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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.019 on January 12, 2004

Annals of Surgical Oncology 11:173-177 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Hyperthermic Isolated Limb Perfusion With Low-Dose Tumor Necrosis Factor-{alpha} and Melphalan for Bulky In-Transit Melanoma Metastases

Carlo Riccardo Rossi, MD, Mirto Foletto, MD, Simone Mocellin, MD, Pierluigi Pilati, MD and Mario Lise, MD

From the Clinica Chirurgica Generale II, Dipartimento di Scienze Oncologiche e Chirurgiche, Università di Padova, Padova, Italy.

Correspondence: Address correspondence and reprint requests to: Carlo Riccardo Rossi, MD, Clinica Chirurgica Generale II, Dipartimento di Scienze Oncologiche e Chirurgiche, Università di Padova, Via Giustiniani, 2, 35128 Padova, Italy; Fax: 39-049-651891; E-mail: carlor.rossi{at}unipd.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Melphalan (L-PAM) hyperthermic isolated limb perfusion (HILP) is currently considered the standard treatment for patients with in-transit metastases from cutaneous melanoma. We here report on the results of L-PAM and low-dose tumor necrosis factor (TNF){alpha} HILP in patients with bulky disease.

Methods: Twenty patients underwent TNF{alpha} (1 mg) and L-PAM (10 mg/L) HILP. Perfusion was performed for 90 minutes, and systemic leakage was strictly monitored. Locoregional toxicity was evaluated according to Wieberdink’s criteria, whereas tumor response was evaluated with physical examination and ultrasound scan with or without fine-needle aspiration of any suspected recurrence.

Results: In all cases, systemic leakage was <5%. No postoperative deaths occurred, and locoregional toxicity was mild (grade 1 or 2) in 95% of patients. A complete tumor response was obtained in 14 patients (70%), and partial responses were obtained in 5 patients (25%). After a median follow-up of 18 months, six patients are alive and disease free, seven are alive with local or distant recurrence or both, and seven have died of disease.

Conclusions: Low-dose TNF{alpha} HILP can achieve tumor responses comparable with those reported with higher doses of cytokine. Moreover, this drug regimen is associated with acceptable local toxicity, carries a smaller risk of systemic toxicity, and incurs lower costs.

Key Words: Melanoma • Isolated limb perfusion • TNF{alpha} • Melphalan


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In-transit disease occurs in an estimated 2% to 10% of all cutaneous melanoma patients,1 and the lower limb is the main location in approximately 70% of cases.2 Surgical resection is indicated when lesions are small and limited in number, and amputation should be considered only if limb function is severely impaired or if hygienic conditions are poor.

When disease extent is a contraindication to surgical excision, hyperthermic isolated limb perfusion (HILP) should be taken into consideration, because amputation does not provide any advantage in terms of disease-free survival and because the activity of systemic chemotherapy against local disease control is low.3 HILP is a well-established locoregional procedure that can deliver high-dose cytostatics to a limb with multiple in-transit melanoma lesions.4 This technique is quite sophisticated and requires accurate monitoring of systemic leakage and limb temperature to avoid major systemic and local side effects. Since its first clinical application, with a reported complete response (CR) rate of approximately 50%, melphalan (L-PAM) has been used as the referral drug.3,4 Other cytostatics, such as nitrogen mustards, dacarbazine, actinomycin D, and cisplatin, have shown no therapeutic advantage over L-PAM in terms of either response duration or response rates.3,4

Since the early 1990s, recombinant human tumor necrosis factor (TNF){alpha} and L-PAM have been used for HILP, with impressive CR rates of up to 90% in several published series.3,4 However, TNF{alpha} administration has potentially lethal side effects if significant systemic leakage occurs during HILP. Particular care must therefore be taken to monitor drug leakage when HILP is performed.5 Despite the large body of reports on TNF{alpha}-based HILP for the treatment of melanoma metastases,4,6 it is not yet clear whether this regimen improves the tumor response rate, because no definitive data are available on a homogeneous population of melanoma patients. Two prospective randomized clinical trials have been undertaken in the United States and Europe that challenge L-PAM versus L-PAM plus TNF{alpha}. In the US trial, the regimen was also combined with interferon-gamma (IFN{gamma}). The European trial was terminated early because of slow recruitment, and no significant difference in tumor CR rate was found between the two study groups.7 The US study showed that the addition of TNF{alpha} and IFN{gamma} improved tumor response rates, especially in the subset of patients with bulky disease.8 However, because the cytokine was used at the dose of 3 to 4 mg, the optimal TNF{alpha} dose in HILP has not yet been clearly established.

Some investigators9 have suggested that low-dose (.5–1 mg) TNF{alpha} might be as active as higher doses. We performed a phase I and II study with L-PAM and escalating dosages of TNF{alpha} under hyperthermic conditions (40.5°C–41.5°C) and found similar tumor response rates but fewer complications in patients treated with .5 to 1.6 mg of TNF{alpha} than in patients treated with higher dosages.10 We therefore started to routinely treat patients with recurrent or bulky in-transit melanoma metastases with 1 mg of TNF{alpha} plus L-PAM HILP. In this article, we report on and discuss the results of our clinical series.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
After a routine preoperative clinical work-up and staging, patients were considered eligible if they had histologically confirmed bulky disease confined to a limb and no evidence of distant metastasis and if their clinical condition was satisfactory. The disease was considered bulky if there were more than 15 metastatic lesions or when 1 or more tumor nodules had a diameter >3 cm. Patients who had gross recurrence after previous L-PAM–only based HILP were also included in the study. HILP was considered feasible if the tumor had not extended to the root of the affected limb. All patients gave their signed informed consent before undergoing HILP.

Perfusion Technique and Postoperative Care
HILP was performed under general anesthesia according to a well-established technique.11–13 Briefly, the main limb vessels were exposed at the root of the limb, dissected free, and encircled with tourniquets. Major tributaries were dissected to identify potential sites of leakage from the perfusion circuit. Moreover, a tourniquet was secured at the root of the limb. Indwelling temperature probes were inserted throughout the limb and connected to a recorder. To monitor the leakage from the perfusion circuit to the systemic circulation, a gamma counter was connected to a rate meter and strip chart recorder and positioned over the heart. After systemic heparinization (200 UI/kg), the main vessels were cannulated and connected to the perfusion circuit, which was already primed with Ringer’s lactate. Arterial flow rates were set at 40 to 80 mL/min per kilogram of limb weight. Perfusate was oxygenated and heated to 42°C in a water bath (arterial line PO2 was >500 mm Hg). A period of 10 to 20 minutes was required for a muscle temperature of 39°C to 40°C (plateau phase) to be reached. Leakage monitoring was performed according to the technique described by Casara et al.14 by using 99mTc-albumin in the perfusion circuit. If no significant leakage was recorded, 1 mg of TNF was bolus-injected into the circuit. After 30 minutes, L-PAM was bolus-injected, and perfusion was continued for 1 hr. Temperatures were continuously monitored and adjusted to prevent the muscle temperature from increasing to >41.5°C.

At the end of perfusion, the circuit was washed out with .9% saline solution and refilled with Normosol-R solution (Fresenius-Kabi, Isola Della Scala, Italy). Cannulae were then removed, and the breaches on the vessels were repaired. Systemic protamine was given to reverse heparinization.

To minimize the risk of acute renal failure due to myoglobin precipitation, 18% mannitol solution, together with generous intravenous fluid support and urine alkalinization, was given during perfusion and the early postoperative course until myoglobin plasma levels returned to normal. Locoregional toxicity was graded according to the scale of Wieberdink et al. (Table 1),15 and systemic toxicity was classified according to the World Health Organization system.


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  		TABLE 1. Locoregional toxicity evaluation scale for isolated limb perfusion
 
Patient Follow-Up
Follow-up included physical examination at 1, 3, and 6 months after HILP and then every 6 months. Chest x-rays and hepatic and lymph node ultrasound scans were undertaken every 6 months. Total-body computed tomographic scan, brain magnetic resonance imaging, and positron emission tomography scan were used if there was a suspicion of distant metastases.

Tumor Response and Clinical Outcome Evaluation
The evaluation of tumor response was mainly clinical; the number of tumors and their greatest diameter were measured.16 Soft tissue ultrasound scan with or without fine-needle aspiration was used to assess deep nodules suspected at physical examination; if nodules were too numerous, photographs of the affected limb were taken.

Tumor response was evaluated 3 months after HILP and was classified as follows: CR, disappearance of all clinical evidence of active tumor for a minimum of 4 weeks; partial response (PR), decrease of 50% or more in the sum of the product of the diameters of measured lesions for at least 1 month without any simultaneous increase in size or the appearance of any new lesions; no change, decrease in tumor size <50% or increase of tumor size <25%; and progressive disease, increase of >25% in the size of any measured lesion, appearance of a new tumor, or both. The clinical outcome of patients was assessed by analyzing local progression-free and overall survival, which was estimated with the Kaplan-Meier method.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From January 1997 to September 2002, 20 patients (14 women and 6 men; mean age, 63 years; range, 32–80 years) who met the previously reported eligibility criteria underwent lower-limb HILP with 1 mg of TNF{alpha} and 10 mg/L of L-PAM. Five patients were also treated with inguinoiliac lymphadenectomy for synchronous lymph node metastases. Eight (40%) of the 20 patients had already undergone L-PAM HILP and were then submitted to low-dose TNF{alpha}-based redo HILP for recurrence; the median interval between the 2 procedures was 12 months (range, 6–48 months).

Regarding HILP parameters, mean systemic leakage was .9% (range, 0%–3.9%); mean muscle and tumor temperature was 41.2°C (range, 41°C–41.5°C) and 41.4°C (range, 41.1°C–41.7°C), respectively. Patients who had disease recurrence or progression underwent surgical excision of nodules (n = 2), radiotherapy (n = 3), or systemic bio/chemotherapy (n = 13).

Postoperative Morbidity
There were no postoperative deaths, nor were there cases of significant systemic toxicity. During the early postoperative course, all patients had augmented plasmatic myoglobin levels, but none developed acute postoperative renal failure. The mean time to normal myoglobin values was 3 days (range, 2–8 days).

No compartmental syndromes were reported. One patient had acute limb ischemia from damage of the intima during cannulation; this required early reoperation and a femorofemoral polytetrafluoroethylene graft repair. Thirteen (65%) patients had grade 1 locoregional toxicity, 6 (30%) had grade 2, and 1 (5%) had grade 3. No patient required amputation because of toxicity.

Tumor Response and Clinical Outcome
Complete and partial tumor responses were observed in 14 (70%) and 5 (25%) cases. The overall response (CR plus PR) rate was therefore 95%. The remaining patient showed a tumor response of <50% (no change).

Overall and local progression–free survival curves are shown in Fig. 1. After a median follow-up of 18 months (range, 10–63 months), six (30%) patients are alive and disease free, four (20%) are alive with local disease recurrence, three (15%) are alive with local disease and distant metastases, and seven have died of distant metastases after developing locoregional recurrence (Table 2). To date, among patients who had a CR (n = 14), eight (57%) have developed local recurrence, and four of the five patients who had a PR have local disease progression. The median time to local progression was 10 months (range, 6–63 months); considering patients with CR, the median local disease–free time was 16 months (range, 8–23 months).



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  		FIG. 1. Overall survival (OS) and local progression–free survival (LPFS) analysis of 20 patients who underwent hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-{alpha} and melphalan for bulky in-transit melanoma metastases.

 

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  		TABLE 2. Tumor characteristics and clinical outcome in 20 patients who underwent hyperthermic isolated limb perfusion with low-dose TNF{alpha} and L-PAM for recurrent/bulky in-transit melanoma metastases
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The introduction of TNF{alpha} in HILP is considered an important breakthrough in the locoregional treatment of limb-confined solid tumors, and this cytokine has been approved by the European Drug Agency for the treatment of limb-threatening soft tissue sarcomas. Among the many uncontrolled trials in patients with melanoma that have been published, some report controversial results, mainly because of poor patient selection.4 Fraker et al.8 recently published the results of a randomized phase III study on 103 patients that showed an advantage in the arm treated with the association of L-PAM plus TNF{alpha} and IFN{gamma} in terms of CR rate, whereas no significant improvement was observed in the overall response rate, the local recurrence rate, or overall survival. A tendency toward better responses in patients with bulky disease has also been observed, although not all the patients enrolled in this study had bulky disease. In this trial, as in most of the published series, TNF{alpha} was used at full dosage (4 and 3 mg for upper and lower limb, respectively) in combination with subcutaneous IFN{gamma}.

In our series, the patient population was carefully selected in terms of tumor burden. Thus, we could analyze the activity of low-dose TNF{alpha} HILP in a quite homogeneous group of patients. The 70% CR rate reported by us is similar to that reported by Fraker et al., although we used much lower TNF{alpha} doses and hyperthermia. Furthermore, the median time to progression (10 months) in our series, which included only patients with bulky tumor, is comparable to that reported by other investigators who enrolled patients regardless of tumor burden.8,16 Finally, locoregional toxicity was quite limited: no patient required amputation or had permanent toxicity, and most patients (95%) had mild (grade 1 or 2) locoregional toxicity. The high activity of this novel therapeutic regimen may depend on some pharmacological and biological factors. The high response rate observed in this series might be related to the fact that 1 mg of TNF{alpha} is sufficient to reach in vivo the saturation of TNF{alpha} receptors, a phenomenon already described in vitro.17 Furthermore, on performing a pharmacokinetic study with low-dose TNF{alpha} HILP for advanced limb sarcomas (unpublished data), we reported TNF{alpha} perfusate concentrations 20-fold greater than those considered cytotoxic in vitro.18 These levels remained steady during HILP, supporting the hypothesis that 1 mg of cytokine is enough to saturate the entire uptake capacity of the limb. However, it is well known that heat, cytostatics, and TNF{alpha} act synergistically and that TNF{alpha} itself increases L-PAM penetration into tumor.3,19–21 Finally, because tumor vasculature is the main target of TNF{alpha}, bulky tumors may be more sensitive to drug regimens containing this cytokine because of their high density of neovascularization.

Although TNF{alpha} seems to play a key role in the management of patients with in-transit melanoma metastases, two major drawbacks must be kept in mind: high costs and potentially lethal systemic toxicity. Regarding costs, TNF{alpha} is available on the market at a price of

2300/mg, with a cost of approximately

6900 and

9200 at full dosage (3–4 mg). Thus, our HILP drug regimen (1 mg of TNF{alpha}) contributes to cutting costs.

Regarding systemic toxicity, the mainstay is accurate leakage control and monitoring. Of course, the lower the TNF{alpha} dose, the lower the risk of severe toxicity.

Overall, these considerations support the use of TNF{alpha} at lower doses than those commonly used. However, a larger comparative study is warranted to confirm the good results we obtained in this subset of patients affected with locally advanced melanoma.


   FOOTNOTES
 
Low-dose tumor necrosis factor (TNF){alpha}-based isolated limb perfusion seems to be active in patients affected with bulky in-transit metastases from cutaneous melanoma. The tumor response rate and the local progression–free interval are comparable with those observed with higher TNF{alpha} doses.

Received for publication March 6, 2003. Accepted for publication September 9, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  6. Kroon BB, Noorda EM, Vrouenraets BC, Nieweg OE. Isolated limb perfusion for melanoma. J Surg Oncol 2002; 79: 252–5.[Medline]
  7. Steinmann G. An open, randomized prospective trial to compare the efficacy and safety of TNFalpha 1a and melphalan with melphalan alone via isolated limb perfusion for metastatic melanoma of the limb. In: Christine Clark, ed. Beromun, Second Expert Meeting. Barcelona, 2001:16–18.
  8. Fraker D, Alexander H, Ross M, et al. A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF) plus interferon gamma (IFN). Ann Surg Oncol 2002; 9: S8.
  9. Hill S, Fawcett WJ, Sheldon J, Soni N, Williams T, Thomas JM. Low-dose tumour necrosis factor alpha and melphalan in hyperthermic isolated limb perfusion. Br J Surg 1993; 80: 995–7.[Medline]
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  12. McBride CM. Sarcomas of the limbs. Results of adjuvant chemotherapy using isolation perfusion. Arch Surg 1974; 109: 304–8.[Medline]
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  15. Wieberdink J, Benckhuysen C, Braat RP, van Slooten EA, Olthuis GA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982; 18: 905–10.[CrossRef][Medline]
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  17. Rosenblum MG, Donato NJ, Gutterman JU. Characterization of human recombinant tumor necrosis factor-alpha antiproliferative effects on human cells in culture. Lymphokine Res 1988; 7: 107–17.[Medline]
  18. Buell JF, Reed E, Lee KB, et al. Synergistic effect and possible mechanisms of tumor necrosis factor and cisplatin cytotoxicity under moderate hyperthermia against gastric cancer cells. Ann Surg Oncol 1997; 4: 141–8.[Abstract]
  19. de Wilt JH, ten Hagen TL, de Boeck G, van Tiel ST, de Bruijn EA, Eggermont AM. Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 2000; 82: 1000–3.[CrossRef][Medline]
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  21. van der Veen AH, de Wilt JH, Eggermont AM, van Tiel ST, Seynhaeve AL, ten Hagen TL. TNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects. Br J Cancer 2000; 82: 973–80.[CrossRef][Medline]



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