Annals of Surgical Oncology

, Volume 12, Issue 6, pp 473–479 | Cite as

Isolated Limb Perfusion With Tumor Necrosis Factor and Melphalan Prevents Amputation in Patients With Multiple Sarcomas in Arm or Leg

  • Dirk J. Grünhagen
  • Flavia Brunstein
  • Wilfried J. Graveland
  • Albertus N. van Geel
  • Johannes H. W. de Wilt
  • Alexander M. M. Eggermont
Article

Abstract

Background

Treatment for extremity soft tissue sarcoma (STS) has shifted in recent years from amputation to local wide excision combined with irradiation. For multiple sarcomas, this limb-sparing approach is often not possible. To avoid amputations, isolated limb perfusion (ILP) with tumor necrosis factor and melphalan is an attractive treatment option for patients with multiple extremity sarcomas.

Methods

We investigated a prospective database at a tertiary referral institute. From July 1991 to July 2003, out of 217 ILPs, 64 ILPs were performed for either multifocal primary sarcomas or multiple sarcoma recurrences in 53 patients. All ILPs were performed under mild hyperthermic conditions by using 1 to 4 mg of tumor necrosis factor and 10 to 13 mg/L of limb volume for leg and arm perfusions, respectively.

Results

The overall response was 88%, with 42% complete response, 45% partial response, 11% no change, and 2% progressive disease. This response rate is significantly better than our experience in 153 locally advanced single-STS cases (88% vs. 69%). The toxicity of the procedure was mild to moderate in almost all cases; no treatment-related amputation had to be performed. The time to local recurrence was 29 months and differed significantly between multiple primary and multiple recurrent STS. The 5-year survival rate was 39%. Limb salvage was achieved in 45 (82%) of 55 treated limbs.

Conclusions

In a group of patients who are uniformly candidates for amputation, ILP can achieve limb salvage in approximately four out of five patients. Because this treatment option provides excellent local control, it should be considered before an amputation is planned.

Keywords

Isolated limb perfusion Soft tissue sarcoma Extremity TNF 

References

  1. 1.
    Landis, SH, Murray, T, Bolden, S, Wingo, PA 1999Cancer statistics, 1999CA Cancer J Clin49831PubMedGoogle Scholar
  2. 2.
    Eggermont, AM, Schraffordt Koops, H, Lienard, D,  et al. 1996Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trialJ Clin Oncol14265365PubMedGoogle Scholar
  3. 3.
    Eggermont, AM, Schraffordt Koops, H, Klausner, JM,  et al. 1996Isolated 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 experienceAnn Surg22475664; discussion 764–5CrossRefPubMedGoogle Scholar
  4. 4.
    Gutman, M, Inbar, M, Lev-Shlush, D,  et al. 1997High 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 preservationCancer79112937PubMedGoogle Scholar
  5. 5.
    Rossi, CR, Foletto, M, Di Filippo, F,  et al. 1999Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusionCancer8617429CrossRefPubMedGoogle Scholar
  6. 6.
    Lejeune, FJ, Pujol, N, Lienard, D,  et al. 2000Limb salvage by neoadjuvant isolated perfusion with TNF alpha and melphalan for non-resectable soft tissue sarcoma of the extremitiesEur J Surg Oncol2666978PubMedGoogle Scholar
  7. 7.
    Hohenberger, P, Kettelhack, C, Hermann, A, Schlag, PM 2001Functional outcome after preoperative isolated limb perfusion with rhTNF alpha/melphalan for high-grade extremity sarcomaEur J Cancer37S345CrossRefGoogle Scholar
  8. 8.
    Noorda, EM, Vrouenraets, BC, Nieweg, OE,  et al. 2003Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremitiesCancer98148390CrossRefPubMedGoogle Scholar
  9. 9.
    Eggermont, AM, de Wilt, JH, ten Hagen, TL 2003Current uses of isolated limb perfusion in the clinic and a model system for new strategiesLancet Oncol442937CrossRefPubMedGoogle Scholar
  10. 10.
    Ruka, W, Emrich, LJ, Driscoll, DL, Karakousis, CP 1989Clinical factors and treatment parameters affecting prognosis in adult high-grade soft tissue sarcomas: a retrospective review of 267 casesEur J Surg Oncol1541123PubMedGoogle Scholar
  11. 11.
    Blair, SL, Lewis, JJ, Leung, D,  et al. 1998Multifocal extremity sarcoma: an uncommon and controversial entityAnn Surg Oncol53740PubMedGoogle Scholar
  12. 12.
    Potter, DA, Kinsella, T, Glatstein, E,  et al. 1986High-grade soft tissue sarcomas of the extremitiesCancer58190205PubMedGoogle Scholar
  13. 13.
    Williard, WC, Hajdu, SI, Casper, ES, Brennan, MF 1992Comparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremityAnn Surg21526975PubMedCrossRefGoogle Scholar
  14. 14.
    Pisters, PW, Leung, DH, Woodruff, J,  et al. 1996Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremitiesJ Clin Oncol14167989PubMedGoogle Scholar
  15. 15.
    Trojani, M, Contesso, G, Coindre, JM,  et al. 1984Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading systemInt J Cancer333742PubMedGoogle Scholar
  16. 16.
    Rijswijk, CS, Geirnaerdt, MJ, Hogendoorn, PC,  et al. 2003Dynamic contrast-enhanced MR imaging in monitoring response to isolated limb perfusion in high-grade soft tissue sarcoma: initial resultsEur Radiol13184958CrossRefPubMedGoogle Scholar
  17. 17.
    Vanel, D, Bonvalot, S, Guinebretiere, JM,  et al. 2004MR imaging in the evaluation of isolated limb perfusion: a prospective study of 18 casesSkeletal Radiol331506CrossRefPubMedGoogle Scholar
  18. 18.
    Wieberdink, J, Benckhuysen, C, Braat, RP,  et al. 1982Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactionsEur J Cancer Clin Oncol1890510PubMedGoogle Scholar
  19. 19.
    Krementz, ET, Carter, RD, Sutherland, CM, Hutton, I 1977Chemotherapy of sarcomas of the limbs by regional perfusionAnn Surg18555564PubMedGoogle Scholar
  20. 20.
    Hoekstra, HJ, Schraffordt Koops, H, Molenaar, WM, Oldhoff, J 1987Results of isolated regional perfusion in the treatment of malignant soft tissue tumors of the extremitiesCancer6017037PubMedGoogle Scholar
  21. 21.
    Klaase, JM, Kroon, BB, Benckhuijsen, C,  et al. 1989Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremitiesCancer6461621PubMedGoogle Scholar
  22. 22.
    Feig, BW, Ross, MI, Hunt, KK 2004A prospective evaluation of isolated limb perfusion with doxorubicin in patients with unresectable extremity sarcomas (abstract 98)Ann Surg Oncol11S80Google Scholar
  23. 23.
    Lev-Chelouche, D, Abu-Abeid, S, Kollander, Y,  et al. 1999Multifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalanJ Surg Oncol701859CrossRefPubMedGoogle Scholar
  24. 24.
    Grünhagen, DJ, Brunstein, F, Graveland, WJ,  et al. 2004One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastasesAnn Surg24093947discussion 947–8CrossRefPubMedGoogle Scholar
  25. 25.
    Lev-Chelouche, D, Abu-Abeid, S, Merimsky, O,  et al. 1999Isolated limb perfusion with high-dose tumor necrosis factor alpha and melphalan for Kaposi sarcomaArch Surg13417780CrossRefPubMedGoogle Scholar
  26. 26.
    Lans, TE, de Wilt, JH, van Geel, AN, Eggermont, AM 2002Isolated limb perfusion with tumor necrosis factor and melphalan for nonresectable Stewart-Treves lymphangiosarcomaAnn Surg Oncol910049CrossRefPubMedGoogle Scholar
  27. 27.
    Lewis, JJ, Boland, PJ, Leung, DH,  et al. 1999The enigma of desmoid tumorsAnn Surg22986672discussion 872–3CrossRefPubMedGoogle Scholar
  28. 28.
    Weitz, J, Antonescu, CR, Brennan, MF 2003Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over timeJ Clin Oncol21271925CrossRefPubMedGoogle Scholar
  29. 29.
    Lans TA, Grünhagen DJ, de Wilt JHW, et al. Isolated limb perfusions with TNF and melphalan for locally recurrent soft tissue sarcoma in previously irradiated limbs. Ann Surg Oncol 2005;12: in press.Google Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2005

Authors and Affiliations

  • Dirk J. Grünhagen
    • 1
  • Flavia Brunstein
    • 1
  • Wilfried J. Graveland
    • 2
  • Albertus N. van Geel
    • 1
  • Johannes H. W. de Wilt
    • 1
  • Alexander M. M. Eggermont
    • 1
  1. 1.Department of Surgical OncologyErasmus MC-Daniel den Hoed Cancer CenterRotterdamThe Netherlands
  2. 2.Department of StatisticsErasmus MC-Daniel den Hoed Cancer CenterThe Netherlands

Personalised recommendations