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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Isolated limb perfusion for malignant melanoma

, M.D. and , M.D.

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Introduction

Isolated chemotherapeutic perfusion for extremity melanomas has experienced a resurgence of interest, marked by an increased number of reports showing significant therapeutic efficacy. The collective data regarding both synchronous and recurrent metastatic melanoma involving the regional skin and subcutaneous tissues (satellite and intransit metastases) is clear; these patterns of metastases are ideally treated with isolated hyperthermic chemotherapeutic perfusion (Taber and Polk 1997; Brobeil et al. 1998; Krementz et al. 1996). When feasible, perfusion in combination with surgical resection of identifiable disease is the best treatment approach for achieving local disease control and enhanced survival.

The value of perfusion for localized primary extremity melanoma is less well-defined and less widely accepted, but patients with poorer prognosis primary lesions are those most likely to benefit (Koops et al. 1998; Edwards et al. 1990).

Melanoma prognosis and therapy

There has been a rapid increase in the frequency of melanoma worldwide, and a parallel increase in surgical cure rates in North America largely due to earlier diagnosis by dermatologists and primary care providers. Four dominant factors influence outcome most:

1.

Thickness of primary tumor (measured in millimeters).

2.

Anatomic site of origin. (Lesions arising on the arms have a better prognosis than those of the legs, which are in turn better than those of the head and neck, which are more favorable than those of the trunk.)

3.

Ulceration of the primary lesion is unfavorable.

4.

Gender. (Outcome worse in men.)

5.

Years of age. (The prognosis in men is worse after 55 years of age; the prognosis in women is worse after 65 years.)

Optimal treatment of the primary lesion includes wide local excision; ideally, a 1 cm peripheral margin should be obtained for each mm depth of invasion. Most melanomas have a good prognosis and require only a wide excision and are, therefore, cured by a simple outpatient operation. In patients with melanoma > 1 mm thickness, sentinel lymph node biopsy is proven effective as the optimal approach for staging nonpalpable regional lymph nodes and should be done at the time of the wide excision. Therapeutic lymphadenectomy is the most effective treatment for regionally metastatic disease detected by palpation or by sentinel lymph node biopsy.

With regard to adjuvant therapy, at least one prospective randomized trial has documented efficacy for interferon alfa-2b for patients with regional nodal metastasis, but subsequent follow-up data have been limited in confirming the initial perception of therapeutic efficacy. If a group of patients with localized melanoma significantly benefit from adjuvant chemotherapeutic limb perfusion, they are those patients with thicker and/or ulcerated primaries who are at increased risk for local recurrent melanoma and intransit disease. As the thickness of the primary lesion advances past 2.0 mm, the value of more aggressive adjuvant treatment becomes more justified (Koops et al. 1998). The decision to add an adjunctive form of therapy to basic wide local excision always should be a function of ratio of patients who are harmed or helped by the practice. The section below addresses an overall look at death and complications of isolated limb perfusion from published large series; it is essential that the risk remain low, and that the benefit be consistently measurable (see table II, section below).

Perfusion technique

Our technique for isolated chemotherapeutic limb perfusion has been modified only minimally over the past 30 years. We use 42 °C inflow hyperthermia, phenylalanine mustard, and actinomycin D and physiologic flow rates. The most common access sites are axillary and femoral, although subclavian and iliac approaches can be done with similar risk and efficacy. The more proximal approaches are appropriate if the disease is proximal and/or in the presence of nodal disease. The key points for a successful procedure in our experience are:

  • Near normal extremity circulation.
  • Oblique or transversely placed skin incisions.
  • Node sampling en route to vessels.
  • Isolation of approximately 2-inch segments of artery and vein.
  • Transverse arteriotomy and venotomy.
  • 42 °C in-flow hyperthermia.
  • Secure tourniquet isolation.
  • Fluorescein assessment of leakage from the extracorporeal circuit.
  • Physiologic (not excessive) flow rates.
  • One-hour pump run with extremity washout.
  • Simple but meticulous vascular repair.

We use actinomycin-D at a dose of 0.5 g for both extremities; L-PAM doses are 1. mg/kg body weight for upper extremity perfusions and 0.7 mg/kg body weight for lower extremities perfusions. Both drugs are administered as a single bolus in the pump reservoir of the extracorporeal circuit. The patient is systemically heparinized just as the vascular isolation is accomplished. Anticoagulation is countered with protamine after completed vascular repair and palpation of intact distal arterial pulsations.

Patient selection

The applicability of any operation is a function of its safety. Isolated chemotherapeutic limb perfusion with the pump oxygenator and the unique particulars of the surgical technique are intimidating for most surgeons who have the opportunity to perform the procedure only infrequently. The recent report by Taber and Polk (1997) is valuable because it clarifies the safety of the procedure at experienced centers with a reported rate of death of 0.6% and a limb loss rate of 0.8%. Both figures are acceptable rates of cancer treatment morbidity and mortality given the documented impact of the treatment for satellite and intransit metastases (Taber and Polk 1997; Brobeil et al. 1998; Krementz et al. 1996). The use of perfusion in localized melanoma is less well justified. Clearly, patients with thinner lesions do not benefit. Patients with thicker lesions, those with ulcerated lesions, and those with palpable regional nodal metastases are at increased risk for developing intransit disease. Efficacy of perfusion for these patients has been suggested in a retrospectively matched comparison (Edwards et al. 1990). Interestingly, this study compared an internal placebo-treated control group (a group perfused with imidazole carboxamide, an agent later found to require hepatic metabolism to be converted to an active metabolite) and found a survival advantage for patients with lesions > 2 mm thickness who were perfused with L-PAM. The largest multi-institutional prospective randomized trial showed no benefit in terms of distant disease-free and overall survival, but confirmed a favorable impact on local disease control (Koops et al. 1998). By limiting the frequency of complications and toxicities, certain centers should perhaps extend the application of the technique. While most complications are tolerable, combined perfusion and groin dissection has a very high rate of lifelong lymphedema.

Collective studies

The purpose of this monograph is to present published series that answer fundamental surgical questions. Table I summarizes a collection of experiences with therapeutic isolated limb perfusion for documented recurrence confined to an extremity; all seven quoted studies of 877 patients showed enhanced locoregional disease control when L-PAM was the primary perfusate drug. Table II addresses the more controversial use of perfusion chemotherapy as an adjunct to the treatment of primary melanomas; here the relative thickness (especially if ulcerated) of the melanoma is critical to offset the risks noted in the section on patient selection.

Summary

This review dealt only with the use of phenylalanine mustard-based chemotherapy; typically mild hyperthermia is added as a complementary therapy. We specifically avoided the more experimental cytokine-based perfusions, which have been studied only in recent years. We believe the weight of this report and the data herein supports the broader use of this technology, especially at centers with documented low rates of limb loss and death.

References

1.
Taber S W, Polk H C Jr. Mortality, major amputation rates, and leukopenia after isolated limb perfusion with phenylalanine mustard for the treatment of melanoma. Ann Surg Oncol. (1997);4:440–445. [PubMed: 9259973]
2.
Brobeil A, Berman C, Cruse C W. et al. Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma. Ann Surg Oncol. (1998);5:376–383. [PubMed: 9641461]
3.
Krementz E T, Sutherland C M, Muchmore J H. Isolated hyperthermia chemotherapy perfusion for limb melanoma. Surg Clin North Am. (1996);76:1313–1330. [PubMed: 8977553]
4.
Koops H S, Vaglini M, Suciu S. et al. Prophylactic isolated limb perfusion for localized, highrisk limb melanoma: Results of a multicenter randomized phase III trial. J Clin Oncol. (1998);16:2906–2912. [PubMed: 9738557]
5.
Edwards M J, Soong S, Boddie A W. et al. Isolated limb perfusion for localized melanoma of the extremity. Arch Surg. (1990);125:317–321. [PubMed: 2306179]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6939

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