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Cryotherapy for Hepatic Colorectal Carcinoma Metastases

Approximately 20 percent of the nearly 160,000 Americans diagnosed with colorectal cancer each year will have liver metastases at presentation. An additional 20 percent to 30 percent will develop liver metastases subsequent to treatment of their primary cancer. Systemic chemotherapy is widely employed for unresectable disease and is associated with only a 20 percent response rate with little impact on long-term survival. As a result, investigators are currently evaluating both regional and systemic treatments in the hope of improving upon this dismal prognosis.

In spite of the poor response of colorectal liver metastases to systemic therapy, regional hepatic arterial infusional (HAI) chemotherapy is associated with response rates of nearly 85 percent in untreated patients (no previous systemic 5-FU) and 52 percent in previously treated patients (received 5-FU within the past 6 months).¹ Complete eradication of hepatic metastases is rarely evident, however, and after stopping therapy, tumor progression in the liver is frequently observed. The inability to achieve a complete response with regional chemotherapy alone, even with prolonged treatment, is part of the problem. Regional chemotherapy is limited by liver toxicity and biliary sclerosis during long-term use.

Cryosurgery has been available for many years but only recently has been applied to the ablation of liver tumors in situ. This is primarily due to improvements in cryotechnology as well as the availability of high-resolution intraoperative ultrasound. The technique involves operative placement of a metal probe into the center of a tumor. Liquid nitrogen flows through this freezing probe and initiates the creation of an ice ball starting in the tumor's center and gradually expanding outward. The formation of the spherical ice ball is monitored by intraoperative ultrasonography and is complete when the ice ball is 1 centimeter beyond the tumor. In this manner, tumor tissue is destroyed with minimal destruction of normal liver tissue.

There are limiting factors to cryotherapy of hepatic metastases. Metastatic tumors more than 5 centimeters in diameter or in close proximity to major vascular structures or bile ducts are difficult to completely freeze safely. Another limiting factor is the number of hepatic metastases. As many as eight small metastases can be frozen, but in patients with four or more tumors it is quite likely that immeasurable smaller hepatic metastases are present. Under these circumstances, it is unlikely that cryotherapy is curative unless other therapies such as regional HAI chemo-therapy also are used.

To address the problems inherent with regional chemotherapy and cryoablation, physicians at Ellis Fischel Cancer Center have initiated a clinical protocol combining these modalities. The hypothesis is that HAI chemotherapy followed by operative cryoablation will produce a higher complete clinical remission of hepatic colorectal metastasis, with concomitant improvement in patient survival. Eligibility for this protocol will include the following:

• Surgically inoperable liver metastasis.
• Age or co-morbid disease precludes a safe major hepatic resection.
• Primary tumor has been resected or will be resected at the time of pump placement.
• Good performance status with serum creatinine less than 2.0 mg/dl, bilirubin less than 2 mg/dl and an SGOT less than four times normal.
• No evidence of extrahepatic disease.

Patients who have never received 5-FU based chemotherapy or who have developed liver metastasis more than six months after completion of 5-FU therapy will receive systemic 5-FU based chemo-therapy. This systemic neoadjuvant chemotherapy program will identify those patients whose liver metastasis are sensitive to 5-FU based chemotherapy while also addressing the control of systemic disease. If the tumors respond to two cycles of systemic chemotherapy, this will continue for four more cycles. If no response is seen after two cycles, then patients go on to HAI chemotherapy consisting of FUDR, leucovorin and decadron. After completion of HAI chemotherapy, cryoablation will be used to achieve complete response in the liver. Patients who have received 5-FU based systemic chemotherapy within the past six months will bypass systemic therapy and go directly to regional HIA chemotherapy and cryoablation. Thus, patients on other systemic chemotherapy protocols with liver-only disease who progress on treatment are still eligible for the present study.

There are a number of theoretical advantages to preoperative systemic and regional chemotherapy for unresectable colorectal carcinoma metastases to the liver. The use of cryotherapy to ablate remaining liver metastasis after chemotherapy should increase the number of patients with a complete clinical response and increase patient survival. This multidisciplinary approach combining systemic and regional chemotherapy followed by cryosurgery is novel and worthy of investigation.

Accrual is open for 38 previously untreated patients and 51 treated patients. Patients can be considered for this treatment by calling (573) 882-8545 and request a telephone conversation with either:

• Boris Kuvshinoff, MD E-mail kuvshinoffb@health.missouri.edu
• David Ota, MD E-mail: otad@health.missouri.edu

References

1. Kemeny N, Canti JA, Cohen A, Campana P, Huang Y, Shi WJ, Botet J, Pulliam S and Bertino JR. Phase II study of hepatic arterial floxuridine, leucovorin and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 12:2288-2295, 1994.