Whole-body hyperthermia combined with ifosfamide and carboplatin causes hypotension and nephrotoxicity

Abstract

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.

Nephrotoxicity of ifosfamide, carboplatin and etoposide (ICE) alone or combined with extracorporeal or radiant-heat-induced whole-body hyperthermia

“…In a subsequent trial by Wiedemann et al the administration of carboplatin (480 mg/m 2 ) and ifosfamide (5±10 g/m 2 ) combined with e-WBH was associated with acute renal failure in 2 patients and a signi®cant rise in serum creatinine in another 4 of 19 patients (Wiedemann et al 1994). These ®ndings are consistent with the possibility that the nephrotoxic effects of ifosfamide are enhanced by WBH more profoundly than those of carboplatin, a ®nding supported by animal studies (Brauer et al 1998).…”

“…In patients from the e-WBH group, however, pathological excretion of low-molecular mass proteins persisted, indicating permanent tubular damage. This disadvantage of e-WBH in our consecutively treated patrients may arise from the need for general anaesthesia and catecholamine support, as suggested earlier (Brauer et al 1998).…”

“…Carboplatin combined with ifosfamide only led to minor histological changes. The combination of e-WBH and chemotherapy, however, caused a signi®-cant decrease in GFR as well as tubular necrosis and loss of tubular function (Brauer et al 1998).…”

“…Ifosfamide and carboplatin are both potentially nephrotoxic, whereas hyperthermia alone does not appear to cause major renal damage (Robins et al 1992(Robins et al , 1993(Robins et al , 1994. Animal studies suggest that e-WBH might enhance ifosfamide-and carboplatin-induced nephrotoxicity in part as a result of e-WBH-associated hypotension (Brauer et al 1998). As e-WBH causes severe systemic hypotension in cancer patients, this WBH methodology was changed to a radiant-heat device (r-WBH), which does not cause severe systemic hypotension (Robins et al 1994).…”

Hyperthermia as an Adjunct to the Standard Treatment of Neoplastic Diseases: Few Cures but some Advances

“…Interestingly, responses were observed in 3 of 12 (25%) refractory sarcoma patients in this (mixed histology) pilot study. Unlike the earlier carboplatin [14] study with radiant heat-induced WBH [5,6], severe cardiopulmonary distress resulted in severe CT-associated renal dysfunction [17]. Nephrotoxicity was dose-limiting.…”