Medical Policy: 02.01.53
Original Effective Date: March 2014
Reviewed: January 2019
Revised: January 2019
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
This medical policy is addressing high intensity focused ultrasound (HIFU). For magnetic resonance (MR) guided focused ultrasound (MRgFUS), see medical policy 04.01.09 MRI Guided High-Intensity Focused Ultrasound (MRgFUS) Ablation.
High intensity focused ultrasound (HIFU) is a minimally-invasive technique that is currently under clinical study for treatment of cancers and other conditions, including but not limited to prostate cancer, renal cancer, pancreatic cancer, breast cancer, central nervous system cancers (gliomas), soft tissue sarcomas, hepatocellular carcinoma, thyroid nodules, benign prostatic hypertrophy (BPH), breast fibroadenoma and vulvar dystrophy (non-neoplastic epithelial disorders of the vulva). Currently, the primary area of study is for use of HIFU in the treatment of prostate cancer.
High intensity focused ultrasound (HIFU) focuses high-energy ultrasound waves on a single location, which increases the local tissue temperature to over 80 degrees Celcius. This causes a discrete locus of coagulative necrosis of approximately 3x3x10 mm. HIFU can be repeated if necessary. This procedure is typically carried out in an outpatient setting and is performed under a spinal or general anesthesia. A proposed benefit to this method is less adjacent tissue damage.
Methods to manage localized prostate cancer include watchful waiting and active surveillance. Treatment options for localized prostate cancer include radical prostatectomy, radiotherapy (EBRT or brachytherapy) and whole gland cryotherapy. High intensity focused ultrasound (HIFU) has been proposed as a method for treating localized prostate cancer. For treatment of the prostate the physician uses a transrectal probe to plan, perform and monitor treatment in real time sequence to ablate the entire gland or small discrete lesions. A cooling balloon surrounding the probe protects the rectal mucosa from the high temperature. Reported post procedure complications include incontinence, bladder neck/urethral stricture and rectourethral fistulae.
In 2016, the Agency for Healthcare Research and Quality (AHRQ) issued a clinician research summary regarding therapies of clinically localized prostate cancer which concluded the evidence is insufficient to permit conclusions about the comparative effectiveness or adverse effects of all other treatments including brachytherapy, cryotherapy, intensity modulated radiation therapy, proton beam radiation therapy, stereotactic body radiation therapy and high intensity focused ultrasound compared in this review. This summary concluded that evidence from two large studies (the SPCG-4 study and PIVOT) showed that metastases can be reduced with radical prostatectomy versus watchful waiting. Evidence related to the comparative effectiveness of radical prostatectomy and watchful waiting for mortality outcomes was rated as insufficient, largely because of the lack of replication in the two large trials. Evidence for other therapies for clinically localized prostate cancer assessed in this updated systemic review is too limited to determine their comparative effectiveness and adverse effects. Evidence is insufficient to determine which subgroups of patients might benefit most from these therapies based on patient disease characteristics. Clear guidance regarding the appropriate patient population for radical prostatectomy, radiation therapy, hormonal therapy, watchful waiting, active surveillance, or one of the other options is difficult to establish. Physicians might take into consideration age, general health status, stage of tumor, PSA level. Gleason score, logistical factors (timing of survery vs radiation therapy), use of androgen deprivation therapy (ADT) as a component of the treatment strategy, patient preferences, nuances in patient recovery and quality of life, and other factors in identifying the most appropriate treatment options. Guidelines from NCCN and the American Urological Association may be informative in this regard.
Based on review of the peer reviewed medical literature for high intensity focused ultrasound (HIFU) and the treatment of localized prostate cancer the literature consists for non-randomized studies, systemic reviews and case series. HIFU may provide quality of life (QOL) advantages for patients in comparison to surgery and radiotherapy, however, there is a lack of consensus on objective response criteria, very limited long-term oncologic data, and no comparative effectiveness data versus traditional treatments available for localized prostate cancer. The long term efficacy, safety and long-term health outcomes of HIFU for the treatment of localized prostate cancer has not been established in controlled clinical trials. Well-designed prospective comparative studies are needed to evaluate risk/benefit of HIFU for the treatment of localized prostate cancer. The American Urological Association (AUA), American Society of Radiation Oncology (ASTRO) and Society of Urologic Oncology (SUO) issued a guideline in 2017 on clinically localized prostate cancer which states “the Panel recommends if HIFU is offered as an alternative treatment modality for localized prostate cancer, it should be done within the context of a clinical trial and clinicians should inform patients considering focal therapy or HIFU that these treatment options lack robust evidence of efficacy”. The evidence is insufficient to determine the effects on net health outcomes.
Benign prostatic hypertrophy (BPH) is a non-cancerous enlargement of the prostate gland. Symptoms of BPH include frequent urination, urgency and excessive urination at night. Drug therapy may benefit patients with mild symptoms. Transurethral resection of the prostate has been established as the standard treatment for moderate to severe BPH. HIFU is one of several less invasive alternatives to surgical resection of the prostate that are currently under clinical study. HIFU delivers targeted high intensity ultrasound that rapidly elevates the temperature in a precise focal zone, thereby ablating excess prostate tissue.
Evidence in the peer reviewed medical literature evaluating HIFU for BPH consists primarily of few case series studies, and therefore, there is insufficient evidence in the peer reviewed medical literature to draw conclusions regarding the safety and efficacy of high intensity focused ultrasound (HIFU) for the treatment of benign prostatic hypertrophy (BPH). Currently no society guidelines include HIFU as a management modality for BPH. The evidence is insufficient to determine the effects on net health outcomes.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The only potentially curative treatments are surgical resection and liver transplantation. The majority of patients with primary or metastatic liver cancers are not suitable candidates for surgical resection at the time of diagnosis. In addition, chemotherapy and radiotherapy rarely produce a complete or sustained response in patients with advanced disease. High intensity focused ultrasound (HIFU) is under investigation for the ablation of unresectable HCC.
Based on review of the peer reviewed medical literature HIFU for the treatment of hepatocellular carcinoma (HCC) the literature includes nonrandomized controlled trials, retrospective cohort study and case series studies with small patient populations. The overall quality of evidence is low due to the lack of randomized controlled trials, and of studies comparing HIFU to other standard treatment modalities. Other limitations included differences between studies in patient characteristics (e.g. tumor size and disease severity), measure of tumor response and length of follow-up also impacted the quality of available evidence. Additional well-designed studies with larger patient populations to include comparative studies are needed to support the safety and effectiveness of high intensity focused ultrasound (HIFU) for the treatment of unresectable hepatocellular carcinoma (HCC). The evidence is insufficient to determine the effects on net health outcomes.
Renal cell carcinoma (RCC), also referred to as kidney cancer is a disease in which cancer cells are found in the lining of the tubules in the kidney. Symptoms of renal cell carcinoma may include: blood in the urine, loss of appetite, pain in the side that doesn’t subside, weight loss and anemia. Standard treatment available for patients with RCC includes surgery, chemotherapy, external or internal radiation therapy, and immunotherapy. Surgical excision in the form of a simple or radical nephrectomy is the accepted, often curative, treatment for stages I, II and III of RCC. HIFU has been proposed as an intervention for small renal masses as well as advanced stage renal malignancy.
Based on the review of the peer reviewed medical literature there are a small amount of studies, primarily case series with small patient populations and insufficient data to draw conclusions. The safety and effectiveness of the use of high intensity focused ultrasound (HIFU) for the treatment of renal cancer has not been established. The evidence is insufficient to determine the effects on net health outcomes.
Based on the review of the peer reviewed medical literature there have been isolated case series studies, minimal randomized controlled studies, meta-analysis and systematic reviews published utilizing high intensity focused ultrasound (HIFU) to treat indications such as central nerve system cancers (gliomas), breast cancer and pancreatic cancer.
Alkins et. al. (2018) noted that ultrasound (US) in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of biological effects, including thermal ablation of brain tumors. Therapeutic US has been studied for many years, but only within the past 10 years has the technology reached a point where it is safe and practical for clinical adoption. Using large, multi-element arrays, US can be focused through the skull, and combined with MRI for image guidance and real-time thermometry, to create lesions in the brain with millimeter accuracy. Using this technology, true non-invasive surgery can be accomplished with immediate tumor killing. Combining the ablative capabilities of focused US with its other unique effects, such as blood-brain barrier (BBB) disruption and radio-sensitization, may eventually result in change of the current glioma treatment paradigm.
The safety and effectiveness of the use of high intensity focused ultrasound (HIFU) for the treatment of central nervous system cancers i.e. gliomas has not been established. Further studies are needed.
In 2015, Peek et. al., reported on a systematic review of high intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least one clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. Nine studies fulfilled the inclusion criteria. The absence of tumor or residual tumor after treatment was reported for 95.8% of patients (160 of 167). No residual tumor was found in 46.2% (55 of 119; range 17-100%), less than 10% residual tumor in 29.4% (35 of 119; range 0-53%), and between 10 and 90% residual tumor in 22.7% (27 of 119; range 0-60%). The most common complication associated with HIFU ablation was pain (40.1%) and less frequently edema (16.8%), skin burn (4.2%) and pectoralis major injury (3.6%). MRI showed an absence of contrast enhancement after treatment in 82% of patients (31 of 38; range 50-100%), indicative of coagulative necrosis. Correlation of contrast enhancement on pretreatment and post-treatment MRI successfully predicted the presence of residual disease. The authors concluded, HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no image modality has been able to confidently predict the percentage of complete ablation. Consistent tumor and margin necrosis with reliable follow-up imaging are required before HIFU ablation can be evaluated within large, prospective clinical trials.
In 2017, Dababou et.al., completed a meta-analysis of palliative treatment of pancreatic cancer with high intensity focused ultrasound (HIFU). The meta-analysis includes a total number of 23 studies with 865 patients, 729 with pancreatic cancer. The population enrolled ranges from 3 patients in the smallest series, up to 61 in the largest study. T2 (variance among studies) was 0.195, and I2 (percentage of variation among studies) was 40% (95% CI: 1–64%); the Q test p-value was 0.026, indicating significant heterogeneity among studies. Among 639 patients treated with HIFU, 567 complained of pancreatic pain before the treatment and 459 patients experienced partial or complete pain relief after treatment. The random effects estimate of the proportion of patients with pain reduction was 0.81 (95% CI: 0.76–86). The authors concluded, HIFU appears to be an effective tool for pain palliation in advanced pancreatic cancer. Studies assessing treatment in patients with pancreatic adenocarcinoma are limited by factors such as small sample sizes and heterogeneity in clinical definitions and assessments. Prospective randomized and standardized studies are necessary to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival.
Based on the review of the peer reviewed medical literature the evidence is insufficient to make any determinations regarding safety and effectiveness for the use of HIFU for these indications. Further prospective randomized studies to include larger patient populations and longer follow-up are needed. The evidence is insufficient to determine the effects on net health outcomes.
Breast fibroadenoma (FA) is a benign tumor, most often detected during self-examination or clinical breast examination. Usually occurring in geno typical women under the age of 30, they are seen in approximately 10% of all geno typical women during their lifetime. FA account for between 30% and 75% of all breast biopsies, depending on the age of the population being sampled. Because of the superficial location, breast FA is suitable for minimally invasive ablation techniques. These techniques can be divided into heat based modalities which include high-intensity focused ultrasound (HIFU), radiofrequency ablation, laser ablation and cryoablation. Based on the review of the peer reviewed medical literature further studies with longer follow up are needed to establish the optimal treatment protocol and to assess the long term efficacy of HIFU for this indication. The evidence is insufficient to determine the effects on net health outcomes.
Based on the review of the peer reviewed medical literature well designed studies comparing high intensity focused ultrasound (HIFU) to cryotherapy, radiofrequency ablation, and/or external beam radiotherapy are needed to ascertain the effectiveness of HIFU for the treatment of bone metastases. HIFU may provide another treatment option for patients with primary bone tumors who are not surgical candidates or who refuse surgery, but this data needs to be confirmed as well. The evidence is insufficient to determine the effects on net health outcomes.
Nodular thyroid tissue is common, however most thyroid nodules are benign. Causes of benign thyroid nodules include goiter and Hashimoto’s thyroiditis. The incidence of malignancy, or thyroid cancer, depends on factors such as age, gender, radiation exposure and family history. Treatment of thyroid cancer depends on the type of cancer, but may include one or more of the following treatments: radioiodine, thyroid hormone suppression and surgical removal of the thyroid gland. Minimally invasive treatments, such as percutaneous ethanol injection sclerotherapy, laser photocoagulation, and high intensity focused ultrasound (HIFU) ablation have been proposed as an alternative to surgery.
Based on the review of the peer reviewed medical literature there are limited studies, primarily case series with small patient populations. These studies suggest that high intensity focused ultrasound (HIFU) may be promising non-invasive tool for nodular thyroid disease, but the available evidence is insufficient data to draw conclusions regarding HIFU for this indication. The evidence is insufficient to determine the effects on net health outcomes.
Lichen sclerosus, lichen planus, and lichen simplex chronicus are three of the most common non-neoplastic epithelial disorders of the vulva. Lichen sclerosus is characterized by intense vulvar itching and can affect women of all ages, but it manifests most commonly in postmenopausal women. Patients with lichen sclerosus have an increased risk of developing squamous cell carcinoma, and they should be monitored for malignancy. Lichen planus is an inflammatory autoimmune disorder that can affect the vulva and the vagina; it peaks in incidence between ages 30 and 60. There are three clinical variants of lichen planus affecting the vulva: erosive, papulosquamous, and hypertrophic. Lichen simplex chronicus is caused by persistent itching and scratching of the vulvar skin, which results in a thickened, leathery appearance. It is thought to be an atopic disorder in many cases and may arise in normal skin as a result of psychological stress or environmental factors. Definitive diagnosis of non-neoplastic disorders depends on the histology of biopsied tissue. All three disorders are treated with topical corticosteroid ointments of varying potency. Lichen sclerosus and lichen planus are not routinely treated with surgery, which is necessary only in patients who have a malignancy or advanced scarring that causes dyspareunia or clitoral phimosis. High intensity focused ultrasound (HIFU) recently has been studied as a treatment modality for non-neoplastic epithelial disorders of the vulva (NNEDV) (vulvar dystrophy).
Ruan et. al. (2010) evaluated the effectiveness of high intensity focused ultrasound (HIFU) in the treatment of patients with non-neoplastic epithelial disorders of the vulva. These researchers reviewed 41 cases of lichen sclerosus, 38 cases of squamous cell hyperplasia, and 17 mixed cases. Biopsy specimens were assessed with light microscopy before and after treatment. Pruritus and signs of vulvar lesions were dramatically improved after HIFU treatment, without severe complications, and 90.2 % of the patients were cured or had their symptoms improved 6 months after treatment. On light microscopy, pigmentation and epithelial structures were recovered and dermal lymphocytic infiltration was reduced. The response rates were lower and complication rates higher among lichen sclerosus than among squamous cell hyperplasia cases (p < 0.05 for both). The authors concluded that treatment with HIFU may be safe and effective in cases of vulvar dystrophy. The findings of this trial need to be validated by well-designed studies with larger number of patients and longer follow-up periods.
In 2016, Zhou et. al. reported on the efficacy of high intensity focused ultrasound (HIFU) for the treatment of non-neoplastic epithelial disorders of the vulva (NNEDV). This was a multi-center, randomized controlled trial in women with NNEDV based on histologic alterations. Enrolled patients were clinically diagnosed with NNEDV. They were randomized into 2 treatment groups: 1) halcinonide for 3 months or 2) HIFU once. A total of 123 patients were biopsied both prior to and after the therapy, and 62 and 61 patients were assigned to the HIFU and halcinonide groups, respectively. The histological changes were then analyzed. After the treatments, the therapeutic effects were observed in both groups. Comparing the diagnosis and alterations in lichenoid and sclerotic patterns and in chronic inflammation, we found statistically significant differences. Furthermore, when compared with the halcinonide group, the HIFU group exhibited enhanced curative effects that were statistically significant (P = 0.039). The authors concluded, based on the histological evidence from this randomized, controlled trial, HIFU represents an effective method for the treatment of NNEDV.
Based on the review of the peer reviewed medical literature there are limited studies, one randomized controlled trial was found. These studies suggest that high intensity focused ultrasound (HIFU) may be promising non-invasive tool for non-neoplastic epithelial disorders of the vulva (NNEDV). Further studies with longer follow up are needed to establish the optimal treatment protocol and to assess the long term efficacy of HIFU for this indication. The evidence is insufficient to determine the effects on net health outcomes.
Based on review of the peer reviewed medical literature the long term efficacy and safety of high intensity focused ultrasound (HIFU) compared to established interventions for various conditions have not been proven in controlled clinical trials for any indication. Additional randomized clinical trials with larger patient populations comparing established interventions are needed to determine the role of HIFU. The evidence is insufficient to determine the effects on net health outcomes.
Local therapies have been investigated for the treatment of localized prostate cancer in the initial disease and recurrent settings, with the goals of reducing side effects and matching the cancer control of therapies. At this time, the panel recommends only cryosurgery and high intensity focused ultrasound (HIFU) as options for radiation therapy recurrence in the absence of metastatic disease.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of thyroid cancer.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of soft tissue sarcoma.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of breast cancer.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of hepatobiliary cancers.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of central nervous system cancers.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of kidney cancer.
The current guideline does not include or indicate the use of high-intensity focused ultrasound (HIFU) in the treatment and management of pancreatic adenocarcinoma.
In 2017, the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO) and Society of Urologic Oncology (SUO) issued a guideline on clinically localized prostate cancer, which included the following guideline statements regarding high intensity focused ultrasound (HIFU):
In 2018, the American Society of Clinical Oncology (ASCO) endorsed the clinical practice guideline of an American Urological Association/American Society of Radiation Oncology/Society of Urologic Oncology guideline for clinically localized prostate cancer (see above).
The 2011 American College of Radiology Expert Panel on Radiation Oncology-Prostate Work Group’s guideline on locally advanced (high risk) prostate cancer does not mention the use of HIFU in the list of treatment options. The summary states that HIFU is currently an experimental therapy.
In 2016, American College of Radiology Expert Panel on Radiation Oncology-Prostate Work Group’s guideline on locally advanced high risk prostate cancer was updated and states, “Ablative treatments including cryotherapy and high-intensity focused ultrasound (HIFU) are other options available to men with high-risk prostate cancer, though data are limited for these modalities. There was insufficient literature using parameters employed for these modalities to be included in the assessment of high-risk prostate cancer”.
The panel did not include other treatment options i.e. ablative treatments cryotherapy and high intensity focused ultrasound (HIFU) in their summary of recommendations.
The National Institute for Health and Clinical Excellence (NICE) issued guidance on the use of focal therapy using high-intensity focused ultrasound (HIFU) for localized prostate cancer in 2012. It concluded that current evidence on HIFU for localized prostate cancer raises no major safety concerns. However, evidence on efficacy is limited in quantity, with concern that prostate cancer is commonly multifocal. Therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
In 2014, the National Institute for Health and Clinical Excellence (NICE) issued guidance on the diagnosis and management of prostate cancer. The recommendations state the following:
In October 2015, the Sonablate 450 (SonaCare Medical) was approved by FDA through a de novo request and classified the device as class II under the generic name “high intensity ultrasound system for prostate tissue ablation”. This device was the first of its kind to be approved in the United States. A similar device, Ablatherme (EDAP TMS), was cleared for marketing by FDA through the 510(k) process shortly thereafter.
See also medical policies 04.01.09 MRI-Guided High-Intensity Focused Ultrasound (MRgFUS) Ablation or 07.01.69 Treating Benign Prostatic Hyperplasia
High Intensity Focused Ultrasound (HIFU) is considered investigational for all indications including but not limited to the following:
Based on the review of the peer reviewed medical literature the long term efficacy and safety of high intensity focused ultrasound (HIFU) compared to established interventions for various conditions has not been proven in controlled clinical trials for any indication. Additional randomized clinical trials with larger patient populations comparing established interventions are needed to determine the role of high intensity focused ultrasound (HIFU). The evidence is insufficient to determine the effects on net health outcomes.
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