Minimally invasive treatment of colorectal cancer metastases: Current status and new directions

Introduction
Colorectal cancer (CRC) metastases and other malignant tumors of the liver result in significant cancer-related mortality in British Columbia and worldwide.[1] CRC ranks second in cancer deaths, with the liver as the primary site for distant metastases.[2] The liver is the primary site for metastases for most malignancies of the gastrointestinal tract, accounting for a large proportion of the morbidity and mortality in those patients.

Surgical resection is the only known potentially curative treatment for patients with primary or metastatic liver tumors. Patients with solitary colorectal metastasis to the liver have up to a 40% 5-year survival, and patients with multiple metastases (up to four lesions) have been reported to have survival rates of 22% if all visible disease can be resected.[3] Unfortunately, fewer than 30% of patients are candidates for curative surgical resection at the time of presentation because of disease burden or anatomical location of the metastases.[4-6]

In addition, 25% of patients with colorectal cancer die of hepatic failure secondary to the metastatic disease.[7,8] Hepatic radiation is very toxic and not normally performed, since it has little impact on survival. Recent developments in systemic chemotherapeutic agents have had some effect, but improvement in survival has not been consistently reported.[9] Thus, other therapies for these lesions, particularly minimally invasive imaging-guided methods, are currently in use or being investigated. The six best evaluated methods include percutaneous ethanol injection, interstitial laser photocoagulation, cryoablation, microwave ablation, chemoembolization, and radiofrequency ablation.[10]

Percutaneous ethanol injection
Of all the minimally invasive therapies, percutaneous ethanol injection has been the most widely used and accepted worldwide. Percutaneous ethanol injection is inexpensive, easy to perform, and produces good clinical results for hepatocellular carcinomas (HCCs).[11] Major complications are uncommon (less than 2% of cases).

These include peritoneal hemorrhage, hemobilia, liver abscess, and tumor seeding.[12-15] A significant disadvantage is that multiple sessions are usually required, each time requiring a short stay in a medical day-care recovery bed. The main limitation of this technique is that the size and shape of the induced necrosis is not always reproducible or predictable. Different types of tumors have different responses. In general, small (<2 cm) hepatomas are the most responsive. HCCs less than 5 cm have a complete ablation rate of approximately 70% to 75%.

In contrast, metastases respond poorly to percutaneous ethanol injection. Metastases tend to have more tightly packed cellular architecture, which may cause uneven ethanol distribution, resulting in incomplete tumor necrosis. As with most of the percutaneous therapies, the procedure is performed in an interventional radiology suite with conscious sedation, usually using ultrasound guidance.

Interstitial thermal ablation
Interstitial thermal ablation or interstitial laser photocoagulation of liver tumors was first reported in 1983.[16] A single, bare laser fibre is inserted percutaneously into a lesion. The fibre scatters light in the optical or near-infrared wavelengths within tissue and is converted into heat. A single fibre can produce a zone of necrosis of approximately 2 cm. Two methods for delivery of light have been described to produce larger volumes of necrosis: multiple bare fibres in an array and cooled-tip diffuser fibres.

The major drawback to this technique is its cost, requiring $30,000 to $75,000 for a portable, solid-state laser and $3000 per set of multiple (50) use fibres.[9] An intense inflammatory response usually occurs after therapy and often requires significant narcotic and non-steroidal anti-inflammatory analgesics. Major complications include segmental infarction, abscess, and tumoral seeding.[10] Interstitial thermal ablation has the benefit of being completely compatible with magnetic resonance imaging (MR). The procedure can be performed with the patient in the MR unit and, thus, MR imaging offers the potential for accurate real-time monitoring of the extent of ablation.

Cryoablation
Cryoablation is the oldest of the thermal ablation techniques.[17] It requires open laparotomy under general anesthesia in the operating room to guide the insertion of multiple cryoprobes.[18] Probe size is significantly larger than other types of ablation probes to accommodate flow of the thermal conductive material. Cell death is thought to occur from denaturation of cellular proteins and cell membrane rupture.[19,20] The presence of extrahepatic disease and inability to undergo general anesthesia are both contraindications to this procedure.

Complications include hepatic capsular cracking and rupture, with associated hemorrhage. Arteriovenous and biliary fistulas, abscess formation, hepatic failure, myoglobinuria, and death have also been reported. The cost of a cryoablation unit ranges upwards from $190,000 and each multi-use probe approximately $3750.[10] In addition, there is a substantial cost to obtain and maintain the cryogenic material, which is achieved most commonly with super-cooled liquid nitrogen or argon gas.

Microwave coagulation
Microwave coagulation therapy involves ultra-high speed (2450 MHz) microwaves emitted from a percutaneously placed probe.[21] A 14-gauge guiding needle is inserted, followed by the microwave probe. It is still a relatively new procedure, essentially being performed only in Japan. In a relatively small study, complete tumor necrosis was achieved in 72% of cases.[22,23] Complications include ascites, pleural effusion, intraperitoneal hemorrhage, and abscess formation. At present, the largest areas of necrosis are less than 3 cm; many lesions require multiple sessions of therapy. A typical microwave generator costs approximately $65,000.

Chemoembolization
The normal liver receives approximately one-quarter of its blood supply from the hepatic artery, with the remaining supply from the portal venus system. Hepatic malignancies, primary or secondary, derive the bulk of their blood supply from the hepatic arterial circulation. Because of this, the hepatic artery can be embolized using various techniques to induce ischemic necrosis of malignant tumors while sparing normal hepatic tissue. The technique of chemoembolization has been widely used throughout East Asia and Europe, and has received considerable attention in the past 10 years in North America.

Chemoembolization consists of the infusion of emulsification of iodinated oil (Lipiodol) with chemotherapeutic agents. In the case of hepatomas and certain types of metastases, i.e., carcinoid and leiomyosarcoma, adriamycin is a preferred agent. Studies have recently been conducted using emulsified Lipiodol with 5-fluorouracil and mitomycin C for the treatment of colorectal metastatic disease.

Some of these have shown promising results, and this technique has been increasingly applied, sometimes in combination with other techniques such as ethanol or radiofrequency ablation. Chemoembolization is particularly attractive in patients who have multiple lesions that may be difficult to treat with other techniques.[24] Many patients who have failed intravenous chemotherapy may still show response to chemoembolization. Regional therapies are usually preferred for more localized lesions.

Contraindications to chemoembolization include significantly impaired hepatic reserve, such as patients who have abnormal clotting parameters, elevated bilirubin, or absent portal venous flow. Obstructive lung disease is a relative contraindication since some oil will embolize to the lung. The equipment required for chemoembolization at one sitting, including the chemotherapeutic agents, costs in the vicinity of $1000. If clinically indicated, patients may undergo re-embolization. Patients with responsive tumors may sometimes go on to three or four repeat embolizations over a period of months or even years.

Complications in properly selected patients are usually minor, consisting of right upper quadrant pain and tenderness, nausea, and low-grade fever. Gallbladder infarction may occur, which increases post-procedural discomfort. However, cholecystectomy is rarely needed as these can be successfully treated as conservatively managed acalculous cholecystitis. Rarely, significant intratumoral or subcapsular hemorrhage may occur, particularly in lesions that extend to the hepatic capsule.

Radiofrequency ablation
Hepatic radiofrequency ablation produces tumoral necrosis by thermal coagulation and protein denaturation.[25,26] High-frequency alternating current flows from uninsulated electrode tips into the surrounding tissue, which differs from direct heating from a probe. As a result of the change in direction of the alternating current, agitation of the tissue occurs and results in frictional heating. The tissues surrounding the electrode (rather than the electrode itself) are the primary source of heat.

The technique results in a precise, reproducible zone of necrosis.[27] Up to 5 cm diameter regions of necrosis can be produced with each ablation through a percutaneously placed 14- or 15-gauge needle. A typical generator costs $25,000 and each single use probe costs approximately $800 to $1200.[10] Radiofrequency ablation is equally effective in treating both primary and secondary malignancies of the liver, with complete ablation rates in the range of approximately 90%.[28-31]

The 3-year survival rates compare favorably to surgery, despite a patient selection bias.[32] Patients considered candidates for surgical resection generally have smaller and/or fewer lesions, better hepatic reserve, and are in better health overall. Despite this bias, the 3-year survival rate is approximately 38%, which is not significantly different from the reported 34% to 43% 3-year survival in the surgical literature.

The procedure requires a day-bed admission and is performed with ultrasound guidance in the interventional radiology suite. Overall, complications—hemorrhage and tumor seeding—are relatively few.[10,33] The major limitation of radiofrequency ablation is the “heat sink” effect, caused by the diffusion of thermal injury by large vessels in close approximation to the tumor.[26,34] Rapid blood flow effectively dissipates the heat generated by the surrounding tissue. This is also seen in other regional thermal ablation techniques, particularly cryoablation.

Summary
Minimally invasive, image-guided treatment options for CRC and other gastrointestinal tract tumor metastases to the liver are rapidly expanding. Currently, radiofrequency ablation, chemoembolization, and percutaneous ethanol injection are the most widely practised in our institution for patients who are not amenable for surgical resection. In general, radiofrequency ablation is much less toxic and better controlled than chemoembolization.

The size of thermal injury created by a single radiofrequency ablation is larger than that created by a single laser ablation; therefore, there is less chance of missing a tumor. Cryoablation requires laparotomy or laparoscopy, and its complications are greater than that for radiofrequency ablation. Radiofrequency ablation appears to be effective for both HCC and hepatic metastases. In addition, radiofrequency ablation requires fewer sessions to treat the same tumor than by percutaneous ethanol injection.

Unfortunately, the high cost of each radiofrequency ablation probe limits its availability, so percutaneous ethanol injection is used as first-line treatment of HCC in our institution. Radiofrequency ablation is used to treat HCC when percutaneous ethanol injection has failed, or when percutaneous ethanol injection is not suitable due to tumor location, size, or other technical reason.

Radiofrequency ablation is used to treat CRC metastases to the liver, and there are currently several research projects investigating the usefulness of radiofrequency ablation for other tumors in the liver, as well as tumors in other organs. Chemoembolization is reserved for widespread or multiple metastases. Ultimately, most appropriate mode of therapy must be determined in a multidisciplinary manner.

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Dr Ho is head, Section of GI Radiology at Vancouver General Hospital and clinical instructor in the Department of Radiology at the University of British Columbia. Dr Munk is a professor of radiology at UBC. Dr Legiehn is a clinical instructor in the Department of Radiology at UBC and acting head, Section of Angiography at Vancouver General Hospital. Dr Chung is associate professor and head, Division of General Surgery, Department of Surgery at UBC. Dr Scudamore is an associate professor and head, Section of Hepatobiliary and Pancreatic Surgery, Department of Surgery at UBC. Mark Lee is a research associate in the Department of Radiology, Vancouver General Hospital.