Skip to main content

Advertisement

SpringerLink
Log in

Systemic Toxicity and Cytokine/Acute Phase Protein Levels in Patients After Isolated Limb Perfusion With Tumor Necrosis Factor-a Complicated by High Leakage

  • Original Articles
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background: Since the introduction of high-dose tumor necrosis factor-α (TNFα) in the settingof isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient ismonitored with great precision for fear of TNF-mediated toxicity. That we observed remarkablylittle toxicity in patients with and without leakage prompted us to determine patterns of cytokinesand acute phase proteins in patients with high leakage and in patients without any leakage.

Methods: TNFa, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 weremeasured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to thesystemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, bothin peripheral blood and in perfusate, were performed in nine patients without systemic leakage.

Results: In patients with systemic leakage, levels of TNFaincreased during ILP, reaching valuesto 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared withpatients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 inboth patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, incontrast, with lower levels in the leakage patients.

Conclusions: High leakage of TNFα to the systemic circulation, caused by a complicated ILP,led to 10-fold to more than 100-fold increased levels of TNFα, IL-6, and IL-8 in comparison withpatients without leakage. The increase of the acute phase proteins was limited. Even when highleakage occurs, this procedure should not lead to fatal complications. The most prominent clinicaltoxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary orrenal toxicity was observed in any patient. It is our experience that, even in the rare event ofsignificant leakage during a TNFα-based ILP, postoperative toxicity is usually mild and can beeasily managed by the use of fluid and, in some cases, vasopressors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Creech OJ, Krementz ET, Ryan RF, Winblad JN. Chemotherapy ofcancer: regional perfusion utilizing an extracorporeal circuit. AnnSurg 1958;148:616–32.

    Google Scholar 

  2. Eggermont AMM. Treatment of melanoma-in-transit metastasesconfined to limb. Cancer Surv 1996;26:335–49.

    PubMed  CAS  Google Scholar 

  3. Lie’nard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. Highdose recombinant tumor necrosis factor alpha in combination withinterferon gamma and melphalan in isolation perfusion of the limbsfor melanoma and sarcoma. J Clin Oncol 1992;10:52–60.

    CAS  Google Scholar 

  4. Lie’nard D, Eggermont AMM, Schraffordt Koops H, et al. Isolatedperfusion of the limb with high dose tumor necrosis factor-alpha(TNFa) and interferon-gamma (IFNg) and melphalan for melanoma stage III: results of a multi-center pilot study. Melanoma Res 1994;4:21–6.

    Google Scholar 

  5. Eggermont AMM, Schraffordt Koops H, Lie’nard D, et al. Isolated limb perfusion with high-dose tumor necrosis factor-a in combination with interferon-gand melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 1996;14: 2653–65.

    CAS  PubMed  Google Scholar 

  6. Eggermont AMM, 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. Ann Surg 1996;274:756–65.

    Google Scholar 

  7. Eggermont AMM, Schraffordt Koops H, Klausner JM, et al. Limb salvage (LS) by isolated limb perfusion (ILP) with TNF and melphalan (M) in 246 patients with advanced soft tissue sarcomas (STS): results of 270 ILPs in 246 patients [Abstract]. Proc Am Soc Clin Oncol 1999;18:A2067.

    Google Scholar 

  8. Selby P, Hobbs S, Viner C, et al. Tumor necrosis factor in man: clinical and biological observations. Br J Cancer 1987;56:803–8.

    PubMed  CAS  Google Scholar 

  9. Feinberg B, Kurzrock R, Talpaz M, Blick M, Saks S, Gutterman JU. A phase-I trial of intravenously administered recombinant tumor necrosis factor alpha in cancer patients. J Clin Oncol 1988; 6:1328–34.

    PubMed  CAS  Google Scholar 

  10. Wiedenmann B, Reichardt P, Ra¨th U, et al. Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas. Cancer Res Clin Oncol 1989;115:189–92.

    CAS  Google Scholar 

  11. Gamm H, Lindemann A, Mertelsmann R, Hermann F. Phase I trial of recombinant human tumor necrosis factor alpha in patients with advanced malignancy. Eur J Cancer 1991;27:856–63.

    PubMed  CAS  Google Scholar 

  12. World Health Organization. Handbook for Reporting Results of Cancer Treatment. Geneva: WHO Offset Publications, 1979.

    Google Scholar 

  13. Van Kooten C, Rensink I, Pascal-Salcedo D, Van Oers R, Aardenr LA. Monokine-production by human T-cells: IL-1a production restricted to memory T-cells. J Immunol 1991;146:2654–8.

    PubMed  CAS  Google Scholar 

  14. Helle M, Boeije L, De Groot ER, De Vos A, Aarden LA. Sensitive ELISA for interleukin 6: detection of IL-6 in biological fluids and sera. J Immunol Methods 1991;138:42–56.

    Google Scholar 

  15. Verbrugh CA, Hart MH, Aarden LA, Swaak AJG. Interleukin-8 (IL-8) in synovial fluid of rheumatoid and nonrheumatoid joint effusions. Clin Rheumatol 1993;12:494–6.

    CAS  PubMed  Google Scholar 

  16. Wolbink GJ, Brouwer MC, Buysmann S, ten Berge IJM, Hack CE. CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes. J Immunol 1996;157:473–9.

    PubMed  CAS  Google Scholar 

  17. Wolbink GJ, Schalkwijk C, Baars JW, Wagstaff J, Van den Bosch H, Hack CE.Therapy with interleukin-2 induces the systemic release of phospholipase-A2. Cancer Immunol Immunother 1995; 41:287–92.

    PubMed  CAS  Google Scholar 

  18. Thom AK, Alexander HR, Andrich MP, Barker WC, Rosenberg SA, Fraker DL. 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;13: 264–73.

    PubMed  CAS  Google Scholar 

  19. Ogilvie AC, Wolbink GJ, Rankin EM. Release of secretory phospholipase A2 during isolated limb perfusion with tumor necrosis factor-a: relation to clinical and inflammatory parameters. In: Ogilvie AC, ed. The Inflammatory-Coagulative Response During Treatment With Biological Response Modifiers [thesis]. Amsterdam: Free University, 1995:95–114.

    Google Scholar 

  20. Ge’rain J, Lie’nard D, Ewalenko P, Lejeune FJ. High serum levels of TNF-a after its administration for isolation perfusion of the limb. Cytokine 1992;4:585–91.

    CAS  Google Scholar 

  21. Eggimann P, Chiole‘ro R, Chassot PG, Lie’nard D, Ge’rain J, Lejeune FJ. Systemic and hemodynamic effects of recombinant tumor necrosis factor alpha in isolation perfusion of the limbs. Chest 1995;107:1074–82.

    PubMed  CAS  Google Scholar 

  22. Schaadt M, Pfreundschuh M, Lorscheidt G, Peters KM, Steinmetz T, Diehl V. Phase II study of recombinant human tumor necrosis factor in colorectal carcinoma. J Biol Response Mod 1990;9:247–50.

    PubMed  CAS  Google Scholar 

  23. Lejeune FJ, Lie’nard D, Eggermont AMM, et al. Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of melanoma. Circ Shock 1994;43:191–97.

    PubMed  CAS  Google Scholar 

  24. Vrouenraets BC, Kroon BBR, Ogilvie AC, et al. Absence of severe toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-a and melphalan. Ann Surg Oncol 1999;6: 405–12.

    PubMed  CAS  Google Scholar 

  25. Dofferhoff AS, Bom VJ, De Vries-Hospers HG, et al. Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med 1992;20:185–92.

    PubMed  CAS  Google Scholar 

  26. Hack CE, Aarden LA, Thijs LG. Role of cytokines in sepsis. Adv Immunol 1997;66:101–95.

    Article  PubMed  CAS  Google Scholar 

  27. Martin C, Boisson C, Haccoun M, Thomachot L, Mege JL. Patterns of cytokine evolution (tumor necrosis factor-alpha and interleukin- 6) after septic shock, hemorrhagic shock, and severe trauma. Crit Care Med 1997;25:1813–9.

    PubMed  CAS  Google Scholar 

  28. Avontuur JAM, Stam TC, Jongen-Lavrencic M, Van Amsterdam JGC, Eggermont AMM, Bruining HA. Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNF-a and nitrite/nitrate in human septic shock. Intensive Care Med 1998;24:673–9.

    PubMed  CAS  Google Scholar 

  29. Neilson IR, Neilson KA, Yunis EJ, Rowe MI. Failure of tumor necrosis factor to produce hypotensive shock in the absence of endotoxin. Surgery 1989;106:439–43.

    PubMed  CAS  Google Scholar 

  30. Ciancio MJ, Hunt J, Jones SB, Filkins JP. Comparative and interactive in vivo effects of tumor necrosis factor alpha and endotoxin. Circ Shock 1991;33:108–20.

    PubMed  CAS  Google Scholar 

  31. Feelders RA, Swaak AJG, Romijn JA, et al. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients. Metabolism 1999;48:324–9.

    PubMed  CAS  Google Scholar 

  32. Ge’rain J, Lie’nard D, Pampallona S, et al. Systemic release of soluble TNF receptors after high-dose TNF in isolated limb perfusion. Cytokine 1997;9:1034–42.

    CAS  Google Scholar 

  33. De Vries MR, Borel Rinkes IHM, Swaak AJG, et al. Acute-phase response patterns in isolated hepatic perfusion with tumor necrosis factor a (TNF-a) and melphalan in patients with colorectal liver metastases. Eur J Clin Invest 1999;29:553–60.

    PubMed  CAS  Google Scholar 

  34. Heuertz RM, Webster RO. Role of C-reactive protein in acute lung injury. Mol Med Today 1997;3:539–45.

    PubMed  CAS  Google Scholar 

  35. Hack CE, Wolbink GJ, Schalkwijk C, Speijer H, Hermens WT, van den Bosch H. A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells. Immunol Today 1997;18:111–5.

    PubMed  CAS  Google Scholar 

  36. Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive protein: structural biology, gene expression, and host defense function. Immunol Res 1997;16:127–36.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, University Hospital Rotterdam-Dr. Daniel den Hoed Cancer Center, Amsterdam, The Netherlands

    Tanja C. Stam MD, Mark R. de Vries MD, Timo L. M. ten Hagen PhD & Alexander M. M. Eggermont MD, PhD

  2. Department of Rheumatology, Zuiderziekenhuis, Rotterdam, Amsterdam, The Netherlands

    Anton J. G. Swaak MD, PhD

  3. Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, Amsterdam, The Netherlands

    Anton J. G. Swaak MD, PhD

  4. Department of Surgical Oncology, Dr. Daniel denHoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands

    Alexander M. M. Eggermont MD, PhD

Authors
  1. Tanja C. Stam MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anton J. G. Swaak MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark R. de Vries MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Timo L. M. ten Hagen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexander M. M. Eggermont MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stam, T.C., Swaak, A.J.G., de Vries, M.R. et al. Systemic Toxicity and Cytokine/Acute Phase Protein Levels in Patients After Isolated Limb Perfusion With Tumor Necrosis Factor-a Complicated by High Leakage. Ann Surg Oncol 7, 268–275 (2000). https://doi.org/10.1007/s10434-000-0268-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10434-000-0268-6

Key Words

Search

Navigation