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. 2020 Jul 23;15(7):e0236026. doi: 10.1371/journal.pone.0236026

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: Medium-term results from a single centre

Yen-Ting Wu 1,‡, Po Hui Chiang 1,2,‡,*
Editor: Jason Chia-Hsun Hsieh3
PMCID: PMC7377399  PMID: 32701978

Abstract

We report medium-term results in men receiving primary whole-gland HIFU (WG-HIFU) and following salvage treatment. One hundred and twenty-eight patients in a single hospital were enrolled. The enrolled patients were treated with WG-HIFU for primary localized prostate cancer. Salvage treatment include androgen deprivation therapy, secondary HIFU and salvage radiation therapy. Our primary outcomes were biochemical recurrence–free survival, salvage treatment–free survival, and metastasis-free survival. Secondary outcomes included urinary incontinence, de novo erectile dysfunction, acute epididymitis, bladder neck contracture, and urethral stricture. The 5-year biochemical recurrence–free survival rates were 85.7%, 82.7%, and 45.2% for D’Amico low-, intermediate-, and high-risk groups, respectively. Multivariate analysis revealed high risk group is the only predictor of significant shorter biochemical recurrence free survival, salvage treatment free survival, and metastasis free survival. Of 38 patients receiving salvage treatment after biochemical recurrence, 29 (76.3%) became free from biochemical recurrence. Rates of the adverse events of urinary incontinence, acute epididymitis, bladder neck contracture or urethral stricture, and de novo erectile dysfunction were 2.3%, 10.9%, 20.3%, 65.6%, respectively. In conclusion, WG-HIFU is an effective treatment option for localised prostate cancer, especially in D’Amico low- and intermediate-risk cases. The success rate of salvage treatment with radiation therapy and secondary HIFU for biochemical recurrence was acceptable. Fewer adverse events were caused by HIFU, especially incontinence and erectile dysfunction, than by radical prostatectomy and radiotherapy.

Introduction

The incidence of prostate cancer in Taiwan, although lower than that in Western countries, has been increasing. According to a Taiwanese annual cancer report in 2016, prostate cancer was the fifth most commonly diagnosed cancer in Taiwan, with a median age at diagnosis of 73 years old [1]. Thus, prostate cancer is becoming a serious health problem, especially in an ageing society. The established and definitive treatment for localised prostate cancer includes radical prostatectomy and radiotherapy; data on long-term outcomes of both treatments are available. However, many patients are concerned about periprocedural adverse events [2, 3], and aged patients, who tend to have comorbidities, have higher perioperative risk [4]; such patients may not tolerate major surgery and tend to be afraid of adverse events from radiotherapy.

Minimally invasive treatment modalities such as cryosurgical ablation of prostate and high-intensity focused ultrasound (HIFU) have been developed for patients with localised prostate cancer [5, 6]. HIFU uses a focused ultrasound wave that mechanically and thermally induces tissue damage, which causes coagulative necrosis through tissue cavitation and temperature elevation [7]. Long-term prospective comparative data on oncological outcomes after primary WG-HIFU are scarce [8]. Tsakiris et al. recommended HIFU, determining it to be oncologically safe for patients with stage T1c to T3 prostate cancer [9]. Data on outcomes of salvage treatment after primary HIFU for localised prostate cancer are also scarce. As HIFU devices evolve, the reported rate of adverse events has been reduced and is now at an acceptable level [6]. In this paper, we present our findings on the functional and medium-term oncological outcomes from our cohort study of men with localised prostate cancer who were treated with primary WG-HIFU. Outcomes of salvage treatment with radiotherapy and secondary HIFU are also presented.

Materials and methods

This retrospective single-institute study was approved by Kaohsiung Chang Gung Memorial Hospital Institutional Review Board (IRB number: 201101264B0). The IRB waived the requirement for informed consent. At our institution, 405 patients with prostate cancer have been treated with HIFU between December 2009 and July 2019. All patients were treated using Ablatherm® Integrated Imaging (EDAP TMS SA, Vaulx-en-Velin, France) with transrectal ultrasonography guidance under general or spinal anaesthesia. From December 2009 to February 2015, 161 patients who were newly diagnosed with prostate cancer were enrolled. Of these patients, 13 patients received HIFU as salvage treatment for advanced prostate cancer. The remaining 148 patients underwent WG-HIFU for localised prostate cancer. Among these patients, 20 patients were excluded because their follow-up durations were less than 30 months. In total, 128 patients were included (Fig 1). All patients underwent either magnetic resonance imaging (MRI) or computed tomography of the pelvis, in addition to a bone scan for preoperative staging. Cancer staging was done according to the American Joint Committee on Cancer (7th edition) prostate cancer staging system. All patients underwent transurethral resection of the prostate 4 weeks before the HIFU procedure (if prostate volume was ≥40 ml) or simultaneously with the HIFU procedure (if prostate volume was <40 ml). Risk of treatment failure was stratified according to D’Amico risk classification into low-, intermediate-, and high-risk groups. Our institutional protocol for follow-up after HIFU is based on the 3-monthly postoperative prostate-specific antigen (PSA) level. Biochemical recurrence, according to the Phoenix definition, is a post-HIFU PSA nadir +2 ng/ml. Post-HIFU prostate biopsy was not routinely arranged. It might be arranged because of biochemical recurrence. It might also be arranged for patients not meeting criteria of biochemical recurrence but worry about continuous elevation of PSA. If biochemical recurrence is detected, salvage treatment is arranged according to prostate biopsy results. In this study population, salvage therapies included secondary HIFU (34.2%) if residual cancer cells were present, in addition to radiation therapy (10.5%) or radiation therapy plus androgen deprivation therapy (ADT; 55.3%). Whether patients receive salvage treatment may be related to the results of prostate biopsy and patient’s preference. Of patients with residual tumor noted, secondary HIFU will be arranged. Of patients with local lymph node metastasis suspected, salvage radiotherapy will be suggested. Salvage radiotherapy with half to one year of ADT is the standard strategy. Primary outcomes were biochemical recurrence–free survival (BRFS), salvage treatment–free survival, and metastasis-free survival.

Fig 1. Outcome after salvage treatment.

Fig 1

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The dose of salvage radiotherapy after HIFU is between 66 and 70 Gy, whereas the dose of primary radiotherapy is usually 74 Gy. The target of salvage radiotherapy includes the prostate and seminal vesicle, but may also include the pelvis lymph node, according to Roach’s formula. The standard mode of delivery for primary HIFU is 100% acoustic power with a 6-s pulse of energy to create each discrete HIFU lesion, with a 4-s delay between each shot. The salvage mode of delivery for secondary HIFU is 90% acoustic power with a 4-s pulse and a 6-s waiting period.

The secondary outcomes were urinary incontinence (defined as one or more pads used daily for more than 3 months), de novo erectile dysfunction, acute epididymitis, bladder neck contracture, and urethral stricture (which required surgical treatment under anaesthesia). From March 2015, prophylactic bilateral vasectomy was performed immediately before HIFU and Bougienage at an outpatient clinic during follow-up to prevent postoperative epididymitis and urethral stricture, respectively.

MedCalc software (version 18.9.1) was used for all statistical analyses. Chi-square tests and two-sample t tests were used for intergroup comparisons, and the Kaplan–Meier test was used for time-to-event analysis. A p value <0.05 was defined as statistically significant.

Results

Baseline demographics

This study included 128 patients. Patient characteristics are summarised in Table 1. Mean age was 68.5 (range: 50.9–88.2). Mean prostate volume was 23.2 ml. According to D’Amico classification, the numbers of patients with low-, intermediate-, and high-risk disease were 14 (11.0%), 52 (40.6%), and 62 (48.4%). Median follow-up duration was 53.7 months (interquartile range [IQR]: 44.0–66.0).

Table 1. Patient characteristics.

Characteristics
Total number of men 128
Age (yr), mean (range) 68.5 (50.9–88.2)
Prostate volume (ml), mean (range) 23.2 (6.7–71.1)
Gleason score, N (%)
 <7 35 (27.3%)
  = 7 59 (46.1%)
 >7 34 (26.6%)
iPSA, N (%)
 <10 59 (46.1%)
 10–20 43 (33.6%)
 >20 26 (20.3%)
Stage
 <T2b 81 (63.3%)
 T2b 11 (8.6%)
 >T2b 36 (28.1%)
D’Amico risk group, N (%)
 Low 14 (11.0%)
 Intermediate 52 (40.6%)
 High 62 (48.4%)
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Oncological outcomes

Overall 5-year biochemical recurrence–free and salvage treatment–free survival rates after primary HIFU were 64.8% and 50.8%, respectively (Table 2). The 5-year biochemical recurrence–free survival rates were 85.7%, 82.7%, and 45.2% for D’Amico low-, intermediate-, and high-risk groups, respectively (Table 2). The 5-year salvage treatment–free survival rates were 71.4%, 69.2%, and 30.6% for D’Amico low-, intermediate-, and high-risk groups, respectively (Table 2). Kaplan–Meier curves revealed significant differences in both biochemical recurrence–free and salvage treatment–free survival rate between different risk groups (Figs 2 and 3). As shown in Table 3, using Cox regression multivariate analysis, high-risk group is significantly associated with shorter biochemical recurrence free survival, salvage treatment free survival, and metastasis free survival. Median time to salvage treatment was 15.3 months after primary HIFU. Metastasis was detected in one patient in the intermediate-risk group and six patients in the high-risk group (Fig 4). Median nadir PSA was 0.10 ng/ml (IQR: 0.02–0.42 ng/ml). Median time to nadir PSA was 2.52 months (IQR: 1.10–3.87 months). We excluded 28 of 128 patients who were undergoing ADT during follow-up (Fig 1). Two patients were lost to follow-up within one year of HIFU. Of the remaining 98 patients, 60 (61.2%) patients had no biochemical recurrence and thus did not require any salvage treatment, and 38 (38.8%) patients received salvage treatment due to biochemical recurrence. The results of post-HIFU biopsy were shown as Tables 4 and 5. In addition, the relationships between post-HIFU PSA and post-HIFU prostate biopsy were shown in Table 6. There were 13, 21, and 4 patients receiving salvage HIFU, salvage radiation therapy with hormone therapy, and salvage radiation therapy without hormone therapy, respectively. Three out of four patients who received salvage radiation therapy were biochemical recurrence free. Fifteen out of 21 patients who received salvage radiation therapy with hormone therapy were biochemical recurrence free. In other words, in patients receiving salvage radiation therapy with or without hormone therapy, more than 70% of them became biochemical recurrence free. Thirteen patients underwent secondary HIFU. Seven patients were biochemical recurrence free. Among the six patients who had biochemical recurrence after secondary HIFU, four patients received salvage radiation therapy with hormone therapy as second-line salvage treatment, and all were biochemical recurrence free. In total, 38 (38.8%) of 98 patients received salvage treatment with radiotherapy or salvage HIFU. Twenty-nine patients (29/38, 76.3%) were biochemical recurrence free.

Table 2. Oncological outcomes.

Characteristics
Follow-up period (mo), median (IQR) 53.73 (43.98–66.02)
Nadir PSA (ng/ml), median (IQR) 0.10 (0.02–0.42)
Time to PSA nadir (mo), median (IQR) 2.52 (1.10–3.87)
Overall biochemical recurrence free survival at 5 yr 64.8%
Biochemical recurrence free survival at 5 yr by D’Amico risk group
 Low 85.7%
 Intermediate 82.7%
 High 45.2%
Overall salvage treatment-free survival at 5 yr 50.8%
Salvage treatment-free survival at 5 yr by D’Amico risk group
 Low 71.4%
 Intermediate 69.2%
 High 30.6%
Overall metastasis free survival at 5 yr 94.5%
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Fig 2. Kaplan–Meier curves illustrating biochemical recurrence–free survival (Phoenix criteria), by D’Amico risk groups, in men undergoing WG-HIFU for prostate cancer.

Fig 2

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Fig 3. Kaplan–Meier curves illustrating salvage treatment–free survival, by D’Amico risk groups, in men undergoing WG-HIFU for prostate cancer.

Fig 3

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Table 3. Cox regression multivariate analysis for oncologic outcome after primary WG-HIFU.

Biochemical recurrence free survival
Characteristics Univariate analysis Multivariate analysis
HR (95% CI) p value HR (95% CI) p value
Age 0.95–1.02 0.36
Gleason score <7 ref.
Gleason score = 7 0.56–2.80 0.58
Gleason score >7 1.29–6.43 0.01
iPSA <10 ref.
iPSA 10–20 0.15–0.66 0.002
iPSA >20 0.14–0.84 0.02
Stage <T2b ref.
Stage = T2b 0.66–5.71 0.22
Stage >T2b 1.67–5.70 0.0003
low risk group ref.
intermediate risk group 0.27–5.75 0.78
high risk group 1.29–22.32 0.02 2.28–8.90 <0.0001
Salvage treatment free survival
Characteristics Univariate analysis Multivariate analysis
HR (95% CI) p value HR (95% CI) p value
Age 0.96–1.03 0.75
Gleason score <7 ref.
Gleason score = 7 0.73–2.64 0.31
Gleason score >7 1.27–4.82 0.008
iPSA <10 ref.
iPSA 10–20 0.23–0.75 0.003
iPSA >20 0.25–0.95 0.03
Stage <T2b ref.
Stage = T2b 0.37–2.96 0.93
Stage >T2b 1.60–4.38 0.0002
low risk group ref.
intermediate risk group 0.44–3.80 0.65
high risk group 1.37–10.61 0.01 1.86–5.21 <0.0001
Metastasis free survival
Characteristics Univariate analysis Multivariate analysis
HR (95% CI) p value HR (95% CI) p value
Age 0.96–1.14 0.32
Gleason score <7 ref.
Gleason score = 7 0.96
Gleason score >7 0.95
iPSA <10 ref.
iPSA 10–20 0.10–2.67 0.43
iPSA >20 0.96
Stage <T2b ref.
Stage = T2b 0.97
Stage >T2b 0.80–16.26 0.10
low risk group ref.
intermediate risk group 0.96
high risk group 0.95 1.03–73.74 0.047
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Abbreviation: ref.: reference

Fig 4. Kaplan–Meier curves illustrating metastasis-free survival, by D’Amico risk groups, in men undergoing WG-HIFU for prostate cancer.

Fig 4

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Table 4. Results of post-HIFU prostate biopsy.

Biopsy methods No. of patients Residual cancer HIFU-biopsy interval (mo), mean
Transurethral biopsy 32 4 13.54
Sonography-guided biopsy 27 10 15.31
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Table 5. Characteristics of patients receiving post-HIFU prostate biopsy.

Characteristics Residual cancer (N = 14) Negative (N = 45)
Age (yr), mean (range) 67.5 (54.0–82.9) 69.0 (57.8–85.1)
Gleason score, N (%)
 <7 2 (14.3%) 14 (31.1%)
  = 7 10 (71.4%) 18 (40.0%)
 >7 2 (14.3%) 13 (28.9%)
iPSA, N (%)
 <10 8 (57.1%) 24 (60.0%)
 10–20 5 (35.7%) 15 (33.3%)
 >20 1 (7.1%) 6 (13.3%)
Stage (%)
 <T2b 10 (71.4%) 27 (60.0%)
 T2b 0 (0.0%) 5 (11.1%)
 >T2b 4 (28.6%) 13 (28.9%)
D’Amico risk group, N (%)
 Low 1 (7.1%) 8 (17.8%)
 Intermediate 7 (50.0%) 13 (28.9%)
 High 6 (42.9%) 24 (53.3%)
Biochemical recurrence, N (%) 8 (57.1%) 19 (42.2%)
Salvage treatment arranged, N (%) 14 (100%) 24 (53.3%)
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Table 6. Relationships between post-HIFU PSA and post-HIFU prostate biopsy.

Sonography-guided biopsy Positive of malignancy (N = 10) Negative of malignancy (N = 17) p value
iPSA, mean (ng/ml) 12.5 22.8 0.29
post-HIFU PSA nadir, mean (ng/ml) 0.3 1.4 0.15
biochemical recurrence, N 7 13 0.72
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Functional outcomes

Functional outcomes are summarised in Table 7. With the same cohort, our previous study reported a 65.6% rate of de novo erectile dysfunction after primary HIFU. The IIEF-5 score was 22.10 ± 2.62 preoperatively and 9.36 ± 6.33 at 24 months after HIFU [5]. Three patients had urinary incontinence. Acute epididymitis developed in 10.9% of patients. Mean onset time of acute epididymitis was 22.6 days after operation (range: 8–71 days). Bladder neck contracture and urethral stricture, which require further surgical treatment under anaesthesia, were found in 20.3% of patients. One instance of rectourethral fistula was noted after salvage radiotherapy in our cohort. The rate of adverse events after salvage treatment was acceptable (Table 8).

Table 7. Adverse events after primary HIFU.

Adverse events N = 128
Urinary incontinence 2.3%
Acute epididymitis 10.9%
Bladder neck contracture / Urethral stricture 20.3%
De novo erectile dysfunction 65.6%
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Table 8. De novo adverse events after salvage treatments.

Adverse events CTCAE v5.0 Salvage HIFU (N = 13) Salvage radiotherapy (N = 25) p value
Urinary incontinence Grade 1–2 0 (0.0%) 4 (16.0%) 0.13
Grade 3 0 (0.0%) 0 (0.0%) 0.05
Urinary tract obstruction Grade 1–2 1 (7.7%) 4 (16.0%) 0.48
Grade 3 2 (15.4%) 3 (12.0%) 0.77
Gastrointestinal disorders Grade 1–2 0 (0.0%) 5 (20.0%) 0.09
Grade 3 0 (0.0%) 1 (4%) 0.47
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Discussion

In Taiwan, the incidence of prostate cancer is increasing during the last decade. becoming a serious health problem. Radical prostatectomy and radiation therapy have been the standard treatments for localised prostate cancer. However, many patients, especially aged patients or patients with multiple comorbidity, may be concerned about adverse events after major surgery and radiation therapy. Minimally invasive treatment modality such as HIFU is a potential alternative option. Sufficient data concerning the long-term oncological outcomes of using HIFU as the treatment of localised prostate cancer remain lacking. Our previous study and another study reported median times to biochemical recurrence of 12.03 and 13.8 months, respectively [10]. Therefore, medium-term data collected after primary HIFU may be used as an indicator of the oncological outcomes of HIFU. Dickinson et al. reported an overall 5-year BRFS rate of 68% in a multicenter cohort where 16% of patients were in the high-risk group [11]. Durán-Rivera et al. also reported a comparable rate of 64.2% after 86.4 months of follow-up in a cohort where 3% were high-risk patients [12]. The proportion of high-risk group patients in our study, at 47%, was larger than those in previous studies, but our observed oncological outcomes are comparable to theirs. In low- and intermediate-risk patients, 5-year salvage treatment–free survival and biochemical recurrence–free survival rates were approximately 70% and 80%, respectively. The overall 5-year BRFS rate after primary HIFU was 64.8%. Median time to nadir PSA was only 2.52 months. Such early biochemical response is consistent with previous studies [13, 14].

There has been no series report on salvage treatment after primary HIFU. Our salvage treatment after primary HIFU included secondary HIFU and radiation therapy. More than 70% of patients who underwent radiation therapy, with or without ADT, were biochemical recurrence free, whereas only approximately half the patients who received secondary HIFU were biochemical recurrence free. In most patients with biochemical recurrence after secondary HIFU, radiation therapy can still be used to achieve BRFS. The overall BRFS rate after primary HIFU, with or without salvage treatment, was 90.6% in our series. Oncological outcomes after primary WG-HIFU are comparable with other treatment modalities for localised prostate cancer. Although the proportion of high-risk patients was disproportionately high in our series, our observed oncological outcomes are comparable to those of other treatment modalities and previous studies of HIFU.

We observed rates of 2.3% for urinary incontinence, 65.6% for de novo erectile dysfunction, 11.5% for acute epididymitis, and 20.3% for urethral stricture and bladder neck contracture. These adverse event rates are comparable with those of other studies [15–17]. As evident in Table 3, the rate of urethral stricture and bladder neck contracture was significantly reduced to 10.5% after routine bougienage. Those who received prophylactic bilateral vasectomy tended to have a lower risk of acute epididymitis. No instance of rectourethral fistula was noted in the primary HIFU. However, one rectourethral fistula occurred after salvage radiotherapy.

According to the EORTC 22991 trial, of 28 patients who received 74 Gy intensity- modulated radiation therapy (IMRT) as primary treatment for localised prostate cancer, 46.4% of patients had grade 1 acute genitourinary toxicity, 25% had grade 2, and 10.7% had grade 3. In the same patient group, 39.3% of patients had grade 1 acute gastrointestinal toxicity and 7.1% had grade 2 [18]. By contrast, in this study, among patients who received salvage radiotherapy (at 66–70 Gy), only 12% had grade 1 acute genitourinary toxicity, and only 8% had grade 1 acute gastrointestinal toxicity. No toxicity grades >1 were reported after salvage radiotherapy. The difference in the incidence of adverse events between patients who received primary and salvage radiotherapy may result from different radiotherapy dosages.

The major limitation of this study was its retrospective design. However, oncological outcomes after primary HIFU for localised prostate cancer were determined to be acceptable relative to radical prostatectomy and radiotherapy. HIFU is an alternative for the treatment of localised prostate cancer with minimal adverse events. Moreover, we identified disease relapse mainly by elevated PSA. However, MRI may provide a more sensitive test. MRI could detect imaging change of residual prostatic tissue where despite not elevating PSA. However, only x/y (%) who meet criteria of biochemical recurrence received post-HIFU MRI due to suspicion of disease relapse.

In general, our study demonstrated a feasible solution for the reduction of postoperative bladder neck contracture, urethral stricture, and acute epididymitis. Our observations of outcomes after salvage treatment with radiotherapy or secondary HIFU were also reported in this paper. In total, 90.6% of patients with localised prostate cancer in our institute could achieve BRFS (at a median of 53.7 months) following primary HIFU or subsequent salvage treatment with secondary HIFU or radiotherapy.

Conclusions

WG-HIFU is an effective treatment option for localised prostate cancer, especially in D’Amico low- and intermediate-risk diseases. Although some patients experienced PSA biochemical recurrence, the success rate of salvage treatment was still acceptable. Salvage radiation therapy may play an important role in biochemical recurrence after primary HIFU. In addition, the complication rate after primary HIFU was lower than that for other treatment modalities. Long-term follow-up of 10 to 15 years is still required for oncological control.

Acknowledgments

This manuscript was edited by Wallace Academic Editing. We appreciate the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital.

Data Availability

All relevant data are within the paper.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Health promotion administration, ministry of health and welfare, Taiwan. Cancer registry annual report, 2016. 2018.
  • 2.Ficarra V, Novara G, Artibani W, Cestari A, Galfano A, Graefen M, et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol. 2009;55(5):1037–63. Epub 2009/02/03. 10.1016/j.eururo.2009.01.036 . [DOI] [PubMed] [Google Scholar]
  • 3.Donovan JL, Hamdy FC, Lane JA, Mason M, Metcalfe C, Walsh E, et al. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med. 2016;375(15):1425–37. Epub 2016/09/15. 10.1056/NEJMoa1606221 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Albertsen PC, Moore DF, Shih W, Lin Y, Li H, Lu-Yao GL. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29(10):1335–41. Epub 2011/03/02. 10.1200/JCO.2010.31.2330 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chiang PH, Liu YY. Comparisons of oncological and functional outcomes among radical retropubic prostatectomy, high dose rate brachytherapy, cryoablation and high-intensity focused ultrasound for localized prostate cancer. Springerplus. 2016;5(1):1905 Epub 2016/11/22. 10.1186/s40064-016-3584-4 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Liu YY, Chiang PH. Comparisons of Oncological and Functional Outcomes Between Primary Whole-Gland Cryoablation and High-Intensity Focused Ultrasound for Localized Prostate Cancer. Ann Surg Oncol. 2016;23(1):328–34. Epub 2015/06/20. 10.1245/s10434-015-4686-x . [DOI] [PubMed] [Google Scholar]
  • 7.Madersbacher S, Marberger M. High-energy shockwaves and extracorporeal high-intensity focused ultrasound. J Endourol. 2003;17(8):667–72. Epub 2003/11/19. 10.1089/089277903322518680 . [DOI] [PubMed] [Google Scholar]
  • 8.Ramsay CR, Adewuyi TE, Gray J, Hislop J, Shirley MD, Jayakody S, et al. Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation. Health Technol Assess. 2015;19(49):1–490. Epub 2015/07/04. 10.3310/hta19490 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Tsakiris P, Thuroff S, de la Rosette J, Chaussy C. Transrectal high-intensity focused ultrasound devices: a critical appraisal of the available evidence. J Endourol. 2008;22(2):221–9. Epub 2008/01/24. 10.1089/end.2007.9849 . [DOI] [PubMed] [Google Scholar]
  • 10.Sung HH, Jeong BC, Seo SI, Jeon SS, Choi HY, Lee HM. Seven years of experience with high-intensity focused ultrasound for prostate cancer: advantages and limitations. Prostate. 2012;72(13):1399–406. Epub 2012/01/19. 10.1002/pros.22491 . [DOI] [PubMed] [Google Scholar]
  • 11.Dickinson L, Arya M, Afzal N, Cathcart P, Charman SC, Cornaby A, et al. Medium-term Outcomes after Whole-gland High-intensity Focused Ultrasound for the Treatment of Nonmetastatic Prostate Cancer from a Multicentre Registry Cohort. Eur Urol. 2016;70(4):668–74. Epub 2016/03/10. 10.1016/j.eururo.2016.02.054 . [DOI] [PubMed] [Google Scholar]
  • 12.Duran-Rivera A, Montoliu Garcia A, Juan Escudero J, Garrido Abad P, Fernandez Arjona M, Lopez Alcina E. High-intensity focused ultrasound therapy for the treatment of prostate cancer: Medium-term experience. Actas Urol Esp. 2018;42(7):450–6. Epub 2018/03/27. 10.1016/j.acuro.2017.11.007 . [DOI] [PubMed] [Google Scholar]
  • 13.Crouzet S, Chapelon JY, Rouviere O, Mege-Lechevallier F, Colombel M, Tonoli-Catez H, et al. Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. Eur Urol. 2014;65(5):907–14. Epub 2013/05/15. 10.1016/j.eururo.2013.04.039 . [DOI] [PubMed] [Google Scholar]
  • 14.Chen PY, Chiang PH, Liu YY, Chuang YC, Cheng YT. Primary whole-gland ablation for localized prostate cancer with high-intensity focused ultrasound: The important predictors of biochemical recurrence. Int J Urol. 2018;25(6):615–20. Epub 2018/05/15. 10.1111/iju.13581 . [DOI] [PubMed] [Google Scholar]
  • 15.Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology. 2004;63(2):297–300. Epub 2004/02/20. 10.1016/j.urology.2003.09.020 . [DOI] [PubMed] [Google Scholar]
  • 16.Rebillard X, Soulie M, Chartier-Kastler E, Davin JL, Mignard JP, Moreau JL, et al. High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology. BJU Int. 2008;101(10):1205–13. Epub 2008/03/08. 10.1111/j.1464-410X.2008.07504.x . [DOI] [PubMed] [Google Scholar]
  • 17.Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU Int. 2006;97(1):56–61. Epub 2005/12/13. 10.1111/j.1464-410X.2006.05864.x . [DOI] [PubMed] [Google Scholar]
  • 18.Matzinger O, Duclos F, van den Bergh A, Carrie C, Villa S, Kitsios P, et al. Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991. Eur J Cancer. 2009;45(16):2825–34. Epub 2009/08/18. 10.1016/j.ejca.2009.07.009 . [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Jason Chia-Hsun Hsieh

13 Feb 2020

PONE-D-20-00019

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: medium-term results from a single centre

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

**********

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Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors provided medium term oncological outcomes of a single institution cohort of 128 men receiving whole gland HIFU for clinically localized prostate cancer.

Major comments:

1. I would specify that the study describes whole gland HIFU. Modify and introduce an abbreviation for whole gland HIFU throughout the manuscript.

2. Abstract does not read well. For example, the first proposition does not fit neither with the background nor with the objective of the study. No information are given regarding the efficacy of salvage treatments. Please address this point.

3. Did all patients received a post whole gland HIFU biopsy? Please clarify

4. A table (or a Kaplan meier in case the follow up biopsy protocol was not standardized) showing the results of the follow up biopsy would be useful.

5. Which were the criteria, if there were any, to choose the salvage treatment strategy? Please describe.

6. If the authors are keen on reporting data regarding the efficacy of salvage treatments is necessary to report also the outcomes of the population receiving any salvage treatment (as subgroup analysis and figures as supplementary)

7. Since all men received a pre mpMRI, isit possible to add any information regarding the presence of visible lesions, PI-RADS score etc?

8. Regarding the functional outcomes, which represent secondary outcomes according to the study’s methods, only data regarding the study population should be reported. All information regarding not included cohort should be removed since not relevant.

9. Unless preop IIEF is available, any data regarding post op IIEF should be removed since not reliable.

10. Adverse events should be put in one single table and, if possible, compared for each procedure (provide a p value if possible)

11. The first sentence of the discussion part is out of context and biased. Please change the beginning of this paragraph

Reviewer #2: 1. The major concern on this works is that it is supported the manuscript a small number of patients and a very short period in this manuscript.

2. Abstract-too much space is spent on descriptive data and not enough space on the main result of the study.

3. The author mentions in materials and methods that 405 patients with prostate cancer have been treated with HIFU from December 2009 to February 2015. From December 2009 to February 2015, 161 patients who were newly diagnosed with prostate cancer were enrolled. In total, 128 patients were included (Figure 1). It is not cleared why the author selected only 128 patients in this study and Fig.1 is confusing to understand.

4. A small group of population main concern.

Out of 161, only 128 enrolled patients were included. Not clear about the missing population in this study. Is it due to side effects? 20 patients were

excluded because of their follow-up durations were less than 30 months (not clear about missing data during that time and follow up).

Excluded 28 of 128 patients who were undergoing ADT during follow-up (Figure 1)??

Two patients were lost to follow-up (not clear)??

A very small group of studies to compare: Of the remaining 98 patients, 60 (61.2%) patients had no biochemical recurrence and thus did not require any salvage treatment, and 38 (38.8%), patients received salvage treatment due to biochemical recurrence.

Conclusion: Large group of the population required for efficacy and safety of the treatment. Clarification required for lost to follow up.

5. Prostate-specific antigen: It is very important to know the PSA levels for prostate cancer patients. So, all patients had PSA levels measured three to six months for the first few years to check how well the HIFU and salvage treatment has worked. So, I would recommend a Table including prostate-specific antigen and histology after high intensity focused ultrasound.

6. MRI analysis: MRI may provide a more sensitive test than PSA, as it can detect disease not elevating PSA but causing a change in the MRI features of residual prostatic tissue. Second, when the disease is detected on MRI, imaging also provides the location of the disease and therefore has the added advantage of being able to guide biopsy and salvage therapy by MRI analysis and the image need to include in the picture.

7. The author showed that patients with the high-risk group had shorter BCR and salvage treatment-free survival than prostate cancer patients with a low and intermediate group (P<0.0001) (Figure 2 and Figure 3). To determine whether the high-risk group has independent prognostic value, univariate and multivariate analysis needs to be performed.

8. I would recommend providing a table of Kaplan-Meier analysis of metastasis-free survival in Figure 4. What is the probability? How do certain personal, behavioral or clinical characteristics chances of survival?

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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Attachment

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PLoS One. 2020 Jul 23;15(7):e0236026. doi: 10.1371/journal.pone.0236026.r002

Author response to Decision Letter 0

9 Apr 2020

Dear editor and reviewers:

Thanks for the time and effort you spent assessing the previous version of the manuscript.

For the previous table 3 (table 7 in the revised manuscript), the IIEF questionnaire was not done for most patients in that time frame, so we typed “N/A” for de novo erectile dysfunction. The column was deleted for irrelevance to the cohort of this article as reviewer’s suggestion. Other responses to the comments are as below and all of your suggestions are incorporated into revised manuscript.

Reviewer #1: The authors provided medium term oncological outcomes of a single institution cohort of 128 men receiving whole gland HIFU for clinically localized prostate cancer.

1. I would specify that the study describes whole gland HIFU. Modify and introduce an abbreviation for whole gland HIFU throughout the manuscript.

--> Thanks for this suggestion. Whole-gland HIFU may be abbreviated as WG-HIFU. It was revised in the manuscript.

2. Abstract does not read well. For example, the first proposition does not fit neither with the background nor with the objective of the study. No information are given regarding the efficacy of salvage treatments. Please address this point.

--> The abstract was revised according to your suggestion. Thanks!

3. Did all patients received a post whole gland HIFU biopsy? Please clarify

--> Post-HIFU prostate biopsy was not routinely arranged. It might be arranged because of biochemical recurrence. It might also be arranged for patients not meeting criteria of biochemical recurrence but worry about continuous elevation of PSA. We will add this paragraph to manuscript (p5, line 122-125).

4. A table (or a Kaplan meier in case the follow up biopsy protocol was not standardized) showing the results of the follow up biopsy would be useful.

--> Tables 4 and 5 showing the results of post-HIFU biopsy was added to the paragraph. Thanks for the suggestion.

5. Which were the criteria, if there were any, to choose the salvage treatment strategy? Please describe.

--> Of patients with residual tumor noted, secondary HIFU will be arranged. Of patients with local lymph node metastasis suspected, salvage radiotherapy will be suggested. Salvage radiotherapy with half to one year of ADT is the standard strategy. We will add this paragraph to manuscript (p6, line 130-134).

6. If the authors are keen on reporting data regarding the efficacy of salvage treatments is necessary to report also the outcomes of the population receiving any salvage treatment (as subgroup analysis and figures as supplementary)

--> Thanks for the suggestion. Experience of post-HIFU salvage treatment is relatively scarce. Therefore, we think we could try to share our experience after years of HIFU use. However, only 38 patients received salvage HIFU or salvage radiation therapy in this study. Their outcome was shown in figure 1. We also added some explanation about salvage treatment.

7. Since all men received a pre mpMRI, is it possible to add any information regarding the presence of visible lesions, PI-RADS score etc?

--> Thanks for this suggestion. Actually, of all 128 patients enrolled, only 12 patients received pre-HIFU mpMRI and the rest 116 patients received pre-HIFU pelvic CT. Since the number of mpMRI is small in this series, we are afraid that we cannot provide any new information about this issue.

8. Regarding the functional outcomes, which represent secondary outcomes according to the study’s methods, only data regarding the study population should be reported. All information regarding not included cohort should be removed since not relevant.

--> The irrelevant sentences and table were removed (p15). Thanks!

9. Unless preop IIEF is available, any data regarding post op IIEF should be removed since not reliable.

--> Preoperative IIEF was added to the paragraph (p15, line 232-233). Thanks for the suggestion.

10. Adverse events should be put in one single table and, if possible, compared for each procedure (provide a p value if possible)

--> The table regarding adverse events was revised and shown in table 8.

11. The first sentence of the discussion part is out of context and biased. Please change the beginning of this paragraph

--> Thanks for the reminder. This paragragh was revised (p16, line 261-266).

 

Reviewer #2:

1. The major concern on this works is that it is supported the manuscript a small number of patients and a very short period in this manuscript.

--> Thanks for the comment. This is a median 5-year follow-up study. We share our HIFU experience because there are only a few papers of HIFU treatment of prostate cancer.

2. Abstract-too much space is spent on descriptive data and not enough space on the main result of the study.

--> The abstract was revised. Thanks for the suggestion!

3. The author mentions in materials and methods that 405 patients with prostate cancer have been treated with HIFU from December 2009 to February 2015. From December 2009 to February 2015, 161 patients who were newly diagnosed with prostate cancer were enrolled. In total, 128 patients were included (Figure 1). It is not cleared why the author selected only 128 patients in this study and Fig.1 is confusing to understand.

--> We are sorry about the misunderstanding. In our institution, we performed the first HIFU in December 2009. From December 2009 to December 2019, when we submitted the original manuscript, there are 405 patients treated with HIFU. With the concern of adequate follow-up period, we only enrolled 161 patients treated with HIFU during December 2009 to February 2015.

4. A small group of population main concern.

Out of 161, only 128 enrolled patients were included. Not clear about the missing population in this study. Is it due to side effects? 20 patients were

excluded because of their follow-up durations were less than 30 months (not clear about missing data during that time and follow up).

Excluded 28 of 128 patients who were undergoing ADT during follow-up (Figure 1)??

Two patients were lost to follow-up (not clear)??

A very small group of studies to compare: Of the remaining 98 patients, 60 (61.2%) patients had no biochemical recurrence and thus did not require any salvage treatment, and 38 (38.8%), patients received salvage treatment due to biochemical recurrence.

Conclusion: Large group of the population required for efficacy and safety of the treatment. Clarification required for lost to follow up.

--> Of the 128 patients, 28 patients received ADT after primary HIFU as a role of salvage treatment because of biochemical recurrence or slight elevation of PSA without biochemical recurrence. Ten of the 28 patients stopped ADT months later and no more PSA elevation occurred. Eleven of the 28 patients still receive ADT currently and PSA level remain stable. Seven of the 28 patients still receive ADT currently, but gradual elevation of PSA is noted. However, they refuse or hesitate about further salvage treatment such as radiation therapy or secondary HIFU.

Since 41 of 45 (91%) suffered from biochemical recurrence within 30 months during follow-up, therefore, we excluded patients whose follow-up duration is less than 30 months to avoid missing biochemical recurrence.

5. Prostate-specific antigen: It is very important to know the PSA levels for prostate cancer patients. So, all patients had PSA levels measured three to six months for the first few years to check how well the HIFU and salvage treatment has worked. So, I would recommend a Table including prostate-specific antigen and histology after high intensity focused ultrasound.

--> Thanks for the suggestion. The relationships between post-HIFU PSA and post-HIFU prostate biopsy was shown in table 6.

6. MRI analysis: MRI may provide a more sensitive test than PSA, as it can detect disease not elevating PSA but causing a change in the MRI features of residual prostatic tissue. Second, when the disease is detected on MRI, imaging also provides the location of the disease and therefore has the added advantage of being able to guide biopsy and salvage therapy by MRI analysis and the image need to include in the picture.

--> Really thanks for your suggestion. We have described this method in the discussion in the revised manuscript (p19, line 330-334).

7. The author showed that patients with the high-risk group had shorter BCR and salvage treatment-free survival than prostate cancer patients with a low and intermediate group (P<0.0001) (Figure 2 and Figure 3). To determine whether the high-risk group has independent prognostic value, univariate and multivariate analysis needs to be performed.

--> Univariate and multivariate analysis were performed and showed in table 3.

8. I would recommend providing a table of Kaplan-Meier analysis of metastasis-free survival in Figure 4. What is the probability? How do certain personal, behavioral or clinical characteristics chances of survival?

--> Associated univariate and multivariate analysis was performed and showed in table 3.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (21.9KB, docx)

Decision Letter 1

Jason Chia-Hsun Hsieh

25 May 2020

PONE-D-20-00019R1

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: medium-term results from a single centre

PLOS ONE

Dear Dr. Chiang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please kindly address the minor issues from the reviewer. 

==============================

Please submit your revised manuscript by Jul 09 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Jason Chia-Hsun Hsieh, M.D. Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please kindly address the minor issues from the reviewer.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors did a pretty good job addressing all the comments.

Further minor comments:

1) Table 3: provide HRs for both univariate and multivariate in a clearer way so that the reader can understand the confounders. logHRs not required

2) Please clarify what endoscopic biopsy means

3) Table 5: provide both raw numbers and percentages for each figures

4) positive/negative of malignancies sounds pretty bad. Rewrite it.

5) Please be consistent with the use of the short WG-HIFU

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Jul 23;15(7):e0236026. doi: 10.1371/journal.pone.0236026.r004

Author response to Decision Letter 1

23 Jun 2020

Reviewer #1:

Further minor comments:

1) Table 3: provide HRs for both univariate and multivariate in a clearer way so that the reader can understand the confounders. logHRs not required

--> Table 3 was revised according to suggestion of the Biostatistics Center of our institution.

2) Please clarify what endoscopic biopsy means

--> Endoscopic biopsy means transurethral biopsy by monopolar loop.

3) Table 5: provide both raw numbers and percentages for each figures

--> In table 5, percentage was added for each figures.

4) positive/negative of malignancies sounds pretty bad. Rewrite it.

--> The terms were revised.

5) Please be consistent with the use of the short WG-HIFU

--> Whole manuscript was examined and the WG-HIFU is used consistently.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (15.5KB, docx)

Decision Letter 2

Jason Chia-Hsun Hsieh

29 Jun 2020

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: medium-term results from a single centre

PONE-D-20-00019R2

Dear Dr. Chiang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Jason Chia-Hsun Hsieh, M.D. Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All the questions were answered adequately.

Reviewers' comments:

Acceptance letter

Jason Chia-Hsun Hsieh

8 Jul 2020

PONE-D-20-00019R2

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: medium-term results from a single centre

Dear Dr. Chiang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Jason Chia-Hsun Hsieh

Academic Editor

PLOS ONE

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