient has low-risk prostate cancer, depending on the circumstances, the preferred management option remains active surveillance.”

“Our hypothesis is that over time, we will see more men treated with focal therapy achieve benefits by delaying or avoiding radical treatment as compared with active surveillance, specifically men with intermediate-risk disease,” Dr. Ehdaie remarked.

Quality-of-Life Outcomes

“Quality-of-life outcomes are important for patients, specifically patient-reported outcomes in regard to erectile function and urinary function,” Dr. Ehdaie said. “It is notable in this study that we use a high threshold for reporting functional erections. Therefore, when comparing with other treatment modalities and other studies, it is important to understand the details of how we define functional erections and urinary continence.”

The study report details follow: “Urinary function was measured with the International Prostate Symptom Score and the International Consultation on Incontinence Questionnaire–Urinary Incontinence Short Form. Erectile function was measured with the 15-item International Index of Erectile Function; this questionnaire also measured intercourse and overall satisfaction.”

Most patients in the trial had moderate or mild lower urinary tract symptoms at baseline and throughout the study period. Although 18 patients reported grade 2 or lower incontinence, none reported stress urinary incontinence requiring the use of pads.

Functional Erections

Among 40 of the 58 men (69%) who reported functional erections at baseline and responded to the 24-month follow-up, 18 reported grade 0 erectile dysfunction; another 18 reported grade 1 or 2 erectile dysfunction; and 4 reported grade 3 erectile dysfunction.

“It is clear in our study that when compared with other cohorts in both retrospective and prospective studies, using the higher threshold of erectile function, and including the utilization, or lack thereof, of erectile medication provides a favorable and superior comparison to whole-gland treatment,” Dr. Ehdaie stated.

“Although the difference in mean erectile function scores was significant, the small difference should be interpreted across the range of the overall score and considered across the time range of 2 years, in which small decreases in erectile function score are expected without treatment, making this change statistically but not clinically significant,” the authors noted. “These functional outcomes compare very favorably to patient-reported outcomes after whole-gland treatments, such as radical prostatectomy and radiotherapy, which, although effective, are associated with substantial and persistent side effects that impact quality of life.”

Data from the trial, Dr. Ehdaie noted, “provide an opportunity for physicians and patients to engage in shared decision-making by reporting erectile function at various time points” and providing guidance on when erectile medication may or may not be needed.

Treatment Failures

At the 6-month biopsy, 19 men had newly detected grade group 2 or higher prostate cancer outside of the treatment area alone. “At that point, those men exited the study with treatment failure and subsequently had counseling with their physicians to undergo either whole-gland treatment or active surveillance,” Dr. Ehdaie explained. “Many of those men continued to avoid treatment and were monitored with active surveillance, because the cancers detected were small-volume or intermediate-risk.”

“Given the short interval between biopsies, rather than representing new sites of cancer, these men most probably harbored these additional undetected cancers before treatment,” according to the study report. “It may suggest that we will need to continue to improve our diagnostic techniques,” Dr. Ehdaie remarked. Previous studies have “demonstrated that upward of 20% to 25% of high-grade prostate cancers may not be either visible or detected with MRI-targeted biopsies.”

“Although the long-term clinical significance of these newly detected low-volume grade group 2 or 3 tumors is unknown, saturation systematic-template prostate biopsy combined with MRI-targeted biopsy cores might be important to minimize short-term treatment failure after focal therapy,” the study authors noted. 

“For this study, we used our traditional systematic biopsy, which included 14 cores, and then added areas that were targeted based on regions of interest on MRI,” Dr. Ehdaie explained. “However, there have been studies that have identified improved higher grade cancer detection using a saturation biopsy template, which includes more than 30 to 40 biopsy cores taken of the prostate gland to better select patients for focal therapy.” 

DISCLOSURE: The trial was funded by Insightec and the National Cancer Institute (ClinicalTrials.gov identifier NCT01657942). Dr. Ehdaie has reported being an unpaid consultant to Insightec and serving as a paid consultant to Myriad Genetics.

REFERENCES

1. Ehdaie B, Tempany CM, Holland F, et al: MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: A phase 2b, multicentre study. Lancet Oncol 23:910-918, 2022.

2. Cooperberg M, Meeks W, Fang R, et al: Active surveillance for low-risk prostate cancer: Time trends and variation in the AUA Quality (AQUA) Registry. 2022 American Urological Association Annual Meeting. Abstract MP43-03. Presented May 15, 2022.

3. Doyle C: Rates of active surveillance rising among men with low-risk prostate cancer but still suboptimal. The ASCO Post. June 25, 2022. Available at https://ascopost.com/issues/june-25-2022/rates-of-active-surveillance-rising-among-men-with-low-risk-prostate-cancer-but-still-suboptimal/. Accessed August 1, 2022.