Skip to main content
Log in

Hyperthermia in soft tissue sarcoma

  • Soft Tissue Sarcomas
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Patients with high-risk soft tissue sarcomas (STS)–FNCLCC grade 2–3, size >5 cm, deep to the fascia—are at risk for developing local recurrence and distant metastasis despite surgical tumor resection. Therefore, the management of high–risk STS requires a multidisciplinary approach. Besides surgery, radiotherapy, and chemotherapy, regional hyperthermia (RHT) has the potential to become the fourth standard treatment modality for the treatment of these patients. RHT means non-invasive selective heating of the tumor area to temperatures within the range of 40–43°C for 60 min by the use of an electromagnetic heating device. Thereby RHT is always applied in addition to radiotherapy or chemotherapy or both but is not effective as a single treatment. Beside direct cytotoxicity, RHT in combination with chemotherapy enhances the drug cytotoxicity mainly by increased chemical reaction and intratumoral drug accumulation. For the neoadjuvant setting, RHT in combination with a doxorubicin- and ifosfamide-based chemotherapy has been shown to dramatically improve the tumor response rate but also prevents from early disease progression as compared to chemotherapy alone. The addition of RHT to a multimodal treatment of high-risk STS consisting of surgery, radiotherapy, and chemotherapy either in the neoadjuvant setting but also after incomplete or marginal tumor resection has been shown to significantly improve local recurrence- and disease-free survival. Based on these results and in conjunction with the low RHT-related toxicity, RHT combined with preoperative or postoperative chemotherapy should be considered as an additional standard treatment option for the multidisciplinary treatment of locally advanced high-grade STS.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Clark MA, Fisher C, Judson I, Thomas JM. Soft tissue sarcomas in adults. N Engl J Med 2005, 353:701–711.

    Article  CAS  PubMed  Google Scholar 

  2. Sapareto A, Hopwood LE, Dewey WC, Ragu MR, Gray JW. Hyperthermic effects on survival and progression of CHO cells. Cancer Res 1978, 38:393–400.

    CAS  PubMed  Google Scholar 

  3. Dewey WC. Arrhenius relationships from the molecule and cell to clinic. Int J Hyperthermia 1994, 10:457–83.

    Article  CAS  PubMed  Google Scholar 

  4. Vaupel P, Kallinowski FK, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic micro-environment of human tumors: a review. Cancer Res 1989, 49:6449–6465.

    CAS  PubMed  Google Scholar 

  5. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004, 14:198–206.

    Article  PubMed  Google Scholar 

  6. Song CW, Shakil A, Griffin RJ, Okajima K. Improvement of tumor oxygenation status by mild temperature hyperthermia alone or in combination with carbogen. Semin Oncol 1997, 24:626–632.

    CAS  PubMed  Google Scholar 

  7. Kampinga HH, Dikomey E. Hyperthermic radiosensitization: mode of action and clinical relevance. Int J Radiat Biol 2001, 77:399–408.

    Article  CAS  PubMed  Google Scholar 

  8. Urano M, Kuroda M, Nishimura Y. For the clinical application of thermochemotherapy given at mild temperatures. Int J Hyperthermia 1999, 15:79–107.

    Article  CAS  PubMed  Google Scholar 

  9. Dahl O. Interaction of heat and drugs in vitro and in vivo. In: Thermoradiotherapy and thermochemotherapy Volume 1. Edited by Seegenschmiedt MH, Fessenden P, Vernon CC. Berlin: Springer; 1995:103–121.

    Google Scholar 

  10. Leopold KA, Dewhirst M, Samulski T, et al. Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas. Int J Radiat Oncol Biol 1992, 22:989–998.

    Article  CAS  Google Scholar 

  11. Baur A, Stäbler A, Wendtner CM, et al. MR-imaging changes of musculoskeletal soft-tissue sarcomas associated with neoadjuvant chemotherapy and hyperthermia. Int J Hyperthermia 2003, 19:391–401.

    Article  CAS  PubMed  Google Scholar 

  12. Sauter B, Albert ML, Francisco L, et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptopic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000, 191:423–434.

    Article  CAS  PubMed  Google Scholar 

  13. Noessner E, Gastpar R, Milani V, et al. Tumor-derived heat shock protein 70-peptide complexes are cross-presented by human dendritic cells. J Immunol 2002, 169:5425–5432.

    Google Scholar 

  14. Gastpar R, Gehrmann M, Bausero MA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 2005, 65:5238–5247.

    Article  CAS  PubMed  Google Scholar 

  15. Stangl S, Gehrmann M, Riegger J, et al. Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci USA 2011, 108:733–738.

    Article  CAS  PubMed  Google Scholar 

  16. Jolesch A, Elmer K, Bendz H, et al. Hsp70, a messenger from hyperthermia for the immune system. Eur J Cell Biol 2011, in press.

  17. Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer. Lancet Oncol 2002, 3:487–497.

    Article  CAS  PubMed  Google Scholar 

  18. Prosnitz LR, Maguire P, Anderson JM, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys 1999, 45:941–949.

    Article  CAS  PubMed  Google Scholar 

  19. Gerad H, van Echo DA, Whitacre M, et al. Doxorubicin, cyclophosphamide, and whole body hyperthermia for treatment of advanced soft tissue sarcoma. Cancer 1984, 53:2585–2591.

    Article  CAS  PubMed  Google Scholar 

  20. Westermann AM, Wiedemann GJ, Jager E, et al. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma. Oncology 2003, 64:312–321.

    Article  CAS  PubMed  Google Scholar 

  21. Issels RD, Prenninger SW, Nagele A, et al. Ifosfamide plus etoposide combined with regional hyperthermia in patients with locally advanced sarcomas: a phase II study. J Clin Oncol 1991, 8:1818–1829.

    Google Scholar 

  22. Lagendijk JJ, van Rhoon GC, Hornsleth SN, et al. ESHO quality assurance guidelines for regional hyperthermia. Int J Hyperthermia 1998, 14:125–133.

    Article  CAS  PubMed  Google Scholar 

  23. Issels RD, Abdel-Rahman S, Wendtner CM, et al. Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk soft tissue sarcomas (HR-STS) of adults: long-term results of a phase II study. Eur J Cancer 2001, 37:1599–1608.

    Article  CAS  PubMed  Google Scholar 

  24. Wendtner CM, Abdel-Rahman S, Baumert J, et al. Treatment of primary, recurrent or inadequately resected high-risk soft tissue sarcomas (HR-STS) of adults: results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia. Eur J Cancer 2001, 37:1609–1616.

    Article  CAS  PubMed  Google Scholar 

  25. Wendtner CM, Abdel-Rahman S, Krych M, et al. Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol 2002, 20:3156–3164.

    Article  CAS  PubMed  Google Scholar 

  26. Issels RD, Lindner LH, Verweij J, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol 2010, 11:561–670.

    Article  CAS  PubMed  Google Scholar 

  27. Issels RD, Lindner LH, Laubender R, et al. Improvement of local progression (LPFS) and disease-free survival (DFS) by regional hyperthermia (RHT) combined with neoadjuvant chemotherapy in non-extremity (NE) high-risk soft tissue sarcoma (HR-STS) with complete (R0/R1) surgical resection [abstract 897755]. Presented at the CTOS 16th Annual Meeting. Paris, France; November 11–13, 2010.

  28. Nickenig C, Buecklein V, Lindner LH, et al. Ifosfamide, carboplatin, and etoposide (ICE) in combination with regional hyperthermia (RHT) in chemotherapy-pretreated nonresponders with locally advanced high-risk soft tissue sarcoma (HR-STS). (ASCO abstract 10581). J Clin Oncol 2009;27:15s.

    Article  Google Scholar 

  29. Fiegl M, Schlemmer M, Wendtner CM et al. Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults. Int J Hyperthermia 2004, 20:661–670.

    Article  CAS  PubMed  Google Scholar 

  30. Romanowski R, Schött C, Issels R, et al. Regional hyperthermia with systemic chemotherapy in children and adolescents: feasibility and clinical follow-up of 34 intensively pretreated patients with prognostically unfavorable tumor diseases. Klin Padiatr 1993, 205:249–256.

    Article  CAS  PubMed  Google Scholar 

  31. Wessalowski R, Schneider DT, Mils O, et al. An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors. Klin Padiatr 2003, 215:303–309.

    Article  CAS  PubMed  Google Scholar 

Download references


L Lindner: consulting fees from Medtherm and travel support from PharmaMar; R Issels: consulting fees and travel support from Novartis, Amgen, PharmaMar and MedTherm.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Lars H. Lindner MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindner, L.H., Issels, R.D. Hyperthermia in soft tissue sarcoma. Curr. Treat. Options in Oncol. 12, 12–20 (2011).

Download citation

  • Published:

  • Issue Date:

  • DOI: