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The Role of Image-guided Tumor Ablation in the Management of Liver Cancer 
  Submitted By: J. Louis Hinshaw, M.D.

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The Role of Image-guided Tumor Ablation in the Management of Liver Cancer


Authors: J. Louis Hinshaw, MD, Paul F Laeseke, PhD, Fred T. Lee, Jr., MD

University of Wisconsin-Madison Department of Radiology


INTRODUCTION

Liver cancer, namely hepatocellular carcinoma (HCC), is one of the most common cancers in the world and is the third most common cause of cancer-related death [1]. If left untreated, liver cancer has a poor prognosis with more than 90% of patients dying of the disease within 5 years of diagnosis [2]. The incidence of HCC is particularly high in Asia and sub-Saharan Africa due to the large number of people infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). Infection with both of these viruses is strongly correlated with hepatic cirrhosis (scarring of the liver), which is the single greatest risk factor for HCC. While the incidence of HCC in the US is substantially lower than in Asia, it has risen dramatically over the past few decades [3] and this trend is almost certain to continue since the number of people infected with HCV is steadily increasing in this country. Non-alcoholic steatohepatitis (NASH) is also a newly recognized and growing cause of HCC [4, 5].

The liver is also a common site for metastatic disease from cancer arising in other organs. In fact, metastases are second only to cirrhosis as a cause of fatal liver disease. The liver's large size, high volume of blood flow, and dual blood supply (the hepatic artery and portal vein) make it particularly vulnerable to invasion by cancerous cells, especially those originating in the colon, rectum, lung and breast. In the US, liver metastases are much more common than primary liver cancer.
If possible, surgical removal of the tumor is standard treatment for liver cancer and gives the patient their best chance at long-term survival. Unfortunately, the majority of patients with liver cancer are not surgical candidates [6]. This may be due to the advanced stage, location, or number of the cancerous masses or the patient may not be able to tolerate surgery because of other medical conditions. Traditional therapies, such as chemotherapy and radiation therapy have little if any long-term benefit for patients with both HCC and metastatic disease to the liver. These therapies may provide a marginal increase in life expectancy, but in most studies, the five year survival is abysmal. As a result, minimally invasive therapies such as image-guided tumor ablation are being developed as alternative treatment options for these patients. Tumor ablation is the chemical or thermal destruction of cancerous masses using image guidance. The technical issues associated with tumor ablation have been covered in our manuscript entitled "Image-guided tumor ablation, a technical overview of a less invasive cancer treatment" also available on the cancernews.com website. The current manuscript discusses the specific issues related to the treatment of liver cancer utilizing the techniques of image-guided tumor ablation.

CHEMICAL ABLATION

Chemical ablation is the injection of a toxic chemical into a tumor through a thin needle. The chemical dehydrates the tumor, results in chemical injury to the organelles, causes vascular thrombosis, and osmotic shifts among other complex effects. The effect is destruction of the cells affected by the chemical. The most commonly used chemical is ethanol. The procedure is referred to as percutaneous (through the skin) ethanol injection (PEI).

PEI is most effective for small (≤ 3 cm) primary liver tumors that frequently arise in a cirrhotic diseased liver. This is because the ethanol diffuses easily within the soft tumor, but not into the firm scarred liver surrounding it. As a result, the ethanol is able to diffuse evenly into the tumor and kill the cancerous cells (Figure 1).

Figure 1: US-guided ethanol ablation of primary hepatocellular carcinoma of the liver



Figure 1: a) Contrast-enhanced CT image through the abdomen prior to ethanol ablation. The hepatocellular carcinoma is identified as an avidly enhancing rounded mass within the liver (arrow).



Figure 1: b) Grey-scale US image during the ablation. The instillation needle (bright line) can be seen within the center of the hyoechoic (dark) hepatocellular carcinoma. As the ethanol is injected, the mass becomes hyperechoic (bright) as microbubbles are formed in the area that is ablated.



Figure 1: c) Contrast-enhanced CT image through the abdomen after the ablation. The majority of the mass is no longer avidly enhancing, showing that it has been devascularized. Note that there is a thin layer of enhancement along the periphery of the ablation, which represents some residual tumor. This will need to be re-treated at a separate setting.


Clinical studies have shown that long-term survival rates with PEI are comparable to surgery in the appropriate patients. The best results are seen with patients who have a single, small liver tumor (5).

PEI is much less effective for liver metastases. These tumors are usually harder than HCCs, which can prohibit uniform diffusion of the chemical throughout the tumor. As a result, portions of the tumor are often incompletely treated, resulting in rapid re-growth of the tumor. Therefore, PEI is almost never utilized for the treatment of metastatic liver tumors, except in the setting of a neuroendocrine tumor.

Complications are very uncommon with PEI, but can include bleeding, infection of the necrotic tissue, and in large volume ablations, systemic multi-organ failure, which can be fatal. The limitations of PEI include: 1) the need for multiple treatments, 2) the difficulty of achieving complete tumor destruction, and 3) a high recurrence rate in comparison to the other ablation modalities.

THERMAL ABLATION

Thermal tumor ablation modalities either freeze or heat tumors to lethal temperatures. These include cryoablation, radiofrequency (RF), microwave, laser and high-intensity focused ultrasound (HIFU).

Cryoablation

Cryoablation utilizes extremely cold temperatures to destroy cancerous cells. Ice crystals form as the tissues are frozen. The crystals damage the cell and its membranes (outer capsule), which results in cellular death at temperatures less than - 20 degress C. Early cryoablation systems utilized liquid nitrogen to cool the tissues and required relatively large probes (≥ 2.4 mm diameter). Because the probes were too large to safely puncture through the skin, procedures with these systems were generally performed in a surgical setting. Smaller probes have been developed for current systems, which use compressed argon gas to freeze the tissues. This advance has made percutaneous image-guided utilization of cryoablation possible, and it has been increasingly employed for the treatment of liver tumors, both percutaneously and at the time of surgery. However, since cryoablation is thought to be associated with a higher risk of bleeding than the heat-based ablation modalities, it has not been used as much for the treatment of HCC. This is because patients with HCC often have cirrhosis and liver disease, which puts them at higher risk for significant bleeding after the ablation. It is used more frequently in the treatment of metastatic liver tumors, although this is still often performed at the time of surgery (Figure 2).

Figure 2: US-guided intra-operative cryoablation of colorectal metastasis to the liver.




Figure 2: a)Contrast enhanced CT image through the liver prior to cryoablation. Two separate metastases were identified in the liver. One is seen as a subtle area of decreased enhancement next to a hepatic vein in the right lobe of the liver (arrow).



Figure 2: b)Contrast enhanced CT images through the liver prior to the ablation. The other metastasis is a large heterogeneous mass in the left lobe of the liver (arrows).



Figure 2: c) Intra-operative US image during cryoablation of the small right lobe metastasis. The left lobe of the liver was surgically resected at the same time as the cryoablation. This image shows the iceball that has formed within the liver, completely encompassing the metastatic lesion (arrows).



Figure 2: d) Contrast enhanced CT image through the liver after cryoablation and resection. The metastatic focus in the right lobe of the liver as well as a cuff of normal liver tissue is devascularized and non-enhancing (arrow) other than the large hepatic vein that traverses the region. The other mass has been surgically resected.


Cryoablation can be used to destroy tumors in the liver that are left behind when there are multiple tumors in the liver and only part of the liver can be surgically removed.

Clinical trials to date have been relatively limited, but have shown a survival advantage in eligible patients with limited metastatic liver disease from colorectal cancer, but only if all visible disease can either be resected or ablated and there is no disease outside of the liver [7, 8].

RF ablation

RF ablation is the most commonly employed ablation modality for liver tumors and is often performed percutaneously. During RF ablation, an electric current is conducted into the body via a needle (electrode) placed into the tumor under imaging guidance (CT, US, or MRI). The current travels through the patient's body and exits through ground pads placed on the patient¡¯s legs. Directly adjacent to the electrode, the electrical current agitates the water molecules, which results in heating of these tissues. Cells die almost instantaneously at temperatures above ~60 degress C, and tissues around the electrode often approach 90 degress C, or more. Technical advances including: electrode cooling [9], energy pulsing [10], saline infusion [11], expandable electrodes [12], and switching between multiple electrodes (10, 11) have significantly increased the volume of tissue that can be destroyed by these systems. As a result, RF ablation can now be used to treat larger tumors more effectively than previously.

RF ablation is used to treat patients with liver tumors (both primary and metastatic) if the patient cannot have the tumor surgically removed, or in those patients who are not eligible for liver transplantation (Figure 3).

Figure 3: US-guided percutaneous RF ablation of primary hepatocellular carcinoma of the liver.




Figure 3: a)Contrast enhanced CT image through the liver prior to cryoablation. Two separate metastases were identified in the liver. One is seen as a subtle area of decreased enhancement next to a hepatic vein in the right lobe of the liver (arrow).



Figure 3:b) Grey-scale US image prior to RF ablation. The hepatocellular carcinoma is identified as a hypoechoic (dark) mass in the right lobe of the liver (arrow).



Figure 3: c) Grey-scale US image during the RF ablation. As the tissues are heated, the cellular water begins to boil and small bubbles are formed in the area of ablation, which appears as a bright cloud on the US image (arrow)



Figure 3: d) Contrast-enhanced CT of the liver after RF ablation. The area of ablation, which includes the hepatocellular carcinoma is no longer enhancing and the tumor has been fully ablated (arrow)



It is also often used to treat patients who develop an HCC while they are waiting for a liver transplantation. The field of RF ablation is relatively new, and thus long-term outcomes, especially from large, well-controlled trials, are sparse. However, there have been two large, randomized controlled trials performed in Europe that compared the results of surgical resection against those obtained with RF ablation, with or without additional therapy with transarterial chemoembolization (TACE), for small (< 5 cm) and intermediate (5-8 cm) sized HCC in patients with cirrhosis. The results of these trials have shown that approximately 50% of patients with early-stage HCC treated with RF ablation are alive after 5 years. These results are comparable to surgical resection¡ªa more invasive procedure with a much higher complication rate (12-14). Intermediate sized HCC also has results comparable to that of surgery, but because of the more advanced state of the disease, only about 30% of these patients are alive at 5 years. As a result of these trials and other smaller trials, RF ablation is now considered the standard of care for the treatment of these tumors in Europe and Asia.

Chemotherapy and radiation therapy for the treatment of metastatic cancer to the liver have a very poor prognosis. In patients with metastatic colon or rectal cancer (the most common metastases to the liver), there are very few long term survivors if the disease cannot be removed surgically. In one large study, there was a 37% 5 year survival in patients where the disease could be surgically removed [13]. However, although chemotherapy has improved and can show median survival of up to 24 months or more, most series have very few long term survivors [14-16]. Several studies have been performed utilizing RF ablation for the treatment of liver metastases from colon or rectal cancer. With approximately 30% alive at five years, the survival rates are starting to approach those of surgical resection (15, 16).

Once again, the most common complication is bleeding, but the risk is relatively low, with major hemorrhage occurring in a small minority of patients (~1-2%). There is also a small risk of injuring the bile ducts and causing associated biliary obstruction. This can lead to damage in the liver tissue peripheral to the ablation. The risk is low for most lesions, but central masses must be approached with caution. There have also been injuries to the structures surrounding the liver, including the lung, bowel, adrenal gland, and kidney. However, these complications are also rare and the risk is highly dependent on the location of the tumor.

Microwave ablation

Microwave ablation devices are now being developed where the applicator is an antenna that emits microwaves into the tissue. Microwaves heat tissue by exciting polar molecules (mainly water). These systems have several theoretical, but as yet clinically unrealized, advantages over RF systems: 1) a larger zone of active heating, 2) higher tissue temperatures, 3) faster heating and shorter application times, and 4) better performance near blood vessels. Finally, multiple-electrode RF systems have to temporally switch between electrodes to avoid undesirable interactions between electrodes. Multiple-antenna microwave systems are more robust and antennas may be powered simultaneously, driven with higher powers, and switched, or steered.
Use of microwave ablation has been most prevalent in Asia, where trials have shown similar efficacy between RF and microwave for small HCC (17). While these studies are promising, technical limitations (e.g. large antennas) of early-generation microwave devices have not, to date, allowed the potential advantages of microwaves to become evident. Preliminary studies with systems that can power several small-diameter antennas from a single generator are promising (18, 19), and it is likely that microwaves will gain more traction as their theoretical advantages are introduced to practice.

Laser

Laser ablation is used more frequently in Europe than in the United States. During laser ablation, fibers are inserted into the tumor and the tumor is irradiated with a laser beam. It is well suited to superficial procedures. However, limited tissue penetration and a heavy reliance on thermal conduction makes laser ablation less suitable for tumor destruction compared to other heat-based modalities since heating is severely limited by local perfusion.

High-intensity focused ultrasound (HIFU)

Thermal ablation with a HIFU beam is an exciting topic since, in contrast to the previously discussed modalities; it does not require the placement of an applicator into the tumor. Tissue heating results from absorption of the focused acoustic energy and does not require a skin puncture. HIFU is often combined with MRI, which can provide real-time temperature measurements and assist in treatment planning. While promising, small ablation zones and expensive, complex systems have limited its practical application. HIFU has yet to find a prominent role in the treatment of liver cancer, in part because respiratory motion makes accurate focusing of the ultrasound beam difficult. The main clinical utility to this point has been in the treatment of uterine fibroids, where it has shown promise.

CONCLUSION

Tumor ablation is playing an increasingly important role in the management of patients with liver cancer. PEI and RF ablation are established modalities for which a survival benefit has been established in patients with early-stage and intermediate-stage HCC. RF ablation has been shown to have a significant impact on the outcome of select patients with metastatic disease to the liver. Laser ablation is also an effective modality with more widespread use in Europe than the United States, but technical limitations. Finally, HIFU and microwave ablation systems are being developed which may further expand the role of tumor ablation by overcoming some of the limitations of existing modalities. 


 


Additional Authors:  

Works Cited:  
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