Although hepatocellular carcinoma and metastatic liver disease require completely separate analysis and study protocols, the technological approach of high-intensity focused ultrasound treatments is similar. Therefore, the two indications will be discussed in parallel as promising pilot studies. In addition, both available guidance methods (ultrasound-guided and MR-guided focused ultrasound) will be considered equally. Both approaches are applicable, and both have advantages and disadvantages.

The American Cancer Society's 2012 estimate for primary liver and bile duct cancers in the United States amounts to 28,720 new cases and 20,550 deaths 1 . Worldwide, liver cancer is the fifth most common cancer in men and the seventh in women. An estimated 748,300 new liver cancer cases occurred during 2008 2 . Primary Liver cancer rates are the highest in East, Southeast Asia, West and Central Africa 2 . Primary liver cancer occurs most commonly in previously damaged livers, as in cases of viral hepatitis, alcohol abuse, obesity, and exposure to aflatoxin.

Treatment of liver cancer involves multiple strategies used independently, or in combination, depending on the stage of the disease. These include liver replacement therapy, local therapy (resection, ablation), and regional therapy. However, to date, only about 25% of the patients with primary liver tumors are considered to be suitable candidates for curative treatment. Reasons for patient non-eligibility for curative treatment include factors such as the underlying parenchymal disease state of the liver, tumor size, location, and multi-focality or multi-centricity. HIFU has the potential to improve these percentages by offering a local therapy which may be less limited in terms of patient selection and one that offers a lower threshold for treatment attempt in terms of patient morbidity and complication. For example the 2010 Treatment Guidelines for hepatocellular carcinoma from the American Association for the Study of Liver Disease 3 stated that radiofrequency ablation should be offered to patients with three or fewer primary tumors of less than 3 cm each, yet HIFU has the potential to target and ablate non-invasively, and in one session, a higher number of lesions with lower treatment-related morbidity.

Patients with more advanced disease are currently offered palliative treatment, including localized transarterial chemoembolization (TACE) or systemic chemotherapy. For this patient population, HIFU can offer the option to combine a low morbidity local therapy.

Metastatic liver tumors are more common than primary tumors in the USA. The most common sites of primary tumors that metastasize to the liver are breast, lung, and colon. Some authors have reported hepatic metastases in as many as 40% to 50% of adult patients with extra-hepatic primary tumors 4 .

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in Europe, with an annual incidence of 400,000 cases and an annual mortality of more than 200,000 patients 5 . Almost 70% of CRC patients develop liver metastases during the course of disease 6 .

Curative treatments for patients with liver metastases can be aggressive in terms of the extent of damage to liver tissue since there is usually no underlying liver disease. The existence of a liver metastasis means that the primary cancer is stage IV and also requires systemic therapy, unless contraindicated by other patient factors.

For patients with CRC metastases, all treatment strategies are intended to cure 7 and are only limited by allowing sufficient parenchyma to remain for survival. Surgical resection can offer a 30%–50% 5-year and 17%–26% 10-year survival after a successful procedure 8 9 . Yet more than 80% of the patients are not surgical candidates because of insufficient residual liver tissue, extra-hepatic disease, anatomic constraints of the tumor, or medical comorbidities.

Without treatment, the median survival of patients with colorectal liver metastases is 6–12 months, and the 5-year survival is less than 10% 10 . Local ablative therapies targeting the liver metastases and surrounding tumor-free margins in patients without extra-hepatic metastases can achieve local tumor control and offer better survival 11 12 , even in patients with more than four metastases 13 and in patients with repeated metastases 14 15 . Laser-induced thermo therapy, radiofrequency ablation, microwave ablation, cryoablation, and trans-vascular embolization have been applied for curative or palliative ablation of liver metastases 16 . Local ablative techniques result in a delayed and reduced residual intra-hepatic tumor growth and peritoneal tumor spread compared with hepatic resection 17 due to a reduced growth factor expression in comparison to surgical resection 18 19 . Also, for patients with liver metastases, HIFU has the potential to offer local therapy which may be less limited in terms of patient selection and one that theoretically should have lower patient morbidity and complication.

(a) MR temperature monitoring in the presence of motion: In order to work, the MR thermometry method must be insensitive to respiratory motion 60 . This requires that both the thermometry processing method and the acquired data are robust in the presence of such movement. For the processing method, multi-baseline 50 51 61 62 , referenceless 63 64 65 and hybrid multi-baseline/referenceless 66 techniques have been developed. With these techniques available in processing the thermometry data, the acquired data has been shown to be robust in the presence of respiratory-like motion in a phantom 67 and a pig model 58 59 .

(b) US monitoring in the presence of motion: Most clinical studies in liver have been performed with B-mode ultrasonic monitoring 23 26 27 28 of a hyperechogenic signature of the treated area. A rate of 20 to 50 frames per second can be achieved, so that such monitoring is not affected by the liver motion. Nevertheless, liver motion has a major impact on US-based temperature monitoring as this relies on tracking apparent displacements due to the heat-related change of the speed of sound 68 69 . Such apparent displacement and liver motion are superimposed, making it difficult to differentiate between each effect. Elastography-based temperature monitoring 70 might be the most practical way of achieving US temperature monitoring in the liver.

The current unmet need is to provide non-invasive, low morbidity, localized tissue destruction to the significant patient population that is currently being offered palliative treatment. HIFU should be able to provide this due to its non-invasive and highly precise nature. HIFU can be used in close proximity to sensitive structures, and it has the potential to target multiple lesions without the need for multiple incisions or needle insertions (which may cause bleeding, infection, and/or tumor spread). Focused ultrasound also has the potential to facilitate focal targeted drug release which in the future may be an option to enhance chemotherapy.

A pilot study should address the feasibility and safety of localized tissue destruction using HIFU and provide the information needed to design a pivotal study. The recommendation of the assembled quorum is to choose patients with localized liver lesions who are scheduled for surgery and to treat these patients using HIFU before the surgery, (i.e., ablate-and-resect study). This approach can provide the following outcomes:

(1) Short-term safety: All patients would be followed for 1 week following their HIFU ablation procedure to record any immediate post-procedural adverse effects (such as bleeding, damage to bowel or adjacent organs, and near-field skin/fat/muscle burns).

(2) Post-treatment radiological follow-up data: Following treatment, patients would be imaged by contrast-enhanced MR imaging and/or computed tomography (CT or PET CT if available) to record the post-treatment appearance of the treated lesion, to correlate it with pathological findings, and to asses targeting accuracy.

(3) Post-treatment pathological findings: The excised specimen would be used as a gold standard in an analysis which evaluates correlation between the planned, imaged, and ablated tissue, and would confirm the completeness of the tissue destruction.

Since the goal of the pilot study is to establish evidence for the efficacy and safety of HIFU for localized thermal ablation of tissue in the liver, the patient population could include both primary and secondary liver tumor patients. However, it would be advisable that the first several patients recruited and treated in this study would be CRC patients in order to reduce the risk of introducing patient/liver-related complications due to the underlying liver disease in primary liver tumor patients.

The proposed pilot study is a single-arm ablate-and-resect study, targeting patients with primary or secondary liver cancer who are candidates for surgical resection. After enrollment, the patients would undergo HIFU treatment and be followed for a period of 1 week. After 1 week, the treated lesion would be excised and sent for pathological analyses. A potential approach to gradually increasing total dose used could be in the initial treatments to partially ablate the targeted tumor tissue and (2) in later treatments to completely ablate the tumors, including a tumor margin.

The pivotal study should target the patient population identified in the unmet need section: primary liver cancer patients who are not candidates for surgical resection and who are receiving palliative treatment. This patient population could include patients with more than three lesions, patients with one lesion bigger than 5 cm, patients with ascites, or patients with lesions close to major blood vessels or other structures that make resection or radiofrequency ablation difficult or impossible. The specifics of what population to include from the list above would take into consideration results and learned lessons on HIFU capabilities in terms of accuracy and treatment speed as were demonstrated in the pilot study. We suggest a double-arm study where the control arm would get TACE and the test arm would get TACE and HIFU. The sample size would be determined by existing evidence in the literature regarding the efficacy of such combination treatment 71 .

The rationale for the study is the need to avoid the risk of withholding existing therapy from a severely ill patient population, while considering the near-term reality of where to maximize clinical benefit; it is expected that these patients would receive combination therapy anyway.

An acceptable procedure, to be done in preparation for the HIFU ablation session, is to insert saline or another fluid into the peritoneal cavity to move the bowels away from the targeted area or into the pleural cavity to move the lungs away from the acoustic pathway. This procedure can be done if necessary for safety, but should not be part of the routine.

Follow-up would include imaging, measurement of alpha fetoprotein levels (although effectiveness may be compromised due to TACE), liver function testing, and record of disease-related events including local, regional and distant recurrences, disease-specific survival, disease-free survival, and overall survival.

As a future second step, it is envisioned that a three-arm study comparing the safety and efficacy of TACE alone, HIFU alone, and the combination of HIFU and TACE will be conducted. This second, three-arm study would be needed to obtain regulatory approval for the usage of HIFU ablation of primary liver tumor as a stand-alone therapy. A separate pivotal trial for the metastatic liver disease indication would be required.

The many aspects and technological improvements in HIFU technology, which are required to treat liver cancer have been researched for years (‘Technological developments’ section). However, as part of our recommendation, we tried to narrow the technical specifications to the minimum required for a future or existing HIFU system to be commercially viable in terms of patient selection, quality and cost of treatment, and technological availability and cost. We have identified the following minimal requirements:

● Treatment rate should be at least 1 cc of ablated tissue per minute.

● The entire procedure should last 4 hours or less (and has a potential of reducing time to 2 hours).

● The system should be able to target at least 80% of the liver volume in a typical patient.

● The system should be able to transmit energy either in between, below, or through the ribs without damaging the ribs or causing a skin burn.

● The system should have an imaging guidance system for targeting tumors.

● It would be beneficial to have closed loop thermometry (MR-based or otherwise)

● It would be beneficial to have beam steering tissue tracking to enable the patient to breathe freely, but this is not a ‘must have’ feature, and carrying out treatment with the patient under general anesthesia using forced apnea is acceptable.

Each of these components has been developed separately or by academic research groups.