Long-Term Outcomes and Prognosis of Transrectal High-Intensity Focused Ultrasound Therapy for Patients with Localized Prostate Cancer—Therapy after Recurrence and Predictive Factors

Objectives: To evaluate the outcomes and prognosis of high-intensity focused ultrasound (HIFU) therapy for patients with localized prostate cancer, and identify suitable candidates for this therapy by investigating the predictive factors. Methods: The 224 patients (low 54, intermediate 111 and high-risk patients 59) with T1-2 stage were treated using the Sonablate device and followed for over 12 months after treatment. Recurrence was determined based on histological findings, prostate-specific antigen (PSA) failure and local or distant metastasis. The factors which are predicting variables with potential effects were investigated by Kaplan-Meier and multivariate analysis. Results: A total of 255 treatment sessions (193 with one, 31 with two) were performed. No patients died of prostate cancer, but 15 died of other causes and 14 patients were lost during follow-up. The 7-year recurrence-free survival (RFS) rates in all patients were 75%, and 5-year RFS rates were 98%, 84% and 59% in the low, intermediate and high-risk patients respectively. In the 216 patients who underwent histological examination at 6 months or later after HIFU, 25 (12%) were positive. In 77 patients with recurrence after first-HIFU, the second treatments were hormonal therapy and HIFU. Of the 31 patients who underwent a second HIFU, the 5-year RFS rates were 64%, and 5-year RFS rates were 100%, 74% and 33% in the low, intermediate and high-risk patients. The significant predictor for recurrence was risk-group, T-stage (T1 vs T2), Gleason score (≤3 + 4 and ≥4 + 3), pretreatment PSA (<10 vs ≥10 ng/ml) and nadir PSA (<0.1 vs ≥0.1 ng/ml). In 111 patients with intermediate-risk, How to cite this paper: Hayashi, M., Hayashi, T., Oka, K., Goto, K., Shinmei, S., Inoue, Y. and Inoue, K. (2017) Long-Term Outcomes and Prognosis of Transrectal HighIntensity Focused Ultrasound Therapy for Patients with Localized Prostate Cancer— Therapy after Recurrence and Predictive Factors. Open Journal of Urology, 7, 87-102. https://doi.org/10.4236/oju.2017.76012 Received: May 9, 2017 Accepted: June 26, 2017 Published: June 29, 2017 Copyright © 2017 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
In recent years, with the high incidence of prostate cancer worldwide, the proportion of early stage prostate cancer has increased. PSA testing and higher male life expectancy have led to increased diagnosis of localized prostate cancer. Several treatment options for this disease are available including the two standard treatment options, radical prostatectomy through open or laparoscopic surgery, and radiation therapy. The morbidity associated with these radical treatments is significant, although the treatment outcomes is good, and the improvement of the procedure and the devices have reduced the associated side effects in recent years [1] [2] [3] [4] [5]. Recently, many alternative and less invasive treatments have been developed for localized prostate cancer [6] [7]. In 1995, Madersbacher et al. [8] reported the effect of high intensity focused ultrasound (HIFU) in an experimental study of 10 patients with prostate cancer. HIFU is a noninvasive technique for thermal ablation of tissue that can induce complete coagulation necrosis of a targeted tumor without requiring surgical exposure or insertion of invasive instruments. Besides, Gelet et al. reported that transrectal HIFU prostate ablation was an effective therapeutic alternative for patients with localized prostatic adenocarcinoma and this treatment had further major advantages [9]. Since May 2003, we have treated patients with localized prostate cancer who were not suitable for, or did not desire radical prostatectomy or radiotherapy, and we have reported the efficacy and safety of HIFU ablation for patients with prostate cancer [10] [11]. According to these experiences, HIFU therapy has the advantages of fewer complications, simplicity of the procedure, shorter treatment times, and the potential for a repeat treatment [11]. Our results suggest that HIFU is an effective treatment in patients with low and intermediate-risk localized prostate cancer, but it is not effective for high-risk patients. Here we retrospectively examine the long-term outcomes of the first and second HIFU therapies, prognosis and RFS, and consider which patients are suitable for this treatment.  The disease was staged with histological findings, digital rectal  examinations, and imaging examinations such as CT, MRI and bone scintigra-phy when deemed beneficial, and then classified by D'Amico risk group [12]. Of these 242 patients who underwent HIFU, 224 patients were followed up for more than 12 months after their last HIFU treatment. For their follow-up examinations, a sextant prostate biopsy and MRI were conducted at 6 months and additional follow-up periods when deemed necessary. The PSA was assayed every 3 months after treatment.

From
None of the patients received adjuvant therapy during the follow-up period. Recurrence free outcome of the HIFU treatment was determined based on negative histological findings on follow-up biopsy, negative biochemical tests using the ASTRO definition in Phoenix [13] (PSA nadir < +2 ng/ml) and no local nor distant metastasis. Actual recurrence-free survival (RFS) rates were calculated according to the Kaplan-Meier curves, and the log-rank test was used to compare the results between the variable groups, such as age (<70 vs ≥70), pretreatment prostate volume (<25 vs ≥25 ml), risk-group, T-stage (T1 vs T2), Gleason score (≤6 vs 3 + 4 vs 4 + 3 vs ≥8), pretreatment PSA (<10 vs ≥10 ng/ml), nadir PSA (<0.1 vs ≥0.1 ng/ml), % of positive cores (<40% vs ≥40%), ADT before HIFU (<for 3 vs ≥3 months) and HIFU device (Sonablate 500 vs version 4). To estimate the prognostic factors, these factors without risk group were calculated by multivariate Cox proportional Hazards regression model. P-value of <0.05 was considered to indicate statistically significant differences. These were calculated on the total and intermediate-risk patients after first HIFU treatment.
We fully informed all patients who received the diagnosis of localized (stage T1 -T2) prostate cancer of their different treatment options and selected the patients who were not suitable candidates for radical surgery and did not desire radical surgery and radiotherapy. All patients who wanted HIFU therapy provided informed consent for the HIFU treatment and accepted self-pay burden for an uninsured therapy in Japan, and the institutional review board for Takanobashi Central Hospital approved these studies.

1)
Overall outcomes of the treatment with HIFU for localized prostate cancer This series included 224 patients who were followed-up for more than 12 months after their last HIFU therapy. The patients had a mean age of 68 years old, a mean prostate volume before HIFU of 23.5 ml and a mean PSA level at diagnosis of 9.7 ng/ml. The percentage of these patients classified by initial PSA level, Gleason scores and clinical T-stages are shown in Table 1. The low, intermediate and high-risk groups included 54, 111 and 59 patients, respectively. Fifty-nine patients (5 low, 23 intermediate, and 31 high risk group) received ADT for more than 3 months before HIFU and 28 patients (9 low, 16 intermediate, and 3 high-risk groups) underwent TUR-P for the treatment of benign prostate hypertrophy (26 cases) and to reduce prostate volume (2 cases).
In this series, the prostate cancer was treated in 193 patients with one procedure, and 31 patients had two procedures of HIFU. In total, 255 HIFU procedures were performed (an average of 1.14 sessions per patient). HIFU treatment was repeated due to PSA failure in 31 cases and 11 cases had positive biopsies.     and 1 has not decided yet ( Table 3). All of recurrent patients were alive well now. And the 5-year CSS and OAS rates in 35 patients with only ADT after recurrence were 100% and 97%, and the 5 and 7-year RFS rates were 82% ( Figure  2(c)).
3) Predictive factors from RFS rates in all patients with first-time HIFU The 5 and 7-year RFS rates of first time HIFU in all patients were 73% and 65%. The 7-year RFS rates were 84%, 66% and 46% in the low, intermediate and high-risk groups, respectively. There was a significant difference between the low and intermediate-risk group (P = 0.027), between the low and high-risk group (P < 0.001) and between the intermediate and high-risk group (P = 0.005) (Figure 3).
The Kaplan-Meier curves of 10 variable factors of RFS after the first-HIFU treatment as determined by ASTRO definition are shown in Table 4. There was a significant difference in the risk-group (P < 0.001), T-stage (P = 0.003), Gleason score (P = 0.003), pretreatment PSA (P < 0.001), nadir PSA (P < 0.001) and HIFU device (P = 0.049) factors, whereas age, prostate volume, % of positive core and ADT before HIFU showed little difference in Table 4. There was a significant difference (P < 0.001) between the Gleason 7 score group of ≤3 + 4 and ≥4 + 3. The multivariate analysis of variable factors with significant difference under Kaplan-Meier analysis is shown in Table 4. These analyses revealed that there is a significant difference in the T-stage (P = 0.040), Gleason score (≤6 vs ≥8; P = 0.002), pretreatment PSA (P = 0.022), nadir PSA (P < 0.001) and HIFU device (P = 0.014). 4) Kaplan-Meier statistical analyses of factors affecting RFS rates in 111 intermediate-risk patients with first-time HIFU and in 31 patients with a second-HIFU (Table 5).
We examined 111 patients with intermediate-risk using the same analyses. By Kaplan-Meier analysis, clinical T-stage and nadir PSA were significantly associated with prognosis. On 5-year RFS rates, there was a clear difference between T1 and T2 of T-stage and ≤3 + 4 and ≥4 + 3 of Gleason scores. We examined the 31 second-time HIFU patients using Kaplan-Meier analysis. Nadir PSA (P = 0.018) was significantly associated with prognosis. Risk-group (low vs high) and Gleason score (≤6 vs ≥8) showed a slightly significant association with prognosis.

Discussion
Since the first clinical application of HIFU for treatment of localized prostate cancer are used by Madersbacher et al. [8]. (Using the Sonablate 200), several investigations of HIFU therapy using Ablatherm or Sonablate systems have been reported for patients with this disease [14] [15] [16]. We have performed transrectal HIFU treatment for localized prostate cancer using the Sonablate device since May 2003. Although all cases were not treated with whole-gland ablation, we analyzed all patients on the same basis because there were only 11 patients with unilateral and focal HIFU. There have been favorable results from the use of focal therapy recently reported [17] [18]. We will report on our experience with focal HIFU therapy in future.
Seven-year CSS and OAS in all patients were 100% and 94%, and no patients died of prostate cancer even in recurrent cases. Although both survival rates will diminish slightly if some of the 14 patients lost during follow-up are included in  death due to prostate cancer, we have proven the favorable prognosis of HIFU therapy as same as other reports [19] [20] [21]. And in our risk groups, there was a significant difference between each group. These RFS rates are equal or superior to the long-term outcomes (49% -61% at 10-year BDFS in all cases, and 74% -88% in low-risk, 62% -83% in intermediate-risk and 47% -68% in high-risk patients at 5-year BDFS) of the articles [19] [20] [21], which included multiple HIFU sessions, as did our study. Although we were able to achieve a good outcome (RFS rate; over 90%) in low-risk patients, the outcomes of intermediate and high-risk patients were lower than the reported outcomes of radiotherapy [5] [6] and prostatectomy [3] [22].
In histological examination, we set the prostate biopsy at 6 month after HIFU. Although the negative biopsy rate was 96% (208/216) at 6month after HIFU, the total negative rate was 88% (190/216), including 18 additional positive patients, who were examined in the follow-up periods. This negative biopsy rate is equal or superior to the rate of some articles (83% -87%) [14] [16] and current review articles (30% -95%) [23] [24]. The histological examinations should be compared at the same time, because these positive rates might vary depending on the multiple follow-up periods.
On the 77 patients who recurred after first-time HIFU, 31 patients chose to receive a second HIFU therapy. Most other patients wanted ADT or radiotherapy. All patients in this study had not chosen an invasive treatment from the start.
Of the 31 patients with a second HIFU, 22 cases were followed without recur- Second-time HIFU is an effective treatment in patients with low-risk. But the outcomes of intermediate-risk patients were less successful, and the high-risk patient's outcomes were poor despite the additional HIFU treatment. These outcome patterns by risk-groups concur with other recent reports [26] [27] [28].
Although most of patients with ADT after recurrence following first HIFU were in the groups of intermediate and high-risk, the 5-year RFS rate was better than that of second-time HIFU. On the other hand, some patients with ADT died of another disease or lost follow-up, and 8 recurrent patients with second-time HIFU are alive and well. From the prognosis of recurrence cases, we think that the repeat HIFU was effective, or patients with second-time HIFU had better strength.
To reveal the outcome predictors of RFS, the Kaplan-Meier and multivariate analyses were examined on the results of the first HIFU treatment (Table 4).
Uchida's clinical outcomes have improved due to mechanical and technological advancements of the HIFU device. In our analysis, the outcomes using the new HIFU system were better than the older ones, and ADT before HIFU did not have a predictive effect. In a multicenter study [29] of a large patient population (including our outcomes) with localized prostate cancer treated using the Sonablate 500 device, variables shown as significant prognostic parameters by multivariate analyses were pretreatment PSA, clinical stage and neoadjuvant ADT (within 3 months). Short-term ADT before HIFU improved the 3-year disease-free survival rate of patients with intermediate and high-risk non-metastatic prostate cancer. This discrepancy in ADT outcome between the long-term study and our results may be due to the difference in the number of patients, the proportion of intermediate-risk with 4 + 3 of Gleason score, number of high-risk patients (66%) with ADT and the difference of ADT periods (<for 3 vs ≥3 months). We chose ADT before HIFU for patients who had large volume prostate or would be expected to have a poor effect by HIFU therapy. Therefore, high-risk patients accounted for over half of the patients with ADT. If we had done this study as a randomized study, patients with ADT before HIFU would have improved outcomes.
To improve the RFS of these HIFU therapies, we studied the statistical analysis of 111 intermediate-risk patients who were the largest group and had insufficient outcomes compared to the low-risk group. From this analysis, T-stage and nadir PSA were important predictive factors. There was a clear difference between ≤3 + 4 and ≥4 + 3 of Gleason score on 5-year RFS rates, however there was no significant difference by the statistical analysis. If there are number of ≤3 + 4 and ≥4 + 3 Gleason score patients, we would expect a significantly difference between the groups, similar to the T-stage analysis.
According to our 13-year experience of 224 patients with clinical stage T1 or T2 prostate cancer, HIFU is an effective treatment in patients with low-risk and intermediate-risk with T1-stage. But even with ADT before HIFU, we think HIFU therapy is not suitable for the patients with high-risk and ≥8 of Gleason score.
Our experience indicated that T-stage, Gleason score, pretreatment PSA and nadir PSA are effective predictors for determination of HIFU therapy outcomes. In particular, nadir PSA was found to be the most important for RFS after HIFU therapy as noted in another large volume report [26]. Therefore, HIFU therapy of localized prostate cancer should be selected for low and intermediate-risk pa-tients with clinical T1-stage, and patients with PSA < 10 ng/ml and ≤3 + 4 of Gleason score. For intermediate-risk patients with stage T2 and high-risk patients, sufficient HIFU sonication and ADT before HIFU are necessary to improve results. As discussed in some reports [20] [21], the outcomes of these higher-risk patients would be improved by the mechanical and technological improvement of HIFU instrument.

Conclusion
Prognosis of HIFU was good for patients with localized prostate cancer and for patients with second-HIFU by recurrence after a first-HIFU. The low and intermediate-risk patients with T1-stage, PSA < 10 ng/ml and Gleason score ≤ 3 + 4 are suitable indications for HIFU. Effective predictors for outcomes were risk-group, T-stage, Gleason score, pretreatment PSA and nadir PSA.