In the past decade, HIFU ablation has emerged as a modality for palliative treatment of pancreatic tumors. Multiple preclinical and non-randomized clinical trials. HIFU appears to be an effective tool for pain palliation in advanced pancreatic cancer. Studies assessing treatment in patients with pancreatic. Request PDF on ResearchGate | HIFU for Palliative Treatment of Pancreatic Cancer | High intensity focused ultrasound (HIFU) is a novel.
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High intensity focused ultrasound HIFU is a novel non-invasive modality for ablation of various solid tumors including uterine fibroids, prostate cancer, hepatic, renal, breast and pancreatic tumors. Multiple cancet and non-randomized clinical trials have been performed to evaluate the cabcer and efficacy of HIFU for palliative treatment of pancreatic tumors.
Substantial tumor-related pain reduction was achieved in most cases after HIFU treatment, and no significant side-effects were observed. This review provides a description of different physical mechanisms underlying HIFU therapy, summarizes the clinical experience obtained to date in HIFU treatment of pancreatic tumors, and discusses the challenges, limitations and new approaches in this modality.
Within the last year more than 42, people in the United States were newly diagnosed with pancreatic cancer, which makes it the fourth leading cause of cancer mortality 1. A majority of patients diagnosed with pancreatic cancer are considered inoperable at the time of the diagnosis due to locally advanced disease or the presence of metastasis, and the efficacy of systemic chemotherapy is limited 2.
The prognosis for these patients is one of the worst among all cancers: Pain is often reported by patients with advanced disease, and palliative treatment methods are commonly employed and palliahive opioid therapy and celiac plexus neurolysis 4. Pslliative, opioids may produce a range of side-effects from dysphoria to respiratory depression, and celiac plexus neurolysis provides limited benefit in pain relief, in addition to being an invasive procedure 56.
High intensity focused ultrasound HIFU therapy is a non-invasive ablation method, in which ultrasound energy from an extracorporeal source is focused within the body to induce thermal denaturation of tissue at the focus without affecting surrounding organs Figure 1. HIFU ablation has been applied to treatment of a wide variety of both benign and malignant tumors including uterine fibroids, prostate cancer, liver tumors and other ;ancreatic tumors that are accessible to ultrasound energy 7 – Preliminary studies have shown that HIFU may also be a useful modality for palliation of cancer-related pain in patients with advanced pancreatic cancer 11 – The objective of this article is to provide an overview of the physical principles of HIFU therapy and to review the current status of clinical application of HIFU for pancreatic cancers.
Ultrasound is a form of mechanical energy in which waves propagate through a liquid or solid medium e. The main parameters that are used to describe an ultrasound wave are its nifu, or the number of pressure oscillations per second, and pressure amplitude, as illustrated in Figure 2C. Another important characteristic of an ultrasound wave is its intensity, or the amount of ppalliative energy per unit surface, which is proportional to the square of hlfu wave amplitude.
Both HIFU devices and diagnostic ultrasound imagers utilize ultrasound waves with frequencies typically ranging from 0.
HIFU for palliative treatment of pancreatic cancer
Diagnostic ultrasound probes transmit plane or divergent waves that get reflected or scattered by tissue inhomogeneities and are then detected by the same probe. In HIFU the radiating surface is usually spherically curved, so that the ultrasound wave is focused at the center of curvature in a similar fashion to the way a traetment lens can focus a broad light beam into a small focal spot Figure 2A.
This can result in amplification of the pressure amplitude by a factor of papliative the focus. Another method of focusing is using ultrasound arrays, as illustrated in Figure 2B: The size and shape of the focal region of most clinically available transducers is similar to a grain of rice: As mentioned above, diagnostic ultrasound and HIFU waves differ in amplitude.
Typical diagnostic ultrasound transducers operate at the pressures of 0. HIFU transducers produce much larger pressure amplitudes at the focus of the transducer: For comparison, one atmosphere is equal to 0. Ultrasound of such intensities is capable of producing both thermal and mechanical effects on tissue, which will be discussed below. The fundamental physical mechanism of HIFU, ultrasound absorption and conversion into heat, was first described in Absorption of ultrasound, the mechanical form of energy, in tissue is not as intuitive as absorption of electromagnetic radiation e.
Tissue can be represented as viscous fluid contained by membranes. When a pressure wave propagates through the tissue, it produces relative displacement of tissue layers and causes directional motion or microstreaming of the fluid. Viscous friction of different layers of fluid then leads to heating Both diagnostic ultrasound and HIFU heat tissue, however, since the heating rate is proportional to the ultrasound intensity, the thermal effect produced by diagnostic ultrasound is negligible.
In HIFU the majority of heat deposition occurs at the focal area, where the intensity is the highest. The focal temperature can be rapidly increased causing cell death at the focal region.
A threshold for thermal necrosis, the denaturing of tissue protein, is calculated according to the thermal dose TD formulation:.
However, it has been shown that this model gives good estimations of the thermal lesion dose for the higher temperatures caused by HIFU. Thus, tissue necrosis occurs almost immediately.
Figure 3A shows an example of a lesion with coagulation necrosis after a single treatment with a 1 MHz HIFU device in ex vivo bovine liver. It is worth mentioning here that ultrasound absorption in tissue increases nearly linearly with ultrasound frequency; hence, more heating occurs at higher frequencies. However, the focus becomes smaller with higher frequency 18and penetration depth is also limited by the higher absorption.
Therefore, HIFU frequency should be chosen appropriately for smaller and shallower targets or larger targets located deeper within the body.
In most applications that utilize the thermal effect of HIFU the goal is to induce cell necrosis in tissue from thermal injury. However, several studies have reported that HIFU can also induce cell apoptosis through hyperthermia, i. In apoptotic cells, the nucleus of the cell self-destructs, with rapid degradation of DNA by endonucleases.
This effect may be desirable in some cases, but may also present a limitation for HIFU ablation accuracy. Since cell death due to apoptosis occurs at lower thermal dose than thermal necrosis, the tissue adjacent to the HIFU target might be at risk from this effect Acoustic cavitation can be defined as any observable activity involving a gas bubble s stimulated into motion by an exposure to an acoustic field. The motion occurs in response to the alternating compression and rarefaction of the surrounding liquid as the acoustic wave propagates through it.
Thus, cavitation activity in tissue may occur if the amplitude of the rarefactional pressure exceeds a certain threshold, which in turn depends on ultrasound frequency with lower frequencies having lower rarefactional pressure thresholds.
Cavitation threshold has been measured in different tissues in a number of studies, but there is still no agreement 21 – 23 For example, cavitation threshold in blood is estimated to be 6.
Once formed, the bubble can interact with the incident ultrasound wave in two ways: When the bubble is exposed to a low-amplitude ultrasound field, the oscillation of its size follows the pressure changes in the sound wave and the bubble remains spherical.
HIFU for palliative treatment of pancreatic cancer
Bubbles that have a resonant size with respect to the acoustic wavelength will be driven into oscillation much more efficiently than others; for ultrasound frequencies commonly used in HIFU the resonant bubble diameter range is microns Inertial cavitation is a more violent phenomenon, in which the bubble grows during the rarefaction phase and then rapidly collapses which leads to its destruction.
The collapse is often accompanied by the loss of bubble sphericity and formation of high velocity liquid jets. If the bubble collapse occurs next to a cell, the jets may be powerful enough to cause disruption of the cell membrane 25 In blood vessels, violently collapsing bubbles can damage the lining of the vessel wall or even disrupt the vessel altogether. One may assume that the disruption occurs due to bubble growth and corresponding distension of the vessel wall.
However, it was shown that most damage occurs as the bubble rapidly collapses and the vessel wall is bent inward or invaginated, causing high amplitude shear stress Microstreaming can produce high shear forces close to the bubble that can disrupt cell membranes and may play a role in ultrasound-enhanced drug or gene delivery when damage to the cell membrane is transient Cavitation activity is the major mechanism that is utilized when mechanical damage to tissue is a goal.
In such treatments the thermal effect is usually to be avoided, therefore, short bursts of very high amplitude ultrasound of low frequency usually below 2 MHz are used. The time-averaged intensity remains low, and the thermal dose delivered to the tissue is not sufficient to cause thermal damage. Cavitation can also promote heating if longer HIFU pulses or continuous ultrasound is used 30 – The energy of the incident ultrasound wave is transferred very efficiently into stable oscillation of resonant-size bubbles.
This oscillatory motion causes microstreaming around the bubbles and that, in turn, leads to additional tissue heating through viscous friction, which can lead to coagulative necrosis.
Nonlinear effects of ultrasound propagation are observed at high acoustic intensities and manifest themselves as distortion of the pressure waveform: This distortion represents the conversion of energy contained in the fundamental frequency to higher harmonics that are more rapidly absorbed in tissue since ultrasound absorption coefficient increases with frequency. As a result, tissue is heated much faster than it would if nonlinear effects did not occur. Therefore, it is critical to account for nonlinear effects when estimating a thermal dose that a certain HIFU exposure would deliver.
HIFU for palliative treatment of pancreatic cancer.
This changes the course of treatment dramatically: The lesion shape becomes irregular, generally resembling a tadpole, as illustrated in Figure 3B. Moreover, the motion of the boiling bubble may cause tissue lysis that can be seen as a vaporized cavity in the middle of the thermal lesion.
Sometimes this effect may be desirable and can be enhanced by using HIFU pulses powerful enough to induce boiling in several milliseconds, and with duration only slightly exceeding the time to reach boiling temperature In that case the temperature rise is too rapid for protein denaturation to occur, but the interaction of the large boiling bubble with ultrasound field leads to complete tissue lysis, as illustrated in Figure 3C Radiation force is exerted on an object when a wave is either absorbed or reflected from that object.
Complete reflection produces twice the force that complete absorption does. In both cases the force acts in direction of ultrasound propagation and is constant if the amplitude of a wave is steady.
However, if the medium is liquid i. This effect has important implications in sonotrombolysis, in which a clot-dissolving agent is driven by streaming towards and inside the clot blocking a vessel There are currently two imaging methods employed in commercially available HIFU devices: The role of these methods in treatment is three-fold: In terms of tumor visualization, both MRI and sonography can provide satisfactory images; MRI is sometimes superior in obese patients 39but is more expensive and labor-intensive.
Unfortunately, to date none of the monitoring methods can provide the image of the thermal lesion directly and in real time as it forms in tissue. The biggest advantage of MRI is that, unlike ultrasound-based methods, it can provide tissue temperature maps overlying the MR image of the target almost in real time.
The distribution of sufficient thermal dose is then calculated and assumed to correspond to thermally ablated tissue. The temporal resolution of MR thermometry is seconds per image, and the spatial resolution is determined by the size of the image voxel which is typically about 2mm x 2mm x 6mm Therefore, MR-guided HIFU is only suitable for treatments in which the heating occurs slowly, on the order of tens of seconds for a single lesion.
Motion artifact due to breathing and heartbeat is also a concern in clinical setting. Ultrasound imaging used in current clinical devices does not have the capability of performing thermometry, but it provides real-time imaging using the same energy modality as HIFU. This is a significant benefit, because adequate ultrasound imaging of the target suggests that there is no obstruction e. One method that is sometimes used for confirmation of general targeting accuracy is the appearance of a hyperechoic region on the ultrasound image during treatment.
Imaging methods to assess HIFU treatment are similar to those used to assess the response to other methods of ablation such as radiofrequency ablation and include contrast enhanced CT and MRI In addition, the use of microbubble contrast-enhanced sonography is also being examined as a method to evaluate the treatment effect of HIFU These methods all examine the change in vascularity of the treated volume. Both devices operate at similar ultrasound frequencies — 0.
B-mode ultrasound is also used in both machines for targeting and image guidance.