Ifosfamide carboplatin and etoposide combined with whole

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					                                                          Lung Cancer 39 (2003) 339 Á/345

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
                                     Medical University of Lubeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
                                                       University of Wisconsin, Madison, WI, USA
                                                   Zentralkrankenhaus Bremen-Ost, Bremen, Germany
                                                            AKH Harburg, Hamburg, Germany
                                                   Krankenhaus Großhansdorf, Großhansdorf, Germany
                                                       Krankenhaus Trostberg, Trostberg, Germany
                                               Uuiversitatsklinik Eppendorf Hamburg, Hamburg, Germany
                                                 Oberschwaben Klinik Ravensburg, Ravensburg, Germany

                       Received 24 July 2002; received in revised form 12 November 2002; accepted 26 November 2002


  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
                                                                             [2]. 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 [1]. 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% [5]. Clearly, improved treatment strategies
                                                                             are needed for this patient population.
  * Corresponding author. Tel.: '/49-451-5000/5002316; fax: '/49-
                                                                                Hyperthermia has exerted antitumor effects preclini-
  E-mail     address:        (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.
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 [12]. Synergistic growth inhibitory
effects have been seen in a pleural mesothelioma cell line         2.3. Chemotherapy
when hyperthermia was combined with ifosfamide [13].
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 [14]. 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 [15].
   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 [18]. 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 [16]. 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 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
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
                                                                                  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

                                                                               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 [3].
                                                                               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% [5]. 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
                                                                               [22]. Follow-up studies of this combination have de-
Toxicity grade                  1            2          3        4             tected lower response rates of 26 and 16% [23]. 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 [4]. 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 [24]. 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 [25].
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
     47 courses of treatment in 27 patients                                    months versus 3.9 months, and 12.1 months versus 9.3
     Common toxicity criteria (National Institute of Health) */version         months, respectively). Toxicity with this regimen was
2.0:                                                  ameliorated with the use of folate and vitamin B12
344                                  A. Bakhshandeh et al. / Lung Cancer 39 (2003) 339 Á/345

supplementation [25]. 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 [26]. 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 [27].
   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
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