With the publication in December 2024 of the study HIFI-01 In European Urology[1]high-intensity focused ultrasound (HIFU) is emerging as a validated alternative, particularly to radical prostatectomy, in the treatment of localized prostate cancer, with the advantage of less urinary and sexual morbidity. The first author of this publication, Pr Guillaume Ploussard (UROSUD urology department, Clinique La Croix du Sud, Quint-Fonsegrives, France) is coordinator of the Prostate Cancer Committee within the Cancerology Committee of the French Urology Association (CCAFU), promoter of HIFI-01 . Interview.
The HIFU technique consists of introducing a focused ultrasound emitter rectally, with a head applied directly to the prostate. The operator modulates the depth of action of the ultrasound to destroy the targeted tissues by cell rupture and coagulation necrosis.
With the publication of the HIFI-01 study, and the favorable opinion of the High health authority (HAS, December 2023) opening the possibility of reimbursement expected in the first months of 2025, in certain cases of localized prostate cancer, high-intensity focused ultrasound (HIFU) could allow many patients to Avoid radical treatment, at least initially.
The HIFI study, promoted by the French Association of Urologycompares the use of the Focal One® HIFU system, based on robotic navigation, to surgery, which remains the reference treatment.
Can you describe your phase 3 clinical study? [1]which Professor Pascal Rischmann, principal investigator of the study, presents “as the largest prospective comparative multicenter study ever conducted to compare different treatments for prostate cancer”[2] ?
Pr Guillaume Ploussard: Between 2015 to 2019, this prospective and multicenter study included 3328 patients distributed in 46 centers: 1967 treated by HIFU and 1361 by total prostatectomy (PT). The median age was 74.7 years for the HIFU group and 65.1 years for the PR group (p < 0.001), while the median PSA was 7.1 ng/ml for the HIFU group and 6 .9 ng/ml for the PR group (p = 0.5). The primary inclusion criterion was low or intermediate risk prostate cancer. The primary endpoint was salvage treatment-free survival (SSTR), with secondary endpoints including metastasis-free survival, prostate cancer-specific survival, overall survival, and functional outcomes.
The HIFI study achieved its primary objective, demonstrating non-inferiority of salvage treatment-free survival after HIFU compared to PT at 30 months: SSTR was not inferior in the HIFU group (relative risk 0.71 , 95% CI: 0.52-0.97; p = 0.008), after adjustment for several variables (age, BMI, ASA score, grade, prostate volume, rate of PSA). This result is also confirmed in the intermediate risk subgroup (HR = 0.66 [IC à 95 %, 0,50-0,86]p = 0,001).
The results not only underline the quality of oncological control by HIFU, of the same order as surgery, but also highlight better functional results compared to surgery?
Indeed, the functional results showed better preservation of urinary and erectile functions in patients treated with HIFU. Specifically, the International Continence Society (ICS) score, which assesses strict urinary continence (“no leak” versus “at least one leak per day”), was significantly less degraded for patients treated with HIFU (29%). ) compared to those treated by total prostatectomy (44%) (RR = 0.66 [IC à 95 %, 0,59-0,74]p < 0.001), all ages combined. Urinary continence was less impaired after HIFU despite a difference in median age of almost 10 years between the groups. This factor is important to consider because patient-reported results in the ProtecT study [3]showed that age represented a major factor in impaired function, regardless of the treatment used.
For its part, the international index of erectile function (IIEF-5) decreased significantly less after HIFU than after PT, with a median difference of -3 (-3.9; -2.1) between the two groups. The advantages of HIFU treatment on erectile function and urinary continence are therefore confirmed, despite a median age of 74.7 years for the HIFU group compared to 65.1 years for the PT group (p < 0.001).
Furthermore, no difference was observed regarding quality of life (QLCQ-30), both before and after treatment, nor between the two groups.
We can read that approximately 10% of patients experienced urinary retention after HIFU. Complications of grade greater than IIIa occurred in 54/1967 cases in the HIFU group and 29/1361 cases in the RA group (p = 0.3). Can we only attribute them to the age difference regarding inclusion in the HIFU or PT groups?
This is our belief. Differences in age and comorbidity profile at baseline probably explain the higher rate of serious adverse events in the HIFU group, collected not only immediately postoperatively, but during the 30 months that the study lasted. . Other reasons could be the lack of a standardized post-HIFU procedure for bladder catheterization and the lack of experience in HIFU treatment for 38% of centers at the start of the study.
Our large, multicenter study provides valuable comparative data, although it is limited by its nonrandomized design, treatment selection bias, patient age within groups, and medium-term follow-up. In accordance with the High Authority of Health and taking into account the age difference between the groups, it was decided to compare the two groups without randomization and to provide an IPTW /Inverse Probability of Treatment Weighting analysis.
Results adjusted for propensity score or selected covariates were similar to the crude univariate results, confirming the non-inferiority of HIFU compared to RA. The 3:2 ratio for HIFU/PR is methodologically acceptable for a comparative study. Furthermore, salvage treatment decisions could have been influenced by the different age between the groups, potentially favoring salvage treatment in the RA group at recurrence, due to the younger age and better profile. health of these patients. Nevertheless, the proportion of patients treated with HIFU and subsequently managed with active surveillance and additional HIFU was low.
-Thus, the data on cancer control are solid and make it possible to move HIFU out of the experimental phase: the cancer control results are comparable between the two approaches, which supports the safety of HIFU. They have the other advantage – as a minimally invasive therapy – of being customizable according to the sextants concerned and the tumor volume. As part of the authorization issued by the High Authority of Health, it was required in HIFI-01 to treat at least 70% of the prostate in order to guarantee patient safety. However, the long-term goal is to target the smallest area possible in order to limit side effects (safety margins of one centimeter). A single session is enough (only 5% of second HIFU treatment).
Note, patient monitoring presents an increased risk of development of another cancer in an untreated prostate area, with a probability of 20%. In this case, a second session may be necessary.
With the HIFI-01 study, urologists will have in a few months a reimbursed alternative to radical therapies (radical prostatectomy, radiotherapy, brachytherapy). The CCAFU published its update in mid-2024. In your opinion, what role will quickly be given to HIFU?
The data from the HIFI-01 study must first be analyzed by the Cancerology Committee, which will decide on the place to be given to this treatment in the therapeutic arsenal. Based on these interesting results, HIFU could be offered, after discussion with the patient, especially since it will soon be reimbursed by Health Insurance, in the management of favorable intermediate risk cancers. Around 2,000 men per year in France could be affected by this treatment.
With the publication of HIFI-01, HIFU treatment could thus be validated as a conservative curative alternative for intermediate-risk prostate cancer, with a grade of recommendations that would remain low, given the absence of long-term data. .
It is important to emphasize that active surveillance is the gold standard treatment for low-risk grade 1 lesions. Radical treatments such as RA and radiotherapy must remain secondary options. Thus, the inclusion of patients with low-risk prostate cancer in the HIFI-01 study could be interpreted as overtreatment. However, the slight change in recommendations clearly favoring active surveillance in low-risk prostate cancer is recent (updated French and European guidelines in 2022 and 2024), while the HIFI -01 study was designed and launched in 2014.
Is it more about avoiding overtreatment at intermediate stages?
That’s correct. As soon as reimbursement is obtained, it will be possible to offer the technique as first-line treatment or in the event of recurrence after external radiotherapy, following a concerted decision between health professionals and the patient.
It may be offered to men with newly diagnosed intermediate-risk prostate cancer, i.e. grade 2, as observed in the HIFI-01 study. There is no specific age for newly diagnosed prostate cancer, whether low or intermediate risk (PSA less than 20ng/ml and Gleason score 6 or 7). However, a maximum age is taken into account: if a patient’s life expectancy is less than 10 years, it is not relevant to treat their prostate cancer.
HAS has established patient selection criteria as part of the HIFI-01 study, including an age greater than 70 years. But these criteria will probably be re-evaluated and expanded in future CCAFU recommendations, with wider age ranges.
The main limitation of the HIFI-01 study remains the medium-term follow-up, which prevents any firm conclusion regarding long-term oncological effectiveness and limits the generalization of the results. To really clarify the role of this ablative therapy in cases of localized prostatic adenocarcinoma, we will have to wait for longer-term results. All patients included in the study continue to be followed.
Links of interest of experts: None. The HIFI study was supported by the General Directorate of Care Organization, through an Innovation Package financed by the Ministry of the Budget, under the control of the HAS as well as the ANSM.
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