Salvage High-intensity Focused Ultrasound (HIFU) Treatment in Prostate Cancer (PCa)

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CMS Publications:

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 14,

10 Coverage of Medical Devices

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 23,

30 Services paid under the Medicare Physicians Fee Schedule

CMS Publication 100-08, Medicare Program Integrity Manual, Chapter 13,

5.1 Reasonable and necessary provisions in LCDs

7.1 Evidence supporting LCDs.

Whole gland HIFU is considered medically necessary as a local treatment for recurrent PCa following radiation therapy (RT) when ALL of the following criteria are met (1,2):

1. Biochemical recurrence (BCR) according to the Phoenix definition (PSA nadir + 2 ng/mL)
2. Positive post-RT transrectal ultrasound guided (TRUS) biopsy
3. Candidate for local curative therapy as evidenced by favorable clinical and pathologic factors (BOTH of the following)
   1. Original (pre-RT)- clinical stage T1-T2, NX or N0
   2. Current (ALL are required)
      1. PSA < 10 ng/mL
      2. absence of distant metastases per National Comprehensive Cancer Network (NCCN) imaging guidelines
      3. no lymph node involvement
      4. interval to biochemical failure > 18 months
      5. International Society of Urological Pathology (ISUP) grade < 4
      6. local recurrence amenable to entire destruction
4. Multi-disciplinary consensus (surgeon, oncologist, radiologist)
5. Hi comorbidity (i.e., not a candidate for radical prostatectomy (RP)) (3)

Exclusion Criteria (NONE of the below are allowed)

1. Life expectancy < 10 years (1,2)
2. PCa subtype other than adenocarcinoma (4)
3. Post-RT ADT (5,6)
4. Post-RT anal/rectal stenosis or rectal wall thickness >6 mm by TRUS or MRI (6)

One third of PCa patients select radiation therapy (RT) as their primary treatment (7). Despite improved techniques and higher dose regimens, biochemical relapse occurs in 30–60% (8), with approximately 20–30% classified as local (4). There is no standard of care for locally radio-recurrent PCa, and patients are at increased, albeit variable, risk of developing metastases, PCa-specific and overall mortality (10 year overall survival (OS) rates are approximately 20% diminished). The vast majority (98%) are managed with observation or palliative treatment with androgen deprivation therapy (ADT) alone (7), despite ADT’s adverse effects on cardiovascular health, metabolic function, and bone strength (8). Four potentially curative local salvage treatment (LST) options for radio-recurrent PCa include RP, brachytherapy, cryoablation, and HIFU (1,9). Major guidelines consider LST appropriate in highly select patients (1,2).

Originally developed in the 1940s, HIFU is an energy-based, minimally invasive, ablative treatment. For PCa, a transrectal ultrasound probe both images the prostate and delivers timed bursts of heat to create coagulation necrosis in a targeted area. A cooling balloon surrounding the probe protects the rectal mucosa from the high temperature. HIFU is typically performed in an outpatient setting under spinal or general anesthesia. It was first employed in Europe in the 1990s for PCa treatment, mostly as primary therapy, and two devices are FDA 510(k) cleared (Ablatherm- 2015 and Sonoblate- 2016) for “prostate tissue ablation.” Salvage HIFU is intended to completely ablate all prostate tissue that remains after primary EBRT. A key side effect is urinary retention due initially to edema from tissue coagulation and then by elimination of necrotic debris. Other reported long-term complications include recto-urethral fistula, rectal or perineal pain, and bladder neck contracture or urethral stricture.

The following chronologically listed, retrospective studies looked at localized radio-recurrent disease treated with whole gland HIFU.

1. In a 2009 review of 167 men, the 5-year overall survival rate was 84% (5). However, the progression-free survival (PFS) rate was significantly worse with higher pre-EBRT risk category (low-53%; intermediate-42%; high-25%) increased pre-HIFU PSA, and with prior ADT (risk ratio 2.8). The authors conclude that HIFU is a curative treatment option with acceptable morbidity but that patient selection is “imperative.”
2. A 2013 analysis of 46 patients focused on potential pre-HIFU MRI prognostic factors (10). The 2-year and 4-year PFS rates were 42% and 31%, respectively. Independent predictors of salvage HIFU failure were PSA level at HIFU treatment (p < 0.012; risk ratio: 1.15, 95% CI: 1.03-1.29) and tumor extension anterior to the urethra (p = 0.046, risk ratio: 2.51, 95% CI: 1.02-6.16). Other clinical factors (neoadjuvanat hormone therapy, PSA velocity, clinical stage, Gleason score) and MRI-derived parameters (prostate volume, tumor volume, extracapsular extension, seminal vesicle invasion, and tumor apical extension) were not independent risk factors.
3. A small 2014 study of 13 patients had a PFS rate of 53.8% during a mean follow-up of 44.5 months (11). The complication rate requiring intervention was 38.5%. The authors conclude that while seemingly effective, the HIFU complication rate is relatively high, and level I studies are needed “to verify the effectiveness of HIFU as a salvage therapy and to manage the expected complications.”
4. A large 2017 multi-center, uncontrolled study of 418 men (mean age 68.6 years) treated between 1995 and 2009 found 7-year OS, cancer-specific survival (CSS) and metastasis-free survival (MFS) rates of 72%, 82%, and 81%, respectively (6). Complication rates decreased after the introduction, in 2002, of specific (post-RT rather than first-line) HIFU parameters, incontinence (grade II or III) decreased from 32% to 19% (P = 0.002); bladder outlet obstruction or stenosis from 30% to 15% (P = 0.003); and recto-urethral fistula from 9% to 0.6% (P < 0.001). The 5-year PFS rate was 49%. Risk factors for lower PFS included pre-RT risk group (58%, 51% and 36% for pre-EBRT low-, intermediate- and high-risk patients, respectively); pre-HIFU PSA level (67%, 42% and 22% for pre-S-HIFU PSA level ≤4, 4–10 and ≥10 ng/mL, respectively); pre-HIFU Gleason score (59%, 41% and 39% for pre-S-HIFU Gleason score of ≤6, equal to 7, and ≥8, respectively); and history of ADT (59% vs. 38% without and with prior ADT, respectively). The authors conclude the data support HIFU as a “definitive treatment option,” but “at a price of significant morbidity,” and that “careful patient selection should be performed and the prospect of salvage treatment should be carefully weighed in the absence of level I evidence.”
5. A 2019 study compared HIFU (n=27) and RP (n=25) outcomes (4). No significant differences were found in estimated 5-year OS (80.9% vs. 61.9%, p = 0.24), CSS (84.0% vs. 74.0%, p = 0.36), and MFS (60.3% vs. 55.2%, p = 0.55) for HIFU vs. RP, respectively. There was a significant difference in incontinence at 12 months (22.2% vs. 56.0%, p = 0.01) and in the number of Clavien ≥ III complications [9 vs. 16, p = 0.027] in favor of HIFU vs. RP, respectively. While concluding the study suggests both HIFU and RP could be considered valuable LST options, the authors admit to several study limitations (retrospective, small size, lack of propensity score matching), and suggest the need for long-term, prospective multicenter group-matched trials.

The following chronologically listed, prospective studies looked at localized radio-recurrent disease treated with whole gland HIFU.

1. One of the first studies (2004) was an analysis of 71 men with a mean age of 67 years, mean PSA level of 7.73, and mean follow-up of 14.9 months (12). After HIFU treatment, 57 (80%) had negative biopsies, 43 (61%) had a nadir PSA level of less than 0.5 ng/mL within 3 months, and 44% had no evidence of disease progression. Adverse events included recto-urethral fistula (6%), grade 3 incontinence (7%), and bladder neck stenosis (17%). No rectal injury occurred with the use of post-RT specific parameters. The authors conclude salvage HIFU is promising with lower morbidity than other types of salvage therapy.
2. A 2012 study of 84 men found 1- and 2-year PFS rates of 59% and 43%, respectively, with intervention for bladder outlet obstruction in 20% (13). The authors conclude that salvage HIFU, while promising, is a “high-risk procedure” and that “strategies to better identify metastatic disease…and reduce local toxicity are needed.”
3. In a 2016 study of 50 consecutive men with a median follow-up of 64 months, 56% achieved a PSA nadir < 0.5 ng/ml (14). The 1, 3 and 5-year PFS rate was 72%, 40% and 31%, respectively. Actuarial 1, 3 and 5-year OS was 100%, 94% and 87%, respectively. These results highlight the discrepancy between disease progression, largely defined by biochemical failure, and survival. Symptoms of bladder outlet obstruction were common and intervention in the form of a bladder neck incision, transurethral resection or urethral dilatation was needed in 27/50 patients (54%). Overall, 3/50 (6%) developed a fistula, and 3/50 (6%) developed osteonecrosis of the pubic symphysis needing prolonged antibiotic treatment. The authors conclude that while whole gland salvage HIFU is promising, “further research on focal salvage ablation in order to reduce toxicity while retaining disease control rates is required.”
4. A 2017 study of 81 men found no residual disease in 65% (41/63) at 6 months (3). The 5-year OS and CSS were 88% and 94.4%, respectively. The rate of rectal fistula and severe incontinence was 3.7% each. A total of 223 complications were recorded in the 180 days after HIFU (Clavien-Dindo grade 1-195, grade II-20, grade III-7, grade IV-1). The authors conclude that HIFU is a viable treatment option for radio-recurrent PCa, and “should especially be given serious consideration in the management of local recurrence in elderly patients and those deemed not suitable or willing for aggressive surgical salvage.”
5. A 2018 multicenter, nonrandomized, open label study in 100 men (mean age of 70 years) with clinically localized recurrent PCa at least 2 years after RT, found a negative prostate biopsy in 81% (63/78) 12 months post HIFU treatment (8). The 1-year endpoint of a prostate specific antigen nadir of 0.5 ng/ml or less plus negative biopsy was achieved in 64% (50/78). Twenty treatment related grade 3 adverse events included rectal fistulas in 5, osteitis pubis in 3, and hematuria requiring intervention in 3. While the authors tentatively endorse HIFU as a reasonable LST option, noting the trial limitations (small study with short follow-up), they conclude: “Further establishment of salvage HIFU as an acceptable treatment alternative will await long-term follow-up regarding oncological effectiveness and quality of life outcomes.”

Table: Outcome Summary (HIFU vs. RP)

A 2016 systematic review and meta-analysis of 63 articles found no significant difference in oncologic outcomes or toxicity between different salvage therapies (RP, HIFU, cryotherapy, brachytherapy), but RP appeared to be associated with more urinary incontinence (19). Focal HIFU treatment (rather than whole gland) is increasingly being explored as a potentially lower complication LST option. However, while a few retrospective studies have showed a trend towards acceptable toxicity rates, larger, prospective investigations are needed to establish adequate long-term outcomes (7).

Guideline recommendations regarding salvage HIFU therapy in the setting of localized radio-recurrent PCa are mixed.

1. NCCN lists HIFU as a possible curative salvage option (category 2A; based upon lower-level evidence, there is uniform consensus that the intervention is appropriate) in very select patients after radio-recurrent PCa. They cite a median PFS of 63 months, 5-year OS of 88%, CSS of 94%, acceptable morbidity (grade III/IV complication rate of 3.6%), and a 48% ADT avoidance at a median follow-up of 64 months (1). It recommends that any primary salvage therapy “needs to be individualized based on the patient’s risk of progression, the likelihood of success, and the risks involved with salvage therapy.”

2. American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology (AUA/ASTRO/SUO) guidelines state that HIFU for localized prostate cancer “should be done within the context of a clinical trial,” though it is unclear if this recommendation is specific to primary therapy, or applies to both primary and salvage therapy (20).

3. European Association of Urology (EAU) – European Society for Radiotherapy & Oncology (ESTRO) – International Society of Geriatric Oncology (SIOG) Guidelines recommend salvage RP as the most likely to achieve local control, citing 5- and 10-yr PFS estimates ranging from 47% to 82% and from 28% to 53%, respectively (9). It says to “offer or discuss” other LST options but “inform patients about the experimental nature of these approaches.”

4. Latest EAU guidelines recommend only RP as a curative LST option (strength rating weak), and even then only in very select patients (low comorbidity, life expectancy > 10 years, pre-RP PSA < 10 ng/mL, biopsy ISUP grade < 4, no lymph node involvement or evidence of distant metastatic disease pre-RP, and initial clinical staging T1 or T2). Regarding HIFU they unambiguously state: “Do not offer HIFU….to patients with proven local recurrence since it is still experimental” (strength rating strong) (2).

5. UpToDate notes that HIFU “lacks robust evidence of efficacy” and that even though is FDA cleared “for destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer” (21). Although mentioned as a salvage treatment option, only RP, cryotherapy, and brachytherapy are recommended (22).

6. A 2019 Hayes review rates salvage HIFU a “C” (the evidence is moderate in size and consistent, but low quality that salvage HIFU is relatively safe and effective over the short to medium term) (23). The review calls for “additional, well-designed studies…to further compare HIFU….with alternative and established salvage therapies before a determination can be made as to its long-term safety and effectiveness, particularly with regard to prostate cancer recurrence and mortality.” Of note, focal HIFU gets a D2 rating (insufficient evidence to assess the efficacy and safety of salvage HIFU in this patient population).

In summary, there is an overall dearth of robust evidence comparing different salvage options with each other or with observation; no Level I evidence exists. Whole gland salvage HIFU prospective and retrospective studies (almost all non-comparative) are relatively small with short follow-up and non-standardized outcome measures. Conversely, the data, while of low quality, is cumulatively moderate in size, and consistently suggest that whole gland HIFU is a safe and effective LST option for a subset of men with localized recurrent prostate cancer after radiotherapy. Guideline recommendations on salvage HIFU span the continuum from RP parity to relegation to experimental status. All agree on the need for careful patient selection and that absence of level I evidence mandates cautious individualization. Given the universal endorsement of RP, one obvious compromise is to limit salvage HIFU to high comorbidity patients otherwise eligible for RP.

1. NCCN Guidelines- Prostate Cancer Version 2.2019. 2019; https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
2. EAU Guidelines: Prostate Cancer, Chapter 6: Treatment. Presented at the EAU Annual Congress Barcelona 2019. 2019; https://uroweb.org/guideline/prostate-cancer/#6. Accessed 7/6/19.
3. Siddiqui KM, Billia M, Arifin A, Li F, Violette P, Chin JL. Pathological, Oncologic and Functional Outcomes of a Prospective Registry of Salvage High Intensity Focused Ultrasound Ablation for Radiorecurrent Prostate Cancer. J Urol. 2017;197(1):97-102.
4. Devos B, Al Hajj Obeid W, Andrianne C, et al. Salvage high-intensity focused ultrasound versus salvage radical prostatectomy for radiation-recurrent prostate cancer: a comparative study of oncological, functional, and toxicity outcomes. World J Urol. 2019.
5. Murat FJ, Poissonnier L, Rabilloud M, et al. Mid-term results demonstrate salvage high-intensity focused ultrasound (HIFU) as an effective and acceptably morbid salvage treatment option for locally radiorecurrent prostate cancer. Eur Urol. 2009;55(3):640-647.
6. Crouzet S, Blana A, Murat FJ, et al. Salvage high-intensity focused ultrasound (HIFU) for locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients. BJU Int. 2017;119(6):896-904.
7. Golbari NM, Katz AE. Salvage Therapy Options for Local Prostate Cancer Recurrence After Primary Radiotherapy: a Literature Review. Curr Urol Rep. 2017;18(8):63.
8. Jones TA, Chin J, McLeod D, Barkin J, Pantuck A, Marks LS. High Intensity Focused Ultrasound for Radiorecurrent Prostate Cancer: A North American Clinical Trial. J Urol. 2018;199(1):133-139.
9. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol. 2017;71(4):630-642.
10. Rouviere O, Sbihi L, Gelet A, Chapelon JY. Salvage high-intensity focused ultrasound ablation for prostate cancer local recurrence after external-beam radiation therapy: prognostic value of prostate MRI. Clin Radiol. 2013;68(7):661-667.
11. Song W, Jung US, Suh YS, et al. High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after radiotherapy. Korean J Urol. 2014;55(2):91-96.
12. Gelet A, Chapelon JY, Poissonnier L, et al. Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. Urology. 2004;63(4):625-629.
13. Uddin Ahmed H, Cathcart P, Chalasani V, et al. Whole-gland salvage high-intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy. Cancer. 2012;118(12):3071-3078.
14. Shah TT, Peters M, Kanthabalan A, et al. PSA nadir as a predictive factor for biochemical disease-free survival and overall survival following whole-gland salvage HIFU following radiotherapy failure. Prostate Cancer Prostatic Dis. 2016;19(3):311-316.
15. Rosoff JS, Savage SJ, Prasad SM. Salvage radical prostatectomy as management of locally recurrent prostate cancer: outcomes and complications. World J Urol. 2013;31(6):1347-1352.
16. Chade DC, Eastham J, Graefen M, et al. Cancer control and functional outcomes of salvage radical prostatectomy for radiation-recurrent prostate cancer: a systematic review of the literature. Eur Urol. 2012;61(5):961-971.
17. Crouzet S, Murat FJ, Pommier P, et al. Locally recurrent prostate cancer after initial radiation therapy: early salvage high-intensity focused ultrasound improves oncologic outcomes. Radiother Oncol. 2012;105(2):198-202.
18. European Association of Urology (EAU) Guidelines on Prostate Cancer. 2015; https://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf.
19. Philippou Y, Parker RA, Volanis D, Gnanapragasam VJ. Comparative Oncologic and Toxicity Outcomes of Salvage Radical Prostatectomy Versus Nonsurgical Therapies for Radiorecurrent Prostate Cancer: A Meta-Regression Analysis. Eur Urol Focus. 2016;2(2):158-171.
20. Sanda MG, Cadeddu JA, Kirkby E, et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part II: Recommended Approaches and Details of Specific Care Options. J Urol. 2018;199(4):990-997.
21. UpToDate: Cryotherapy and other ablative techniques for the initial treatment of prostate cancer. 2019; UpToDate
22. UpToDate: Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy. 2019; UpToDate
23. Hayes: High-Intensity Focused Ultrasound for Salvage Therapy of Recurrent Prostate Cancer. 2019; https://evidence.hayesinc.com/report/dir.hifurecurrent3948.