Dietrich Pfeiffer, Department of Urology, Asklepios Hospital Hamburg-Barmbek, Ruebenkamp 220, D-22291 Hamburg, Germany. e-mail: firstname.lastname@example.org
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
High-intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence.
The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low-risk disease, with rates of efficacy declining in intermediate- and high-risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low-risk disease.
• To report cancer control results after a single application of high-intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification.
PATIENTS AND METHODS
• In a retrospective single-centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP-TMS, France).
• Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands.
• Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to ≥0.5 ng/mL if PSA doubling time was ≤6 months. Kaplan–Meier analysis was performed for survival estimates.
• A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51–82) years, and 38, 34 and 28% of these patients were in the low-, intermediate- and high-risk groups, respectively.
• The median (range) follow-up was 52.8 (0.2–79.8) months.
• At 5 years, overall and cancer-specific survival rates were 86.3% and 98.4%, respectively.
• Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5-year biochemical-free survival rates were 84.8%, 64.9% and 54.9% (P < 0.01), and 5-year disease-free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively.
• Single-session HIFU is recommended as a curative approach in elderly patients with low-risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU.
The majority of elderly men with localized prostate cancer (PCa) receive active treatment with curative intent. Radiotherapy (RT) with external beam irradiation or brachytherapy is more widely used in the treatment of men aged 65–75 years, while radical prostatectomy (RP) is used less often in this age group [1,2]. High-intensity focused ultrasound (HIFU) is a non-surgical, minimally invasive procedure that ablates the prostate in situ. Oncological outcomes were first reported in 1995  and 1996 , and subsequently, the use of HIFU therapy has expanded to include the treatment of localized PCa with a high risk of tumour progression . As a result of several reports of long-term efficacy, HIFU is now considered an alternative to RT [6,7].
A primary advantage of treatment with HIFU over RT and RP is the ability to repeat treatment in cases of local failure , and long-term studies have shown retreatment rates between 30 and 40% [6,7]; however, as most of the published HIFU efficacy rates include the results of retreatment , there is a lack of data on the efficacy from a single HIFU application in the treatment of PCa.
In the present retrospective single-centre study, we evaluated the oncological outcomes of single-session HIFU treatment of localized PCa. Treatment-related morbidity and urological aftercare are also discussed.
PATIENTS AND METHODS
Since December 2002, elderly patients or patients with significant medical comorbidities diagnosed with clinically localized PCa were offered HIFU as a first-line therapy with curative intent. All the patients were unsuitable candidates for RP and unwilling to undergo RT. The study was approved by the local ethics committee and all patients provided written informed consent. Extracapsular tumour extension and lymph node status were assessed using pelvic CT or MRI. Staging included a bone scan in patients with PSA ≥ 10 ng/mL, and laparoscopic lymphadenectomy was recommended in patients with PSA > 20 ng/mL. Excluded from the study were patients with nodal extension or metastatic disease. Androgen deprivation therapy (ADT) was discontinued at the time of HIFU therapy. Treatment involved the use of the Ablatherm Maxis® or (after February 2006) the Ablatherm Integrated Imaging® HIFU device (EDAP-TMS SA, Lyon, France). The treatment goal was destruction of the prostate with a safety margin of 6 mm from the apex to preserve the urethral sphincter. In patients with enlarged prostate glands (anterior–posterior diameter >3 cm [as measured by TRUS]), TURP or transvesical adenomectomy were performed before HIFU to reduce the gland size.
Postoperative follow-up included PSA measurements at 2, 3 and 6 months, and every 3 months thereafter. Control biopsies were recommended after 6 months and in cases where the PSA level had increased. Evaluation for metastasis was initiated in cases of PSA progression. Patient status was assessed periodically, and treatment-related morbidity was recorded during the initial 12 months of follow-up using self-administered questionnaires. Cause of death was identified from physician correspondence.
The retrospective evaluation of cancer control included the results of all PSA tests, biopsies, and imaging procedures. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (the Stuttgart definition) , or as a PSA rise to ≥0.5 ng/mL, if the PSA doubling time (PSA-DT) was ≤6 months . Oncological failure was expressed as biochemical relapse or positive biopsy, whichever occurred first. Patients were stratified into subgroups according to risk of tumour recurrence : low risk: clinical stage T1–T2a, preoperative PSA ≤10 ng/mL and biopsy Gleason score ≤6; intermediate risk: stage T2b or PSA > 10 to ≤20 ng/mL or Gleason score 7; and high risk: stage T2C or PSA > 20 ng/mL or Gleason score ≥8. Criteria for the high-risk category were modified to include patients with pathological stages cT3a and cT3b. The follow-up period was defined as the interval between HIFU treatment and last available monitoring data or the date of death.
Quantitative variables were expressed as median values and ranges in the whole study population and as median values and interquartile ranges (IQR) in subgroups. The preoperative tumour characteristics were summarized in frequency tables and oncological outcomes were cross-tabulated with the D'Amico risk groups. The Kaplan–Meier method was used to construct survival curves, which were compared using the log-rank test, and a Cox regression model was used in the univariate and multivariate analysis of the prognostic relevance of age, risk group, prostate volume, ADT and postoperative nadir PSA on disease progression, as confirmed by the manifestation of oncological failure. In patients without ADT, the sensitivity, specifity and positive (PPV) and negative predictive value (NPV) of the nadir PSA threshold <0.3 ng/mL, previously shown to be associated with long-term HIFU success , were calculated to determine its predictive usefulness in oncological outcomes. A P value < 0.05 was considered to indicate statistical significance.
A total of 191 patients were treated consecutively between December 2002 and October 2006. The median (range) patient age was 69.7 (51–82) years. According to the criteria of the American Society of Anesthesiologists (ASA), 75 patients (39.3%) had an elevated perioperative risk (ASA III–IV).
Tumour characteristics are shown in Table 1. In all, 81 patients (42.4%) received ADT before HIFU for a median (range) duration of 10 (1–266) weeks. Only seven patients received ADT > 1 year, and 94 (49.2%) underwent procedures to reduce the prostate size (TURP, n = 92; adenomectomy, n = 2). Patients treated with the Ablatherm Maxis® and the Ablatherm Integrated Imaging® HIFU device were 156 (81.7%) and 35 (18.3%), respectively. Median (range) treatment duration was 155 (40–275) min with a median 625 (174–1086) single shots delivered, resulting in a median treatment volume of 39 (9–75) mL volume.
Table 1. Baseline tumour characteristics in 191 patients
With only two patients lost to follow-up, cancer control data were available for 189 (98.9%) patients. Median (range) follow-up was 52.8 (0.2–79.8) months. At 5 years, the overall and cancer-specific survival rates were 86.3 and 98.4%, respectively (Fig. 1). Three men died from PCa at 2, 3 and 4 years after HIFU treatment.
Nadir PSA occurred at a median (range) 9.5 (1–40) weeks. A median nadir PSA of 0.09 (0.01–26.5) ng/mL was observed, with no significant difference between the 81 patients who had undergone previous ADT and the 108 patients who had not (median [IQR] 0.05 [0.02–0.21] ng/mL vs 0.1 [0.03–0.29] ng/mL; P = 0.65). A nadir PSA < 0.3 ng/mL was observed in 140 (74.1%) men.
Biochemical relapse occurred in 56 patients; 36 PSA failures were defined solely using the Stuttgart definition, and 20 PSA failures were identified by a short PSA-DT (n = 4) or by both failure definitions (n = 16). The biochemical failure-free survival rate (BFSR) at 5 years was 69.2%, and was significant higher in the low-risk group (84.8%) than the intermediate-risk (64.9%; P < 0.002) and high-risk (54.9%; P < 0.001) groups.
Control biopsies of the prostate were available for 152 patients. The median (range) interval between HIFU and biopsy was 8.1 (2–72) months. The median (range) prostate volume (determined using TRUS) at the time of biopsy was 5.5 mL (0.5–15) and a median of 5 (1–12) core biopsies were taken. Of the entire sample, control biopsies were negative in 110 (72.4%) patients, and negative biopsy rates of 84.2, 63.6, and 67.5% were found in patients in the low-, intermediate-, and high-risk groups, respectively (P = 0.033; Table 2). In 66% (28/42) of patients with positive biopsies, PSA relapse also occurred.
Table 2. Prostate biopsy results by D'Amico risk group ]
Patients with biopsy
Biopsy negative, n (%)
P = 0.032.
Metastases were detected in seven (3.7%) patients after PSA relapse, including two patients with intermediate-risk tumours and five with high-risk tumours. Bone metastases were detected in four patients and lymph node involvement in the remainder.
In total, 70 patients experienced oncological failure. The 5-year disease-free survival rate was 62.8% in the overall sample, and significantly higher in patients in the low-risk group than in the intermediate- and high-risk groups, 81.7% vs. 53.2% and 51.2% (P = 0.001 and P < 0.001), respectively (Fig. 2). The median (range) time to oncological failure was 9.3 (1.0–70.7) months, and 81.4% (57/70) of failures occurred within the first 2 years of HIFU treatment.
Preoperative risk category (P < 0.01) and postoperative nadir PSA (P < 0.01) were associated with risk of oncological failure (Table 3), while multivariate analysis eliminated ADT as an independent predictor of oncological failure. Nadir PSA values above <0.3 ng/mL were associated with increased risk of progression (hazard ratio 7.3; 95% CI 4.4–12.0; P < 0.001). The predictive value of this threshold in oncological outcomes was tested in the 108 patients who had not previously undergone ADT. The test characteristics are shown in Table 4.
Table 3. Univariate and multivariate analysis of oncological failure predictors
HR, hazard ratio.
D'Amico risk group*
Table 4. Predictive value of nadir PSA < 0.3 ng/mL in oncological outcomes after HIFU treatment of 108 patients without previous ADT
Estimated value %
Salvage therapy was administered to 53 (28.0%) patients. Eight (4.2%) underwent repeat HIFU treatment for local failure and 45 (23.8%) underwent non-HIFU salvage therapy. Elderly patients and patients with comorbidities received ADT (n = 33), younger patients with longer life expectancies and persistent local tumour received salvage RT (n = 6) or RP (n = 5), one patient received chemotherapy, and 17 (9.0%) patients with residual local tumour were monitored closely and did not receive salvage therapy.
In 99 (51.5%) patients BOO was found within 12 months of single-session HIFU, with 36 (18.7%) requiring transurethral intervention. Transient urinary incontinence was reported in 75 (39.0%) patients, including grade I (safety pad during the day) in 51 (26.5%), grade II (2–3 pads daily, dry at night) in 12 (6.3%), and grade III (>3 pads daily and/or wet at night) in 2 (1.6%) patients. Recurrent UTIs occurred in 51 (26.5%) patients, and three (1.6%) patients experienced rectourethral fistulas. Surgical repair was achieved via a transanal, perineal, and retropubic approach. Preservation of erectile function was not a treatment goal in this sample of elderly patients or patients with comorbidities.
In the present study, oncological outcomes of single-session HIFU treatment were evaluated using the D'Amico tumour recurrence risk group classification system . Durable cancer control was achieved in over 80% of patients with low-risk disease, with rates of efficacy declining in patients with intermediate- and high-risk tumours. The divergent results suggest the understaging of a considerable proportion of tumours in the intermediate- or high-risk groups before therapy, a finding also observed in studies on patients who underwent RP .
By contrast to our results, high negative biopsy rates across all risk groups were reported by the European multicentric study , the French multicentric database  and the @-Registry database . Notably, in these reports the overall outcomes included patients who received repeat HIFU treatment, with a mean of 1.3–1.4 HIFU treatments per patient. A comparison of our findings with the reported local control rates suggests that single-session HIFU treatment is efficacious in low-risk disease (84.2% vs. 84.9–91%), but that patients with intermediate-risk tumours (63% vs. 73.5–86.4%) or high-risk disease (67% vs. 72–82.1%) would probably benefit from the additional efficacy of repeat HIFU treatment. Similarly, the 5-year BFSR reported in the French multicentre database  and the @-Registry database  are similar to our results in low-risk disease but superior in patients with higher risk disease, suggesting that multiple HIFU treatment influences the biochemical outcome by improved local tumour control.
Cancer control efficacy with HIFU can be determined within 9–10 weeks of treatment, with nadir PSA approaching castration level. We quantified the predictive value of a PSA nadir <0.3 ng/mL, which was determined in previous reports to positively correlate with a 91% success rate with HIFU treatment [7,15]. In the present study, the low sensitivity (61%) and PPV (70%) indicated that a PSA nadir <0.3 ng/mL was inaccurate as a threshold for differentiating between patients with subsequent tumour progression and those without; however, the high specificity (89%) and NPV (84%) provides a preliminary estimate of treatment success in patients with this nadir value. The present study also found that most (80%) oncological failures occurred within 2 years of HIFU treatment. This distinguishes the timing of oncological failure with HIFU from cancer control failure after RT, which is characterized by a late rise in biochemical failure occurring >4 years after treatment .
Early recognition of oncological failure with HIFU can be facilitated by the choice of method of monitoring biochemical response. Specifically, we selected the Stuttgart definition of PSA relapse , which provides a more appropriate evaluation of HIFU outcome than the Phoenix definition (PSA nadir plus 2 ng/mL) which was originally designed to monitor biochemical response after RT . The lower threshold of biochemical failure with the Stuttgart definition requires that more biochemical events be considered as PSA relapse, even at short-term follow-up . We also considered a rise in PSA level to ≥0.5 ng/mL with a short PSA-DT as an early indicator of clinical recurrence, a definition first proposed by Patel et al. , and found a 36% rate of PSA failure using this definition. We recommended that patients receive a control biopsy after 6 months. Some degree of residual PSA is expected after HIFU since a benign portion of the prostate gland is left intact to create a safety margin at the apex. This capacity of the untreated non-cancerous portion of the prostate to generate PSA corresponds to the residual PSA production which is notable if prostate glands are left behind during nerve-sparing prostatectomy . Residual tumour must, however, be ruled out as the source of residual PSA level. In the present study, 34% of local failures were detected with early TRUS-guided control biopsy. Other imaging procedures, including CT and MRI, proved to be of minor value for an early recognition of disease progression. This could be explained by the definition of biochemical failure used; a less pronounced rise in PSA level implies smaller residual cancer foci which are difficult to detect by imaging.
Treatment-related morbidity associated with HIFU is well established, with BOO, urinary incontinence and UTIs being the most frequent complications . BOO attributable to necrotic debris, bladder neck stenosis or urethral stricture may necessitate transurethral interventions as reported by Blana et al. . Transient urinary incontinence is caused by the passage of necrotic tissue. Severe complications are rare. Rectourethral fistulas were observed in 1.6% of patients in the present study, a rate consistent with those reported in the literature (0–3%) . All three cases of fistulae occurred 3–4 weeks after treatment and all needed surgical repair. In our experience, urinary diversion is never required .
The present study found that patients in the higher risk groups were less likely to attain long-term cancer control with a single application of HIFU. In patients in the low-risk group, 81.7% achieved disease-free status, while 50% of patients with intermediate- or high-risk disease experienced oncological failure. Most of these patients were suitable candidates for salvage therapy. Repeat HIFU treatment is a valid option in cases of local failure. Other salvage therapy methods include curative RT or RP, or palliative ADT. In the first report on long-term efficacy with HIFU by Blana et al. , 6.9% vs. 23.5% of patients with low- and intermediate-risk PCa received non-HIFU salvage therapy, respectively. The French multicentre analysis by Crouzet et al.  reported salvage therapy rates of 16, 32 and 48% in patients with low-, intermediate- and high-risk tumours, respectively. Thus, single-session HIFU treatment appears to be a promising curative approach in low-risk PCa, while in many patients with higher risk tumours, HIFU may represent the first step of a multimodal treatment approach. Considering this, it remains unclear whether HIFU treatment will gain acceptance as an alternative to the contemporary standard therapies for localized PCa with increased risk of progression.
In elderly men with localized PCa, RT is an established primary treatment method . The published rates of 5-year BFSR (Phoenix definition) with escalated-dose RT (74–75.6 Gy) are 85–91% in patients with low-risk disease, 79–88% in patients with intermediate-risk disease, and 57–74% in patients with high-risk disease [24–26]. Compared with single-session HIFU, results from these studies indicate equivalent efficacy rates in low-risk disease, even if the strict PSA failure criteria of the present study are considered. PSA outcome has become a surrogate marker of treatment efficacy after RT; however, local control has not been confirmed in most studies since post-treatment biopsies were not routinely performed. Zelefsky et al.  evaluated local cancer control independently of PSA level for 2.5 years after RT, and found a positive biopsy rate of 42% in the absence of biochemical failure. Thus, control biopsy may be useful to estimate the true cancer control rate with RT. Whether HIFU represents a curative alternative to RT in patients with tumours of different risk levels requires evaluation in prospective randomized trials with uniform outcome evaluation methods in both treatment arms.
Low-risk PCa has been increasingly diagnosed during the PSA era . Against this background, expectant management with either watchful waiting (WW) or active surveillance (AS) has gained acceptance as an alternative to active therapy in elderly patients with low-risk disease . A consideration in outcome evaluation is that low-risk PCa may harbour a heterogeneous combination of favourable and unfavourable pathology . If the selection criteria for WW/AS are narrowly defined and limited to men with low-volume, low-risk disease to minimize the chance of tumour progression, a considerable proportion of patients will remain candidates for active treatment. Barocas et al.  reviewed the CaPSURE database and found that only 42% of patients with low-risk disease were eligible for WW/AS, suggesting that active treatment will play an important role even in low-risk PCa. As a minimally invasive procedure, HIFU could be a valuable option for many of these patients. A synchronous TURP increases the level of invasiveness, but the management is similar to the treatment method used after a TURP for benign indications .
The present study has some limitations, which include its retrospective nature, small sample size and median follow-up of <5 years. Validated questionnaires to measure functional outcome were not used. Prospectively designed studies with longer patient follow-ups are needed to confirm the present results.
CONFLICT OF INTEREST
Dietrich Pfeiffer acted as a Trainer for EDAP-TMS.