Top

Annals of Surgical Oncology

Published in:

01-01-2007

Isolated Limb Perfusion With Melphalan and Tumor Necrosis Factor α for Advanced Melanoma and Soft-Tissue Sarcoma

Authors: Andrew J. Hayes, MD, PhD, Susan J. Neuhaus, MD, PhD, Matthew A. Clark, MD, J. Meirion Thomas, MD

Published in: Annals of Surgical Oncology | Issue 1/2007

Abstract

Background

Isolated limb perfusion (ILP) with melphalan is used in the treatment of advanced in-transit melanoma but has no real efficacy for irresectable soft tissue sarcomas arising in the extremities. The addition of tumor necrosis factor (TNF)-α may increase response rates for bulky melanoma and for sarcoma, but the potential for major systemic toxicity has limited its use.

Methods

Between October 2000 and April 2004, 49 ILPs were performed with melphalan and TNF-α. All procedures were performed with continuous leakage monitoring and regional hyperthermia.

Results

Forty-nine ILPs were performed for melanoma (n = 30), sarcoma (n = 16), or other tumors (n = 3). The most common indications were widespread in-transit disease for melanoma (n = 29) and irresectable primary disease for sarcoma (n = 9). Complete and partial responses for melanoma were 40% and 37%, and for sarcoma they were 20% and 33%. At a median follow-up of 14 months, 66% of melanoma patients who responded had not experienced local progression, compared with only 37% of sarcoma patients. Progression-free survival was significantly less for patients with sarcoma than melanoma (P = .0476). Four of 16 patients with sarcoma subsequently required amputation for progressive disease.

Conclusions

ILP with melphalan and TNF-α is a valuable treatment for advanced in-transit melanoma. Significant response rates were also seen in irresectable sarcoma, although the duration of response was limited.

Creech O Jr, Krementz E. Techniques of regional perfusion. Surgery 1966; 60:938–47PubMed

Aigner K, Hild P, Henneking K, Paul E, Hundeiker M. Regional perfusion with cis-platinum and dacarbazine. Recent Results Cancer Res 1983; 86:239–45PubMed

Vaglini M, Belli F, Marolda R, Prada A, Santinami M, Cascinelli N. Hyperthermic antiblastic perfusion with DTIC in stage IIIA-IIIAB melanoma of the extremities. Eur J Surg Oncol 1987; 13:127–9PubMed

Schraffordt-Koops H, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 1998; 16:2906–12

Bulman AS, Jamieson CW. Isolated limb perfusion with melphalan in the treatment of malignant melanoma. Br J Surg 1980; 67:660–2PubMedCrossRef

Klaase JM, Kroon BB, van Geel AN, Eggermont AM, Franklin HR, Hart AA. Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan. Surgery 1994; 115:39–45PubMed

Di Filippo F, Buttini GL, Calabro AM, et al. Thermochemotherapy for soft tissue sarcoma. Cancer Treat Res 1989; 44:111–27PubMed

Lejeune FJ, Deloof T, Ewalenko P, et al. Objective regression of unexcised melanoma in-transit metastases after hyperthermic isolation perfusion of the limbs with melphalan. Recent Results Cancer Res 1983; 86:268–76PubMed

Rossi CR, Foletto M, Pilati P, Mocellin S, Lise M. Isolated limb perfusion in locally advanced cutaneous melanoma. Semin Oncol 2002; 29:400–9PubMedCrossRef

10.

Grunhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg 2004; 240:939–47PubMedCrossRef

11.

Renard N, Lienard D, Lespagnard L, Eggermont A, Heimann R, Lejeune F. Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNF alpha). Int J Cancer 1994; 57:656–63PubMedCrossRef

12.

Nooijen PT, Eggermont AM, Schalkwijk L, Henzen-Logmans S, de Waal RM, Ruiter DJ. Complete response of melanoma-in-transit metastasis after isolated limb perfusion with tumor necrosis factor alpha and melphalan without massive tumor necrosis: a clinical and histopathological study of the delayed-type reaction pattern. Cancer Res 1998; 58:4880–7PubMed

13.

Hayes AJ, Clark MA, Harries M, Thomas JM. Management of in-transit metastases from cutaneous malignant melanoma. Br J Surg 2004; 91:673–82PubMedCrossRef

14.

Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992; 10:52–60PubMed

15.

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; 80:995–7PubMedCrossRef

16.

Vaglini M, Belli F, Ammatuna M, et al. Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan. Cancer 1994; 73:483–92PubMedCrossRef

17.

Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 1996; 14:479–89PubMed

18.

Lienard D, Eggermont AM, Schraffordt-Koops H, et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 1999; 9:491–502PubMedCrossRef

19.

Lejeune FJ, Lienard D, Leyvraz S, Mirimanoff RO. Regional therapy of melanoma. Eur J Cancer 1993; 29A:606–12PubMedCrossRef

20.

Cornett WR, Fraker DL, Ross MJ, et al. A prospective randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone versus melphalan with tumour necrosis factor. Ann Surg Oncol 2005; 12(Suppl 18): 32

21.

Krementz ET, Carter RD, Sutherland CM, Hutton I. Chemotherapy of sarcomas of the limbs by regional perfusion. Ann Surg 1977; 185:555–64PubMedCrossRef

22.

Pommier RF, Moseley HS, Cohen J, Huang CS, Townsend R, Fletcher WS. Pharmacokinetics, toxicity, and short-term results of cisplatin hyperthermic isolated limb perfusion for soft-tissue sarcoma and melanoma of the extremities. Am J Surg 1988; 155:667–71PubMedCrossRef

23.

Klaase JM, Kroon BB, Benckhuijsen C, van Geel AN, Albus-Lutter CE, Wieberdink J. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer 1989; 64:616–21PubMedCrossRef

24.

Rossi CR, Vecchiato A, Foletto M, et al. Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas. Cancer 1994; 73:2140–6PubMedCrossRef

25.

Eggermont AM, Schraffordt Koops H, Klausner JM, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 1996; 224:756–64PubMedCrossRef

26.

Eggermont AM, Schraffordt Koops H, Lienard D, et al. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 1996; 14:2653–65PubMed

27.

Santinami M, Deraco M, Azzarelli A, et al. Treatment of recurrent sarcoma of the extremities by isolated limb perfusion using tumor necrosis factor alpha and melphalan. Tumori 1996; 82:579–84PubMed

28.

Gutman M, Inbar M, Lev-Shlush D, et al. High dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation. Cancer 1997; 79:1129–37PubMedCrossRef

29.

Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BB. Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities. Cancer 2003; 98:1483–90PubMedCrossRef

30.

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; 18:905–10PubMedCrossRef

31.

Krementz ET, Carter RD, Sutherland CM, Muchmore JH, Ryan RF, Creech O Jr. Regional chemotherapy for melanoma A 35-year experience. Ann Surg 1994; 220:520–34PubMedCrossRef

32.

Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975; 72:3666–70PubMedCrossRef

33.

Eggermont AM, de Wilt JH, ten Hagen TL. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol 2003; 4:429–37PubMedCrossRef

34.

Rossi CR, Foletto M, Di Filippo F, et al. Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion. Cancer 1999; 86:1742–9PubMedCrossRef

35.

Rossi CR, Foletto M, Mocellin S, Pilati P, Lise M. Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases. Ann Surg Oncol 2004; 11:173–7PubMedCrossRef

36.

Gibson SC, Byrne DS, McKay AJ. Ten-year experience of carbon dioxide laser ablation as treatment for cutaneous recurrence of malignant melanoma. Br J Surg 2004; 91:893–5PubMedCrossRef

37.

Pitcher ME, Ramanathan RC, Fish S, A’Hern R, Thomas JM. Outcome of treatment for limb and limb girdle sarcomas at the Royal Marsden Hospital. Eur J Surg Oncol 2000; 26:548–51PubMedCrossRef

38.

Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635–48PubMed

Title: Isolated Limb Perfusion With Melphalan and Tumor Necrosis Factor α for Advanced Melanoma and Soft-Tissue Sarcoma
Authors: Andrew J. Hayes, MD, PhD
Susan J. Neuhaus, MD, PhD
Matthew A. Clark, MD
J. Meirion Thomas, MD
Publication date: 01-01-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 1/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-006-9040-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Isolated Limb Perfusion With Melphalan and Tumor Necrosis Factor α for Advanced Melanoma and Soft-Tissue Sarcoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2007

Radiation-Induced Cellular DNA Damage Repair Response Enhances Viral Gene Therapy Efficacy in the Treatment of Malignant Pleural Mesothelioma

Treatment of Advanced Gastrointestinal Stromal Tumor: a Marriage of Targeted Therapy and Surgery?

Abdominal Sacral Resection for Posterior Pelvic Recurrence of Rectal Carcinoma: Analyses of Prognostic Factors and Recurrence Patterns

Positron Emission Tomography (PET) and Mammography (PEM) for Breast Cancer: Importance to Surgeons

Risk Factors for Non-Sentinel Lymph Node Metastases in Patients with Breast Cancer. The Outcome of a Multi-institutional Study

Predictors for Patterns of Failure after Pancreaticoduodenectomy in Ampullary Cancer