[CANCER RESEARCH 44, 1688-1692, April 1984]

Experimental and Clinical Activity of Mitomycin C and c/s-Diamminedichloroplatinum in Malignant Mesothelioma1

A. Philippe Chahinian,2 Larry Norton, James F. Holland, Lenina Szrajer, and Ronald D. Hart

Department of Neoplastia Diseases, Mount Sinai School of Medicine of the City University of New York, New York, New York 10029 [A. P. C., L. N., J. F. H., L S.], andDepartment of Medicine, St. Luke's Hospital, Milwaukee, Wisconsin 53215 [R. D. H.]

ABSTRACT

Little information is available regarding the effectiveness ofchemotherapeutic agents in malignant mesothelioma. Humanmalignant mesothelioma specimens from two patients were successfully transplanted and maintained in homozygous nude mice.Screening of chemotherapeutic agents revealed that cisplatinwas the most active single agent in one line, and mitomycin C inthe other. The combination of mitomycin C and cisplatin, however, was the most effective regimen for both lines of xeno-

grafted human mesothelioma. Based on these results in nudemice, a clinical trial of mitomycin C and cisplatin was undertaken.Four of 12 patients showed objective response (one completeand three partial). These clinical results support the usefulnessof the nude mouse model for malignant mesothelioma.

INTRODUCTION

Malignant mesothelioma is a disease of growing importance.As predicted (25), its incidence is increasing (17) as a result ofthe widespread use of asbestos, its major etiological agent.Results of various therapies for malignant mesothelioma havebeen generally poor (5, 8). Neither surgery nor radiotherapy iscurative. Very little information is available regarding the activityof chemotherapeutic agents (4, 8).

The availability in our laboratory of 2 distinct cell lines of humanmalignant mesothelioma serially transplanted into nude mice (6)allowed us to study systematically the activity of chemotherapeutic agents alone and in combination in this model. Onecombination, mitomycin C and cisplatin, exhibited efficacyagainst both lines in the nude mouse system (7). Based on thisresearch, a clinical trial of this combination was initiated in 12consecutive patients with malignant mesothelioma.

MATERIALS AND METHODS

Nude Mouse Xenografts. Two lines of human malignant mesothelioma (designated BG and ES) have been serially transplanted s.c. since1978 in nude mice, as previously described (6). For these experiments,8- to 10-week-old homozygous female nude (nu/nu) mice were obtained

from the Animal Genetics and Production Branch of the National CancerInstitute, Bethesda, MD. Filtered air and sterilized bedding, cages, food,and water were used. Serial transplantation of tumors was carried outby excision of tumors under light anesthesia by inhalation with methox-

yflurane (Penthrane; Abbott Laboratories, North Chicago, IL). The tumorspecimens were dissected under sterile conditions in a Petri dish con-

taining Roswell Park Memorial Institute Medium 1640 (Grand IslandBiological Co., Grand Island, NY) and trimmed of cutaneous, connective,and adipose tissues under a fiberglass tissue culture hood (FisherScientific Co., Pittsburgh, PA). Small tumor cubes measuring 1 to 2 mmwere inserted in a trocar and transplanted s.c. into 4 sites/mouse in theright and left groin and axilla, or into one site/mouse in the right axilla.

Since single-cell suspensions were not used, the number of cells

transplanted in these specimens can only be determined on histologicalsections. For that purpose, tumor specimens were fixed in 10% neutralformalin and embedded in paraffin after dehydration in alcohol. Five- toe-^m sections were made and stained with hematoxylin and eosin.

Histological sections were examined with a Nikon light microscope(Nikon, Inc., Garden City, NY) equipped with an ocular micrometercalibrated with a hemacytometer (American Optical Scientific Instruments, Buffalo, NY). The number of tumor cells per cu mm was determined by numerical analysis in 20 random fields at x400 for each lineBG and ES (9), after correction for section thickness, fixation shrinkage(2), and proportional tumor cell content. Under these conditions, thenumber of tumor cells per cu mm was [4.8 ±0.18 (S.E.)] x 10s for BGxenografts, and [3.3 ±0.32] x 105 for ES xenografts.

Mice were observed every weekday and weighed once weekly. Bothlines BG and ES have retained their original histological, histochemical,and ultrastructural features despite serial transplantation (6, 30). Kary-

otypes have confirmed their human nature (6). Line BG is an epithelialmalignant mesothelioma, and line ES is a mixed or biphasic, but predominantly epithelial malignant mesothelioma (6). After the growth of s.c.implants was established, cohorts of mice transplanted with the sametumor specimen (one or 4 s.c. implants/mouse) were randomized between chemotherapy (2 to 6 animals/group), and control with 0.9% NaCIsolution (2 animals/group). All injections were given i.p.

Quantification of Antineoplastic Activity. Tumor volume was measured with calipers once or twice weekly, using the formula for a prolateellipsoid

1Supported in part by Cancer Center Grant CA-23102 from the National Cancer

Institute, and by the T. J. Marteli Memorial Foundation for Leukemia and CancerResearch. Presented in part at the 74th Annual Meeting of the American Associationfor Cancer Research, San Diego, May 25 to 28, 1983 (7).

2To whom requests for reprints should be addressed.

Received September 13, 1983; accepted January 6, 1984.

where L is the greatest length and W is the perpendicular width of thetumor corrected for skin thickness (12, 19) (Fig. 1). Overall treatmenteffect was measured using the mean ratio T/C (expressed as a percentage) of the tumor volumes between Days 35 to 49 after tumor implantations for treated animals (T) over the tumor volumes of correspondingcontrols (C) (12). A T/C ratio of 42% or less is considered to be anindication of activity (12). Life span was measured from the time of tumorimplantation to death. Statistical comparison of means between treatedanimals and controls was carried out using Student's f test, with modi

fication for small numbers.In addition, a method of quantification of antineoplastic effect was

designed which did not assume a preconceived pattern of growth butwhich examined the efficacy of therapy as reflected in the shrinkage oftumor mass in each individual experiment. For individual tumors, regarded as independent, each tumor volume N(t) as a function of time fwas fit by a polynomial spline technique (10, 23), and integrated analytically from the time of initiation of therapy at f„to the time td of lastvolume measurement prior to death. The parameter A, which can beconceptualized as an average tumor volume between f„and td wastherefore calculated as

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= (ta- r N(t)dt

Parameter A ¡sfunctionally related to the ratio of growth rates in theperturbed (treated) versus unperturbed (control) situation, as previouslydescribed (18). Values for A for each tumor line and each therapeuticsituation were transformed logarithmically to stabilize variances, compared by an analysis of variance, and then compared pairwise byStudent's f tests, one-tailed.

Patients. Twelve consecutive patients with malignant mesotheliomawere treated between the end of 1981 and the beginning of 1983 withthe best regimen found in the nude mouse system. Pretreatment evaluation procedures, performance status categories, and criteria of response to chemotherapy using clinically palpable tumors, roentgeno-

grams, and/or computed tomography, have been previously described(8). All patients had advanced disease at the initiation of chemotherapy(Stages III and IV from a TNM (tumors-nodes-metastases) classification

(4) for patients with pleural mesothelioma). Ten patients had a history ofprior asbestos exposure. Cell type was epithelial, except for Patient 1,who had a biphasic or mixed type. All patients gave informed consent.All patients had normal hematological and renal functions. The initial 5patients had all been treated previously with doxorubicin-containing

regimens and were in progression. In Patients 1 to 4, these regimensincluded doxorubicin, 25 mg/sq m/day i.v. on Days 1 to 3, and 5-

azacytidine, 120 mg/sq m/day by continuous i.v. infusion on Days 1 to5, cycles being repeated every 4 weeks (8). After 7 cycles, doxorubicinwas discontinued and replaced by cyclophosphamide, 200 mg/sq m/dayi.v. on Days 1 to 3. The total number of such cycles was 11 for Patient1, 22 for Patient 2, 21 for Patient 3, and 23 for Patient 4. Patient 5 waspreviously treated with a combination of doxorubicin (45 mg/sq m i.v.)and cyclophosphamide (450 mg/sq m i.v.) once every 4 weeks for 10cycles.

RESULTS

Nude Mouse System. Initial results3 of single agent chemo

therapy in nude mice bearing human malignant mesotheliomaxenografts revealed that 5-azacytidine, doxorubicin, 5-fluorou-

racil, methotrexate, vincristine, and vindesine were inactive forboth lines ES and BG. Active single agents for ES (by decreasingorder of activity) were mitomycin C, dacarbazine, 1,3-bis(2-chloroethyl)-1-nitrosourea, bleomycin, and cyclophosphamide.

Only cisplatin and bleomycin (by decreasing order of activity)were active in line BG. A combination of mitomycin C andcisplatin, the most active single agents for line ES and BG,respectively, was then compared to mitomycin C alone andcisplatin alone. Experiments were carried out to determine theacute toxicity of mitomycin C and cisplatin in these nude micebearing human mesothelioma xenografts. Mitomycin C alone ata dose of 3 mg/kg i.p. weekly for 3 weeks resulted in the acutedeath of 4 of 5 animals; a dose of 1.5 mg/kg i.p. weekly for 3weeks was acceptable with an acute death rate of only 3 of 16animals (19%). Cisplatin alone at a dose of 10 mg/kg i.p. weeklyfor 3 weeks was lethal for 4 of 8 animals, and the survivinganimals developed cachexia and total body weight loss of 25 to39%. Cisplatin alone at a dose of 6 mg/kg i.p. weekly for 3weeks still resulted in 3 of 5 acute deaths, whereas a dose of 4mg/kg i.p. weekly for 3 weeks produced an acceptable level ofacute deaths (5 of 21 animals, or 24%). Therefore, unit doses ofmitomycin C of 1.5 mg/kg and of cisplatin of 4 mg/kg wereselected. These 2 agents given simultaneously at these doses

Malignant Mesothelioma

i.p. weekly for 3 weeks resulted in 4 of 22 acute deaths (18%),which is about equitoxic to each drug given as a single agent atthese doses. In the experiments detailed below, treatment wasstarted between Days 13 and 20 after tumor transplantation.The overall results of these experiments, summarized in Table1, revealed that this combination of mitomycin C and cisplatinwas the most active regimen for both lines ES and BG in nudemice. No difference was seen between mice bearing one or 4xenografts each.

Quantification of antineoplastic effect in a representative experiment shown in Chart 1 and Table 2 (BG, 29th generation;ES, 31st generation) revealed that, for tumor line ES, there wasno significant difference between control tumors and thosetreated wtih cisplatin. Mitomycin C caused tumors smaller thanthose of controls, but this did not achieve statistical significancein this particular experiment, where the number of tumors wassmall (p = 0.1). The combination of the ineffective drug cisplatinwith mitomycin C, however, produced a significant differencebetween tumors so treated and controls (p < 0.005). In addition,tumors treated with the combination were significantly differentfrom those treated with mitomycin C alone (p < 0.01). Tumor

Table1Overall results of the effect of mitomycin C and cisplatin alone and in combination

in nude mice with human malignant mesothelioma xenografts

The mean volume ratio of treated tumors over control tumors was calculatedbetween Days 35 and 49 after tumor implantation. Treatments were startedbetween Days 13 and 20 after tumor implantation. T/C of 42% or less indicatesactivity (12). Statistical comparison of means was earned out using Student's f

test.

AgentsMitomycin

C, 1.5 mg/kg/wk i.p. for 3 wk

Cisplatin, 4 mg/kg/wk¡.p.for 3 wk

Mitomycin C, 1.5 mg/kg/wk i.p. for 3 wk,and cisplatin, 4 mg/kg/wk i.p. for 3 wkUneBG8%T/C°

%ILS70

±10d 131±1417

± 6 142 ±17(p< 0.001)10 ± 3 120 ±22(p< 0.0001)Une

ES6%T/C

%ILS22

±10 131 ±43(p< 0.001)77 ±10 116 ±610

± 2 185 ±18°

(p< 0.0001)

Generations 28 and 29, 8 to 15 tumors/group." Generations 31 and 32, 12 to 13 tumors/group.c T/C, ratio of treated tumors to control tumors; ILS, increase in mean life span

of treated animals compared to control animals." Mean ±S.E.8p < 0.01 by Student's i test.

IO4

5 io'

IO

Line BG(29thgenerotion)

f t t

: Line ES I—*C~ (3lstgenerotion)f

io-

io'

t t t

IO 20 30 40 50 60 O IO 20 30 40 50 60 70 80DAYS FROM IMPLANTATION

3A. P. Chahinian, unpublished results.

Chart 1. Growth curves of human malignant mesothelioma xenografts in nudemice. Results of one experiment in lines BG and ES. Treatments were all given i.p.once a week for 3 weeks (arrows), starting on Day 13 for BG and on Day 20 forES. C, controls treated with 0.9% NaCI solution; M, mitomycin C, 1.5-mg/kg dose;P, cisplatin, 4-mg/kg dose; M + P, combination of mitomycin C and cisplatin at thesame doses as above. Each treatment group includes 2 mice with 4 s.c. xenograftseach. Bars, S.E. of the mean tumor volume which were generated using Student's

t test distribution.

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A. P. Chahinian et al.

line BG displayed an opposite pattern of sensitivity. While cispla-

tin was ineffective against line ES, mitomycin C was ineffectiveagainst line BG. However, tumors of line BG treated with cisplatinwere significantly smaller than those of controls (p < 0.05). Thecombination of mitomycin C and cisplatin in line BG caused afurther effect, so that tumors so treated were significantly different from those treated with cisplatin alone (p < 0.01), and ofcourse, from controls (p < 0.0005). Hence, for each tumor line,the ineffective drug (cisplatin for ES and mitomycin C for BG)significantly augmented the antineoplastic effect of the othereffective drug of this combination (Table 2).

Clinical Investigations. Following these experiments in nudemice, it was decided to evaluate the most active regimen, acombination of mitomycin C and cisplatin, in patients with malignant mesothelioma. Treatment included mitomycin C, 10 mg/sqm i.V., and cisplatin, 50 mg/sq m i.V., after adequate i.v. hydration.Antiemetic agents usually included a combination of metoclo-

pramide (1 mg/kg i.v. every 4 hr for 4 doses, then as needed,and started 4 hr before cisplatin) and lorazepam (0.04 mg/kg i.v.once, 1 hr before cisplatin). Cycles were repeated every 4 weeksin the absence of residual toxicity. Dose adjustments for mitomycin C in case of residual hematological toxicity were asfollows: 100% if peripheral blood leukocytes were 4,000 or moreper n\ and/or platelets were over 100,000/í¿l;50% if leukocyteswere between 3,000 and 3,999, and/or platelets were between80,000 and 99,000; 25% if leukocytes were between 2,000 and2,999, and/or platelets were between 70,000 and 79,000; and0% if leukocytes were below 2,000, and/or platelets were below70,000. Initial patients had failed prior chemotherapy with dox-orubicin-containing combinations (Table 3). After the response

Table 2Average tumor volumeA tor experimentsshown in Chart 1

See text for details on calculation and statistical analysis.

Av. tumor volume (cu mm)

Xenografts Controls Mitomycin C Cisplatin Combination

Line ESLine BG2480

±606"

934 ±1761510±278

920 ±1791890+443475± 94706

±121163 ± 29

BMean ±S.E.

seen in Patient 1 (Fig. 2), it was decided to use this regimen forpreviously untreated patients as well. Overall results showedobjective response in 4 of 12 patients (one complete and 3 partialresponses), occurring in 1 of 5 previously treated and 3 of 7previously untreated patients (Table 3). Responses were usuallyslow to occur, requiring an average of 3 cycles. Patient 10relapsed after 7 cycles, and subsequently responded to a combination of doxorubicin and 5-azacytidine.

Toxicity was moderate. Thrombocytopenia (platelets<100,000/ííl)occurred in 7 patients, with a median nadir at45,000 (range, 24,000 to 73,000). Four of these patients hadpreviously been treated with chemotherapy. Leukopenia (leukocytes <3,000/í¿l)occurred in 4 patients (range, 2,600 to 2,900),including 2 previously treated patients. Hematological toxicitywas usually reversible within 2 weeks, but dose adjustmentswere made if necessary. Nausea and vomiting were expectedwith cisplatin but were tolerable with the use of antiemetics.Serum blood urea nitrogen and creatinine, urinalysis, and creat-

inine clearance were obtained before each cycle. Renal toxicityoccurred in only one patient with a serum blood urea nitrogen at37 mg/100 ml and serum creatinine at 2.1 mg/100 ml after 6cycles of therapy. Patient 7 developed acute shortness of breathand bilateral pulmonary infiltrates after the fourth cycle of chemotherapy, while in complete remission. He responded quickly toprednisone, but mitomycin C, the most probable responsibleagent (3, 20), was discontinued. He relapsed within 3 months,and subsequently failed to respond to doxorubicin and cisplatin.

DISCUSSION

Malignant mesothelioma is notorious for its poor prognosis.Although some anecdotal cases of prolonged survival withouttreatment have been reported, median survival usually does notreach 1 year from diagnosis (4, 5, 8). Few chemotherapeuticagents have been clinically evaluated (4, 5, 8). Among themdoxorubicin, alone and in combination, has been the most widelyused. Our own results with such therapy have been disappointing. A response rate of 21% was obtained in 14 patients with

TablesMitomycin C and cisplatin in 12patients with malignantmesothelioma

Patient123456789101112SexMMMMMMMMMMMMAge(yr)635961635860525248617860SitePleura,

leftPleura,rightPeritoneumPleura,

rightPeritoneumandpleura,

rightPleura,leftPleura,rightPleura,leftPleura,leftPleura,leftPleura,rightPleura,

rightPerform

ance status8311341131002Prior

chemotherapy*YesYesYesYesYesNoNoNoNoNoNoNoNo.

cyclesofmitomy

cin C andcisplatin101172110444764Response0Partial"StableStable0ProgressionProgression0Partial0CompletePartial0Stable0StableStable0Progression0Duration

ofresponse

(mos)9>158136>4367Survival

fromfirstmitomy

cin C and cisplatin(mos)12>15>942>1512>5>5>13>86

a Classified according to the Cancer and Leukemia Group B scale: 0, ambulatory without symptoms; 1, ambulatory with symptoms; 2, bedridden less than

50% of daytime; 3, bedridden more than 50% of daytime; 4, totally bedridden.6 Doxorubicin, 5-azacytidine, and cyclophosphamide in Patients 1 to 4; doxorubicin and cyclophosphamidein Patient 5.c Complete response, complete regression of all clinical and radiologicalevidence of disease; partial response, partial regression with more than 50% decrease in the

sum of 2 perpendiculardiameters of measurable lesions without appearanceof a new lesion elsewhere;stable disease, less than 50% regression of measurablelesions,or stabilization, or regression of évaluablebut not measurable lesions; progression, clinical and/or radiologicalprogression with more than 25% increase in measurablelesions.

0 Denotes presence of measurable lesion(s)

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Malignant Mesothelioma

pleural malignant mesothelioma treated with high-dose doxorub-

icin (90 mg/sq m over 3 days) combined with radiotherapy (8).Another trial of doxorubicin (60 mg/sq m every 3 weeks) combined with radiotherapy yielded only one measurable responseamong 10 patients with pleural malignant mesothelioma (27). Ina cooperative group trial, objective response to doxorubicin wasseen in only 7 of 51 patients (14%) with malignant mesothelioma(16). A more recent trial comparing 2 dose schedules of doxorubicin alone (70 mg/sq m every 3 weeks, or 20 mg/sq m onDays 1 to 3 and 15 mg/sq m weekly) versus a combination ofdoxorubicin (60 mg/sq m on Day 1) and dacarbazine (250 mg/sq m on Days 1 to 3) every 3 weeks yielded a total of only 7 of66 objective responses (11%), with no differences among the 3treatment programs (15). The evaluation of other regimens ofchemotherapy is therefore highly desirable. The small number ofpatients with malignant mesothelioma, however, precludes asystematic evaluation of these therapies. It is unlikely that empirical clinical trials will lead to the discovery of active regimensfor such a refractory disease.

Development of a predictive system as an experimental modelfor malignant mesothelioma may circumvent this problem. Ahamster mesothelioma obtained by i.p. injection of asbestosfibers has been described (14), but such tumors are not of humanorigin. In vitro clonogenic assays have met with limited successin mesothelioma (31). The cloning efficiency of human malignantmesothelioma in such a system seems to be low (28). Recently,a number of human tumors have been successfully transplantedinto immune-deficient mice (13, 21, 22, 29), including malignant

mesothelioma (1, 6). Such xenografts usually retain the originalhuman morphological and biological features, and results ofchemotherapy in other tumor types have correlated rather wellwith clinical experience (13, 21, 22, 29), and even with resultsobtained in the original donors (26). The advantages of the nudemouse model for a rare tumor such as mesothelioma, for whichfresh specimens are not routinely or repeatedly available, areobvious. The xenografts can be serially transplanted for prolonged periods of time, they constitute a permanent source offresh tissue, and they allow the screening of many agents aloneand in combination. Doxorubicin did not show activity againstlines BG and ES in our nude mouse model. After exploratorythoracotomy and transplantation of the tumor into nude mice,Patient B. G. was treated with a combination of doxorubicin and5-azacytidine without any response. Patient E. S. died shortly

after surgery without receiving chemotherapy.Our results with mitomycin C and cisplatin in 12 patients with

malignant mesothelioma seem to confirm the usefulness of thenude mouse model for this disease. Some clinical data areavailable for cisplatin alone in malignant mesothelioma, includingone complete response from 9 patients with pleural mesothelioma in one trial (11), and one complete response out of 6patients in another (24). No meaningful information is availableregarding the activity of mitomycin C as a single agent. Ourdecision to evaluate clinically the combination of mitomycin Cand cisplatin was entirely based on the nude mouse model,where this combination was the most active for both lines. Thelimited number of patients with malignant mesothelioma did notallow exploration of multiple dose schedules, nor random comparison with either drug given alone in an attempt to fully verifythe experimental results obtained in the nude mouse model.

ACKNOWLEDGMENTS

We are indebted to Drs. Y. Suzuki and M. Kaneko for review of pathologicalmaterial; to Drs. L. Chusid. G. Hyman, E. Petrick. C. Rabin, and A. Teirstein forcollaboration in treating patients; and to R. D'Agostino, R. Fleming,G. Green, and

P. Schwartz for technicalassistance.

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Fig. 1. Nude mouse with 4 human malignant mesothelioma xenografts. Line ES, first generation, Day 68 after tumor implantation. The s.c. tumors are easilymeasurable and grew progressively faster after serial transplantation in nude mice.

Fig. 2. Chest roentgenogram of patient 1, left pleural mesothelioma, biphasic type. A, September 1981, immediately before mitomycin C and cisplatin, duringprogression after 11 cycles of doxorubicin and 5-azacytidine; ß,January 1982, after 5 cycles of mitomycin C and cisplatin.

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1984;44:1688-1692. Cancer Res   A. Philippe Chahinian, Larry Norton, James F. Holland, et al.   -Diamminedichloroplatinum in Malignant Mesothelioma

cisExperimental and Clinical Activity of Mitomycin C and

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