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Original Article |
1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
2 Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
3 Department of Anesthesiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
Correspondence: Address correspondence and reprint requests to: Mary S. Brady, MD, FACS; E-mail: bradym{at}mskcc.org.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Eligible patients had American Joint Committee on Cancer stage IIIB or IIIC melanoma or unresectable soft tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet was inflated, and a normothermic, low-flow, hypoxic infusion of melphalan and dactinomycin was circulated through the involved limb for 20 minutes. The tumor response was assessed by using standard criteria at 3 months. Morbidity was determined in the hospital and at 2, 6, and 12 weeks.
Results: Twenty-five patients were accrued to the trial, and 32 ILIs were performed (8 patients had 2 ILIs); 1 patient was not treated. Of the 22 assessable patients, 11 (50%) had a significant response at 3 months: 23% of patients had a complete response, and 27% of patients had a partial response. The median duration of complete response was 1 year (range, 6–32 months). Morbidity was acceptable. Peak morbidity occurred at 2 weeks and was considered moderate in most patients. Limb edema and erythema were common. No patient developed compartment syndrome or required amputation.
Conclusions: ILI is well tolerated. Half of the patients experienced a complete or partial response.
Key Words: Isolated limb infusion • Melanoma • Soft tissue sarcoma • Regional chemotherapy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Current regional treatment options for these patients include surgical resection, intralesional therapy with sclerosing agents or immune adjuvants, isolated limb perfusion (ILP) with melphalan, systemic chemotherapy, or amputation. Surgical excision is a reasonable procedure when the lesion(s) can be encompassed without extensive skin grafting or are few in number. Intralesional therapy with bacillus Calmette-Guérin or interferon can provide relief for small lesions that are primarily dermal.3,4 Major amputation is uncommonly performed for recurrent melanoma or soft tissue sarcoma (STS), even when it is confined to the extremity. In a highly selected group of patients with melanoma limited to the extremity, however, amputation can be associated with a 5-year survival of 15% to 35%.5
Palliation of regional disease is a less common problem for patients with STS of the extremity. Excellent local control is usually achieved with a combination of limb-sparing surgery and radiotherapy.6 Select patients, however, present with primary or recurrent tumors not amenable to a conservative surgical approach. ILP with melphalan alone or in combination with other agents can be an effective treatment in these patients: 40% to 90% of these patients experience a complete response (CR) to the therapy.7,8
A major disadvantage of ILP is that it is a technically complex and highly invasive surgical procedure. It is performed by open surgical cannulation of the vessels at the root of the extremity. Isolation of the limb is achieved by ligation of vascular collaterals and placement of a proximal tourniquet. The limb is then placed on a pump oxygenator, which provides a high-flow, hyperoxic, hyperthermic circuit. Isolated limb infusion (ILI) is conceptually similar but much easier to perform.9 Infusion catheters are placed percutaneously by interventional radiologists. There is no need for a pump team or cardiopulmonary bypass circuit. John Thompson and colleagues, of the Sydney Melanoma Unit, have reported response rates to ILI similar to those seen with ILP.10 For this reason, we conducted the first North American trial of ILI in patients who would normally be candidates for ILP. Our goal was to determine the efficacy and morbidity of this innovative new procedure.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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ILI was performed by using the same technique as had been previously described by investigators at the Sydney Melanoma Unit.9 Preinfusion biopsies were performed as necessary to document disease before treatment. The surgeon identified measurable lesions (index lesions) before infusion, and the size and location of these were recorded on a preinfusion data sheet. In patients with extensive small deposits of tumor, a description of the size and approximate number was sufficient for preinfusion documentation. Preinfusion photographs were used to facilitate documentation of disease burden and index lesion size and location. Deep lesions difficult to assess by surface inspection were measured and documented by using computed tomography or magnetic resonance imaging.
The following technique of ILI was used throughout the study and continues to be performed as described, except where indicated. On the day of infusion, by using the Seldinger technique, 6F multi–side hole angiographic catheters are placed from the contralateral groin. The catheters are positioned in the popliteal or brachial artery and vein of the involved limb, just above the knee or elbow joint. Angiography is performed to document the status of the runoff vessels. The position of the catheter tip within the artery and vein is then marked on the patient’s skin with indelible marker. The patient is given 5000 IU of heparin intravenously as a bolus and then begun on a constant infusion. Ten thousand units of heparin are diluted in 500 mL of normal saline. The constant infusion is administered into the arterial catheter via a pump at a rate of 18 IU/kg/ hour, but the minimum dose infused is 1250 IU/hour. The venous catheter is infused with normal saline at a rate that maintains catheter patency. The patient is then transported to the operating room holding area.
In the operating room, the patient is placed on a warming blanket, a proximal tourniquet is placed on the involved extremity, and temperature probes are placed on the skin and within the muscle of the limb. The limb is wrapped in cotton padding, and a pediatric warming blanket heated to 42°C is wrapped around the limb. Granisetron 1 mg and dexamethasone 20 mg are administered. This dose is effective prophylaxis against chemotherapy-induced nausea.
When the skin temperature of the limb reaches 37°C degrees, 60 mg of papaverine is injected into the arterial catheter, and the tourniquet is inflated to 350 mm Hg. Melphalan and dactinomycin are rapidly infused into the arterial catheter. Through most of the trial, a patient weight–based calculation was used to determine the dosage. This was done because it was logistically easier than calculating the limb volume by using water displacement.11 Melphalan was used at a dose of .6 to .8 mg/kg body weight for the lower extremity and .25 to .4 mg/kg body weight for the upper extremity. Dactinomycin was given at a dose 6 to 10 µg/kg body weight for the lower extremity and 2.5 to 4 µg/kg body weight for the upper extremity. Ranges were chosen to allow for modification of dosing during the trial according to observed toxicity. In practice, we used the middle dose of the range in the great majority of patients who underwent an initial infusion. For patients who underwent ILI of the lower extremity, this was .7 mg/kg body weight of melphalan and 8 µg/kg body weight of dactinomycin. More recently, the trial was modified to be consistent with a proposed national trial of ILI, and volume-based dosage was instituted after protocol amendment. Melphalan was used at a dose of 5 to 10 mg/L limb volume, and dactinomycin was used at a dose of 50 to 100 µg/L limb volume. The most common initial dosage of melphalan currently used is 7.5 mg/L limb volume (maximum, 100 mg), and that of dactinomycin is 75 µg/L limb volume (maximum, 500 µg/ L). Limb volume was calculated by taking circumferential limb measurements from the distal extremity to the proximal extremity at 1.5-cm longitudinal intervals. The last proximal measurement was taken at the inferior aspect of where the blood pressure cuff would rest at the time of ILI. An Excel-based (Microsoft Corp., Redmond, WA) software program provided by Dr. Douglas Tyler, Duke University Medical Center, was used to calculate the cylindrical volume of the limb.
The chemotherapy is administered via a blood warmer set at 40°C and bubble excluder. Once the chemotherapy is administered, the infusion begins by extracting 60 mL from the venous catheter and reinjecting it into the circuit to pass through the blood warmer and back into the limb via the arterial catheter (Fig. 1
). The chemotherapy is circulated through the limb for 20 minutes. During this period, the infusate becomes quite dark (hypoxic), and resistance in the circuit increases. At the completion of the infusion, the limb is infused with crystalloid (approximately .800–1 L), and an equal volume of effluent is extracted from the venous catheter and discarded. The tourniquet is then deflated, the arterial and venous catheters are removed, and protamine is administered. Manual compression is applied to the puncture sites for 20 minutes.
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Patients were hospitalized for approximately 2 to 3 days. Bed rest was maintained the evening of the ILI, and the limb was elevated. Ambulation was resumed the next day. Complete blood count, creatine phosphokinase, and liver function tests were drawn on postoperative days 1 and 2, and the limb was examined in the hospital for at least 2 days. Low-dose subcutaneous heparin was administered after ILI until discharge from the hospital. Limb morbidity was assessed by using the Wieberdink scale—standard criteria used for ILP.12 Additional toxicity was graded by using the National Cancer Institute Common Toxicity Criteria (version 2.0). Morbidity was assessed in the hospital and at 2, 6, and 12 weeks after ILI in the outpatient clinic.
Response assessment was performed 3 months from the day of the last infusion. Patients whose disease progressed or who had less than a CR were considered for a second ILI, as deemed appropriate by the treating surgeon. A CR was defined as the disappearance of all clinical evidence of disease by 3 months from the last ILI. A partial response was defined as a 
50% decrease in the sum of the largest diameters of the index lesions without the appearance of new lesions. A minor response was defined as a 25% to 49% decrease in the sum of the largest diameters of the index lesions. Flattened, pigmented lesions remaining after ILI underwent biopsy to assess for viable tumor cells. Any patient with less than a minor response or a response of <3 months from the last infusion was considered a nonresponder. Patients who had new lesions or who had an increase in the size of their index lesion or other lesions after ILI were considered nonresponders. Patients who did not return for evaluation or who commenced other treatment before final response assessment were considered nonassessable.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Skin and muscle temperatures of the involved limb were 37°C before chemotherapy in most patients treated. The median temperature of the skin in the 32 procedures performed was 38.1°C (range, 33.1°C–40.0°C). The median muscle temperature was 37.9°C (range, 33.2°C–39.9°C). The median volume of infusate circulated through the limb was 1680 mL (range, 400–3300 mL) for the lower extremity (22 patients; 28 procedures). The two patients (four procedures) who underwent upper extremity ILI had a median infusate volume of 1365 mL (range, 150–2820 mL). A summary of the technical details of the procedure is presented in Table 1.
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Of the 24 treated patients, 22 were assessable. One patient with STS required amputation before 3 months after ILI because of pain that was present before the infusion and was, therefore, not assessable for response. One patient with regional melanoma underwent injection therapy before 3 months from ILI.
Eleven patients had a significant clinical response to the treatment. Of these, five patients had a CR, and six patients had a partial response. One patient had a minor response, and 10 patients were nonresponders. The median duration of CR was 12 months (range, 6–32 months). The median duration of partial response was 11 months (range, 6–43 months). Examples of patients with complete and partial responses are provided in Figs. 2 and 3, respectively.
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Morbidity assessment was performed in the hospital and at 2, 6, and 12 weeks after ILI. Table 2 summarizes the median morbidity scores at each interval, as well as the maximum score reported. In general, morbidity was quite mild in the hospital; most patients experienced some mild swelling and erythema. Thirteen patients (54%) reported nausea on the initial morbidity form, which was completed on postoperative day 1 or 2. The highest morbidity scores were noted at 2 weeks after ILI, and most patients experienced some pain or discomfort, swelling, and erythema (Fig. 4). This was resolved in most patients by 6 weeks, and there were very few residual side effects of the ILI by 3 months, with the exception of some increase in edema of the limb and hyperpigmentation of the extremity (Fig. 5). The median morbidity scores after ILI at each time point are listed in Table 2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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ILI was developed at the Sydney Melanoma Unit by Thompson et al.9,16 as a simple alternative to ILP. Percutaneously placed catheters replace open surgical cannulation, and the chemotherapy is recirculated manually so that no pump oxygenator is needed. Operating room time is approximately 1 hour, compared with the 4 or 5 hours needed to perform ILP. Most importantly, Thompson et al. report that ILI has an efficacy similar to that of ILP. They reported significant clinical responses in 135 patients treated with ILI, with 41% complete and 44% partial responses.10 The morbidity of the procedure, in their experience, is low.9,16
We observed a lower response rate in our initial experience with ILI. Several factors may have contributed to this. Patient selection is likely to play a significant role in obtaining more consistent responses to the treatment. We did not have an established regional chemotherapy program in place when the study began, and patients referred from outside hospitals tended to have very advanced disease. Lindner et al. have reported a higher response rate in patients with a lower burden of disease.10 Many or most of our patients had a significant limb tumor volume. In addition, our general policy has been to use less invasive techniques, such as surgical excision, when the lesions are small and few. Regional control with ILI is more likely if patients are treated before their disease is bulky or extensive.
Another factor that may have contributed to the lower response rate observed in our initial experience with ILI when compared with that reported by Thompson et al.9 is the relatively short infusion and tourniquet time we used. We chose a 20-minute infusion because this was what was used by Thompson et al. when we began our study. This undoubtedly contributed to the relatively high median pO2 and pH recorded at the end of the infusion in the study patients (Table 1
). The investigators at the Sydney Melanoma Unit subsequently reported that response rates seemed to be associated with longer tourniquet times and modified the procedure to increase the length of the infusion and the overall tourniquet time.17 In addition, as we gained experience with ILI, we were able to achieve normothermia in the treated limb more consistently. Several of the early patients on our trial had suboptimal limb temperatures at the onset of treatment.
Our results represent the first North American experience with this new technique. We observed significant clinical responses in half of the patients treated. In addition, we confirmed the low morbidity of the procedure. ILI has effectively replaced ILP at our institution and is likely to gain increasing use in the United States and Europe. Because of its ease of administration and low morbidity, ILI will certainly facilitate testing new and promising regional chemotherapy agents individually or in combination.
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ACKNOWLEDGMENTS |
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Received for publication May 10, 2005. Accepted for publication January 20, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  D. Tyler Regional Therapeutic Strategies in Melanoma: Not Just Local Disease Control, but an Opportunity to Develop Novel Therapeutic Strategies with Potential Implications for Systemic Therapy Ann. Surg. Oncol., November 1, 2008; 15(11): 2987 - 2990. [Full Text] [PDF]
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G. M. Beasley, R. P. Petersen, J. Yoo, N. McMahon, T. Aloia, W. Petros, G. Sanders, T.-Y. Cheng, S. K. Pruitt, H. Seigler, et al. Isolated Limb Infusion for In-Transit Malignant Melanoma of the Extremity: A Well-Tolerated but Less Effective Alternative to Hyperthermic Isolated Limb Perfusion Ann. Surg. Oncol., August 1, 2008; 15(8): 2195 - 2205. [Abstract] [Full Text] [PDF]
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