Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma

Extremity sarcomas are a heterogeneous group of malignant tumors with a varied propensity for local recurrence. This review focuses on factors associated with local recurrence and survival, diagnostic workup, management, outcomes, and surveillance. Local recurrence is more common in patients with previous local recurrence, positive margins, high-grade histology, and deep tumors. In the absence of metastases, the mainstay of treatment is limb-sparing surgery, with radiation to improve local control. Modalities such as brachytherapy or proton therapy may be valuable in the setting of previous irradiation. Systemic chemotherapy is typically limited to the treatment of distant disease, although chemotherapy can be delivered locally via limb perfusion or infusion for locally advanced or recurrent disease. Amputation is used if local control cannot be achieved while preserving adequate limb function or as a palliative option for pain, bleeding, or fungating tumors. Prognostic factors associated with poor survival include tumors that recur with high-grade histology, with a large size (> 5 cm), or within a short interval (< 16 months). Reports of 5-year overall survival in patients with locally recurrent sarcomas vary from 36 to 65%. Surveillance includes physical examination, cross-sectional imaging, and chest x-ray. Genetic profiling and intratumoral injections provide novel therapeutic targets. This review contains 1 figure, 4 tables and 40 references. Key words: chemotherapy, hyperthermic isolated limb perfusion, intratumoral injection, isolated limb perfusion, local recurrence, margin status, radiation, soft tissue sarcoma, wide local excision

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Randomized Multicenter Trial of Hyperthermic Isolated Limb Perfusion With Melphalan Alone Compared With Melphalan Plus Tumor Necrosis Factor: American College of Surgeons Oncology Group Trial Z0020

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.5152 ◽

2006 ◽

Vol 24 (25) ◽

pp. 4196-4201 ◽

Cited By ~ 153

Author(s):

Wendy R. Cornett ◽

Linda M. McCall ◽

Rebecca P. Petersen ◽

Merrick I. Ross ◽

Henry A. Briele ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Response Rate ◽

Complete Response Rate ◽

Locally Advanced ◽

Complete Response ◽

Isolated Limb Perfusion ◽

Limb Perfusion ◽

Tnf Α ◽

Necrosis Factor

Purpose To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-α) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. Patients and Methods Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-α during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. Results The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-α arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-α arm, and one disease progression–related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-α arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-α arm (P = .435 and P = .890, respectively). Conclusion In locally advanced extremity melanoma treated with HILP, the addition of TNF-α to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-α plus melphalan was associated with a higher complication rate.

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