[CANCER RESEARCH54, 5346-5350, October 15, 19941

ABSTRACT

The purposeof this studywas to evaluatethe pharmacokinetics,biological interactions, and toxicities of ifosfamide and carboplatin combinedwith 41.8°Cwhole-body hyperthermia (WBH) for 1 h in a pilot clinicalstudy. Nineteen patients with refractory sarcoma or malignant teratomawere treated. To obtain baseline pharmacokinetic data for ifosfamide, the

first chemotherapy course was given without WBH in six patients. Thisenabledcomparisonofsystemictoxicityandpharmacokineticsofthe drugcombination with and without WBH (±WBH). All other patients receivedthree thermochemotherapy treatments every 3 weeks. Ifosfamide wasescalated from 5 to 10 g/m2 with a fixed carboplatin dose of 480 mg/rn2.WBH was induced by extracorporafly heated blood (in a hernodialysisapparatus)withgeneralanesthesia.The drugsweregivenat targetternperature. A total of 49 thermochernotherapy treatments was adminis

tered. The use of the hemodialysis device resulted in an approximateone-third reduction of blood concentrations of 4-hydroxyifosfamide, oneactivated intermediate metabolite of ifosfamide and carboplatin, but in an

increase ofchloroacetaldehyde, the other main Ifosfamide metabolite. TheWBC counts and the platelet nadirs (up to WBH grade 4) were notsignificantly different ±WBH. Of 19 evaluable patients, 7 partIal rernissions, 8 disease stabilizations (average duration, 3 months), and 4 patientswith progressive disease were observed. There was no WBH-related mortality. Toxicities observed included mild (anasarca, diarrhea, pressuresores, and perioral herpes simplex) and severe (reversible neuropathy,cardiopulmonary distress, and severe renal dysfunction). No hepatic orcentral nervous system toxicity occurred. Nephropathy was the dose

limiting toxicity. In conclusion, ifosfamide and carboplatin can be administered with extracorporally induced WBH with acceptable toxicity. Resuits obtained are consistent with continued evaluatIon of this combinedmodality approach.

INTRODUCTION

In preclinical studies on human tumor xenografts growing in nudemice, we have shown that hyperthermia enhances the cytotoxic effectsof antineoplastic drugs, especially of alkylating agents (1—3).In theseexperiments, WBH3 was studied in combination with high-dose IFO.This combination significantly enhanced neoplastic cell kill for agiven dose of IFO without a concomitant rise of myelotoxicity (1),suggesting an increase of therapeutic index, i.e., the ratio of neoplasticto normal tissue cell kill. Beyond this, in a series of in vitro and in vivostudies, it has been demonstrated that hyperthermia increased both thedose-enhancement ratio (4, 5) and therapeutic index (6) of carboplatin. Additionally, hyperthermia has also been shown to overcomeacquired platinum drug resistance (7—9).

Received 4/1/94; accepted 8/18/94.The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

I This work was supported by Deutsche Forschungsgemeinschaft DFG (Grant Wi

1152/1—1)and Werner und Klara Kreitz-Stiftung, Kid, Germany.2 To whom requests for reprints should be addressed.

3 The abbreviations used are: WBH, whole-body hyperthermia; IFO, ifosfamide;

CBDCA, carboplatin; CAA, chioroacetaldehyde; G-CSF, granulocyte colony-stimulatingfactor; LDH, lactate dehydrogenase; DLT, dose-limiting toxicity.

To extrapolate some of the above-mentioned preclinical researchfindings to humans, Robins et a!. (10) carried out a Phase I clinicaltrial; they reported that CBDCA at a dose of 480 mg/m2 with WBH(41.8°Cfor 1 h) was well tolerated. The clinical results of this studywere in accord with the preclinical data, predicting increased efficacyfor combination therapy with no significant increase in toxicity. Toexpand on these results and on our own laboratory investigations, weelected to study the combination of CBDCA and IFO in a pilot clinicaltrial. The study design evaluated increasing doses of IFO with a fixeddose (480 mg/m2) of carboplatin (10) and 41.8°CWBH (1 h) (10).The patient population studied consisted of individuals with sarcoma,malignant neuroepithelial tumors, or malignant teratoma refractory to

standard therapy.In the report to follow, we summarize our toxicity, pharmacoki

netic, and response data for this multimodality approach.

PATIENTS AND METHODS

Patient Selection. Patients with histologically confirmed advanced and/ormetastatic sarcoma or malignant teratoma were eligible. The protocol requiredthe presence of at least one measurable lesion (measured in the two largest

perpendicular diameters), progressing under conventional therapy. Liver enlargement was measured as the sum of the distances from the inferior liveredge to the xiphoid notch and right margin in the mid-clavicular line inmid-inspiration. Osseous lesions and pleural effusions were not considered asmeasurable lesions. Only patients with a WHO performance status of 2 or

better and a life expectancy of at least 3 months were included in the study.Patients older than 60 years and/or with evidence of central nervous systemmetastasis were excluded. Further prerequisites were: an adequate bone marrow function (WBC > 3.5 k/mI, absolute granulocyte count >1.6 k/ml, andplatelet count > 100 k/mi); adequate hepatic function (total bilirubin < 1.5mg/100 ml), and liver function tests and adequate renal function (creatinine < 1.5 mg/dl or a creatinine clearance of > 60 mt/mis and blood ureanitrogen < 30 mg/dl), with calcium and electrolytes within normal limits, and

a normal coagulation profile.Patients with a history of malignant hyperthermia associated with general

anesthesia, documented coronary artery disease, history of angina, congestiveheart failure, or serious dysrhythmias were excluded. The protocol also cx

cluded patients with severely compromised respiratory status, i.e., any param

eter of a full pulmonary function test being less than 60% of predicted.Neurological bases for exclusions were central nervous system involvement by

tumor, previous spinal cord, or brain irradiation, documented peripheral neuropathy, paraneoplastic or otherwise, or a history of emotional instability.

The demographic profiles of the 19 patients (49 treatments) studied arelisted in Table 1.The patientswere treatedbetweenNovember1992and December 1993. Written informed consent was Obtained from all patients. The study wasapprovedby the Ethics Commissionof the MedicalUniversityof Lubeck.

Pretreatment Evaluation. Evaluationincludeda completehistoryand physical examination; chest X-ray, computerized axial tomography scan of the brainand, if indicated, of the chest and abdomen; a full analysis ofblood chemistry anda hematological survey; and full pulmonary function tests, electrocardiogram and

echocardiography.Full details of the screening of the patients have been previously describedby Robinset a!. (10, 11) and Van der Zee et aL (12).

TreatmentProtocol.Six patients(Table1, nos. 1—6)of the 19 patientsreceived the first course of IFO and CBDCA chemotherapy without WBH.Baseline pharmacokinetics were obtained from that treatment. All subsequent

5346

Ifosfamide and Carboplatin Combined with 41.8°CWhole-Body Hyperthermia inPatients with Refractory Sarcoma and Malignant Teratoma'

Günter J- Wiedemann,2 Floriane d'Oleire, Erdmute Knop, Sawas Eleftheriadis, Peter Bucsky, Stephanie Feddersen,

Miriam Kiouche, Jürgen Geisler, Martin Mentzel, Peter Schmucker, Thomas Feyerabend, Christoph Weiss, andThomas Wagner

Departments of Internal Medicine 1G. J. W., E. K., M. M., J. G., T. WI, Anesthesiology (S. E., P. 5.1, Immunology (M. K.J, Radiotherapy IT. Fl, and Physiology (S. F.. C. WI,University of Lubeck, Ratzeburger Allee 160, D-23538, and University Children ‘sHospital, liAbeck [P. B.J, and University Children ‘sHospital, Tilbingen (F. d'O.), Germany

on June 12, 2020. © 1994 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Table 1Demographic profile andclinicalresponse ofpatienzs receiving IFO/CBDCA andWBHPalnPatient

no.!before/afterinitialsAge/sexDiagnosisTumorsitePS―PriortreatmentResponsetreatment1

M. T.24!MMal. teratomaLiver, LN1Surgery, RT, CDDP,CYCPR+!-2S. B.401MOsteosarcomaBony met2Surgery, RT, CDDP, CYC, IFO, CBDCA, ADR, DTIC,VCRNC+++/-35. H.18/FRhabdomyosarcomaLung met0Surgery, RT, CDDP, CYC, ADR, IFO, DTIC,VCRNC-!4H. S.30/FChondrosarcomaPelvis2Surgery, RT, CYC, ADR, IFO, DTIC,VCRPR+++!-55. K.211MChondrosarcomaHumerus/lung met1Surgery, RT, CYC, ADR, DTIC,VCRNC-!-6K. J.17/FPNETBony met, BM2Surgery, RT, CYC, ADR, DTIC, VCR,IFOProgression(+)!(+)7T. B.44/FLeiomyosarcomaUterus0Surgery, RT, CYC,CDDPNC-/-8E. R.54/FLeiomyosarcomaLiver met0Surgery, RT, CYC,CDDPNC-!-9J. S.35/MOsteosarcomaBony met2Surgery, RT, CYC, ADR, DTIC,VCRNC+++!-10M. M.281MEwing sarcomaBony, lung+ LN met2Surgery, RT, CYC, ADR, VCR,CBDCAPR+++/+11H. B.541MMal. histiocytomaLung met0Surgery, RT, IFO,CDDPPR-!-12A. K.50/FLeiomyosarcomaLN met0Surgery, CYC, CBDCA,IFOProgression-!-13U. R.29/FPNETSkin, pelvic met1Surgery, RT, CYC, CDDP, CBDCA,ADRProgression++/++14C. A.12/FOsteosarcomaLung met1Surgery, RT, CYC, ADR, VCR, DTIC,CBDCANC-!-15A. M.33/MMal. teratomaLiver, LN met1Surgery, RT, CYC,CDDPPR-!-16J. H.36/MPNETLung, bony met2CBDCA, ADR, ETO, VCR,IFONC-!-170. S.31/FPNETBony met1Surgery, CBDCA, IFO,ADRPR+!+18E. J.7.3/MOsteosarcomaBony met2Surgery, RT, IFO, ADR, CDDP, VCR,IFOProgression-!-19K. S.30/FSmall cell carcinomaLiver met1IFO, CBDCA, ELD, ADRPR-!-

12 16

[hJ

THERMOCHEMOTHERAPYIN CANCER PATIENTS

a p@ performance status (14); CYC, cyclophosphamide; CDDP, cisplatin; ADR, Adriamycin; DTIC, imidazole carboxamide; VCR, vincristine; ETO, etoposide; EU), eldesine;

MTX, methotrexate; RT, radiation therapy; LN, lymph node; BM, bone marrow; PR, partial response; NC, no change; met, metastasis.

chemotherapy courses were combined with WBH. The patients were retreatedwhen hematological recovery occurred, usually about 3 weeks after the lasttherapy. WBH treatments were discontinued when disease progression wasdocumented or after a total of three combined courses were given in the settingof disease stabilization.

Six patients (nos. 1—6)received 5 g/m2, three patients (nos. 7—9)6 g/m2,three patients (nos. 10—12)7.5 g/m2, three patients (nos. 13—15)9 g/m2, andfour patients (nos. 16—19)10 g/m2of IFO. If WHO grade 4 myelosuppressionwas observed during the previous cycle, in the subsequent course of therapythe next lower dose of IFO was given. Mesna (Uromitexan®,ASTA, Germany)was administered according to the IFO dose 20 mm before therapy andcontinued over 8 h after the treatment. CBDCA was always given at a dose of480 mg/rn2.

WBH Treatment Procedure. WBH (41.8°Cfor 60 mm) was achieved byreinfusion of extracorporally heated blood, a method modified by Willnow eta!. (13) after Parks and Smith (14). The blood was warmed up during thepassage through a hemodialyzer by the heated dialysate. The desired bodytemperature was adjusted and controlled by changing the volume flow of thewarmed (45°C)reinfused blood.

During all hyperthermia treatments, the patients were under general anesthesia. Heart rate, stroke volume, respiratory rate, and cardiac rhythm were

continuously monitored. Cardiac output was calculated every 10 mm. Arterialblood pressure was monitored in the radial artery. The arterial line also servedas an access for repeated determinations of blood gases. Urinary output wasmeasured hourly by a Foley catheter connected to a closed drainage system.

Rectal temperature and also the temperature of the blood in the pulmonaryartery were continuously recorded. Before each treatment, the temperatureprobes were calibrated against a mercury thermometer standard (sensitivity ±0.05°C).

Patients received high-dose heparin during the WBH treatment because ofthe activation of coagulation due to the hemodialyzer. They received i.v. 5%glucose in 0.45% normal saline with 10 mfiq potassium chloride per liter. Theinitial fluid rate was 1000 ml/h at the onset of heating; this rate was subse

quently adjusted to maintain a minimum systolic blood pressure of 90—100mm Hg and a urine flow greater than 50 ml/h. Twelve of 19 patients received1000 to 1400 ml/h ofthe above solution during heating. Fifteen patients neededcatecholamines to keep their blood pressure within the above-mentioned range.Electrolyte replacement was adjusted according to the results of serial deter

minations of blood levels. A typical WBH treatment session lasted 4 h, 2 h to

reach target temperature and 60 mm at 41.8°C,i.e., the actual period ofhyperthermia, and a 1-h cooling period. Subsequently, the patients werereturned to an intensive care unit and discharged 24 h after observation. Afterthermochemotherapy, patients received an infusion of 500 to 1000 ml ofnormal saline to keep systolic blood pressure above 100 mm Hg. Usuallyposttreatment fluids were tapered over 10 h to 150 mI/b. Patients who developed

a weightgain greater than 1.5kg within 24 h were given 40 mg of furosemidei.v.Patients receivedondansetron0.15 mg/kg as antiemeticprophylaxis.

Rationale for Timing of the Combination Therapy. CBDCA was i.v.infused within 20 mis after the hyperthermia plateau phase (41.8°C in thepulmonary artery) was attained. In a pilot phase of this study on six patients,the blood concentrations of IFO and of 4-OH-IFO were determined during the60-mm lasting infusions of 5 g/m2 WO i.v. ±WBH. In Fig. 1, the IFOconcentration in the blood at 37°Cand 41.8°Crectal temperature is plottedagainst time. At both temperatures, the peak level of IFO and its activatedform, 4-OH-IFO, is reached approximately 60 mm after start of the druginfusion (Fig. 2). As previously shown in vivo (1), the half-life of 4-OH-IFO

under normothermia and under 41.8°CWBH is not significantly different. Toachieve peak drug level at the period of therapeutic WBH (15), we administered IFO i.v. in a 60-mm infusion after reaching 39°Cin the pulmonary artery,with the increase of temperature from 39°Cto 41.8°Ctaking about 1 h in thisvessel.

Posttreatment Evaluation. Patients were monitored weekly for toxicity.The WHO common toxicity criteria were used to grade toxicities (16). Response to the treatment, i.e., complete responses, partial responses, and nochange were evaluated using standard WHO criteria for reporting results ofcancer treatment (16).

Phannacokinefics and Statistical Evaluation. IFO, 4-OH-IFO, and CAApharmacokinetics were assessed in paired courses of IFO (5 g/m2) with orwithout WBH in 6 patients (Table 1, nos. 1—6).Blood samples (10 ml) were

i03

.1:,00.0— 102

0E:1

1010 4 8 20 24

Fig. 1. Time courses of the mean concentrations of ifosfamide without WBH and withWBH in the blood of six cancer patients. At 0 time, start of ifosfamide infusion with a 1-hWBH session (41.8°C)within the first 24 h.

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Table 2 Number ofpatients with thermochemotherapy-related toxicity (Wsystem; Ref 16) at each ifosfamide dose levelHO

gradingIfosfamide

dose(g/m2)5

6 7.5910Patient

nos. 1—6 7—9 10—12 13—15(Table1)16—19Toxicity°

Hematological 6/6 3/3 3/3 3/3Grade 2 2 3 3Max.obs. 3 3 3 44/4

44Renal

1/6 0/3 1/3 2/3Grade 1 1 1—2Max.obs. 1 1 23/4

34Neural

6/6 3/3 3/3 3/3Grade 1 1 1 1Max.obs. 1 1 3 34/4

11Gastrointestinal

6/6 3/3 3/3 3/3Grade 1 1 1 1Max.obs. 2 2 2 24/4

12Liver

2/6 2/3 2/3 3/3Grade 1—2 1—2 1—2 2Max.obs. 2 2 2 32/4

22Cardiac

3/6 1/3 0/3 2/3Grade 1 2 1Max.obs. 1 2 2214

12Metabolic

0/6 0/3 1/3 0/3Grade 2Max. obs. 20/4

THERMOCHEMOTHERAPYIN CANCER PATIENTS

drawn at 0, 0.5, 1, 1.5,2, 4, 6, 9, and 24 h followingthe start of the IFO infusion.For the determinationsof 4—OH-LFO(activated IFO) and CAA, whole bloodsamples were processed immediately as described earlier (1, 17—20).

The term “activated―IFO as used in this paper denotes the sum of all IFOderivatives (4-hydroxyifosfamide, its acyclic tautomer aldoifosfamide, and4-(SR)-sulfidoifosfamide constituting reversible detoxification metaboliteswith thiols) which liberate acrolein (19).

From the concentration versus time profiles, the half-life of IFO and4-OH-IFO were calculated by using a pharmacokinetic computer program(TOPF@Fversion 2.0; Ref. 21). The areas under the curve versus time curveswere calculated according to the trapezoidal rule. For comparison of thepharmacokinetic data from different body temperature groups, the MannWhitney test was used.

Induction of G-CSF by WBH. Plasma was obtained from six patientsbefore (15 min), during and after (3 and 6 h) WBH. The plasma was immediately separated and stored at —70°C(22). The plasma concentration ofG-CSF was assayed using a commercial kit (R&D Systems, Inc., Minneapolis,MN). With this assay, the minimum detectable level was 10 pg/mI G-CSF.

RESULTS

Toxicity

Systemic Toxicity. Overall, patients tolerated therapy well. Nausea or vomiting was well controlled with antiemetics. There wereepisodes of WBH-related diarrhea (grade 1) in all patients. Serumconcentrations of lactate dehydrogenase (LDH), alkaline phosphatase(AP), and aspartate aminotransferase (AST) were determined beforeand after WBH. Since these enzymes can also be synthesized by cellsof nonhepatic origin, their serum concentration can increase withouthepatic cell damage as a consequence of thermochemotherapy. Aspreviously suggested by Robins et a!. (11), we defmed four categoriesof enzyme changes. Five of our patients were in the first category, i.e.,nochangeafterWBH; 11patientswerein thesecondcategorywithtransient LDH elevation without concomitant rise of AP and aspartateaminotransferase. One patient was in category 3; the LDH concentration reached approximately twice the pretreatment value. It returned tobelow pre-WBH values 3 days after the last thermochemotherapytreatment. No WBH-related death occurred.

Hematological/Bone Marrow. Chemotherapy-induced myelosuppression was the major toxicity observed. There was no significantdifference in WBC and platelet nadirs. The highest toxicity gradeobserved in each patient, based on the median WBC and platelet countnadirs, was used to assess the significance of the difference. WhenCBDCA and IFO were given without WBH, the WBC and plateletnadirs were 2.2 ±0.37 k/ml (range, 1.6—3.9)and 67 ±19 k/mi(range, 29—122),respectively. When WBH was added to the combination chemotherapy, the WBC nadir reached 2.6 ±0.41 k/ml (range,1.7—4.9)and the platelet nadir 58 ±17 k/ml (range, 27—130).Thedifferences were not statistically significant. This shows that the bonemarrow toxicity of given doses of CBDCA and of IFO is not increasedby WBH. The lowest nadirs of WBC and platelets (grade 4) occurredin patients 15—19,who received 10 g/m2 of ff0. Patients with plateletcounts less than 20 k/mi received platelet transfusions. There were noepisodes of bleeding. With regard to anemia, there were 18 grade 1 and7 grade 2 episodes. All patients received packed RBC transfusions.

Cardiopulmonary Function. In accordance with data obtained byRobins et al. (11), heart rate and cardiac output of our patientsincreased with rising core temperature, whereby the heart rate roseconsiderably more than the stroke volume.

In 47 WBH treatments, stable mean blood pressure, pulmonaryartery mean pressure, and pulmonary artery wedge pressure wereachieved by fluid substitution and the administration of catecholamines. Two WBH treatments had to be discontinued because of

a@ numberof patientswithsymptomsof toxicity/numberof patientstreatedin thisgroup; Max@obs, maximum observed toxicity.

Renal Function. We studied the impact of high-dose IFO cornbined with CBDCA and WBH on renal function of patients with aninitially normal function. Normal renal function was defined as aserum creatinine level less than or equal to 97 mmollliter and acreatinine clearance greater than or equal to 80 mI/ruin. Renal dysfunction was graded according to the increase of serum creatinine abovebaseline: mild corresponds to an increase of 45 to 70 mmol/liter, mod

crate, to an increase of 90 to 210 mmol/l, and severe, to an increase of 220mmol/liter or greater (23, 24). Four patients of 14 showed signs of mild

toxicity. Two patients suffered from severe renal toxicity (272 mmol/literabove baseline). They eventually developed acute renal failure 5—6weeks post therapy, which required hemodialysis. One patient recoveredafter 3 weeks; the other is still undergoing treatment.

Neurotoxicity. Fatigue following thermochemotherapy was expenenced by all patients. In only one patient, severe objective sensoryloss and objective weakness with impairment of function (plexusbrachialis) occurred. In one case, severe somnolence occurred. Noother signs of neurological impairment were observed.

Skin. Mild anasarca following WBH was experienced by all patients after (up to 3 days) every WBH treatment. Perioral herpessimplex occurred in eight patients and resolved without specifictreatment or sequels. Perioral herpes simplex was only noted after thefirst WBH treatment. Two patients experienced pressure sores atcontact points with blankets.

To illustrate typical data obtained in this study, Table 2 presents thetoxicity level (graded according to WHO common toxicity criteria;Ref. 16) of all patientsat each dose level of IFO.

PharmacoUnelics

Half-life in the Blood of ff0, 4-OH-IFO, and Chioroacetaldehyde at 37°Cand 41.8°CThe areaunderthe curve of IFO (Fig. 1;Table 3), 4-OH-IFO (Fig. 2; Table 3), and CAA (Fig. 3; Table 3)derived from the time courses of the drug concentrations in the bloodat 37°Cand 41.8°C are significantly different (P < 0.001). Thelung edema before the desired body temperature was reached.

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TemperatureCmax― (nmol/ml)AUC (nmolX h X ml@1)t@0@)IFO

37°C41.8°C688

±50659±477044

±5794132±5815.71

±0.45.78±0.54-OH-IFO

37°C41.8°C5.33

±0.34.32 ±1.167

±5.240 ±4.0CAA

37°C41.8°C11.07±1.423.97 ±4.285±9.7 98 ±16

A

4 i@@!@ A 41.8C

@ 1 •37C

j•\•

:@. .@@

THERMOCHEMOTHERAPYIN CANCER PATIENTS

of action combined with 41.8°CWBH was beneficial to some patientswith tumors refractory to conventional therapy. Seven of 19 assessable patients responded to thermochemotherapy (Table 1). We observed a remarkable and sustained pain relief in four patients after thefirst WBH treatment (Table 1). Since two of these patients had stabledisease, the latter observation could be explained by the report ofRobins et al. (26) who found rises ofplasma-@3-endorphin, ACTH, andcortisol levels in patients undergoing WBH which were associatedwith prolonged palliation of pain. In their discussion, they point outthat the central nervous system levels of endorphin do not correlatewith plasma levels, which are only temporarily elevated (26). Hence,a full explanation for sustained pain relief may involve changes on acentral level which require further investigation.

In our study, drug dosing was critical since a hemodialysis apparatus was used to induce WBH. This unavoidably leads to the dimination of a certain amount of the drugs. According to our measurements of IFO and 4-OH-IFO in the blood and in the dialysate undernormothermia and under WBH, approximately 30% of the substanceswere eliminated by dialysis (Figs. 1 and 2; Table 3). According toMotzer et a!. (27), 25 to 30% of the CBDCA dose is eliminated after4 h of hemodialysis. In contrast to the blood concentrations ofIFO and4-OH-IFO, the concentration of CAA was significantly increased duringWBH (Fig. 3). Since it is known that CAA reduces the level of tissueglutathione, thus inhibiting the degradation of oxygen radicals, this mayexplain the increased therapeutic efficacy of IFO on the tumor cells, aswell as the increased nephrotoxicity of this drug under WBH.

A combination chemotherapyof IFO plus CBDCA, in a similar

@000.0

0E:1

12Ihi

Fig. 2. Time courses of the mean blood concentrations of 4-OH-ifosfamide in sixpatients without WBH and with WBH (41.8°Cfor 1 h within the first 24 h of the timescale). At 0 time, start of ifosfamide infusion.

@000

.0

0E

Table 3 Pharmacokinetic parameters of fF0, activated fF0 (4-OH-JFO), and CM insix patients (nos. 1—6;Table 1) with or without WBH (41.8°C WBH), following iv.

application of fF0 (5 2)

aAUC,areaundertheconcentration-timecurve;Cmax,maximalconcentration;t@,half-life. Values are mean ±SE.

concentrations of IFO and of 4-OH-IFO are lower at 41.8°C(Figs. 1 and2). This differenceis due to the loss of drugby hemodialysis;we foundabout 30% of the drug dose given either in the form of IFO or as4-OH-IFO in the dialysate (data not shown). However, in spite of hemodialysis, the concentration of CAA is higher during WBH than at normotherinia. The pharmacokinetic data are summarized in Table 3.

Cytokine Induction

G-CSF Blood Concentrations under Thermochemotherapy.WBH induced G-CSF in all patients tested in a pattern similar to thatdescribed earlier (22).

Response to Therapy

Seven of 19 evaluable patients demonstrated a partial response.Two of those patients experienced progression of their disease approximately 5 months after therapy. Eight patients had no change, andfour progressed with thermochemotherapy. Furthermore, it is noteworthy that severe pain in four patients improved markedly after thefirst WBH treatment (Table 1).

DISCUSSION

Laboratory research involving murine as well as human tumormodels has demonstrated an increase of therapeutic index if CBDCA(6) or IFO (1) were combined with 41.8°CWBH. In these studies, thethermal enhancement ratio ranged from 3 to 5 for CBDCA (5) and 2to 3 for IFO (1). Since 41.8°CWBH itself is nonmyelosuppressiveand can potentiate the tumoricidal effects of myelosuppressive alkylating agents (1—3,25), the use of WBH in combination with alkylating agents is an attractive strategy, assuming it does not increasechemotherapy-related toxicity.

Robins et a!. (10) confirmed in an NCI Phase I clinical trial thepreclinical predictions derived from studies of the therapeutic effect ofthe combination of 41.8°C WBH and CBDCA. They found that41.8°CWBH did not increase CBDCA-induced myelosuppression butproduced complete and partial remissions in patients (some of whomwere previously refractory to platinum therapy). The pharmacokinetics of CBDCA were not altered by 41.8°CWBH. The combination ofWBH and CBDCA was well tolerated up to 575 mg/rn2. These dataallowed extrapolation of a carboplatin dose, i.e., 400—480 mg/rn2 tobe used in an eventual Phase II clinical trial (10). Additionally, it wasshown that WBH increased CBDCA adduct formation. As a corollaryto this study, d'Oleire et a!. (22) demonstrated WBH-induced G-CSFand interleukin 1. This cytokine induction could in part explain thelack of increased myelosuppression observed with the combination ofWBH and CBDCA (22).

The results of our pilot clinical study suggest that the simultaneousadministration of two chemotherapeutic agents with different modes

20

15

10

“0 4 8 12

[h]

16 20 24

Fig. 3. Time courses of the mean blood concentrations of chloroacetaldehyde in sixpatients without WBH and with WBH (41.8°Cfor 1 h within the first 24 h of the timescale). At 0 time, start of ifosfamide infusion.

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hyperthermia enhances cyclophosphamide, ifosfamide, and cis-diamminedichloroplatinum(ll) cytotoxicity on human-derived breast carcinoma and sarcoma xenograftsin nude mice. J. Cancer Res. Clin. Oncol., 118: 129—135,1992.

4. Cohen, J. D., Robins, H. I., and Schmitt, C. L Tumoricidal interactions of hyperthermia with carboplatin, cisplatin and etoposide in human leukemia cells in vitro.Cancer LeSt, 44: 205—210,1989.

5. Cohen, J. D., and Robins, H. I. Thermal enhancement of tetraplatin and CarbOplatinin human leukemia cells in vitro. Int. J. Hyperthermia, 6: 1013-1017, 1990.

6. Tapazoglou, E., Cohen, J., Schmitt, C. L, Khatana, A., Sapareto, S. A., and Robins,H. I. Whole body hyperthermia (WBH) and carboplatin: cytotoxicity for murineleukemia and normal bone marrow. Br. J. Cancer, 64: 528—530, 1991.

7. Cohen, J. D., Robins, H. I., and Javid, M. Sensitization of C6 glioma to carboplatincytotoxicity by hyperthermia and thymidine. J. Neurooncol., 9: 1-8, 1990.

8. Obno, S., Siddik, Z. H., and Baba, H. Effect of carboplatincombinedwith whole-bodyhyperthermia on normal tissue and tumor in rats. Cancer Res., 51:2994-3000,1991.

9. Wallner, K. E., DeGregorio, M. W., and Li, G. C. Hyperthermic potentiation cisdiamminedichloroplatinum(1I) cytotoxicity in Chinese hamster ovary cells resistant tothe drug. Cancer Res., 46: 6242—6245,1986.

10. Robins, H. I., Cohen, J. D., Schmitt, C. L, Tutsch, K. D., Feierabend, C., Arzoomaman, R. Z., Alberti, D., d'Oleire, F., Longo, W., Heiss, C., Rushing, D., Love, R., andSpriggs, D. 3. Phase I clinical trial of carboplatin and 41.8°Cwhole-body hyperthermia in cancer patients. J. Gin. Oncol., 11: 1787—1794,1993.

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THERMOCHEMOTHERAPYIN CANCER PATIENTS

dose range, has been used in Phase I and II studies (28—30).In thesestudies, the DLT in the bone marrow was observed at doses ofCBDCA between 300—480mg/rn2 combined with IFO doses between5—7g/m2. Nephropathy and esophagitis were the DLT in a studywhere this drug combination was used at high doses followed byautologous bone marrow rescue (31). In the present study, a combination of CBDCA (300 mg/m2) plus IFO (7 g/m2) and WBH causedgrade IV bone marrow toxicity and severe nephropathy (Table 2).Although hematological suppression was significant, our hematological data suggest that hyperthermia did not enhance toxicity beyondthat of drug alone. This is consistent with earlier observations (10). Anincreased level of G-CSF was found in our patients undergoing WBH.Thus, our data confirm the previously published demonstration of

cytokine induction by WBH in humans (22). The DLT in this studywas the nephropathy and not bone marrow toxicity. The latter toxicitycould be further reduced by the administration of exogenous G-CSF.

Taking into consideration the aforementioned toxicities, safe dosesof CBDCA should be 300 mg/m2 with IFO 5 g/m2 and WBH(41.8°Cx 1 h) for Phase II trials in adult patients. If WBH is inducedby a hemodialysis apparatus, the “administered“drug doses could beincreased to 480 mg/m2 CBDCA and 7.5 g/m2 IFO.

Above, we have discussed drug-specific side effects associated withthe general use of WBH. A number of side effects specifically relatedto extracorporally induced WBH have presented a critical problem inthe past. This has precluded the widespread use of this type of WBHtogether with cytotoxic therapy. Extracorporally induced WBH hasbeen associated with pulmonary edema, arrhythmias, liver necrosis,peripheral neuropathy, transverse myelitis, seizures, rhabdomyolysis,hemorrhage, protracted diarrhea, hepatitis, coagulopathies, electrolyteabnormalities, pressure sores, and infection (reviewed in Ref. 24).Willnow et al. (13) used the same WBH method as our group inseventeen children. Their therapy-related toxicity included one death,encephalopathies with coma, reversible neuropathy, coagulopathies,cardiomyopathy (under concomitant doxorubicin administration), andreversible worsening of liver function tests. Interestingly, they describe a very high response rate at comparatively low drug doses. Inthe presented study, treatment-induced morbidity included mild toxicity (anasarca, diarrhea, pressure sores, and perioral herpes simplex)severe toxicity (reversible neuropathy and cardiopulmonary distress).Two patients developed acute renal failure, one of which was reversible. Two WBH treatments of 49 treatments had to be interruptedbecause of pulmonary edema, although patients were carefully prescreened for organic heart disease.

The data described above taken collectively is consistent with furtherclinical investigation of WBH in combination with cytotoxic therapy.Since most University centers use hemodialysis, the method of extracorporally induced WBH combined with CBDCA and IFO could be studiedin selectedcancerpatients.Beyondthis, the presenteddatahave implications for the use of CBDCA and IFO for other WBH technologies.

ACKNOWLEDGMENTS

We are grateful to Professor I. H. Robins (University of Madison, Wisconsin) for thoughtful advice during the course of this study as well as his reviewand suggestions regarding the preparation of the manuscript.

REFERENCES

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2. Wiedemann,G. J., Melts, 0., Roszinsld,S., Weiss,C., and Wagner,T. Local hyperthermisenhancesmitoxantronecytotoxicityonhumanderivedbreastcarcinomaandsarcomaxenograftsin nude mice. lot. J. Radial.OncoLBiol. Phys., 24: 669—673,1992.

3. Wiedemann, G. J., ROSZ1nSki,S., Biersack, A., Weiss, C., and Wagner, T. Local

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1994;54:5346-5350. Cancer Res   Günter J. Wiedemann, Floriane d'Oleire, Erdmute Knop, et al.   Malignant TeratomaHyperthermia in Patients with Refractory Sarcoma and Ifosfamide and Carboplatin Combined with 41.8°C Whole-Body

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