Jean Yves Chapelon

Transrectal High Intensity Focused Ultrasound for the Treatment of Localized Prostate Cancer: Factors Influencing the Outcome

Objectives: Efficacy evaluation of high intensity focused ultrasound (HIFU) treatment for localized prostate cancer and identification of the factors affecting the outcome. Patients and Methods: 102 patients with prostate cancer stage T1–T2 and noncandidates for radical prostatectomy have been treated with HIFU (Ablatherm™, EDAP–Technomed). The disease progression (failure) was strictly defined by any positive sample at control biopsies, whatever the prostate–specific antigen (PSA) level, or by 3 consecutive increases in PSA levels in case of negative biopsies. Results: At inclusion, patients’ baseline characteristics were (mean ± standard deviation): age 70.8 (±6.13) years, PSA 8.38 (±4.8) ng/ml, prostate volume 33.3 (±16.71) cm3. The population mean follow–up was 19 months (3–76 months). The overall success rate was 66%. Statistically significant variations of the overall success with a more favorable outcome were observed when (1) the initial PSA level was ≤10 ng/ml (73 vs. 50%, p = 0.02), (2) the Gleason score was ≤6 (81 vs. 46%, p<0.001) and (3) the pretreatment sextant biopsy evidenced 1–4 positive samples (68 vs. 40%, p = 0.01). Conclusion: Results observed after HIFU treatment in localized prostate cancer are now challenging those obtained after radiation therapy. The success rate is influenced by disease–related prognostic factors.

LOCAL CONTROL OF PROSTATE CANCER BY TRANSRECTAL HIGH INTENSITY FOCUSED ULTRASOUND THERAPY: PRELIMINARY RESULTS

PURPOSE We conducted a phase I/II study to evaluate the efficacy of transrectal high intensity focused ultrasound in the treatment of localized prostate cancer and to assess associated complications. The efficacy of a new high intensity ultrasound device was evaluated using post-treatment prostate specific antigen (PSA) levels and histological results from prostate biopsies as end points. MATERIALS AND METHODS A total of 113 transrectal high intensity focused ultrasound sessions were performed in 50 patients with localized prostate cancer, who were not suitable candidates for radical prostatectomy. Of these patients 2 underwent salvage ultrasound treatment for locally recurrent cancer following definitive radiation therapy. Mean plus or minus standard deviation patient age, PSA and prostate volume were 70.7+/-4.54 years, 9.61+/-7.42 ng./ml. and 37.3+/-19.1 cc. The 2 different high intensity ultrasound prototypes were successfully used, and the latter prototype included several safety devices to reduce morbidity. Median followup was 24 months (range 3 to 46). Control parameters were changes in PSA and random control sextant biopsies at 1 to 3, 3 to 12, 12 to 24, 24 to 36 and 36 to 48 months. RESULTS For the evaluation of therapy patients were divided into 4 groups. Group 1 (complete response) included 28 patients (56%) with no residual cancer and PSA less than 4 ng./ml. (mean 0.93), group 2 (biochemical failure) 3 patients (6%) with no residual cancer and PSA greater than 4 ng./ml. (mean 6.22), group 3 (biochemical control) 9 patients (18%) with residual cancer (mean positive biopsy 1.1 of 6) and PSA less than 4 ng./ml. (mean 0.90), and group 4 (failures) 10 patients (20%) with residual cancer (mean positive biopsies 1.9 of 6) and PSA greater than 4 ng./ml. (mean 8.9). Of the 10 cases in group 4 hormone therapy was required in 3 and radiotherapy in 5. Complication rate with the first prototype device was 50% and it decreased to 17% with the second prototype. CONCLUSIONS Morbidity associated with high intensity focused ultrasound treatment is currently minimal. Local control of the localized prostate cancer was observed in groups 1, 2 and 3 (80%). Repeat sessions were deferred in groups 2 and 3 based on changes in PSA. These preliminary data suggest that high intensity focused ultrasound represents a valid alternative treatment strategy for patients with localized prostate cancer who are unsuitable for surgery.

Treatment of localised prostate cancer with transrectal high intensity focused ultrasound

With the advent of PSA dosing, an increasing number of prostate cancers are being detected at a local stage. Since 1989, our group has been developing a research project with the aim of establishing treatment of localised prostate cancer by means of HIFU. The treatment is performed transrectally, using ultrasound imaging guidance only. The quality of HIFU treatment depends on four factors: the intensity of the transmitted pulse, the exposure time, the signal frequency, and the time between two firing bursts. The lesions are created by a thermal effect. Their slightly conical form is due to the absorption of ultrasound by tissue, enhanced by cavitation bubbles. Results obtained since 1993 demonstrate that transrectally administered HIFU treatment achieves local control of localised prostate cancer in 80% of cases, with 70% complete success and 30% partial response. The use of an annular array probe with variable focus and frequency should significantly improve results in the future. Finally, real time visual display of the damaged tissue via differential imaging of the attenuation coefficient should give the surgeon an instant appreciation of the result of the sequence. It would thus be possible to repeat treatment of insufficiently covered zones in the same session.

High-intensity focused ultrasound experimentation on human benign prostatic hypertrophy

High intensity-focused ultrasound (HIFU) has been used transrectally to induce an intraprostatic coagulation necrosis lesion in human prostatic adenoma. The device to produce HIFU combines a firing system (power amplifier and therapy transducer) and an imaging system (ultrasound scanner). Nine patients have been treated on epidural anaesthesia with an ultrasound intensity similar to or higher than the acoustic intensity used in previous experiments on canine prostates. Intraprostatic lesions were obtained without any damage to the rectal wall. These lesions were also histologically determined to be coagulation necrosis with a complete destruction of the glandular tissue. These studies confirm the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall. The destruction of localised prostatic cancer would seem to be possible in the near future by using HIFU delivered by the transrectal route.

MRI Appearance of Prostate following Transrectal HIFU Ablation of Localized Cancer

Objectives: To evaluate the accuracy of gadolinium–enhanced MRI in gauging the extent of the tissue damage induced by transrectal high intensity focused ultrasound (HIFU) therapy and to assess how well the results obtained with this modality correlate with histological findings (control biopsies). Methods: Twenty–one patients with biopsy–proven prostate cancer (T1–T2–T3a, Nx, M0) who gave informed consent were included in the protocol. They underwent pre– and postoperative (2–5 days after HIFU treatment) MR examinations. Fifteen patients also underwent a follow–up MR examination 1–5 months postoperatively. MR findings were compared with the results of postoperative transrectal biopsy examinations. Results: The prostate volume increased after the HIFU session from 43.9±18.6 to 52.1±21 cm3 by day 2 (p<0.001). On fat–saturated gadolinium–enhanced T1–weighted images, the treated area appeared as a hypointense zone surrounded by a peripheral rim of enhancement in all patients. A positive correlation (r = 0.75) was found between the volume of the hypointense zone measured at days 2–5 (30±11 cm3, 67% of the posttreatment prostate volume) and the theoretical target volume (22±5 cm3, 61% of the initial prostate volume). MRI showed that the anterior part of the base was not reached by the ultrasound beam. The mean volume of the untreated zone (prostate without any MRI modifications) was 8 cm3 (range, 0.4–36). No correlation was found between the MRI appearance of the treated area and the intensity of the necrosis or the presence of foci of residual, viable cancer. Conclusion: Gadolinium–enhanced MRI is an accurate way of determining the extent of tissue damage induced in HIFU ablative therapy, but cannot predict histological results.

Whole-gland Ablation of Localized Prostate Cancer with High-intensity Focused Ultrasound: Oncologic Outcomes and Morbidity in 1002 Patients

BACKGROUND High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa). OBJECTIVE The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study. DESIGN, SETTING, AND PARTICIPANTS Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence. INTERVENTION Whole-gland prostate ablation with transrectal HIFU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2-13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression. RESULTS AND LIMITATIONS A total of 1002 patients were included. The median nadir prostate-specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA ≤0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients. CONCLUSIONS HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity.

Venous thrombosis generation by means of high-intensity focused ultrasound

Sclerotherapy of superficial varicose veins is now performed with chemical agents since physical agents have given only poor clinical results. We investigated the possibility of using high intensity focused ultrasound energy to achieve this goal in an animal model, the rat femoral vein. A specially designed probe delivering ultrasonic energy at a central frequency of 7.31 MHz was constructed and evaluated. Femoral veins of six rats were surgically exposed to a set of between four and seven 3-s exposures at 1-mm increments at a power level of 167 W/cm2. At 2 days following the irradiation, control veins were patent while occlusive thrombus was documented by Doppler flow and histological studies in all six of the irradiated veins. No damage to the surrounding soft tissues was noted. We concluded that high-intensity focused ultrasound can be used to induce thrombosis in this animal model.

New piezoelectric transducers for therapeutic ultrasound

Therapeutic ultrasound (US) has been of increasing interest during the past few years. However, the development of this technique depends on the availability of high-performance transducers. These transducers have to be optimised for focusing and steering high-power ultrasonic energy within the target volume. Recently developed high-power 1-3 piezocomposite materials bring to therapeutic US the exceptional electroacoustical properties of piezocomposite technology: these are high efficiency, large bandwidth, predictable beam pattern, more flexibility in terms of shaping and definition of sampling in annular arrays, linear arrays or matrix arrays. The construction and evaluation of several prototypes illustrates the benefit of this new approach that opens the way to further progress in therapeutic US.

Differential Attenuation Imaging for the Characterization of High Intensity Focused Ultrasound Lesions

High intensity focused ultrasound (HIFU) is an effective technique for creating coagulative necrotic lesions in biological tissue, with a view to treating localized tumors. Although good results have already been obtained, notably in urology, current systems lack a real time monitoring system to check the efficacy of the treatment procedures. This study describes the development and assessment of a noninvasive system for making local measurements of attenuation variations during HIFU treatment procedures. An apparatus (Ablatherm, Edap-Technomed, France), combining a 2.5 MHz therapeutic transducer and a 5.5 MHz twin plane imaging probe (connected to an ultrasound scanner), was used to produce lesions. The rf signals needed to calculate the attenuation were recorded as outputs from the ultrasound scanner, before and after the high intensity firing sequences, which were performed on ten pieces of porcine liver. Each firing sequence involved producing a lesion volume comprising 42 individual lesions. A number of recordings were also made without producing lesions, in order to test the reproducibility of the measurements. The attenuation function was evaluated locally using the centroid and the multinarrowband methods. Initially, changes in the integrated attenuation αbar; (mean attenuation in the 4–7 MHz range) and the attenuation slope β were examined for the lesion volume. β values did not vary significantly within this range, whereas α values varied significantly (in the region of 86% of the initial level) in comparison to measurements performed without forming lesions. The differential attenuation Δα (representing local variations in α) was subsequently used to generate images revealing the lesion areas. There was a strong similarity between these ‘Δα images’ and the lesion volumes defined by the operator. ‘Δα images’ offer several advantages over existing attenuation imaging techniques. Any problems related to the heterogeneity of the medium are eliminated, since only the change in attenuation is taken into account. Furthermore, there is no need to compensate for diffraction when estimating Δα, as the rf signals are captured in exactly the same positions before and after treatment. This technique can be used during in vivo treatment procedures. It can be implemented in real time, since the computational algorithms (based primarily on FFT calculations) are very fast. The technique should provide clinical practitioners with valuable qualitative and quantitative information for use in HIFU ultrasound surgery.

Design and preliminary results of an ultrasound applicator for interstitial thermal coagulation

The extracorporeal high-intensity focused ultrasound (HIFU) techniques are not still transposable for tumors of the digestive tract because of their locations. This study was designed to evaluate the feasibility of interstitial applicators (3.8 mm O.D.) to comply with this therapeutic lack and to demonstrate the possibility of producing coagulation necrosis by a specially designed probe and with a short exposure time (20 s). The active surface of the applicators consists of plane water-cooled PZT transducers working at 10 or 5 MHz. They were evaluated in terms of acoustic power emitted as a function of the frequency, and applied electrical input (electroacoustic efficiency of 75% at their working frequency) and in vitro and in vivo pig liver tissue destruction. The in vitro and in vivo necroses depth from the applicator surface ranged from 8 to 20 mm. This showed the advantage of a nondivergent source: the pressure decay is only due to the tissue absorption in the Fresnel zone. The lesions dimensions are slightly dependent on perfusion: 8 +/- 2 mm deep in vitro for a 10.7-MHz transducer working at 14 W/cm2 against 10 mm in vivo. Operating at 5 MHz makes it possible to increase the therapeutic heating depth. For example, at a similar close-to-transducer temperature, the 5-MHz applicator induced, at a depth of 10 mm, a temperature elevation of 27 degrees C against 15 degrees C for that working at 10 MHz.