Abstract

Background

We evaluated the efficacy and feasibility of high-intensity-focused ultrasound (HIFU) for localized prostate cancer.

Methods

Seventy patients received HIFU using Sonablate® 500 (Focus Surgery, IN, USA). In patients whose cancer was confined to only one lobe by multi-regional biopsies, total peripheral zone and a half portion of transitional zone were ablated (focal therapy). Otherwise, patients received whole organ ablation (whole therapy). Scheduled biopsies were performed at 6 and 12 months after treatment. Pre- and post-HIFU serum testosterone levels were measured.

Result

The 2-year biochemical disease-free survival (DFS) rates in patients at low, intermediate and high risk were 85.9, 50.9 and 0%, respectively, (P = 0.0028). After 12 months, 81.6% (40/49) of patients were biopsy negative; 84.4% in patients who received whole therapy, whereas 76.5% in those with focal therapy. The 2-year biochemical DFS rates for the patients at low and intermediate risk was 90.9 and 49.9%, respectively, in patients with whole therapy, whereas 83.3 and 53.6% in patients with focal therapy. In patients without neoadjuvant androgen deprivation, serum testosterone levels continuously decreased after whole therapy, whereas no changes were seen in those with focal therapy. The patients whose follow-up biopsies were positive tended to have significantly higher changes in prostate-specific antigen levels than biopsy-negative patients.

Conclusions

In patients with low-risk prostate cancer, HIFU monotherapy resulted in comparable immediate cancer control with other modalities. Particularly, focal therapy might offer a feasible minimally invasive therapeutic option, which maintained serum testosterone level. To our knowledge, this is the first report that whole, but not focal, therapy affects the serum testosterone level.

INTRODUCTION

The incidence of prostate cancer had traditionally been lower in Japan than in Western countries, although the mortality rate of prostate cancer is rapidly increasing in Japan (1). Increased public awareness and serum prostate-specific antigen (PSA) screening have resulted in a change in the stage of prostate cancer noted at the time of diagnosis (2). Organ-sparing treatments are becoming increasingly popular among the patients with low-stage disease (3). In addition to cancer control, there are concerns about the frequency and the extent of side effects, such as urinary incontinence and erectile dysfunction, which affect the quality of life (QOL) patients. Currently, such concerns tend to have a significant impact on the choice of treatment for localized prostate cancer (4). High-intensity-focused ultrasound (HIFU) is a new modality that can be used for local tumor ablation therapy. During HIFU treatment, focused ultrasound waves are emitted from a transducer and are absorbed in the target area, thereby inducing coagulation necrosis without causing damage to the tissue in the path of the ultrasound beam (5,6). The first clinical application of HIFU was done by Gelet et al. (7) in the treatment of organ-confined prostate cancer. Currently, two HIFU devices are available: Ablatherm HIFU device (EDAP SA, Lyon, France) and Sonablate® 500 (Focus surgery, IN, USA). The efficacy and safety of Ablatherm HIFU device for the treatment of localized prostate cancer has been established (7–14). The Sonablate® 500 was introduced in Japan in 1999. The advantage of this device is that one can monitor the prostate in situ with ultrasonography during treatment (15,16). Uchida et al. (15) reported an overall biochemical disease-free rate of 75% in 47 patients following Sonablate® 500 treatment.

Prostate cancer has been recognized to be a multifocal disease (17). However, the current evidence suggests that the clinical significance of the tumor depends on the index or the size of the largest cancer lesion (18). This evidence prompted us to use HIFU for the focal therapy of a limited area of the prostate in low-risk patients. We herein report the efficacy and the safety of treatment with HIFU using the Sonablate® device, particularly with respect to its use for focal therapy.

MATERIALS AND METHODS

Patients

Seventy patients presenting with localized prostate cancer from July 2003 to August 2006 were included in this study. The selection criteria for this study were as follows: those who was >60 years old,TNM stage T1c-T2N0M0, and biopsy and magnetic resonance imaging (MRI) of the prostate indicating localized disease. All patients were either unsuitable for radical prostatectomy because of comorbidities or preferred to the treatment with HIFU over surgery or radiation therapy. All patients provided written informed consent before entering the study. Patients who were on anticoagulant therapy, such as warfarin or aspirin, were kept on their anticoagulant regimens before the procedure. The study protocol was approved by the ethics committee in our hospital. Informed consent was obtained from all patients.

HIFU Treatment

All 70 patients received HIFU treatment using the Sonablate® device under general anesthesia. Patients were placed in the supine position with their legs apart so that they could be given transrectal HIFU. The treatment was performed using a transrectal probe that includes a 4 MHz piezoelectric treatment transducer and a 4 MHz ultrasound imaging probe. Contiguous HIFU shots were delivered 1.8 mm apart with a 4-s shot duration and a 12-s interval between shots. The volume to be treated was determined by an urologist, who used a longitudinal and transverse ultrasound imaging system. The area of ablation with HIFU was determined based on the results of digital rectal examination, multi-regional transrectal ultrasound-guided biopsy more than 12 cores and preoperative pelvic MRI. We ablated the peripheral zone of both lobes and the ipsilateral transitional zone upon the patients' consent when it was likely that the signature cancers were localized in one lobe (focal therapy). Otherwise, the whole organ was ablated with HIFU (Fig. 1). The patients were discharged on the next day after the HIFU.

Figure 1.

The shaded portion indicates the ablative area. Open circle: urethral preservation. (a) Whole therapy: the whole organ was ablated with high-intensity-focused ultrasound (HIFU) without urethra. (b) Focal therapy: when multi-regional biopsies more than 12 cores revealed the localization of cancers in one lobe, the ipsilateral transitional zone and the peripheral zone of both lobes were ablated without urethra.

Figure 1.

The shaded portion indicates the ablative area. Open circle: urethral preservation. (a) Whole therapy: the whole organ was ablated with high-intensity-focused ultrasound (HIFU) without urethra. (b) Focal therapy: when multi-regional biopsies more than 12 cores revealed the localization of cancers in one lobe, the ipsilateral transitional zone and the peripheral zone of both lobes were ablated without urethra.

Follow-up

Scheduled biopsies were done 6 and 12 months after treatment. During the follow-up period, PSA was measured at 3, 6, 12, 18, 24 and 36 months. Serum PSA was analyzed with chemiluminescent enzyme-linked immunoassay (normal range, 4.000 ng/ml). The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition for biochemical failure, i.e. three consecutive increases in PSA level after a nadir, was used to define biochemical failure (19). Time to biochemical failure was defined as a midway between the PSA nadir and the first of the three consecutive PSA increases. Distributions of biochemical disease-free survival (DFS) times were calculated according to the Kaplan Meier curves and the log-rank test used to determine the differences between the curves. The risk classification is based on D'Amico et al. (20). Low risk is defined as clinical T stage T1c, T2a, Gleason score ≤6 and PSA <10 ng/ml. Conversely, patients with clinical stage T2c disease, a PSA >20 ng/ml or a biopsy Gleason score of ≥8 have been identified to be at high-risk group. For the remaining patients with PSA levels higher than 10 and 20 ng/ml or lower, a biopsy Gleason score of 7 or clinical stage T2b has been identified to be at intermediate risk. Serum testosterone levels (normal range: 225–1039 ng/dl) were measured by the chemiluminescent immunoassay at 6 months and 1 year. In all patients, a follow-up sextant biopsy, uroflowmetery and the disease-targeted questionnaire using University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) and International Prostate Symptom Score questionnaires (IPSS) were performed at 6 months and 1 year.

Statistical Considerations

Student's t and Fisher's exact tests were used to compare the quantitative and categorical variables, respectively. All P-values <0.05 reflected statistically significant differences.

RESULTS

Patient Characteristics

Table 1 summarizes the baseline clinical characteristics of the patients. Median age was 72 (range, 61–80) years. Mean prostate volume was 33.0 (range, 9.0–62.8) cc and the median pre-HIFU PSA was 4.6 ng/ml (range, 0.0–29.5). The mean number of positive cores at diagnosis based on a prostate biopsy was 1.6, and the median Gleason score was 6 (range from 4 to 10). Twenty-four cases (34.3%) received androgen deprivation therapy prior to the procedure, which was discontinued after HIFU treatment. Twenty-nine cases (41.4%) received focal therapy, whereas 41 cases (58.6%) had whole organ treatment. There was no significant difference in age, initial PSA, PSA density and prostate volume between the focal and whole therapy groups (Tables 1 and 2). T-stages were distributed as follows: T1c, 32 (78.0%); T2a, 4 (9.8%); T2b, 5 (12.2%) in whole therapy group and T1c, 25 (86.2%); T2a, 4 (13.8%) in focal therapy (Table 1).

Table 1.

Patient characteristics

 Total Whole therapy Focal therapy P 
Number of patients (%) 70 41 (58.6) 29 (41.4)  
 Age (years)     
 Median 72 73 72 0.45 
 Range 61–80 61–79 62–80  
Follow-up periods (M)     
 Median 34 37 32 0.66 
 Range 8–45 8–44 9–45  
PSA at diagnosis (ng/ml)     
 Median 6.8 7.0 5.4 0.29 
 Range 1.8–29.5 3.3–29.5 1.8–25.1  
Pre-HIFU PSA (ng/ml)     
 Median 4.6 4.6 5.4 0.77 
 Range 0.0–29.5 0.0–29.5 0.2–25.1  
Pre-operative Gleason score (%)     
 5 or less 5 (7.1) 3 (7.3) 2 (6.9)  
 6 32 (45.8) 18 (43.9) 14 (48.3)  
 7 21 (30.0) 15 (36.6) 6 (20.7)  
 8–10 8 (11.4) 3 (7.3) 5 (17.2)  
 Unknown 4 (5.7) 2 (4.9) 2 (6.9)  
Pre-operative T-stage (%)     
 T1c 57 (81.4) 32 (78.0) 25 (86.2)  
 T2a 8 (11.4) 4 (9.8) 4 (13.8)  
 T2b 5 (7.1) 5 (12.2) 0 (0.0)  
Location of positive biopsy (%)     
 Unilateral 41 (29.3) 12 (29.3) 29 (100.0)  
 Bilateral 29 (70.7) 29 (70.7) 0 (0.0)  
Number of patients with hormone therapy at the time of the treatment (%) 24 (34.3) 17 (41.5) 7 (24.1) 0.32 
 Total Whole therapy Focal therapy P 
Number of patients (%) 70 41 (58.6) 29 (41.4)  
 Age (years)     
 Median 72 73 72 0.45 
 Range 61–80 61–79 62–80  
Follow-up periods (M)     
 Median 34 37 32 0.66 
 Range 8–45 8–44 9–45  
PSA at diagnosis (ng/ml)     
 Median 6.8 7.0 5.4 0.29 
 Range 1.8–29.5 3.3–29.5 1.8–25.1  
Pre-HIFU PSA (ng/ml)     
 Median 4.6 4.6 5.4 0.77 
 Range 0.0–29.5 0.0–29.5 0.2–25.1  
Pre-operative Gleason score (%)     
 5 or less 5 (7.1) 3 (7.3) 2 (6.9)  
 6 32 (45.8) 18 (43.9) 14 (48.3)  
 7 21 (30.0) 15 (36.6) 6 (20.7)  
 8–10 8 (11.4) 3 (7.3) 5 (17.2)  
 Unknown 4 (5.7) 2 (4.9) 2 (6.9)  
Pre-operative T-stage (%)     
 T1c 57 (81.4) 32 (78.0) 25 (86.2)  
 T2a 8 (11.4) 4 (9.8) 4 (13.8)  
 T2b 5 (7.1) 5 (12.2) 0 (0.0)  
Location of positive biopsy (%)     
 Unilateral 41 (29.3) 12 (29.3) 29 (100.0)  
 Bilateral 29 (70.7) 29 (70.7) 0 (0.0)  
Number of patients with hormone therapy at the time of the treatment (%) 24 (34.3) 17 (41.5) 7 (24.1) 0.32 

PSA, prostate-specific antigen; HIFU, high-intensity-focused ultrasound.

Table 2.

Total prostate volume and transitional zone volume before and after HIFU therapy

 Whole Focal P value 
Total prostate volume (ml)    
Pre-HIFU 31.0 ± 14.0 35.8 ± 11.4 0.1902 
6 months 17.2 ± 6.7 26.9 ± 13.1 0.0008 
12 months 15.5 ± 6.7 30.3 ± 16.2 0.0001 
Transitional zone volume (ml)    
Pre-HIFU 14.2 ± 8.0 14.8 ± 6.3 0.7548 
6 months 7.0 ± 3.1 13.1 ± 8.8 0.0008 
12 months 7.2 ± 3.7 14.7 ± 7.8 0.0001 
 Whole Focal P value 
Total prostate volume (ml)    
Pre-HIFU 31.0 ± 14.0 35.8 ± 11.4 0.1902 
6 months 17.2 ± 6.7 26.9 ± 13.1 0.0008 
12 months 15.5 ± 6.7 30.3 ± 16.2 0.0001 
Transitional zone volume (ml)    
Pre-HIFU 14.2 ± 8.0 14.8 ± 6.3 0.7548 
6 months 7.0 ± 3.1 13.1 ± 8.8 0.0008 
12 months 7.2 ± 3.7 14.7 ± 7.8 0.0001 

Among the whole therapy group, 29 of 41 patients (70.7%) had bilateral positive cores. No patients in focal therapy group had bilateral positive cores at diagnosis based on a prostate biopsy (Table 1). The mean HIFU treatment time was 93.6 min (whole therapy, 109.7 ± 38.5 min; focal therapy, 71.8 ± 28.3 min, P = 0.0000).

Oncological Results

At a median follow-up of 34 (range, 8–45) months, the efficacy of HIFU treatment was examined in all patients. By the time of this study was undertaken, no patients had died. The biopsy-negative rates at 6 months and 1 year were 59 of 67 (88.1%) and 40 of 49 (81.6%), respectively (Table 3). No difference was seen in the biopsy-negative rates between the focal and whole therapy groups (6 months: P = 0.8489, 12 months: P = 0.7698) (Table 3). No difference was seen in the biopsy-negative rates between the androgen deprivation therapy prior to the HIFU group and no neoadjuvant hormone therapy groups (6 months: 90.9% versus 86.7%, P = 0.7076; 12 months: 89.5% versus 76.7%, P = 0.4536). Patients who had positive biopsies at follow-up preferred to receive androgen deprivation therapy even though other treatment options were proposed. PSA levels significantly decreased after HIFU (at 3 months, 1.78 ± 2.55 ng/ml: P = 0.0000; at 6 months, 2.26 ± 2.87 ng/ml: P = 0.0004; at 9 months, 2.55 ± 2.55 ng/ml: P = 0.0051; at 12 months, 2.74 ± 2.69 ng/ml, P = 0.0066; at 24 months, 3.05 ± 3.13 ng/ml, P = 0.0935; at 36 months, 1.89 ± 1.51 ng/ml, P = 0.0357) (Table 4). The 2-year biochemical DFS rates in patients at low, intermediate and high-risk were 85.9, 50.9 and 0%, respectively (Fig. 2a). No significant differences were noted in the 2-year biochemical DFS rates for the patients at low and intermediate risk treated with between whole (90.9 and 49.9, respectively) and focal therapy (83.3 and 53.6, respectively) (P = 0.8864 and 0.8843, respectively) (Fig. 2b and c).

Figure 2.

(a) Kaplan–Meier biochemical disease-free survival (DFS) curves according to risk group. (b) Kaplan–Meier biochemical DFS curves in the treatment of low-risk group. Biochemical DFS did not differ between the whole and focal therapy groups. (c) Kaplan–Meier biochemical DFS curves in the treatment of intermediate-risk group. Biochemical DFS did not differ between the whole and focal therapy groups. M, months.

Figure 2.

(a) Kaplan–Meier biochemical disease-free survival (DFS) curves according to risk group. (b) Kaplan–Meier biochemical DFS curves in the treatment of low-risk group. Biochemical DFS did not differ between the whole and focal therapy groups. (c) Kaplan–Meier biochemical DFS curves in the treatment of intermediate-risk group. Biochemical DFS did not differ between the whole and focal therapy groups. M, months.

Table 3.

The results of prostate biopsy after HIFU: PB × 6 months: the results of prostate biopsy after 6 months after HIFU, PB × 12 months: the results of prostate biopsy after 12 months after HIFU

 Total Whole Focal P value 
PB × 6 months     
n 67 39 28  
Negative(%) 59 (88.1) 34 (87.2) 25 (89.3) 0.8489 
Positive(%) 8 (11.9) 5 (12.8) 3 (10.7)  
PB × 12 months     
n 49 32 17  
Negative(%) 40 (81.6) 27 (84.4) 13 (76.5) 0.7698 
Positive(%) 9 (18.4) 5 (15.6) 4 (23.5)  
 Total Whole Focal P value 
PB × 6 months     
n 67 39 28  
Negative(%) 59 (88.1) 34 (87.2) 25 (89.3) 0.8489 
Positive(%) 8 (11.9) 5 (12.8) 3 (10.7)  
PB × 12 months     
n 49 32 17  
Negative(%) 40 (81.6) 27 (84.4) 13 (76.5) 0.7698 
Positive(%) 9 (18.4) 5 (15.6) 4 (23.5)  

PB, prostate biopsy.

Table 4.

PSA levels significantly decreased after HIFU

 Pre-HIFU 3 months 6 months 9 months 12 months 24 months 36 months 
Whole 4.92 ± 5.73 1.14 ± 1.58 1.59 ± 1.84 2.04 ± 2.29 2.45 ± 2.73 2.84 ± 3.42 2.07 ± 1.76 
Focal 5.36 ± 5.89 2.74 ± 3.37 3.17 ± 3.70 3.37 ± 2.79 3.14 ± 2.64 3.42 ± 2.67 1.52 ± 0.92 
P value 0.7539 0.0134 0.0258 0.0838 0.3622 0.6673 0.5305 
 Pre-HIFU 3 months 6 months 9 months 12 months 24 months 36 months 
Whole 4.92 ± 5.73 1.14 ± 1.58 1.59 ± 1.84 2.04 ± 2.29 2.45 ± 2.73 2.84 ± 3.42 2.07 ± 1.76 
Focal 5.36 ± 5.89 2.74 ± 3.37 3.17 ± 3.70 3.37 ± 2.79 3.14 ± 2.64 3.42 ± 2.67 1.52 ± 0.92 
P value 0.7539 0.0134 0.0258 0.0838 0.3622 0.6673 0.5305 

ΔPSA And The Treatment Efficacy

To evaluate the amount of focused ultrasound energy absorbed by the prostate, we examined the change in the PSA level after the procedure. The PSA increased on the day after the procedure, presumably due to the destruction of prostate tissue by HIFU. The increase in the PSA level from the preoperative values 1 day after the operation (ΔPSA) was correlated with the total ablative energy of HIFU that was used (R = 0.5420, P < 0.0001). ΔPSA was significantly higher in patients with negative biopsies at 6 months and 1 year after HIFU monotherapy [ΔPSA (ng/ml): at 6 months, 128.5 ± 114.0 versus 53.3 ± 39.4 (biopsy negative versus biopsy positive), P = 0.019; at 12 months, 124.3 ± 102.6 versus 32.8  ± 29.0 (biopsy negative versus biopsy positive), P = 0.043]. Therefore, ΔPSA might be an alternative method for predicting the outcome of cancer control.

QOL And Side Effects

The QOL questions (IPSS, Urinary function and bother of UCLA-PCI) did not differ between the focal therapy and the whole therapy groups (Table 5). Actually, in the results of uroflowmetry, maximum and average flow rates did not differ between these groups (Table 5). The period of indwelling urethral catheter after HIFU was significantly decreased in focal therapy group when compared with the patients in the whole therapy group (15.2 ± 4.4 versus 19.7 ± 7.6 days, P = 0.0213). The frequency of urethral stricture and symptomatic urinary tract infection tended to be higher in whole therapy group [3/35 (8.6%), 4/35 (11.4%), respectively) when compared with the patients in focal therapy group (1/25: 4.0%, 1/25: 4.0%, respectively), although statistically non-significant. Transient urinary retention was noted in four patients (5.7%) who received transurethral resection of prostate (TURP). Of the 52 patients who were continent before surgery, 49 were also continent after HIFU. These results indicate that HIFU treatment did not affect QOL status of the patients.

Table 5.

Urinary symptoms, testosterone and uroflowmetery scores before and after HIFU

 Whole Focal P value 
IPSS    
 Pre-HIFU 8.58 ± 7.14 10.20 ± 6.14 0.3737 
 6 months 6.50 ± 7.00 10.21 ± 7.11 0.1935 
 12 months 8.13 ± 5.50 9.25 ± 7.29 0.6827 
Urinary bother    
 Pre-HIFU 81.25 ± 18.85 84.38 ± 12.94 0.6884 
 6 months 89.29 ± 18.90 75.00 ± 31.62 0.2220 
 12 months 85.71 ± 24.40 80.00 ± 20.92 0.6812 
Urinary function    
 Pre-HIFU 88.62 ± 18.30 83.33 ± 16.64 0.5202 
 6 months 88.57 ± 20.72 86.10 ± 17.63 0.8021 
 12 months 87.21 ± 11.42 86.04 ± 20.83 0.9019 
   
 Pre-HIFU 378.23 ± 141.62 454.54 ± 171.58 0.1481 
 6 months 312.64 ± 91.65 465.69 ± 154.77 0.0006 
 12 months 262.13 ± 151.37 488.11 ± 186.10 0.0002 
Maximal flow rate    
 Pre-HIFU 16.76 ± 6.87 15.29 ± 6.82 0.5126 
 6 months 15.31 ± 8.74 15.48 ± 6.82 0.9421 
 12 months 12.77 ± 7.09 11.98 ± 5.78 0.7711 
Average flow rate    
 Pre-HIFU 9.17 ± 3.38 7.70 ± 4.46 0.2766 
 6 months 8.58 ± 5.54 8.26 ± 3.70 0.8269 
 12 months 7.38 ± 4.36 6.90 ± 3.59 0.7756 
 Whole Focal P value 
IPSS    
 Pre-HIFU 8.58 ± 7.14 10.20 ± 6.14 0.3737 
 6 months 6.50 ± 7.00 10.21 ± 7.11 0.1935 
 12 months 8.13 ± 5.50 9.25 ± 7.29 0.6827 
Urinary bother    
 Pre-HIFU 81.25 ± 18.85 84.38 ± 12.94 0.6884 
 6 months 89.29 ± 18.90 75.00 ± 31.62 0.2220 
 12 months 85.71 ± 24.40 80.00 ± 20.92 0.6812 
Urinary function    
 Pre-HIFU 88.62 ± 18.30 83.33 ± 16.64 0.5202 
 6 months 88.57 ± 20.72 86.10 ± 17.63 0.8021 
 12 months 87.21 ± 11.42 86.04 ± 20.83 0.9019 
   
 Pre-HIFU 378.23 ± 141.62 454.54 ± 171.58 0.1481 
 6 months 312.64 ± 91.65 465.69 ± 154.77 0.0006 
 12 months 262.13 ± 151.37 488.11 ± 186.10 0.0002 
Maximal flow rate    
 Pre-HIFU 16.76 ± 6.87 15.29 ± 6.82 0.5126 
 6 months 15.31 ± 8.74 15.48 ± 6.82 0.9421 
 12 months 12.77 ± 7.09 11.98 ± 5.78 0.7711 
Average flow rate    
 Pre-HIFU 9.17 ± 3.38 7.70 ± 4.46 0.2766 
 6 months 8.58 ± 5.54 8.26 ± 3.70 0.8269 
 12 months 7.38 ± 4.36 6.90 ± 3.59 0.7756 

T, testosterone; IPSS, International Prostate Symptom Score questionnaires.

Changes In The Serum Testosterone Levels After The HIFU Monotherapy

We examined the serum testosterone levels before and after HIFU monotherapy. In patients without neoadjuvant hormone therapy group who received whole therapy, the testosterone levels decreased at 6 and 12 months after HIFU, whereas no changes were seen in patients who received focal therapy without neoadjuvant hormone therapy group. Serum testosterone levels (ng/ml) were: pre-HIFU, 454.5 ± 171.6 versus 378.2 ± 141.6 (focal therapy versus whole therapy), P = 0.148; at 6 months, 465.7 ± 154.8 versus 312.6 ± 91.7 (focal therapy versus whole therapy), P = 0.0006; at 12 months, 488.1 ± 186.1 versus 262.1 ± 151.4 (focal therapy versus whole therapy), P = 0.0002 (Table 5).

DISCUSSION

The treatment efficacies of the some modalities to localized prostate cancer are different by a risk category. For low-risk disease, all of the currently available treatment modalities (i.e. radical prostatectomy (21,22), cryoablation (23,24), brachytherapy (21,25), three-dimensional conformational radiotherapy (26) and external-beam radiotherapy (21,27)) achieve excellent local and systemic control. Although the follow-up periods are short, HIFU, in this study, achieved excellent biochemical control for low-risk disease. When compared with the results for low-risk patients, more uncertainty arises in determining the optimal approach for patients with intermediate- and high-risk disease. Despite treatment, a significant proportion of these men will experience PSA-defined failure and cancer-specific death. A drop in efficacy can be observed for all therapies with increasing disease risk (20–24,26,28–31). Correspondingly, in this study, the 2-year biochemical DFS rates after HIFU in patients at high risk were significantly inferior than those in patients at low risk. Marberger (32) reported if an adequate PSA nadir is not reached within 3–4 months, curative therapy is probably failing and repeat HIFU or a change in therapy should be considered. From our results, for patients with intermediate-risk prostate cancer, combination therapy of HIFU and other modalities (e.g. hormone therapy) should be considered. But for patients with high-risk prostate cancer, HIFU monotherapy did not result in satisfactory cancer control.

Previous reports have shown that the negative biopsy rates after HIFU treatment based on sextant core biopsies ranged from 75 to 93% (8,9,11,15). In our study, since the time series, post-HIFU PSA levels and positive rates at scheduled biopsy did not differ significantly between patients who had focal therapy and those who had whole therapy (Tables 3 and 4), cancer control with focal therapy could considered to be equivalent to that of whole therapy. Although the median follow-up time (34 months) was relatively short, nevertheless, these results suggest the efficacy of focal therapy. However, restricting the region of ablation in the prostate is not congruent with the traditional view that prostate cancer usually manifests as a multifocal disease (17). Previous attempts at prostatic lumpectomy with HIFU have so far been impeded by the unreliable localization of the index lesions (33). In 1995, Madersbacher et al. (34) treated 10 patients with T2a–b prostate cancer with one positive core in a unilateral palpable nodule, with HIFU of the tumor-bearing lobe only. Histologic evaluation after subsequent radical prostatectomy showed that the tumor was always correctly targeted. However, because of unexpected tumor distribution, only 3 of the 10 patients' tumors were completely ablated. The conclusion from this at the time was that because of the unpredictable tumor location the entire prostate has to be always ablated. However, this report did not clarify the way of clinical preoperative diagnostic criteria, including prostate biopsy (e.g. how many cores, sextant or more?) and imaging studies. Today's advances in imaging and biopsy techniques seem to permit more reliable detection of index cancers. Especially by the increasing number of multi-regional biopsies more than 12 cores such as adopted in this study, the cancer distribution is now more accurately diagnosed (35). In the current study, the majority of cancer treated was staged as T1C. By providing focal therapy, it was possible that the treatment missed the transitional zone cancer in the ipsilateral side. However, transition zone cancers in stage T1c tumors, if any, have a favorable pathology (36). Thus, there may be a little chance that focal therapy missed the treatment of significant cancer. Indeed, the incidence of new cancer lesion in the follow-up biopsies was small in this study (data not shown).

Recently, Carroll et al. (37) have identified three potential clinical parameters (lower stage, the number of positive biopsy core at diagnosis and prostate volume) that correlate with unifocal disease. The use of some parameters to correlate with unifocal disease may need to establish the focal therapy to localized prostate cancer.

In our results, the total volume and the transitional zone volume of the prostate were not changed after focal therapy in spite of decreasing PSA levels. Sequential anatomical imaging showed that a gradual shrinkage of treated volumes occurred by the whole therapy, which indicates the replacement of the necrotic region with fibrous scar tissue. A previous report showed the size of the gland decreased after HIFU to a 41% of the initial size (8). Since the contralateral transitional zone was not ablated in focal therapy group, these areas might have been spared for the circulation, and hence, maintained its size.

It is still debatable whether PSA is the adequate measure to define the recurrence.

Although Uchida et al. (38) reported that there was an association between the PSA nadir and the risk of treatment failure after HIFU, our data showed no correlation between PSA nadir and oncological results (data not shown). During HIFU treatment, the temperature at the ablative focus can rise rapidly to >80ºC, and this should lead to effective cell destruction. This increase in tissue temperature depends on the emitted mechanical energy and the absorbance of the specific tissue. ΔPSA may reflect the extent that HIFU injures the prostate parenchyma. Our results might indicate that ΔPSA could be used as a predictor for successful treatment.

If the entire prostate is not ablated, morbidity could be reduced. Regarding the voiding function and QOL, there was no difference between the focal and the whole therapies (Table 5). However, the period of indwelling urethral catheter after HIFU was significantly decreased in focal therapy group compared with the patients in whole therapy group. Clearly, the toxicity and results of HIFU depend on the volume of prostate treated. If cancer volume is low and only the cancer-bearing part of the prostate is treated, morbidity is minimized: this is the theory behind focal therapy (32). Considering that previously reported HIFU causes urinary stricture in high frequency and needs transurethral resection as an adjunct therapy at many institutions (39), focal therapy may be useful for maintaining normal urination after HIFU.

Moreover, whole therapy, but not focal therapy, without neoadjuvant hormone therapy decreased the serum testosterone levels. The magnitude of the changes in the androgen levels may not have a direct influence on cancer control. However, several results fit into a growing body of data, suggesting that the persistent decline in the androgen levels may have an impact on the QOL of the patients' by influencing their mood, physical abilities and sexual function (40). Sarosdy et al. (41) even propose that testosterone-replacement therapy after prostate brachytherapy treatment for early-stage prostate cancer can be performed safely in selected and carefully monitored patients. Thus, when focal therapy results in cancer control equivalent to that of whole therapy, it might be beneficial since it can maintain testosterone level. It has been known that the radiation therapy for prostate cancer causes a transient decline in serum testosterone levels (42). This decline in testosterone levels after radiation has been attributed to the scatter effect of the radiation on the testis. However, since whole but not focal therapy with HIFU affected the serum androgen levels, this decline in serum androgen levels might not represent damage to the testis, but rather indicate that the destruction of a large number of prostatic cells could have a negative feedback on testicular function. To our knowledge, this is the first report about the effect of whole, but not focal, therapy on the serum testosterone level. It still needs to be determined whether the decreased androgen levels seen in patients following whole therapy subsequently recover, as is seen following radiation therapy.

The limitation of this study is the small number of treated patients and the short duration of the follow-up. Both focal and whole therapy groups have shown that HIFU did not affect the UCLA-PCI and IPSS scores. As a result, HIFU can be considered to be a QOL-oriented therapy (43). Currently, no definite image studies are available routinely to circumvent biopsy to know the exact localization of the prostate cancer. However, when modalities to identify the localization of prostate cancer developed, the focal therapy would possibly be a feasible way of choice in the treatment of small-volume prostate cancer.

In conclusions, HIFU can be considered to be a feasible minimally invasive therapy for low-risk of localized prostate cancer. HIFU focal therapy was equivalent to whole therapy with respect to the short-term efficacy of cancer control. Furthermore, focal therapy maintained serum testosterone levels.

Funding

Funding to pay the Open Access publication charges for this article was provided by Shigeo Horie.

Conflict of interest statement

None declared.

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