Cryotherapy for Liver Tumors

Introduction

Primary and metastatic liver tumors are a common cause of cancer-related mortality worldwide. In 1997, the estimated annual incidence of primary liver tumors in the United States was 13,600, with an estimated mortality of 12,400.[1] Although the relative incidence of primary liver tumors in the United States is low (2.5% of all new cancers), hepatocellular carcinoma constitutes one of the most common cancers in other parts of the world, including certain areas of Asia and Africa. Overall, however, the incidence of malignant hepatic tumors is dominated by metastatic disease.

The estimated annual incidence of colorectal cancer in the United States during 1997 was 131,200.[1] As many as 75% of patients with colorectal cancer will develop synchronous or meta-
chronous liver metastases, and about 25% of these, or approximately 25,000 to 30,000 patients, will have disease limited to the liver. Moreover, of the estimated 70,000 patients who succumbed to colorectal cancer in 1997, approximately 25% had metastases confined to the liver.

The natural course of untreated primary liver cancer is characterized by rapid progression, with median survival times of 2 to 4 months and few long-term survivors (Table 1).[2-4] Most patients have disease limited to the liver at diagnosis, and approximately 90% will have isolated hepatic disease at the time of death.[5]

Historically, complete surgical resection has been the only form of curative therapy available for patients with hepatic carcinoma, resulting in 5-year survival rates of 10% to 40% (Table 2). Unfortunately, underlying hepatic disease, including cirrhosis, hepatitis B, hemochromatosis, and alpha-1-anti-trypsin deficiency, is common and can markedly complicate surgical resection or render resection impossible. In fact, 70% to 90% of primary liver cancers are surgically unresectable.

Although hepatic transplantation has been associated with 5-year survival rates of 20% to 40%, it is contraindicated in many patients and unavailable to most. Other treatment options, including palliative resection and regional or systemic chemotherapy, have had little impact on overall survival. Clearly, the prognosis for patients with unresectable primary liver tumors has been dismal.

The natural history of patients with hepatic metastases depends on several factors, including tumor histology,the extent of metastases, and the presence or absence of extrahepatic disease (Table 1). A collective review of 673 untreated patients with colorectal liver metastases cited a median survival duration of 6 to 13 months.[6] When only 142 untreated patients with isolated liver metastases (defined as unilobar, localized disease consisting of fewer than four lesions) were considered, the median survival time was 18 months with a 5-year survival rate of 1%.

Systemic chemotherapy generally achieves response rates of 20% to 30% in patients with liver metastases but offers no significant survival advantage compared to the natural course of untreated disease.[7] In addition, regional chemotherapy, delivered via hepatic artery infusion, results in a prolonged disease-free interval but has not improved overall survival compared with systemic fluorouracil(Drug information on fluorouracil) alone.[8-11]

Again, complete surgical resection offers the only potentially curative therapy for patients with colorectal liver metastases. The Hepatic Registry Group data of 859 patients treated with surgical resection indicate a 5-year overall survival of 33%.[7] Several other series report 5-year survival rates of 25% to 40% in patients with surgically resected colorectal metastases (Table 2).

Other less frequent, yet potentially still curable, tumors that metastasize to liver include neuroendocrine, renal, adrenal, uterine, ovarian, and cervical cancers; sarcoma; melanoma; and, perhaps, breast cancer. Surgical resection of these noncolorectal liver metastases has resulted in 5-year survival rates of 10% to 40% (Table 2).[12-15] Unfortunately, 70% to 90% of patients diagnosed with isolated hepatic metastases have surgically unresectable lesions.

It has become clear that primary and metastatic liver tumors represent a significant therapeutic challenge and increasingly important health-care problem. Driven by the low resectability rate, limited treatment options, and correspondingly dismal prognosis, recent emphasis has focused on regional ablative therapies, including cryosurgery, alcohol(Drug information on alcohol) or laser ablation, interstitial radiation, hyperthermia, chemoembolization, and radiofrequency ablation. Of these various modalities, accumulating data suggest that cryotherapy is a safe, efficacious treatment alternative for many patients with surgically unresectable tumors. In fact, cryoablation of selected unresectable primary and metastatic liver tumors may result in long-term survival rates similar to those reported in series of surgically resected hepatic tumors.

History of Cryosurgery

Initial attempts at performing cryotherapy date back to the early 1800s. Simple techniques using iced saline solutions were employed to try to alleviate pain in patients with advanced breast or cervical cancer. Since then, significant advances in cryogenics have allowed for the application of this technique to local tissues as a means of controlling various cancers, including tumors of the skin, breast, prostate, oropharynx, larynx ,and lung.[16-19]

However, it was not until 1963 that Irving Cooper, a neurosurgeon using cryosurgery to treat Parkinson’s disease and other neuromuscular disorders, suggested the possible use of this technique for the management of primary and metastatic liver tumors.[20] Although Cooper was instrumental in developing the cryosurgical apparatus and delivery system for liquid nitrogen, limitations in the accurate imaging of tumors prohibited the safe application of this technique to deeper tissues, including the liver.

This obstacle was eventually overcome with the advent of intraoperative ultrasound (IOUS). Today, liver tumors can be accurately imaged and real-time monitoring of the freezing process can be effectively achieved utilizing IOUS. Accordingly, hepatic cryosurgery has now emerged as a viable therapeutic strategy for unresectable liver tumors.

Principles of Cryotherapy

The fundamental effect of cryosurgery is based on in situ tissue destruction using subzero temperatures. Cell death results from complex physiologic mechanisms that rely on direct and indirect mechanical effects. These effects include ice crystal formation and cellular anoxia during the frozen state, followed by microvascular thrombosis. Experimental evidence also suggests an adaptive immunologic tumor response in the post-frozen state. The overall results are cell membrane destruction, enzyme denaturation, osmotic dehydration, anoxia, and cellular necrosis.[21]

Although the mechanism of cryo-ablation is tissue-nonspecific, different tissues have inherently variable sensitivities to the cryogenic effect. Similarly, within the liver itself, different cells have varying degrees of sensitivity to subzero temperatures. Hepatocytes, bile duct epithelial cells, and connective tissue cells demonstrate resiliency to temperatures as low as -10 °C but are completely destroyed at -40 °C. In contrast, larger blood vessels seem to be resistant to temperatures of these extremes. This effect, which may be due, in large part, to the thermal sink effects of warm blood within the vessel itself, serves to protect the vessel intima and media.

Experimental evidence suggests that complete perivascular and intralesional tissue necrosis results following hepatic cryoablation near large vessels.[22] Exploiting this phenomenon allows for the application of this technique to the hepatic tissue surrounding these vessels. By using IOUS guidance, malignant lesions can be completely encompassed and ablated while the remaining liver tissue is preserved. Thus, the fundamental principle of cryosurgery is the ablation of malignant tumor deposits while selectively sparing normal hepatic parenchyma that would otherwise require removal by formal surgical resection.

Patient Selection

General indications for hepatic cryosurgery include the following:

1.  A documented primary or metastatic liver tumor,

2.  The absence of extrahepatic metastasis,

3.  Surgically unresectable disease, and/or

4.  Tumor involving surgically resected margins.

Following the diagnosis of a primary or metastatic liver tumor, a careful preoperative evaluation and staging work-up are essential. Preoperative liver imaging is important to determine the extent of hepatic tumor involvement and to exclude the presence of extrahepatic disease.

Tumor markers are often measured preoperatively and may be important in the postoperative follow-up period as well. These include alpha-fetoprotein (AFP) for hepatocellular carcinoma, carcinoembryonic antigen (CEA) for colorectal liver metastases, and/or 5-hydroxyindoleacetic acid (5-HIAA) for metastatic carcinoid tumors.