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Isolation perfusion
Isolation Perfusion An Adjunct to Surgical Excision in the Primary Treatment of Melanoma of the Extremities
E. MEREDITH ALRICH, MD, Charlottesville, Virginia J. LAURENCE MANWARING, MD, Charlottesville, Virginia J. SHELTON HORSLEY, Ill, MD, Charlottesville, Virginia
Melanoma is a malignant tumor which metastasizes by way of both the lymphatic and vascular pathways. The standard mode of therapy for many years has been wide local excision alone or combined with regional lymph node dissection, particularly when the dissection can be carried out in continuity with the primary site or when there are suspicious nodes palpable. In 1958 Creech and his associates [Z] first reported their experience with an isolation perfusion technic wth phenylalanine mustard, utilizing an extracorporeal pump oxygenator. The ratilonale was to deliver a high dose of cytotoxic agent directly to the tumor and its venous and lymphatic drainage-a dose which would be fatal if administered systemically. Oxygenation was carried out to enhance the action of the phenylalanine mustard based on the fact that it has a radiomimetic effect, and ionizing radiation is potentiated by high oxygen tension in the tissues. Initially this approach to melanoma was used in patients with cutaneous and nodal metastases on the lower extremities that occurred after excision of the primary tumor. There were some rather remarkable regressions. Material and Methods
Starting in 1960 we 121 offered patients with primary melanoma of the extremities with no clinically demonstrable metastases, either in the regional lymph nodes or distally, the following therapeutic approach: regional lymph node dissection, axillary or superficial groin, isolation perfusion with phenylalanine mustard* and wide local excision of the primary lesion. Nineteen * Alkeran@
brand
of melphalan,
Wellcome (Iz Company, Research
donated Triangle
by Burroughs Park, North
Carolina. From the Department of Surgery, University of Virginia Medical Center, Charlottesville. Virginia 22901. This investigation was partially supported by NIH Training Grant #l T12 CA 8019.01 from the National Cancer Institute
Volume
121,
May
1971
patients accepted this regimen as their primary treatment ,and are reported in this paper. All diagnoses
were confirmed by the Department
of Pathology of the
University of Virginia Medical Center. Four of the nineteen patients had melanomas that histologically were more superficial than the others and it was anticipated that they would have a better prognosis. Seventeen of the nineteen patients h,ad their lesions on the lower extremity: five on the foot, nine on the lower part of the leg, and three on the thigh. Two melanomas were on the upper extremity. The patients ranged in age from nineteen to sixty-four years with an average age of forty-three years. There were fourteen female and five male patients. The appropriate regional lymph node dissection was carried out initially after the histology had been definitely established by excisional or incisional biopsy. Patients with lesions on the upper extremity had radical axillary lymph node dissections. When the primary lesion was located on the lower extremity, superficial groin dissection with removal of the inguinal and femoral lymph nodes was performed in all patients except one who had a primary lesion with two satellite lesions on his heel. This patient had radical groin dissection with removal of iliac and obturator lymph nodes as well as inguinal ,and femoral lymph nodes. None of the regional lymph node dissections were in continuity because of the distal locations of the primary melanoma. The major venous and arterial supply of the limb, axillary vessels in the upper extremity and common femoral into the superficial femoral vessels in the lower extremity, were cannulated and attached to an extracorporeal pump oxygenator primed with 500 cc of heparinized blood. A tourniquet consisting of doubled % inch latex surgical tubing was tightly applied at or above the sites where the cannulas were placed. After the perfusion flow was stable, papaverine, 2 mg per kg of body weight, was added to the perfusate to reduce arterial spasm. Ten minutes later when the flow was stable, phenylalanine mustard, 1.5 mg per kg of body weight (not to exceed 90 mg), divided into two equal doses, was added to the perfusate at ten minute intervals. The limb was perfused for one hour unless there
583
Alrich,
TABLE
Manwaring, and Horsley
I
Follow-Up Summary of Nineteen Patients with Melanoma Treated Prophylactically with Isolation Perfusion
of the Extremities
Years Summary
1
2
3
4
5
6
7
No evidence of disease
2
1
1
2
1 5 ............... ......
...
Dead of disease Living with disease
4 ............
1
1
was evidence of leakage into the systemic circulation or technical difficulties were encountered. At the completion of the perfusion the perfusate was flushed out of the extremity with 1,000 to 1,500 cc dextran 6 per cent, and then 500 cc of hep.arinized blood was replaced and the perfusion discontinued. The tourniquet and cannulas were removed and the arteriotomy and venotomy were repaired with a continuous vascular suture. In the past several years we have transplanted the sartorius muscle over the femoral vessels, suturing it to the inguinal ligament, to give additional protection to these vessels. The primary site was then excised with a 3 to 4 cm margin of grossly uninvolved skin removing the underlying fascia, and in almost every case a split thickness skin graft was required for coverage of the defect. Results
All nineteen patijents had no clinical evidence of metastases to the regional lymph nodes. However, two patients did have microscopic metastases on pathologic examination. One of these patients died of metastatic melanoma within nineteen months and the other survives after forty-two months with no evidence of disease. The duration of follow-up examinations and the results are listed in Table I. The only patients among the seventeen with no metastases to regional lymph nodes who have demonstrated recurrent disease were as follows: (1) A sixty-four year old man with satellite nodules about the primary lesion who had radical groin dissection removing ilio-inguinal-femoral lymph nodes (all negative for metastases), isolation perfusion, and radical local excision. This patient died one year later from a lesion in the lung, presumably metastatic melanoma. (2) A fifty-one year old woman with local recurrence in the lower part of her leg eight years after primary treatment of superficial groin dissection, isolation perfusEon, and local radical excision with all regional lymph nodes free of metastases. (3) A twenty-four year old woman treated originally with superficial groin dissection with all lymph nodes free of metastases, isolation perfusion, and radical lrocal excision, in whom local recurrence developed fifty-four months later.
584
.........
8
9
10
.........
1
......
There were no operative deaths in this group of patients undergoing prophylactic isolation perfusiton. The average hospital stay was twenty-two days. There were the following significant complications in sixteen patients: seroma of the wound in eight patients, wound infection in five, anemia in two, and temporary sensory and motor deficit in the upper extremity in one patient. We have treated seven patients with isolation perfusion as an adjunct to surgical excision in the primary treatment ‘of melanoma of the extremity who are eligible for five year follow-up study. Six of these patients are alive and free of disease, and in one local recurrence has developed in the leg eight years after initial therapy and she has had reperfusion. An additional seven patients were treated two to five years ago and six are alive and free of disease and ‘one has had a local recurrence at her knee fifty-four months after primary treatment. There were four patients whose primary melanoma was called “superficial melanoma” on histologic examination. The regional lymph nodes in all of these patients were free of metastases. Three lesions were on the leg and one was on the arm. All patients are alive and without evidence of disease three to seven years after initial treatment. No amputations were performed in the primary treatment of these patients. Comments
This series of cases is too small to be of statistical significance. There are, however, several observatisons worthy of discussion. The first twenty-four months after treatment are of great importance since, if regional recurrences are to occur, they will do so in 80 per cent of patients within this two year interval [3]. We had fourteen patients who were two years or more from their primary treatment and in two local recurrence developed at fifty-four and one hundred months, respectively, and they have had reperfusion recently. The other twelve patients are alive and well, without evidence of disease. This would suggest that isolation perfusion might be delaying
The American
Journal
of Surgery
isolation
the appearance of the regional recurrence. Most surgeons agree that when the lesion is adjacent to the regional lymph nodes, regardless of enlargement, the best treatment is excision of the primary tumor with in continuity lymphadenectomy. There is usually agreement that lymph node dissection should be performed when the regional lymph nodes are clinically involved and there is no evidence ‘of distal m&stases, even when the primary site is not located to make in continuity resection feasible. However, when the primary lesion is located at a distance from the regional nodes which are not enlarged, there is controversy regarding the aldvisability of their removal [ 3-71. In our series, microscopic metastases were found in two patients (11 per cent) with clinically uninvolved regional lymph nodes. Other groups have reported occult metastases in 20 to 35 per cent of patients. Because of these results, we have employed prophylactic regi,onal lymph node dissection as an integral part of our primary therapy. The experience of prophylactic isolation perfusion for melanoma of an extremity is limited. Results with the extensive series of patients reported by Krementz, Creech, and Ryan [8] and Stehlin and Clark [9] continue to show real promise. More recently Stehlin [IO] has modified his approach to perfusion by using hyperthermia, heating the blood to 115” F (46.1” C), and increasing the duration of the ‘perfusion to two hours. In his experience these changes have led to improved tumor response but also increased morbidity. However, more time is needed to properly evaluate the efficacy of this approach. We have used the term “superficial” to describe those lesions of melanoma in which the dermal invasion is limited to the upper half of the dermis, the superficial dermis. At the present time, because of the favorable prognosis of this type of melanoma, we would use wide local excision only in these cases where there was no evidence of involvement of the regional lymph nodes [ 111.
Volume 121. May
1971
Perfusion
Summary
We have presented our experience with nineteen patients with melanoma of an extremity with regional lymph nodes clinically free of metastases, treated by regional lymphadenectomy, isolation perfusion with phenylalanine mustard, and wide local excision. The rationale for this approach is reviewed. Our series is too small to be of statistical significance, but our own experience added to that of others utilizing this plan of treatment has encouraged us to continue this vigorous attack on melanoma located on an extremity. Acknowledgment: We wish to express our appreciation to Dr M. Shannon Allen of the Department of Pathology, who reviewed the slides of the patients in this study. References 1. Creech 0 Jr, Krementz ET, Ryan RF, Winblad JN: Chemotherapy of cancer: regional perfusion Utilizing an extracorporeal circuit. Ann Surg 148: 616, 1958. 2. Christlieb II, Alrich EM: Isolation perfusion as an adjunctive treatment for melanoma of the extremities. Virginia Med Monthly 91: 57, 1964. 3. Stehlin JS Jr: Malignant melanoma: an appraisal. Surgery 64: 1149, 1968. 4. Block GE. Hartwell SW Jr: Malignant melanoma: a study of 21> cases. II. Treatme% effect. Ann Surg 154 (Suppl): 88, 1961. 5. Guiss LW, MacDonald I: The role of radical regional lymphadenectomy in treatment of melanoma. Amer J Surg 104: 135, 1962. 6. Mundth ED, Guralnick EA, Raker JW: Malignant melanoma: a clinical study of 427 cases. Ann Surg 162: 15, 1965. 7. Sandeman TF: Elective treatment of lymph nodes in malignant melanoma. Lancet 1: 345, 1965. 8. Krementz ET, Creech 0 Jr, Ryan RF: Evaluation of chemotherapy of cancer by regional perfusion. Cancer 20: 834, 1967. 9. Stehlin JS Jr, Clark RL: Melanoma of the extremities, experiences with conventional treatment and perfusion in 339 cases. Amer J Surg 110: 366, 1965. 10. Stehlin JS Jr: Hyperthermic perfusion with chemotherapy for cancer of the extremities. Surg Gynec Obstet 129: 305,1969. 11. DeCosse JJ, McNeer G: Superficial melanoma: a clinical study. Arch Surg 99: 531, 1969.
585
E. MEREDITH ALRICH, MD, Charlottesville, Virginia J. LAURENCE MANWARING, MD, Charlottesville, Virginia J. SHELTON HORSLEY, Ill, MD, Charlottesville, Virginia
Melanoma is a malignant tumor which metastasizes by way of both the lymphatic and vascular pathways. The standard mode of therapy for many years has been wide local excision alone or combined with regional lymph node dissection, particularly when the dissection can be carried out in continuity with the primary site or when there are suspicious nodes palpable. In 1958 Creech and his associates [Z] first reported their experience with an isolation perfusion technic wth phenylalanine mustard, utilizing an extracorporeal pump oxygenator. The ratilonale was to deliver a high dose of cytotoxic agent directly to the tumor and its venous and lymphatic drainage-a dose which would be fatal if administered systemically. Oxygenation was carried out to enhance the action of the phenylalanine mustard based on the fact that it has a radiomimetic effect, and ionizing radiation is potentiated by high oxygen tension in the tissues. Initially this approach to melanoma was used in patients with cutaneous and nodal metastases on the lower extremities that occurred after excision of the primary tumor. There were some rather remarkable regressions. Material and Methods
Starting in 1960 we 121 offered patients with primary melanoma of the extremities with no clinically demonstrable metastases, either in the regional lymph nodes or distally, the following therapeutic approach: regional lymph node dissection, axillary or superficial groin, isolation perfusion with phenylalanine mustard* and wide local excision of the primary lesion. Nineteen * Alkeran@
brand
of melphalan,
Wellcome (Iz Company, Research
donated Triangle
by Burroughs Park, North
Carolina. From the Department of Surgery, University of Virginia Medical Center, Charlottesville. Virginia 22901. This investigation was partially supported by NIH Training Grant #l T12 CA 8019.01 from the National Cancer Institute
Volume
121,
May
1971
patients accepted this regimen as their primary treatment ,and are reported in this paper. All diagnoses
were confirmed by the Department
of Pathology of the
University of Virginia Medical Center. Four of the nineteen patients had melanomas that histologically were more superficial than the others and it was anticipated that they would have a better prognosis. Seventeen of the nineteen patients h,ad their lesions on the lower extremity: five on the foot, nine on the lower part of the leg, and three on the thigh. Two melanomas were on the upper extremity. The patients ranged in age from nineteen to sixty-four years with an average age of forty-three years. There were fourteen female and five male patients. The appropriate regional lymph node dissection was carried out initially after the histology had been definitely established by excisional or incisional biopsy. Patients with lesions on the upper extremity had radical axillary lymph node dissections. When the primary lesion was located on the lower extremity, superficial groin dissection with removal of the inguinal and femoral lymph nodes was performed in all patients except one who had a primary lesion with two satellite lesions on his heel. This patient had radical groin dissection with removal of iliac and obturator lymph nodes as well as inguinal ,and femoral lymph nodes. None of the regional lymph node dissections were in continuity because of the distal locations of the primary melanoma. The major venous and arterial supply of the limb, axillary vessels in the upper extremity and common femoral into the superficial femoral vessels in the lower extremity, were cannulated and attached to an extracorporeal pump oxygenator primed with 500 cc of heparinized blood. A tourniquet consisting of doubled % inch latex surgical tubing was tightly applied at or above the sites where the cannulas were placed. After the perfusion flow was stable, papaverine, 2 mg per kg of body weight, was added to the perfusate to reduce arterial spasm. Ten minutes later when the flow was stable, phenylalanine mustard, 1.5 mg per kg of body weight (not to exceed 90 mg), divided into two equal doses, was added to the perfusate at ten minute intervals. The limb was perfused for one hour unless there
583
Alrich,
TABLE
Manwaring, and Horsley
I
Follow-Up Summary of Nineteen Patients with Melanoma Treated Prophylactically with Isolation Perfusion
of the Extremities
Years Summary
1
2
3
4
5
6
7
No evidence of disease
2
1
1
2
1 5 ............... ......
...
Dead of disease Living with disease
4 ............
1
1
was evidence of leakage into the systemic circulation or technical difficulties were encountered. At the completion of the perfusion the perfusate was flushed out of the extremity with 1,000 to 1,500 cc dextran 6 per cent, and then 500 cc of hep.arinized blood was replaced and the perfusion discontinued. The tourniquet and cannulas were removed and the arteriotomy and venotomy were repaired with a continuous vascular suture. In the past several years we have transplanted the sartorius muscle over the femoral vessels, suturing it to the inguinal ligament, to give additional protection to these vessels. The primary site was then excised with a 3 to 4 cm margin of grossly uninvolved skin removing the underlying fascia, and in almost every case a split thickness skin graft was required for coverage of the defect. Results
All nineteen patijents had no clinical evidence of metastases to the regional lymph nodes. However, two patients did have microscopic metastases on pathologic examination. One of these patients died of metastatic melanoma within nineteen months and the other survives after forty-two months with no evidence of disease. The duration of follow-up examinations and the results are listed in Table I. The only patients among the seventeen with no metastases to regional lymph nodes who have demonstrated recurrent disease were as follows: (1) A sixty-four year old man with satellite nodules about the primary lesion who had radical groin dissection removing ilio-inguinal-femoral lymph nodes (all negative for metastases), isolation perfusion, and radical local excision. This patient died one year later from a lesion in the lung, presumably metastatic melanoma. (2) A fifty-one year old woman with local recurrence in the lower part of her leg eight years after primary treatment of superficial groin dissection, isolation perfusEon, and local radical excision with all regional lymph nodes free of metastases. (3) A twenty-four year old woman treated originally with superficial groin dissection with all lymph nodes free of metastases, isolation perfusion, and radical lrocal excision, in whom local recurrence developed fifty-four months later.
584
.........
8
9
10
.........
1
......
There were no operative deaths in this group of patients undergoing prophylactic isolation perfusiton. The average hospital stay was twenty-two days. There were the following significant complications in sixteen patients: seroma of the wound in eight patients, wound infection in five, anemia in two, and temporary sensory and motor deficit in the upper extremity in one patient. We have treated seven patients with isolation perfusion as an adjunct to surgical excision in the primary treatment ‘of melanoma of the extremity who are eligible for five year follow-up study. Six of these patients are alive and free of disease, and in one local recurrence has developed in the leg eight years after initial therapy and she has had reperfusion. An additional seven patients were treated two to five years ago and six are alive and free of disease and ‘one has had a local recurrence at her knee fifty-four months after primary treatment. There were four patients whose primary melanoma was called “superficial melanoma” on histologic examination. The regional lymph nodes in all of these patients were free of metastases. Three lesions were on the leg and one was on the arm. All patients are alive and without evidence of disease three to seven years after initial treatment. No amputations were performed in the primary treatment of these patients. Comments
This series of cases is too small to be of statistical significance. There are, however, several observatisons worthy of discussion. The first twenty-four months after treatment are of great importance since, if regional recurrences are to occur, they will do so in 80 per cent of patients within this two year interval [3]. We had fourteen patients who were two years or more from their primary treatment and in two local recurrence developed at fifty-four and one hundred months, respectively, and they have had reperfusion recently. The other twelve patients are alive and well, without evidence of disease. This would suggest that isolation perfusion might be delaying
The American
Journal
of Surgery
isolation
the appearance of the regional recurrence. Most surgeons agree that when the lesion is adjacent to the regional lymph nodes, regardless of enlargement, the best treatment is excision of the primary tumor with in continuity lymphadenectomy. There is usually agreement that lymph node dissection should be performed when the regional lymph nodes are clinically involved and there is no evidence ‘of distal m&stases, even when the primary site is not located to make in continuity resection feasible. However, when the primary lesion is located at a distance from the regional nodes which are not enlarged, there is controversy regarding the aldvisability of their removal [ 3-71. In our series, microscopic metastases were found in two patients (11 per cent) with clinically uninvolved regional lymph nodes. Other groups have reported occult metastases in 20 to 35 per cent of patients. Because of these results, we have employed prophylactic regi,onal lymph node dissection as an integral part of our primary therapy. The experience of prophylactic isolation perfusion for melanoma of an extremity is limited. Results with the extensive series of patients reported by Krementz, Creech, and Ryan [8] and Stehlin and Clark [9] continue to show real promise. More recently Stehlin [IO] has modified his approach to perfusion by using hyperthermia, heating the blood to 115” F (46.1” C), and increasing the duration of the ‘perfusion to two hours. In his experience these changes have led to improved tumor response but also increased morbidity. However, more time is needed to properly evaluate the efficacy of this approach. We have used the term “superficial” to describe those lesions of melanoma in which the dermal invasion is limited to the upper half of the dermis, the superficial dermis. At the present time, because of the favorable prognosis of this type of melanoma, we would use wide local excision only in these cases where there was no evidence of involvement of the regional lymph nodes [ 111.
Volume 121. May
1971
Perfusion
Summary
We have presented our experience with nineteen patients with melanoma of an extremity with regional lymph nodes clinically free of metastases, treated by regional lymphadenectomy, isolation perfusion with phenylalanine mustard, and wide local excision. The rationale for this approach is reviewed. Our series is too small to be of statistical significance, but our own experience added to that of others utilizing this plan of treatment has encouraged us to continue this vigorous attack on melanoma located on an extremity. Acknowledgment: We wish to express our appreciation to Dr M. Shannon Allen of the Department of Pathology, who reviewed the slides of the patients in this study. References 1. Creech 0 Jr, Krementz ET, Ryan RF, Winblad JN: Chemotherapy of cancer: regional perfusion Utilizing an extracorporeal circuit. Ann Surg 148: 616, 1958. 2. Christlieb II, Alrich EM: Isolation perfusion as an adjunctive treatment for melanoma of the extremities. Virginia Med Monthly 91: 57, 1964. 3. Stehlin JS Jr: Malignant melanoma: an appraisal. Surgery 64: 1149, 1968. 4. Block GE. Hartwell SW Jr: Malignant melanoma: a study of 21> cases. II. Treatme% effect. Ann Surg 154 (Suppl): 88, 1961. 5. Guiss LW, MacDonald I: The role of radical regional lymphadenectomy in treatment of melanoma. Amer J Surg 104: 135, 1962. 6. Mundth ED, Guralnick EA, Raker JW: Malignant melanoma: a clinical study of 427 cases. Ann Surg 162: 15, 1965. 7. Sandeman TF: Elective treatment of lymph nodes in malignant melanoma. Lancet 1: 345, 1965. 8. Krementz ET, Creech 0 Jr, Ryan RF: Evaluation of chemotherapy of cancer by regional perfusion. Cancer 20: 834, 1967. 9. Stehlin JS Jr, Clark RL: Melanoma of the extremities, experiences with conventional treatment and perfusion in 339 cases. Amer J Surg 110: 366, 1965. 10. Stehlin JS Jr: Hyperthermic perfusion with chemotherapy for cancer of the extremities. Surg Gynec Obstet 129: 305,1969. 11. DeCosse JJ, McNeer G: Superficial melanoma: a clinical study. Arch Surg 99: 531, 1969.
585