Regional Perfusion for Melanoma of the Extremities

_____________ _ A common cause for treatment failure in patients with malignant melanoma is local or regional recurrence of the disease. It is presumed that the poor treatment response rate is due to occult metastases present during the initial treatment phase. In an effort to improve response rate and survival, 15 patients with malignant melanoma of an extremity underwent isolated regional limb perfusion combined with hyperthermia and the cytotoxic drug Imidazole Carboxamide (DTIC). Study objectives include examination of response, subsequent tumor behavior after treatment, and the side effects of hyperthermia on the extremity. The 0-2 year response rate is 100%. None of the patients developed local recurrence, intransit or lymph node metastases, or disseminated tumor. There have been no surgical deaths and only a few patients developed some symptomatology of the known toxic side effects of the chemotherapeutic agent. Our early experience justifies the continued employment of regional hyperthermic chemotherapeutic isolation perfusion as an ideal treatment for patients who have malignant melanoma confined to an extremity. Introduction _____________ _ In the past, primary treatments for malignant melanoma of the extremities have been accomRequests for Reprints to: Robert 0. pfefferkom, C.C.P., CardioSciences, Inc., 2500 Townsgate Road, Suite E, Westlake Village, CA 91361. Presented at AmSECT's 20th International Conference, Hollywood, FL, April 23-25 1982. Volume 14, Number 6, 1982 panied by high incidence of local or regional recurrence. This recurrence usually appears within 20-24 months after initial treatment. The manifestations are in the form of local recurrence, when the tumor nodule appears in the scar of the previous incision; satellitosis, when single or multiple tumor nodules occur within 3 em distance of the previous excision site; intransit metastases, identifiable when the recurrent tumor nodules appear between 3 em distance of the primary site and the regional lymph nodes. Prognosis of recurrent malignant melanoma is extremely grave. McNeer and Cantin reported a 20% 5-year survival rate. 1 Others have reported the survival rate to be as low as 14%. 2 Treatment for both high risk and recurrent malignant melanoma of the extremity has included radical amputation, wide excision and systemic chemotherapy. Radical amputation of the extremity has been accompanied by a survival rate of 12% in patients who had positive regional lymph nodes and 34% in those with negative lymph nodesY Overall survival figures from a variety of different series fall in 12-30% range indicating a poor result from such a radical approach.4.1 Another highly recommended treatment has been wide re-excision of the locally recurring lesion. Frequently, however, these lesions are multiple with intransit metastases. Some are located subfascially which, combined with other factors, make it nearly impossible to achieve a successful wide excision of the tumor. Systemic chemotherapy, the third modality, has been used extensively for the treatment of advanced malignant melanomas. When used with various drugs or drug comThe Journal of Extra-Corporeal Technology 475 binations, the response rates have been in the range of 15-40%.58 The side effects of systemic chemotherapy, however, are usually pronounced and can be expected in greater than 60% of the patients treated. An ideal treatment for patients who have malignant disease confined to an extremity is regional chemotherapeutic isolation perfusion. This modality has been in use since Creech and his associates introduced it in 1957.9 The aim of isolated regional chemotherapy is to achieve a high drug concentration in the target tissue thus maximizing tumor cell kill without producing the serious side effects of systemic toxicity in those organs not affected by the cancer. The response rates for this method have been reported to be as high as 60-80% with excellent prolongation of survival. • When hyperthermia is combined with isolation perfusion, there is even greater cell kill and better results are thus achieved. The primary benefits of hyperthermia are that it ( 1) increases the binding rate of long-acting alkylating chemotherapeutic agents and, (2) increases the degree of vasodilatation allowing for greater exposure of the tumor to the circulating drug. In one reported series, the 5-year survival for locally recurrent malignant melanoma after hyperthermic isolation perfusion was 48.2% as compared with 20-34% after conventional surgical excision. 10 A number of drugs including Melphalan, Actinomycin, Nitrogen Mustard, and Thio-tepa have been used for isolation perfusion chemotherapy. Melphalan has been most widely used as it appeared to be the most active of all in treating a malignant melanoma. Recently, however, Imidazole Carboxamide (DTIC)a has shown to provide the highest response rate when used for either systemic intra-venous or intra-arterial infusion.12·13 Although the exact mechanism of OTIC's action is unknown, it is thought to inhibit DNA synthesis by acting as a purine analog. This eventually causes cell death by interfering with DNA's role in cell replication. It is also thought to be an alkylating agent which attacks a purine base in the ON A structure. OTIC safely lends itself to hyperthermic techniques as it is stable at temperatures up to 42 degrees C. The rate of decrease in OTIC concentration is approximately 2% per hour a Dome Div., Miles Laboratories, West Haven, CT 06516 476 The Journal of Extra-Corporeal Technology over three consecutive hours and the plasma half-life after I. V. administration is approximately 19 minutes. 14 Symptoms of anorexia, nausea, and vomiting are the most frequent toxic reactions with hemopoietic depression of leukocytes and platelets, the least experienced, but most severe of reactions. The recommended dose is 250 mg/m2/ day I. V. for five days for systemic therapies. In our study, the dose was initially calculated at 600 mg/m2 and now approximates 2 gm/m2. Because this concentration is nearly eight times the systemic dose, the perfused extremity must be washed out with dextran and saline at the end of the procedure to avoid systemic toxicity. Materials and Methods. _______ _ After the patient is anesthetized, a surgical prep is performed to include the entire limb, chest, and shoulder for upper extremity perfusions and the limb, abdomen, and gluteal area for lower extremity perfusions. For upper extremities, radical axillary lymph node dissection is performed before the perfusion if it has not already been done. For lower extremity perfusions, the external iliac vessels are explored and the common and external lymph nodes are biopsied. In the lower extremity, the external iliac vessels are cannulated with a 12-16 Fr. arterial cannula and a 10-12 Fr. cannula is placed in the axillary vein for upper extremity perfusions. To check the proper placement of the arterial cannula, 10 cc of fluorescin dye is injected through the cannula and flow of the dye is followed with an ultra-violet lamp. Appearance of the dye in the distal arterial circulation within 20-30 seconds would indicate adequate placement of the arterial cannula. The perfusion circuit consists of a Travenollow flow modular pumph, 114" I. D. arterial and venous tubing, a Bentley BOS-se oxygenator and a Pall EC 1440ct infant arterial line filter with filter bypass. A Harvey H 700 P cardiotomy reservoir containing the washout solution is Y-connected to the arterial line on the negative side of the pump head to control the rate of washout infusion at the end of the procedure. 100% oxygen and 100% carbon dioxide gases are blended to achieve arterial "Travenol Laboratories, Deerfield, IL 60015 ,. Bentley Laboratories, Inc., Irvine, CA 92714 "Pall Bio-Medical Products, Glen Cove, NY 11542 ' Bard Cardiopulmonary, Santa Ana, CA 92700 Volume 14, Number 6, 1982 TABLE I Sex/Extremity Distribution