Advances of high intensity focused ultrasound (HIFU) for pancreatic cancer

Abstract

High intensity focused ultrasound (HIFU) is a novel therapeutic modality. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumours, including pancreatic cancer. Preliminary studies suggest that HIFU may be useful for the palliative therapy of cancer-related pain in patients with unresectable pancreatic cancer. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges.

• High intensity focused ultrasound
• pancreatic cancer
• review
• therapy

Introduction

Ultrasound (US) is one of the most useful diagnostic tools in current clinical practice. Most clinicians are familiar with diagnostic US; however, the use of HIFU for therapeutic purposes is an emerging medical technology that many physicians are unfamiliar with. In the 1950s, Fry et al. [1] applied HIFU to the human brain with the intent to create discrete lesions to treat hyperkinetic disorders such as Parkinson’s disease. After a long period of relative inactivity, US technology has been developed to use focused US energy for therapeutic purposes, such as tissue ablation. HIFU is a completely non-invasive method to achieve ablation in solid tissue using focused US energy from an extracorporeal source to a target within the body. Because of its non-invasive nature, this technology has attracted the attention of clinicians, investigators and companies from around the world as an innovative, interventional tool that might provide virtually complication-free therapy [2]. The first report on the clinical use of HIFU for prostate cancer was published in 1994, and was followed by many additional clinical studies on its use on a variety of body organs [3].

Pancreatic cancer has a dismal prognosis, approximately 80% of patients have unresectable disease at the time of diagnosis with an overall 5-year survival rate of less than 1%. The median survival of patients with pancreatic cancer is less than 3 months without therapy and less than 6 to 12 months with therapy [4]. Therefore, the primary goals of treatment for advanced pancreatic cancer patients are to improve overall survival, and palliation. Gastrointestinal Tumor Study Group trials [5] showed a survival benefit for patients with locally advanced pancreatic cancer (LAPC) who were treated with external-beam radiotherapy and 5-fluorouracil compared with patients who were treated with radiotherapy alone. Although palliative chemoradiation may be used to gain a survival benefit, no effective modality has been demonstrated for the treatment of patients who are not candidates for curative resection. In this regard, many studies have focused on developing more effective chemotherapeutic drugs and enhancing drug delivery to the cancers. Now gemcitabine has become the standard drug to treat pancreatic cancer, even though its clinical benefit response is only 23.8%. Besides erlotinib with gemcitabine, most chemotherapy doublets with gemcitabine have not produced better survival outcomes. Nevertheless, as reported in a phase III trial by Vickers et al., erlotinib with gemcitabine, which seems to be more effective than standard gemcitabine, could only prolong median overall survival by a further 10 days [6]. It cannot be said that the results of chemotherapy are sufficient for unresectable pancreatic carcinoma. Therefore, new advances in therapy are required for these patients. Many studies were designed to evaluate local ablation therapies in patients with pancreatic cancer, such as cryosurgery, radiofrequency ablation therapy, and HIFU therapy.

A MEDLINE search was carried out using the terms ‘HIFU’ and ‘pancreatic cancer’. Only original articles were included; review articles and letters were excluded. An additional, more selective search was then carried out to identify the largest case series reported from each medical centre with the purpose of eliminating population overlapping. Studies carried out on more than 10 patients were eligible for inclusion. Studies that provided clinical outcomes and treatment-related complications were sought for the present review. The comparison methodology was based on different criteria for each category of outcomes, and was also dependent on the available evidence.

Mechanisms of HIFU

HIFU has the ability to ablate deep tissues inside the body using HIFU from an external source. HIFU can cause cell destruction and tissue necrosis and differs from traditional hyperthermal therapy. The combination of thermal, mechanical (cavitation), and biological effects can result in cell death and tissue necrosis. Thermal effects from HIFU result from heat generation at the focus due to absorption of acoustic energy in tissue. Previous animal experiments have shown transient temperatures of between 70° and 100 °C at the focal area inside the body. Mechanical effects include acoustic cavitation, radiation force, shear stress and acoustic streaming/microstreaming. At the level of biological effects, high intensity US can result in tissue heating and necrosis, cell apoptosis, and cell lysis. Coagulation necrosis occurs in tissue exposed to high intensity US when the temperature of the tissue is elevated to a certain level for a certain time. Moreover, although most initial cell death in tissues exposed to HIFU is caused by cell necrosis from thermal injury, HIFU can also induce apoptosis. Non-linear effects are observed at high acoustic intensities, resulting in faster attenuation of the US energy and faster tissue heating [7].

HIFU systems

New kinds of HIFU systems have been developed by several companies recently. Of these, it is expected that the FEB-BY Serial HIFU System (China Medical Technologies, Beijing, China) and Chongqing HIFU (Chongqing, China) are the HIFU system which will receive the most attention.

Some hospitals treated patients using a continuous (not pulsed) HIFU machine (Chongqing HIFU) with a very high acoustic intensity of 5–20 kW/cm², which required general anaesthesia or spinal anaesthesia because these intensities delivered as a continuous beam cause intolerable pain and severe injury to the adjacent organs due to subtle target movement. The therapeutic US transducer is different. It is a 200-mm diameter transducer with a focal length of 135 mm operating at a frequency of 0.85 MHz. The US imaging probe situated in the centre of the therapeutic transducer can provide real-time sonography to target the lesions and to assess acute coagulation necrosis in the targeted tissue during the therapeutic procedure. Every patient in the study received HIFU treatment only once. During the treatment, HIFU was performed under sedation analgesia. The patient was placed prone and carefully positioned so that the skin overlaying the lesion to be treated was in contact with degassed water. Real-time US was used to target the tumour by moving the integrated probe, and the tumour was divided into slices with 5 mm separation using US images. By scanning the HIFU beam in successive sweeps from the deep to the shallow regions of the tumour, the targeted regions on each slice were completely ablated. The total therapeutic time excluding making plans for the patients ranged from 45 min to 3.2 h. During HIFU ablation, the real-time US scans obtained immediately before and after individual exposures were compared to determine whether the echogenic changes of the HIFU-treated region had covered the desired treatment area.

Researchers have recently begun to focus more on pulsed HIFU therapy with low energy because animal and human research has indicated its potential to enhance the chemotherapeutic effect. In addition, pulsed HIFU with low energy (the FEB-BY Serial HIFU System) employs much lower acoustic energy intensities (<3 kW/cm²) than continuous HIFU, and exposure to these levels does not require hospitalisation or general anaesthesia and it has a low complication rate. The pulsed HIFU therapy system has the capacity to deliver HIFU from an external source deep into tissues, with a large convergence angle. The focus is oval in shape and is approximately 3 mm in diameter and 10 mm in length. The main characteristics of this system are as follows: (1) Treatment for a broad range of tumours: the two-transducer system enables the HIFU therapy system to target a wide range of tumours including those of the liver, breast, kidney, pancreas and so on. (2) Minimal side effects: the large aperture of the transducer produces less intense US waves at the point of skin penetration, significantly reducing the likelihood of skin burns and collateral damage to healthy body tissue. (3) High degree of safety: treatment can be performed without anaesthesia and does not cause significant discomfort, skin-burn, or haemorrhage [8]. During treatment the patient lay on a treatment table facing down. Echo jelly was painted thickly over the bombardment area. A B-mode US scanner monitoring system was used to define the treatment range, treatment layers, and power, and then the treatment probe was moved according to the planned procedure. HIFU therapy was performed four times over the course of 10 days, each treatment lasting about 1.5 h.

The HIFU therapeutic unit has an output power of 1–2 kW, an effective treatment depth of 3.5–14.0 cm, a therapy medium of degassed water, a practical focused volume of 0.3 cm × 0.3 cm × 0.8 cm, and an effective focused volume of 0.6 cm × 0.6 cm × 1.0 cm. Larger tumours can be fully treated by dividing them into several treatment segments. Energy is delivered in a pulsed mode. Treatment parameters were: transmit time (t1), interval time (t2), input power, and number of pulses. Primary parameters are: output power of 1–2 kW; transmit time (t1) of 0.1–0.28 s; an interval between shots of t2, t1:t2 = 2:1; and number of treatment shots at each spot (T) of 30–80 times. All of the parameters can be properly adjusted according to the location and depth of the tumour, the density of the tumour tissue, and the attenuation of US [9].

Primary HIFU in pancreatic cancer

Survival benefit

Some reports from China investigated the use of HIFU as a monotherapy or as combination therapy with chemotherapy (Table 1). An early clinical study concluded that HIFU was safe and feasible for the treatment of advanced pancreatic cancer with a median overall survival (OS) of 11.25 months (range: 2–17 months). Their results suggested that HIFU offers survival benefits. Furthermore, no significant adverse effects were reported in any of these studies. However, there have been no comparative studies performed to demonstrate that treatment with HIFU confers a survival benefit. Zhao’s study [10] showed that gemcitabine with concurrent HIFU therapy was active and well tolerated as first-line therapy in patients with LAPC. The 1-year OS rate of 50.6% in this study is comparable with recently published phase II trials on chemoradiotherapy in LAPC. In Wang’s study [11], the median OS time was 10 months for patients with stage III disease, and 6 months for patients with stage IV disease. The cases in this study are in their relatively late stage.

Pain control

Serious abdominal pain is very common among pancreatic cancer patients, and it significantly decreases their quality of life. This pain can be both neuropathic and inflammatory, resulting from both tumour expansion and tumour invasion of the celiac and mesenteric plexus. Palliative therapy for pain relief is an important aspect of managing these patients. Although there are an increasing number of effective opioids available for mitigating the pain, there are often some adverse effects of these analgesics such as vomiting and constipation. Anaesthetic blocking of the celiac plexus by means of injection of a chemical solution, external radiation therapy, and chemotherapy was used to palliate pain in patients with pancreatic cancer. These modalities can achieve pain control, but the duration of pain relief is limited. The ideal palliative treatment is to improve the symptoms and the quality of life with minimal adverse effects. In recent years, research has shown that HIFU is helpful in controlling abdominal pain. In rabbits, the results of experiments performed by Foley et al. [12] about the ablative effect of HIFU on the coeliac ganglion showed that HIFU could damage coeliac ganglion in a short time without the injury of the adjacent aorta and spinal cord. This may suggest that non-invasive HIFU treatment could take the place of invasive chemical neurolytic coeliac plexus block (NCPB) to relieve pancreatic cancer pain.

In Zhao’s study [10], pain was relieved in 22 (78.6%) of 28 patients after HIFU treatment. Complete remission of pain (0 pain score and no need for opioid analgesics) was observed in nine patients (32.1%), and partial remission of pain (decrease in pain score by 2 or more) was observed in 13 patients (46.4%). HIFU might be an effective treatment option for pain control, particularly in patients with tumours infiltrating the celiac plexus and in whom conventional pain treatments are not considered an effective option. An interesting finding was that 84% of patients with pain due to pancreatic cancer obtained significant relief of their pain after treatment with HIFU. Initial non-randomised open-label human studies in China have provided additional evidence to suggest that HIFU treatment of pancreatic tumours indeed relieves pancreatic adenocarcinoma-related pain and focally ablates malignant tissue. Although HIFU is a non-invasive, non-surgical treatment that has the potential to eliminate or significantly reduce pain associated with pancreatic cancer, no rigorously conducted prospective randomised controlled trials have been conducted to determine whether treatment of pancreatic tumours with HIFU will result in local tumour response or a clinically beneficial outcome by improving pain, functional status, quality of life, or survival.

Table I. Summary of HIFU clinical outcomes of focal therapy.

Author	Study period	Method	No. of patients	OS (months)	Relief from pain (%)
Wang et al. [11]	2007∼2009	HIFU	40	8	87.5
Lee et al. [13]	2008∼2010	HIFU + Gem	3	26, 21.6, 10.8 respectively	NR
		HIFU	9	10.3
Zhao et al. [10]	2006∼2008	HIFU + Gem	39	12.6	78.6
Wu et al. [14]	2000∼2002	HIFU	8	11.25	100
Wang et al. [15]	2000∼2002	HIFU	15		100
Sung et al. [16]	2006∼2009	HIFU	46	12.4	NR
Xie et al. [17]	2006∼2007	HIFU	16	NR	87.5
Bian et al. [18]	2004∼2007	HIFU + Gem + DDP	56	NR	66.7
Zhong et al. [19]	2006∼2009	HIFU + Gem	48	16.72	NR
Liu et al. [20]	2004∼2006	HIFU	32	5.5	65.6

DDP, cisplatin; Gem, gemcitabine; NR, not reported; OS, overall survival.

Monitoring systems

Although HIFU offers tremendous potential for non-invasive therapy of malignancies, particularly those that are widespread or inoperable, the usefulness of HIFU has limitations, and risk is associated with its use that could result in adverse outcomes. Because HIFU is essentially US, any artefacts related to US would apply to HIFU as well, such as acoustic shadowing, reverberation, and refraction. Most importantly, an adequate acoustic window is essential for effective and predictable ablation of pancreatic tumours [21]. Obstruction of the acoustic beam by bowel gas will prevent effective transmission of the acoustic energy to the target for effective ablation. Furthermore, the presence of bowel gas in the path of the acoustic beam increases the risk of complications such as thermal injury to the bowel. Refraction artefacts can result in energy deposition in the soft tissues adjacent to the target area, and energy deposition can occur superficially to the target if the US beam is not carefully focused into a small point. Respiratory movement of the tumour during treatment must be considered and minimised. Respiratory motion tracking techniques to achieve safer and more effective therapy are currently in development. Great care will be necessary in treating patients with HIFU to ensure that complications do not occur.

Guidance and monitoring of acoustic therapy is most important to ensure that the desired region is treated and to minimise damage to adjacent structures. Mainstream research efforts to guide and monitor HIFU therapy are concentrated on image-guided solutions based on either magnetic resonance imaging, which is the current gold standard but cost prohibitive, or US imaging, which is economical but lacks precision and accuracy and often involves complex signal processing and model-based schemes [22–23]. Temperature monitoring using sonography is not yet available, although sonographic thermometry is being actively investigated and a clinical HIFU device in China has an incorporated sonographic thermometry system. In some instances when tissue contrast is not sufficient to visualise a tumour in the background of normal tissue, elastography may prove helpful [24–25]. Three-dimensional sonography may provide information that would be valuable to the performance of HIFU. Three-dimensional sonography is likely to better delineate a volume of tissue to be treated than just a single plane or orthogonal planes, and most commercially available HIFU systems display with 2D sonography systems. Therefore, the application of 3D sonography techniques is an exciting area of future opportunity, especially for HIFU treatment planning and monitoring [26]. These methods all examine the change in vascularity of the treated volume. Another method currently being examined in oncological applications is the use of positron emission tomography (PET) to assess for changes in metabolic activity, and PET will be the best evaluative examination after HIFU therapy.

Complications

Dubinsky et al. [27] suggest that the reflection of the US beam in bowel gas could produce burning of the abdominal wall and even the bowel walls. Injuries of the ribs and the soft tissue around the ribs could be explained with the absorption and accumulation of US beams by the ribs and resultant thermally induced damages of the corresponding area. This injury of the abdominal wall is a kind of coagulation necrosis or is simply described as burn [28]. Cavitation is the formation of gas bubbles within a liquid at low-pressure regions that occur in places where the liquid has been accelerated to high velocities. During HIFU exposure, microbubbles are formed within the intracellular water, and cavitation develops by the growth and violent collapse of bubbles due to the acoustic pressure wave. This cavitation can also produce damage of the targeted and surrounding tissues.

Early studies showed that doctors treated patients using a continuous (not pulsed) HIFU machine with a very high acoustic intensity of 5–20 kW/cm², which required general anaesthesia or spinal anaesthesia because these intensities delivered as a continuous beam cause intolerable pain and severe injury to the adjacent organs due to subtle target movement. Recently, Li et al. [29] reported that the complications of HIFU in patients with recurrent and metastatic abdominal tumours may be severe. Complications arising from HIFU treatment for hepatic and pancreatic tumours can be divided into two general categories: those related to thermal injury adjacent to the organ or the US beam pathway, due to either shallower areas of the target lesion or unwanted deep penetration over target areas, and those related to the artificial pleural effusion.

Some reports have found that skin burns and pain in the treated regions were common and that severe complications such as gastrointestinal perforation and superior mesenteric artery infarction occurred after treatment with HIFU. However, such side effects should be avoided in patients with unresectable pancreatic cancers for the following reasons: they can destroy the quality of the remaining life, they can postpone chemotherapy, which is vital in these patients, and they can impair the patient’s performance status. Indeed, a good performance status is known to be significantly associated with the median OS of pancreatic cancer patients.

Nowadays, the HIFU therapy system has some advantages in comparison with early systems [30]. These include US imaging guidance, no anaesthesia needed, two transducers, spherical direct focus, and temperature monitoring. Furthermore, this device has been recently updated to add some new functions, such as a temperature monitoring system, a respiratory monitoring system, three-dimensional treatment planning, and real-time monitoring. Monitoring the focal temperature produces more effective therapy and is achieved by analysing the echo signals acquired by the system before and after HIFU exposure. It reduces the targeting of unintended tissue caused by movement. The device automatically analyses the respiratory status of the patient using real-time B-mode US images, allows consistent delivery of HIFU energy during either end expiration or inspiration, allows for accurate targeting of the tumour regardless of the geometry, and provides B-mode images of the treatment plane which are captured between pulse emissions. Zhao’s study [10] showed that the major grade 3 and 4 toxicities were haematological and gastrointestinal toxicities when gemcitabine was combined with HIFU therapy. This study shows that there were no severe complications or adverse events related to HIFU therapy observed in any of the patients treated.

Conclusion

HIFU is being increasingly used for limited applications in Asia and Europe; however, these studies have all been preliminary, and further investigation will be necessary before the widespread use of HIFU can be recommended. With advances in imaging and transducer technology and better understanding of HIFU-related bioeffects, HIFU will likely gain acceptance clinically as a technique for non-invasive ablation of tissue for oncological applications [31]. HIFU treatment cases should be gathered, and randomised controlled trials should be conducted to determine the results of HIFU treatment for pancreatic carcinoma in terms of local tumour response and clinically beneficial outcomes, e.g. by improving pain, functional status, quality of life, or survival.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.