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Lung Cancer 39 (2003) 339 Á/345 www.elsevier.com/locate/lungcan Ifosfamide, carboplatin and etoposide combined with 41.8 8C whole body hyperthermia for malignant pleural mesothelioma A. Bakhshandeh a,*, I. Bruns a, A. Traynor b, H.I. Robins b, K. Eberhardt c, A. Demedts c, E. Kaukel d, G. Koschel d, U. Gatzemeier e, Th. Kohlmann a, K. Dalhoff a, E.M. Ehlers a, Y. Gruber a, R. Zumschlinge f, S. Hegewisch-Becker g, S.O. Peters a, G.J. Wiedemann h a Medical University of Lubeck, Ratzeburger Allee 160, 23538 Luebeck, Germany ¨ b University of Wisconsin, Madison, WI, USA c Zentralkrankenhaus Bremen-Ost, Bremen, Germany d AKH Harburg, Hamburg, Germany e Krankenhaus Großhansdorf, Großhansdorf, Germany f Krankenhaus Trostberg, Trostberg, Germany g Uuiversitatsklinik Eppendorf Hamburg, Hamburg, Germany ¨ h Oberschwaben Klinik Ravensburg, Ravensburg, Germany Received 24 July 2002; received in revised form 12 November 2002; accepted 26 November 2002 Abstract We performed a phase II study combining 41.8 8C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m2), carboplatin (300 mg/m2) and etoposide (150 mg/m2 on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonaive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate ¨ was 20% (five partial remissions; 95% CI 8.9 Á/39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4 Á/87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4 Á/34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Whole body hyperthermia; Chemotherapy; Malignant pleural mesothelioma 1. Introduction tory, with overall survival measuring 12 months or less . Single or combined modality treatments using Malignant mesothelioma is the most common tumor curative or debunking resection, adjuvant radiotherapy, of the pleura. Although rare, its incidence is increasing and adjuvant or palliative chemotherapy have yet to due to prior occupational exposure to asbestos, and this consistently impact on survival [3,4]. A meta-analysis trend is expected to continue until at least 2020 . The examining 55 phase II trials determined that cisplatin incidence of malignant pleural mesothelioma in Europe was the most active single chemotherapeutic agent, with is 1.6 cases per 100 000. Treatment remains unsatisfac- a response rate of 18.8%, while cisplatin and doxorubi- cin was the most active combination, with a response rate of 29.7% . Clearly, improved treatment strategies are needed for this patient population. * Corresponding author. Tel.: '/49-451-5000/5002316; fax: '/49- 451-5002356. Hyperthermia has exerted antitumor effects preclini- E-mail address: email@example.com (A. cally and in patients with various malignancies, such as Bakhshandeh). gastrointestinal tumors, lung cancer, and sarcoma [6,7]. 0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(02)00536-6 340 A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345 Neoplastic cells appear more sensitive to the effects of full pulmonary function tests being less than 60% of hyperthermia greater than 41 8C, compared to normal predicted. Neurologic bases for exclusion were previous cells [6,8,9]. Mechanisms of the antitumor actions of spinal cord or brain irradiation, documented peripheral hyperthermia include inhibition of the DNA repair neuropathy (paraneoplastic or otherwise), or a history enzyme poly (ADP/ribose) polymerase, via reduced of emotional instability. levels of NAD'/, induction of apoptosis and inhibition of neoangiogenesis [6,10,11]. 2.2. Treatment plan The combination of hyperthermia and carboplatin has demonstrated the ability to overcome platinum All eligible patients were treated in 28 day cycles resistance in patients with ovarian cancer, while not according to the schema outlined in Fig. 1. worsening toxicity . Synergistic growth inhibitory effects have been seen in a pleural mesothelioma cell line 2.3. Chemotherapy when hyperthermia was combined with ifosfamide . Lastly, preclinical data have demonstrated that the 2.3.1. ICE treatment procedure sequential use of VP-16 after WBH (in combination Ifosfamide (IFO; ASTA Medica Oncology, Frank- with ifosfamide and carboplatin) down regulates glucose furt, Germany) at 5 g/m2 was infused (i.v.) over 60 min related stress protein 78 (GRP-78), which confers after 37 8C rectal temperature was attained by heating resistance to VP-16 . Together, these data provide the patient. Carboplatin (CBDCA; Bristol-Meyers the rationale for combining radiant heat hyperthermia Squibb, NJ, USA) at 300 mg/m2 was infused (i.v.) using the Aquatherm device with ICE chemotherapy in over 20 min; 10 min after achieving 41.8 8C by patients with malignant pleural mesothelioma. esophageal temperature. Etoposide (VP-16; Bristol- Meyers Squibb) at 150 mg/m2 was given (i.v.) over 60 min on days 2 and 3 post-WBH. Mesna (Uromitexan, 2. Materials and methods ASTA Medica) was administered intravenously before the start of IFO infusion and every 4 h thereafter for a 2.1. Patient selection total of three administrations. Each Mesna dose was 20% (1 g/m2) of the amount of IFO given per day. Patients with histologically confirmed advanced ma- The actual body surface area was used to calculate lignant pleural mesothelioma enrolled in this trial chemotherapy doses; both actual and ideal surface areas between April 1999 and February 2001. Patients were were calculated. If actual was B/12.5% above ideal, the informed about the investigational nature of this study actual surface area was utilized. If actual was E/12.5% and signed an informed consent form previously above the ideal, the maximum surface area to be used approved by the Human Subjects Committee. Patients was 2.0. had to be over 18 and below 65 years of age and had to Granulocyte colony stimulating factor at 5 mg/kg BW have a projected life expectancy of at least 12 weeks and per day (Filgrastim; Amgen, Inc., CA, USA) was an ECOG performance status of 0/2. Patients were administered subcutaneously beginning 24 h after the required to have pre-therapy baseline physical exams last day of chemotherapy for 5 days. Patients with and CT scans. No other chemotherapeutic agents could platelet counts less than 20 )/109/1 received platelet be given on study. Patients were staged using Classifica- transfusions. tion of International Mesothelioma Interest Group . Patients were required to have adequate bone marrow 2.4. WBH treatment procedure and supportive care function (defined as WBC !/3000 cells/ml, an absolute granulocyte count E/1000 cells/ml and a platelet count of The WBH treatment procedure was defined as raising E/100 000 cells/ml), adequate liver function (total bilir- a patient’s systemic temperature, (maximum tempera- ubin 0/1.5 mg%, alkaline phosphatase and AST 0/3 )/ ture recorded by either rectal or esophageal/axillary normal; total protein not less than 15% of lower limit of probe) to 41.89/0.2 8C )/60 min [16,17]. When this normal), adequate renal function (creatinine B/1.2 temperature was achieved, the patient was removed mg%, and BUN 0/30 mg%, or creatinine clearance E/ from the WBH device and systemic temperatures were 60 ml/min) and normal metabolic parameters (calcium maintained by keeping a vapor barrier on the patient to and serum electrolyte values). minimize evaporative losses. To terminate a hyperther- Patients with a history of an allergy to lidocaine, mia treatment, at the end of 60 min, the vapor barrier malignant hyperthermia associated with general an- was removed to allow physiological temperature regula- esthesia, documented coronary artery disease, angina, tion. congestive heart failure, or serious dysrhythmias were The Aquatherm system for delivering WBH (patented, excluded. The protocol excluded patients with severely Cancer Research Institute, NY, NY) has been pre- compromised respiratory status, i.e. any component of viously described . During all hyperthermia treat- A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345 341 Fig. 1. ICE-chemotherapy and whole body hyperthermia treatment schema. ments, patients received nasal oxygen at 2 Á/6 l/min. observed after treatment for 20 Á/24 h prior to dis- Heart rate, respiratory rate, oxygen saturation, and charged. All patients received ondansetron or granise- cardiac rhythm were continuously monitored. Blood tron with dexamethasone for emetic prophylaxis. pressure (systolic/diastolic) was monitored at least every 10 min. Esophageal, rectal, skin, and ambient air tempera- 2.5. Duration of treatment tures were monitored continuously and recorded at a minimum of 10 min intervals. Temperature probes were Patients received a second cycle of therapy 4 weeks calibrated at least monthly against defined external after the first cycle if sufficiently recovered from toxicity. standards (9/0.02 8C); data were analyzed using a linear Patients were required to have adequate bone marrow regression method; corrections were made from 37.0 to function prior to each cycle, and treatment was delayed 43.0 8C. Temperature probes were cleaned using a until bone marrow recovery, defined as WBC !/3000 standard procedure pre- and post-WBH treatment. cells/ml, an absolute granulocyte count E/1000 cells/ml Patients received 0.75 Á/1.0 l of intravenous 5% dex- and platelet count of E/100 000 cells/ml. Responding trose in 0.25 normal saline per hour alternating with 5% patients or those with stable disease (SD) could receive dextrose in 0.5 normal saline plus approximately 7.5 up to 2 additional cycles of therapy, unless there was mEq of potassium chloride per liter. Urinary output (75 evidence of progression. Patients with progressive dis- ml/h), and electrolytes were monitored to assure fluid ease (PD) were removed from the study after 2 cycles. and electrolyte homeostasis during and after the proce- Other reasons to be removed from the study were the dure. A typical WBH treatment session lasted 4 h, patient’s decision to withdraw, significant changes in the including 1.3 h to reach target temperature, 1 h at patient’s medical condition that would render the 41.8 8C, and a 1 h cooling phase. Post-treatment, patient unacceptable for treatment in the judgment of patients received normal saline 500 Á/1000 ml as needed the investigator (e.g. significant progression), develop- to maintain systolic blood pressures greater than 90 mm ment of central nervous system disease while on study, Hg. Patients were sedated during WBH with a combina- and treatment delay for E/4 weeks. tion of i.v. thiopental (Â/4 mg /min) and i.v. lidocaine (Â/4 mg/min); the details and rationale for this have been previously described . Patients also received 2.6. Evaluation incremental boluses of i.v. midazolam (2 Á/5 mg) and i.v. fentanyl (25 Á/50 mg). Droperidol (1.25Á/5 mg) was administered during the first 30 min of WBH therapy 2.6.1. Toxicity evaluation for both its sedative and antiemetic effects. The aim of Toxicities were assessed using the Common Toxicity sedation was to have a patient who could respond to Criteria (NCI CTC) (National Institute of Health- verbal stimulation and continue spontaneous respira- version 2.0: available from http://ctep.info.nih.gov). All tions at a rate greater than 10 breaths/min. Patients were patients were considered evaluable for toxicity. 342 A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345 2.6.2. Response evaluation Table 1 Patients were required to undergo at least two cycles Demographic proﬁle and patient characteristics of therapy to be evaluable for response. Patients were Patients entered 27a followed with physical exams and standard laboratory Patients evaluable for response 25 evaluation. Thoracic CT scans were used in all cases to ECOG performance status 0 Á/2 range evaluate treatment response and were performed after 1 mean the second and fourth treatment cycles. All CT scans Age, years 47 Á/65 range were reevaluated by an independent radiologist and our 58 mean centrally radiologist upon completion of the study. The No prior chemotherapy 27 depth of the tumor was measured on contiguous slices Gender obtained at the level of the thickest lesions. The three Male/female 22/3 thickest lesions were chosen as the parameter for Histologies response. The determination of the levels of the control Epithelial 16/25 scans was adjusted with regard to different landmarks Sarcomatous 2/25 within the mediastinum, depending on the location of Mixed/biphasic 7/25 the tumor. Complete response (CR) required disappear- Stage of the disease ance of all clinically detectable malignant disease with- Ib 5/25 II 4/25 out development of new malignant lesions lasting for at III 14/25 least 4 weeks. Partial response (PR) was defined as E/ IV 2/25 50% decrease in tumor size or thickness lasting for at a least 4 weeks without increase in size of any area or Two patients received only 1 course of treatment because of cardiac complication (cardiac arrhythmia during hyperthermia thickness of known malignant disease or appearance of 41.3 8C, and were therefore not evaluable for response. new areas of malignant disease. Minor response (MR) was defined as a decrease in tumor size or thickness of profile of patients is presented in Table 1. The majority less than 50% but greater than 25% for at least 4 weeks of patients enrolled in this study had epithelial histology. without signs of progression. SD was defined by no Also, most patients had stage III disease. Twenty-five significant change in measurable disease for at least 8 patients were evaluable for response. All patients were weeks, no increase in size of any known malignant evaluable for toxicity. disease, and no appearance of new areas of malignant Table 2 presents response results for the overall disease. PD was defined as a E/25% increase in the size patient population. The overall response rate was 20% or thickness of lesions present at the start of therapy or (five partial remissions; 95% CI 8.9 Á/39.1%), with MRs appearance of new metastatic lesions. seen in 12% of patients and SD occurring in 44% of patients. 2.7. Statistical planning and analysis Fig. 2 displays the Kaplan Á/Meier estimate for overall survival for the study participants. Median overall Sample size considerations were based on the overall survival time from the start of treatment for all patients response rate. We computed 95 percent confidence was 76.6 weeks (95% CI 65 Á/87.8 weeks). Median intervals for response rates of 20, 30 and 40% assuming survival time from initial diagnosis was 83.8 weeks sample sizes between 25 and 40 patients. With an overall (95% CI 73.9 Á/93.8 weeks) for all patients. Fig. 3 response rate of 20% the length of the confidence displays the KaplanÁ/Meier estimate for progression interval in a sample of 25 patients is approximately free survival for the patients evaluable for response in 30% points. Increasing sample size would result in a this study. Progression free survival for all patients from reduction of the confidence interval to 29, 27 and 25% the start of treatment measured 29.6 weeks (95% CI points in samples of 30, 35, and 40 patients, respectively. 24.4 Á/34.7 weeks). The 1 and 2 year overall survival rates Similar results were obtained with response rates of 30 were 68 and 20%, respectively, with 5 patients still alive and 40%. Given these results it was decided that the as of October 2002. minor reduction of confidence interval width would not justify to increase the sample size beyond 25 patients. 3.2. Toxicity 3. Results Toxicity data according to the NCI CTC are sum- marized in Table 3. Myelosuppression was significant 3.1. Response to therapy but manageable. There was 1 death associated with PD and sepsis. Patients became neutropenic and/or throm- Twenty-seven patients enrolled into this study from bocytopenic between days 7 and 10 after WBH treat- April 1999 through February 2001. A demographic ment. Two cardiac complications (cardiac arrhythmia A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345 343 Table 2 Percent (%) responses in different patient cohorts Patient population RR (%) RR (%) 95% CI CR (%) PR (%) MR (%) SD (%) PD (%) Total (n0/25) 20 8.9 Á/39.1 0 20 12 44 24 n , number of patients; RR, overall response rate; CI, confidence interval; CR, complete response; PR, partial response; MR, minor response; SD, stable disease; PD, progressive disease during hyperthermia at 41.3 8C) were observed despite the use of prophylactic lidocaine during WBH. No episodes of heart failure or myocardial infarction occurred. The data from this ICE'/WBH study demonstrated no differences in blood count nadirs for WBH'/ICE as compared to reports of patients treated with ICE alone [7,19]. 4. Discussion Fig. 2. Overall survival for all patients from start of treatment. Treatment for malignant pleural mesothelioma has failed to date to consistently prolong survival, likely due to poor patient selection, pathologic misdiagnoses, and ineffective therapies [3,4]. Surgical resection with pleur- opneumonectomy requires patients with excellent pre- morbid exercise tolerance without dyspnea . Favorable prognostic factors identified in surgical and medical series include pure epithelial histology, good performance status, female gender, absence of lymph node involvement, and absence of leucocytosis [20,21]. Preliminary results from a 1999 meta-analysis that reviewed 55 phase II studies of chemotherapy in malignant pleural mesothelioma identified cisplatin as the most active single agent, with a response rate of Fig. 3. Progression-free time for all patients from start of treatment. 18.8%, and the combination of cisplatin and doxorubi- cin as the most active regimen, with a response rate of 29.7% . A phase II study of 21 patients treated with the combination of cisplatin and gemcitabine yielded a Table 3 response rate of 47% and overall survival of 10 months Percent incidencea, toxicityb . Follow-up studies of this combination have de- Toxicity grade 1 2 3 4 tected lower response rates of 26 and 16% . Anti- folates have also demonstrated activity in phase II trials, WBC 8.0 4.0 24.0 50.0 with response rates of 25% for edatrexate and 37% for Infection 10.0 6.0 5.0 0.0 Platelet 18.0 22.0 15.0 18.0 methotrexate . Four patients achieved partial remis- Hgb 22.0 35.0 9.0 1.0 sion in a phase I study of the multitargeted antifolate GI 13.0 8.0 1.0 0.0 pemetrexed in combination with cisplatin . As such, Nausea 51.0 8.0 9.0 0.0 a large, international phase III trial, comparing cisplatin Vomiting 41.0 4.0 4.0 0.0 alone with cisplatin plus pemetrexed was conducted . Hepatic 14.0 3.0 0.0 0.0 Fatigue 4.0 0.0 0.0 0.0 In that study of 456 chemonaive patients, antitumor ¨ Skin 3.0 0.0 3.0 0.0 response, time to progression, and median survival were Renal 8.0 3.0 0.0 0.0 all statistically significantly improved in patients receiv- ing the combination therapy (41% versus 17%, 5.7 WBC, neutropenia; Hgb, hemoglobin; GI, gastrointestinal a 47 courses of treatment in 27 patients months versus 3.9 months, and 12.1 months versus 9.3 b Common toxicity criteria (National Institute of Health) */version months, respectively). Toxicity with this regimen was 2.0: http://ctep.info.nih.gov ameliorated with the use of folate and vitamin B12 344 A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345 supplementation . Another novel compound under This clinical trial demonstrates the feasibility of investigation for its use in mesothelioma is ranpirnase, performing a large multicenter cooperative group study an antineoplastic ribonuclease derived from frog eggs. involving WBH. These findings, taken together with the In a recent phase II trial of this compound, a median preclinical studies and earlier clinical studies, support survival of 8.3 months resulted in good prognosis the continued investigation of this multimodality ap- patients . The combination of doxorubicin and proach in this poor prognosis patient population. We ranpirnase is to be tested against doxorubicin alone in propose the outcome of this study provides a strong an upcoming phase III trial. Lastly, recent studies of foundation for a phase III randomized clinical trial of immunotherapy using intrapleural interleukin-2 or sys- chemotherapy with and without WBH. temic interferon a-2b have revealed encouraging results that require confirmation . Hyperthermia has enhanced the cytotoxicity of radio- therapy or chemotherapy when used in combination in Acknowledgements preclinical models [6,7]. An improvement in the ther- apeutic index of carboplatin was seen when adminis- Support: the Cancer Research Institute, Inc. NYC, tered with WBH, with increased adduct formation and NY; DFG, Bonn; Hauptverband der gewerblichen simultaneous mitigation of myelosuppression, second- Berufsgenossenschaften, St. Augustin, Germany. ary to the WBH-induced expression of myeloprotective cytokines, such as Il-6, Il-3, Il-8, GCSF, GMCSF, and TNF-a . 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