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. 1996 Dec;224(6):756–765. doi: 10.1097/00000658-199612000-00011

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.

A M Eggermont 1, H Schraffordt Koops 1, J M Klausner 1, B B Kroon 1, P M Schlag 1, D Liénard 1, A N van Geel 1, H J Hoekstra 1, I Meller 1, O E Nieweg 1, C Kettelhack 1, G Ben-Ari 1, J C Pector 1, F J Lejeune 1
PMCID: PMC1235474  PMID: 8968230

Abstract

OBJECTIVE: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. SUMMARY BACKGROUND DATA: To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. METHODS: In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. RESULTS: A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. CONCLUSIONS: In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

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Selected References

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  1. Benckhuijsen C., Kroon B. B., van Geel A. N., Wieberdink J. Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol. 1988 Apr;14(2):157–163. [PubMed] [Google Scholar]
  2. Blick M., Sherwin S. A., Rosenblum M., Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 1987 Jun 1;47(11):2986–2989. [PubMed] [Google Scholar]
  3. Boring C. C., Squires T. S., Tong T., Montgomery S. Cancer statistics, 1994. CA Cancer J Clin. 1994 Jan-Feb;44(1):7–26. doi: 10.3322/canjclin.44.1.7. [DOI] [PubMed] [Google Scholar]
  4. Braat R. P., Wieberdink J., van Slooten E., Olthuis G. Regional perfusion with adriamycin in soft tissue sarcomas. Recent Results Cancer Res. 1983;86:260–263. doi: 10.1007/978-3-642-82025-0_43. [DOI] [PubMed] [Google Scholar]
  5. CREECH O., Jr, KREMENTZ E. T., RYAN R. F., WINBLAD J. N. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg. 1958 Oct;148(4):616–632. doi: 10.1097/00000658-195810000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Di Filippo F., Calabrò A. M., Cavallari A., Carlini S., Buttini G. L., Moscarelli F., Cavaliere F., Piarulli L., Cavaliere R. The role of hyperthermic perfusion as a first step in the treatment of soft tissue sarcoma of the extremities. World J Surg. 1988 Jun;12(3):332–339. doi: 10.1007/BF01655666. [DOI] [PubMed] [Google Scholar]
  8. Eggermont A. M., Schraffordt Koops H., Liénard D., Kroon B. B., van Geel A. N., Hoekstra H. J., Lejeune F. J. 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 Oct;14(10):2653–2665. doi: 10.1200/JCO.1996.14.10.2653. [DOI] [PubMed] [Google Scholar]
  9. Eilber F. R., Mirra J. J., Grant T. T., Weisenburger T., Morton D. L. Is amputation necessary for sarcomas? A seven-year experience with limb salvage. Ann Surg. 1980;192(4):431–438. doi: 10.1097/00000658-198010000-00001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eilber F. R., Morton D. L., Eckardt J., Grant T., Weisenburger T. Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy. Cancer. 1984 Jun 15;53(12):2579–2584. doi: 10.1002/1097-0142(19840615)53:12<2579::aid-cncr2820531202>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  11. Feinberg B., Kurzrock R., Talpaz M., Blick M., Saks S., Gutterman J. U. A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol. 1988 Aug;6(8):1328–1334. doi: 10.1200/JCO.1988.6.8.1328. [DOI] [PubMed] [Google Scholar]
  12. Fraker D. L., Alexander H. R., Thom A. K. Use of tumor necrosis factor in isolated hepatic perfusion. Circ Shock. 1994 Sep;44(1):45–50. [PubMed] [Google Scholar]
  13. Gaynor J. J., Tan C. C., Casper E. S., Collin C. F., Friedrich C., Shiu M., Hajdu S. I., Brennan M. F. Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol. 1992 Aug;10(8):1317–1329. doi: 10.1200/JCO.1992.10.8.1317. [DOI] [PubMed] [Google Scholar]
  14. Gustafson P., Röser B., Rydholm A. Is local recurrence of minor importance for metastases in soft tissue sarcoma? Cancer. 1991 Apr 15;67(8):2083–2086. doi: 10.1002/1097-0142(19910415)67:8<2083::aid-cncr2820670813>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  15. Hill S., Fawcett W. J., Sheldon J., Soni N., Williams T., Thomas J. M. Low-dose tumour necrosis factor alpha and melphalan in hyperthermic isolated limb perfusion. Br J Surg. 1993 Aug;80(8):995–997. doi: 10.1002/bjs.1800800820. [DOI] [PubMed] [Google Scholar]
  16. Hoekstra H. J., Schraffordt Koops H., Molenaar W. M., Oldhoff J. Results of isolated regional perfusion in the treatment of malignant soft tissue tumors of the extremities. Cancer. 1987 Oct 15;60(8):1703–1707. doi: 10.1002/1097-0142(19871015)60:8<1703::aid-cncr2820600802>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  17. Klaase J. M., Kroon B. B., Benckhuijsen C., van Geel A. N., Albus-Lutter C. E., Wieberdink J. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer. 1989 Aug 1;64(3):616–621. doi: 10.1002/1097-0142(19890801)64:3<616::aid-cncr2820640309>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  18. Klaase J. M., Kroon B. B., van Geel A. N., Eggermont A. M., Franklin H. R. Systemic leakage during isolated limb perfusion for melanoma. Br J Surg. 1993 Sep;80(9):1124–1126. doi: 10.1002/bjs.1800800918. [DOI] [PubMed] [Google Scholar]
  19. Krementz E. T., Carter R. D., Sutherland C. M., Hutton I. Chemotherapy of sarcomas of the limbs by regional perfusion. Ann Surg. 1977 May;185(5):555–564. doi: 10.1097/00000658-197705000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lehti P. M., Moseley H. S., Janoff K., Stevens K., Fletcher W. S. Improved survival for soft tissue sarcoma of the extremities by regional hyperthermic perfusion, local excision and radiation therapy. Surg Gynecol Obstet. 1986 Feb;162(2):149–152. [PubMed] [Google Scholar]
  21. Lejeune F., Liénard D., Eggermont A., Schraffordt Koops H., Kroon B., Gérain J., Rosenkaimer F., Schmitz P. Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of advanced melanoma. Circ Shock. 1994 Aug;43(4):191–197. [PubMed] [Google Scholar]
  22. Lienard D., Ewalenko P., Delmotte J. J., Renard N., Lejeune F. J. 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 Jan;10(1):52–60. doi: 10.1200/JCO.1992.10.1.52. [DOI] [PubMed] [Google Scholar]
  23. Manusama E. R., Nooijen P. T., Stavast J., Durante N. M., Marquet R. L., Eggermont A. M. Synergistic antitumour effect of recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat. Br J Surg. 1996 Apr;83(4):551–555. doi: 10.1002/bjs.1800830438. [DOI] [PubMed] [Google Scholar]
  24. Manusama E. R., Stavast J., Durante N. M., Marquet R. L., Eggermont A. M. Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach. Eur J Surg Oncol. 1996 Apr;22(2):152–157. doi: 10.1016/s0748-7983(96)90671-x. [DOI] [PubMed] [Google Scholar]
  25. McBride C. M. Sarcomas of the limbs. Results of adjuvant chemotherapy using isolation perfusion. Arch Surg. 1974 Aug;109(2):304–308. doi: 10.1001/archsurg.1974.01360020164032. [DOI] [PubMed] [Google Scholar]
  26. Nawroth P., Handley D., Matsueda G., De Waal R., Gerlach H., Blohm D., Stern D. Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas. J Exp Med. 1988 Aug 1;168(2):637–647. doi: 10.1084/jem.168.2.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nieweg O. E., Pruim J., Hoekstra H. J., Paans A. M., Vaalburg W., Oldhoff J., Schraffordt Koops H. Positron emission tomography with fluorine-18-fluorodeoxyglucose for the evaluation of therapeutic isolated regional limb perfusion in a patient with soft-tissue sarcoma. J Nucl Med. 1994 Jan;35(1):90–92. [PubMed] [Google Scholar]
  28. Nooijen P. T., Eggermont A. M., Verbeek M. M., Schalkwijk L., Buurman W. A., de Waal R. M., Ruiter D. J. Transient induction of E-selectin expression following TNF alpha-based isolated limb perfusion in melanoma and sarcoma patients is not tumor specific. J Immunother Emphasis Tumor Immunol. 1996 Jan;19(1):33–44. doi: 10.1097/00002371-199601000-00004. [DOI] [PubMed] [Google Scholar]
  29. Pogrebniak H. W., Witt C. J., Terrill R., Kranda K., Travis W. D., Rosenberg S. A., Pass H. I. Isolated lung perfusion with tumor necrosis factor: a swine model in preparation of human trials. Ann Thorac Surg. 1994 Jun;57(6):1477–1483. doi: 10.1016/0003-4975(94)90104-x. [DOI] [PubMed] [Google Scholar]
  30. Potter D. A., Kinsella T., Glatstein E., Wesley R., White D. E., Seipp C. A., Chang A. E., Lack E. E., Costa J., Rosenberg S. A. High-grade soft tissue sarcomas of the extremities. Cancer. 1986 Jul 1;58(1):190–205. doi: 10.1002/1097-0142(19860701)58:1<190::aid-cncr2820580133>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  31. Renard N., Liénard 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 Jun 1;57(5):656–663. doi: 10.1002/ijc.2910570508. [DOI] [PubMed] [Google Scholar]
  32. Renard N., Nooijen P. T., Schalkwijk L., De Waal R. M., Eggermont A. M., Liénard D., Kroon B. B., Lejeune F. J., Ruiter D. J. VWF release and platelet aggregation in human melanoma after perfusion with TNF alpha. J Pathol. 1995 Jul;176(3):279–287. doi: 10.1002/path.1711760310. [DOI] [PubMed] [Google Scholar]
  33. Rossi C. R., Vecchiato A., Foletto M., Nitti D., Ninfo V., Fornasiero A., Sotti G., Tregnaghi A., Melanotte P., Lise M. Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas. Cancer. 1994 Apr 15;73(8):2140–2146. doi: 10.1002/1097-0142(19940415)73:8<2140::aid-cncr2820730819>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  34. Rouëssé J. G., Friedman S., Sevin D. M., le Chevalier T., Spielmann M. L., Contesso G., Sarrazin D. M., Genin J. R. Preoperative induction chemotherapy in the treatment of locally advanced soft tissue sarcomas. Cancer. 1987 Aug 1;60(3):296–300. doi: 10.1002/1097-0142(19870801)60:3<296::aid-cncr2820600305>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  35. Shiu M. H., Hilaris B. S., Harrison L. B., Brennan M. F. Brachytherapy and function-saving resection of soft tissue sarcoma arising in the limb. Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1485–1492. doi: 10.1016/0360-3016(91)90323-v. [DOI] [PubMed] [Google Scholar]
  36. Sijens P. E., Eggermont A. M., van Dijk P. V., Oudkerk M. 31P magnetic resonance spectroscopy as predictor of clinical response in human extremity sarcomas treated by single dose TNF-alpha + melphalan isolated limb perfusion. NMR Biomed. 1995 Aug;8(5):215–224. doi: 10.1002/nbm.1940080506. [DOI] [PubMed] [Google Scholar]
  37. Spriggs D. R., Sherman M. L., Michie H., Arthur K. A., Imamura K., Wilmore D., Frei E., 3rd, Kufe D. W. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. J Natl Cancer Inst. 1988 Sep 7;80(13):1039–1044. doi: 10.1093/jnci/80.13.1039. [DOI] [PubMed] [Google Scholar]
  38. Stehlin J. S., Jr, de Ipolyi P. D., Giovanella B. C., Gutierrez A. E., Anderson R. F. Soft tissue sarcomas of the extremity. Multidisciplinary therapy employing hyperthermic perfusion. Am J Surg. 1975 Dec;130(6):643–646. doi: 10.1016/0002-9610(75)90413-4. [DOI] [PubMed] [Google Scholar]
  39. Stotter A. T., A'Hern R. P., Fisher C., Mott A. F., Fallowfield M. E., Westbury G. The influence of local recurrence of extremity soft tissue sarcoma on metastasis and survival. Cancer. 1990 Mar 1;65(5):1119–1129. doi: 10.1002/1097-0142(19900301)65:5<1119::aid-cncr2820650515>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  40. Sugarman B. J., Aggarwal B. B., Hass P. E., Figari I. S., Palladino M. A., Jr, Shepard H. M. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985 Nov 22;230(4728):943–945. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  41. Suit H. D., Proppe K. H., Mankin H. J., Wood W. C. Preoperative radiation therapy for sarcoma of soft tissue. Cancer. 1981 May 1;47(9):2269–2274. doi: 10.1002/1097-0142(19810501)47:9<2269::aid-cncr2820470928>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  42. Suit H. D., Tepper J. E. Impact of improved local control on survival in patients with soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 1986 Apr;12(4):699–700. doi: 10.1016/0360-3016(86)90083-0. [DOI] [PubMed] [Google Scholar]
  43. Swaak A. J., Lienard D., Schraffordt Koops H., Lejeune F. J., Eggermont A. M. Effects of recombinant tumour necrosis factor (rTNF-alpha) in cancer. Observations on the acute phase protein reaction and immunoglobulin synthesis after high dose recombinant TNF-alpha administration in isolated limb perfusions in cancer patients. Eur J Clin Invest. 1993 Dec;23(12):812–818. doi: 10.1111/j.1365-2362.1993.tb00735.x. [DOI] [PubMed] [Google Scholar]
  44. Thom A. K., Alexander H. R., Andrich M. P., Barker W. C., Rosenberg S. A., Fraker D. L. Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan. J Clin Oncol. 1995 Jan;13(1):264–273. doi: 10.1200/JCO.1995.13.1.264. [DOI] [PubMed] [Google Scholar]
  45. Thompson J. F., Gianoutsos M. P. Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J Surg. 1992 Mar-Apr;16(2):227–233. doi: 10.1007/BF02071525. [DOI] [PubMed] [Google Scholar]
  46. Trojani M., Contesso G., Coindre J. M., Rouesse J., Bui N. B., de Mascarel A., Goussot J. F., David M., Bonichon F., Lagarde C. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984 Jan 15;33(1):37–42. doi: 10.1002/ijc.2910330108. [DOI] [PubMed] [Google Scholar]
  47. Wanebo H. J., Temple W. J., Popp M. B., Constable W., Aron B., Cunningham S. L. Preoperative regional therapy for extremity sarcoma. A tricenter update. Cancer. 1995 May 1;75(9):2299–2306. doi: 10.1002/1097-0142(19950501)75:9<2299::aid-cncr2820750919>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  48. Watanabe N., Niitsu Y., Umeno H., Kuriyama H., Neda H., Yamauchi N., Maeda M., Urushizaki I. Toxic effect of tumor necrosis factor on tumor vasculature in mice. Cancer Res. 1988 Apr 15;48(8):2179–2183. [PubMed] [Google Scholar]
  49. Wieberdink J., Benckhuysen C., Braat R. P., van Slooten E. A., Olthuis G. A. 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 Oct;18(10):905–910. doi: 10.1016/0277-5379(82)90235-8. [DOI] [PubMed] [Google Scholar]

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