Intensive Care Med (1999) 25: 898±900 Ó Springer-Verlag 1999

H.I. Robins W. Longo

ED ITO R IA L

Whole body hyperthermia: simple complexities

Accepted: 2 July 1999

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H.I. Robins ( ) Whole Body Hyperthermia Program and Departments of Medicine, Neurology, and Human Oncology, University of Wisconsin School of Medicine, 600 Highland Avenue, Madison, WI 53792, USA W. Longo Bone Marrow Transplant Program and Department of Medicine, University of Wisconsin School of Medicine, 600 Highland Avenue, Madison, WI 53792, USA

The articles by Kerner et al. [1] and Pereira Arias et al. [2] in this issue of Intensive Care Medicine reflect both a revitalized interest in whole body hyperthermia (WBH) by the European oncological community, as well as in what has been a traditional concern about the potential toxicities of this treatment modality. The potential morbidity and mortality of WBH (generally administered with a maximum target temperature of up to 42 C) may relate to direct physiological changes secondary to fever or the sequelae of its use in a combined modality approach. In this regard, the utilization of WBH for the treatment of neoplastic disease should be restricted to its use as an adjunct to other forms of therapy. (The only exceptions to this caveat are phase I studies to evaluate new technologies, or phase I studies in which WBH alone is being directly compared to a combined modality approach.) The basis for this axiomatic statement relates to the fact that disease-response durations produced by WBH alone (which do occur in thermally sensitive malignancies) are meaninglessly short, that is, days to a few weeks at best [3]. Although the toxicities encountered with WBH are generally dependent upon the agents it is used in combination with (e. g., chemotherapy, ionizing irradiation or immunotherapy), clinical complications

are also contingent on the methodology used to induce systemic hyperthermia. The issue of technology specific toxicity has been reviewed in detail elsewhere [3]. An interesting illustration of this phenomenon relates to Wiedemann et al. report of the intrinsically toxicity-laden extracorporeal WBH [4] in combination with potentially nephrotoxic chemotherapy; this combination resulted in life threatening renal failure. This toxicity was later successfully eliminated [5] with the application of the same chemotherapy combined with a radiant heat WBH technology [6, 7]. Interestingly, this renal toxicity, related to extracorporeal WBH and its associated hypotension, was predicted by animal modeling [8]. The reports presented here [1, 2] address the acute toxicities of WBH in combination with chemotherapy. The study presented by the Berlin group [1] represents a detailed analysis of WBH toxicity. It is clear that the two patients who experienced transient complications in retrospect should have been excluded from study. Alcohol abuse with resultant hepatic disease (which was hidden from the research team ) is a clear contraindication to WBH. Beyond this, patients with organic heart disease should similarly be excluded from treatment in our view. Further, it is our view that patients with anemia should be transfused to a hematocrit of 32 %. There is no question that careful patient selection is a key element to any WBH program. (Needless to say, there is a learning curve with any new technology.) We agree with the authors that careful comparison of their technology (Iratherm) to others, i. e., Aquatherm, is warranted. It should be noted, however, that a review of the literature [6, 7, 9±16] for the two different radiant heat systems developed at the University of Wisconsin (first the Enthermic Device and later their preferred Aquatherm) suggest that these systems may have several readily apparent advantages over the Iratherm including the following: the absence of central nervous system toxicity, the absence of skin burning, the absence

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of hypotension requiring catecholamines, obviation of the need for general anesthesia, and (in the case of the Aquatherm) somewhat faster heating times. It is of course with the type of detailed comprehensive studies provided by these investigators that such initial comparisons can be made. The data presented by the Amsterdam group [2], we believe highlights an important issue regarding the use of WBH with myelotoxic chemotherapy, but we disagree to some extent with the authors' pathophysiological conclusions. In our view (as well as those of the critical care and infectious disease specialists at our institution) the postulation of the hither-to undescribed WBH associated ªsystemic inflammatory response syndromeº (SIRS) as well as the multiple organ dysfunction syndrome requires the exclusion of more likely etiologyn for example, urosepsis in a patient with urethral obstruction and neutropenia. (We have not observed this syndrome previously in our collective experience of over 2000 radiant heat WBH treatments). The existence of negative cultures, followed by positive cultures for Bacteroides distasonis and Candida stellatoidea at a minimum raises the possibility of these organisms as the etiological basis for these observations. Indeed, the use of empirical antibiotic therapy in the setting of neutropenic fever is predicated on the inability to culture patients successfully early on in their clinical courses. We believe the clinical significance of this interesting case report may have a different point of focus. It is interesting to note that in a series of 90 patients treated as part the Systemic Hyperthermia Oncological Working Group study (SHOWG) [17] there were only three episodes of life threatening sepsis: two of these, includ-

ing this reported case, resulted in death. All three cases were associated with ureteral obstruction. These were the only patients with ureteral obstruction in the series. As a consequence, the SHOWG protocol was amended to exclude patients with ureteral obstruction and/or ureteral stents. Thus, we have concluded that patients in this clinical setting are at high risk for sepsis. The speculation by the authors regarding the earlier reports of cytokine induction and SIRS is nevertheless intriguing. It is interesting that this same cytokine induction by WBH appears to reduce the myelosuppression of chemotherapy±and radiotherapy±induced myelosuppression both in humans and in animal models [5, 13, 18± 20]. A complete review of this area, as well as newly derived data regarding WBH induction of cytokines at the level of the bone marrow (i. e., interleukin-3 and granulocyte-macrophage colony stimulating factor) is available elsewhere [20]. It may also be germane to the discussion to recognize that the combination of WBH, tumor necrosis factor and chemotherapy have successfully been combined with insignificant toxicity [15]. A thousand years have passed since physicians first conceived of the therapeutic uses of fever. Induced WBH has been studied for at least a century. During the past two decades an unequivocal laboratory base has evolved in support of the use of WBH. We believe the next 5 years will be critical in extending and extrapolating both clinical and laboratory research (in the context of controlled clinical trials) to establish WBH as a defined adjunct to other forms of therapy. The two reports reviewed are clearly consistent with this ongoing effort.

References 1. Kerner T, Deja M, Ahlers O, Löffel J, Hildebrandt B, Wust P, Gerlach H, Riess H (1999) Whole body hyperthermia: a secure procedure for patients with various malignancies? Intensive Care Med 25: 959±965 2. Pereira Arias AM, Wester JPJ, Blankendaal M, Schilthuis MS, Kuijper EJ, Rademaker BMP, Stautenbeek CP, Rietbroek RC (1999) Multiple organ dysfunction syndrome induced by whole body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus. Intensive Care Medicine 25: 1013±1016 3. Robins HI, Neville AJ, Cohen JD (1992) Whole body hyperthermia:biological, and clinical aspects. In: Gautherie M (ed) Clinical thermology. Springer Berlin Heidelberg New York.

4. Wiedemann GJ, Robins H I, Gutsche S, Mentzel M, Deeken M, Katschinski DM, Eleftheriadis S, Crahe R, Weiss C, Storer B, Wagner T (1996) Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 C whole-body hyperthermia in patients with refractory sarcoma. Eur J Cancer XXXIIA:888±892 5. Wiedemann GJ, Robins HI, Katschinski DM, Mentzel M, d'Oleire F, Kutz M, Wagner T (1997) Systemic hyperthermia and ICE chemotherapy for sarcoma patients:rationale and clinical status. Anticancer Res XVII:2899±2902 6. Robins HI, Schmitt-Tiggelaar CL, Cohen JD, Woods JP, Heiss C, Gillis W, d'Oleire F (1994) A new technological approach to radiant heat whole body hyperthermia. Cancer Lett 79: 137±145

7. Robins HI, Dennis WH, Neville AJ, Shecterle L, Martin PA, Grossman J, Davis TE, Neville S, Gillis W, Rusey BF (1985) A non-toxic system for 41.8 C whole body hyperthermia:results of a phase I study using a radiant heat device. Cancer Res 45: 3937±3944 8. Brauer L, Prieshof B, Wiedemann G, Weiss C, Kris W, Schramm U, Robins H, Pagel H (1998) Whole-body hyperthermia combined with ifosfamide and carboplatin causes hypotension and nephrotoxicity. J Cancer Res Clin Oncol 124: 549±554 9. Robins HI, Longo WL, Lagoni RK, Neville AJ, Riggs C, Schmitt CL, Hugander A, Young C (1988) A phase I trial of lonidamine with whole body hyperthermia in advanced cancer. Cancer Res., 48: 6587±6592

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10. Robins HI, Longo WL, Steeves RA, Lagoni RK, Hugander A, Neville AJ, O'Keefe S, Giese W, Schmitt C L (1988) A pilot study of whole body hyperthermia and local irradiation for advanced non-small cell lung cancer confined to the thorax. Int. J. Radiat. Oncol. Biol. Phys., 15: 427±431 11. Robins HI, Sielaff KM, Storer B, Hawkins MJ, Borden EC (1989) A phase I trial of human lymphoblastoid interferon with whole body hyperthermia in advanced cancer. Cancer Res 49: 1609±1615 12. Robins HI, Longo WL, Steeves RA, Cohen JD, Schmitt CL, Neville AJ, O'Keefe S, Lagoni R, Riggs C (1990) Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B cell neoplasms:a report of two pilot clinical trials and laboratory investigations. Int J Radiat Oncol Biol Phys 18: 909±920

13. Robins HI, Cohen J D, Schmitt CL, Tutsch KD, Feierabend C, Arzoomanian RZ, Alberti D, d'Oleire F, Longo W, Heiss C, Rushing D, Spriggs D (1993) Phase I clinical trial of carboplatin and 41.80 C whole body hyperthermia in cancer patients. J Clin Oncol 11: 1787±1794 14. Robins H, Rushing D, Kutz M, Tutsch K, Tiggelaar C, Paul D, Spriggs D, Kraemer C, Gillis W, Feierabend C, Arzoomaniam R, Longo W, Alberti D, d'Oleire F, Qu R, Stewart J, Wilding G (1997) Phase I clinical trial of melphalan (L-PAM) and 41.8 C whole body hyperthermia (WBH) in cancer patients. J Clin Oncol 15: 158±164 15. Robins HI, Katschinski DM, Longo W, Grosen E, Wilding G, Gillis W, Kraemer C, Tiggelaar CL , Rushing D, Stewart J A, Springgs D, Love R, Arzoomanian RZ, Feierabend C, Alberti D, Morgan K, Simon K, d'Oleire F (1999) A pilot study of melphalan, tumor necrosis factor alpha and 41.80 C whole body hyperthermia. Cancer Chemother Pharmacol 43: 409±414 16. Robins HI, Longo WL, Hugander A, Bozdech M, Schwartz B, Steeves RA, Flynn B, Triggs M, Sondel PM (1986) Whole body hyperthermia combined with total body irradiation and chemotherapy as a preparative regimen for allogenic bone marrow transplantation in a patient with Burkitt's lymphoma. Cancer J 1: 180±183

17. Robins HI (1995) Meeting report: Systemic Hyperthermia Oncological Working Group. Oncology Int J Cancer Res and Treat 52: 260±263 18. Robins HI, Kutz M, Wiedemann G, Paul D, Katschinski DM, Grosen E, Tiggelaar CL, Spriggs D, Gillis W, d'Oleire F (1995) Cytokine induction by 41.80 C whole body hyperthermia. Cancer Lett 97: 195±201 19. d'Oleire F, Robins HI, Cohen JD, Schmitt CL, Spriggs D (1993)Cytokine induction in humans by 41.80 C whole body hyperthermia. J Natl Cancer Inst 85: 833±834 20. Katschinski D M, Wiedemann GJ, d'Oleire FR, Longo W, Robins HI (1999) Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev (in press)