Diamminedichloroplatinum in Malignant Mesothelioma1

[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.], and Department of Medicine, St. Luke's Hospital, Milwaukee, Wisconsin 53215 [R. D. H.]

ABSTRACT taining Roswell Park Memorial Institute Medium 1640 (Grand Island Biological Co., Grand Island, NY) and trimmed of cutaneous, connective, Little information is available regarding the effectiveness of and adipose tissues under a fiberglass tissue culture hood (Fisher chemotherapeutic agents in malignant mesothelioma. Human Scientific Co., Pittsburgh, PA). Small tumor cubes measuring 1 to 2 mm malignant mesothelioma specimens from two patients were suc were inserted in a trocar and transplanted s.c. into 4 sites/mouse in the cessfully transplanted and maintained in homozygous nude mice. right and left groin and axilla, or into one site/mouse in the right axilla. Screening of chemotherapeutic agents revealed that cisplatin Since single-cell suspensions were not used, the number of cells was the most active single agent in one line, and mitomycin C in transplanted in these specimens can only be determined on histological the other. The combination of mitomycin C and cisplatin, how sections. For that purpose, tumor specimens were fixed in 10% neutral ever, was the most effective regimen for both lines of xeno- formalin and embedded in paraffin after dehydration in alcohol. Five- to e-^m sections were made and stained with hematoxylin and eosin. grafted human mesothelioma. Based on these results in nude Histological sections were examined with a Nikon light microscope mice, a clinical trial of mitomycin C and cisplatin was undertaken. (Nikon, Inc., Garden City, NY) equipped with an ocular micrometer Four of 12 patients showed objective response (one complete calibrated with a hemacytometer (American Optical Scientific Instru and three partial). These clinical results support the usefulness ments, Buffalo, NY). The number of tumor cells per cu mm was deter of the nude mouse model for malignant mesothelioma. mined by numerical analysis in 20 random fields at x400 for each line BG and ES (9), after correction for section thickness, fixation shrinkage (2), and proportional tumor cell content. Under these conditions, the INTRODUCTION number of tumor cells per cu mm was [4.8 Â±0.18 (S.E.)] x 10s for BG xenografts, and [3.3 Â±0.32] x 105 for ES xenografts. Malignant mesothelioma is a disease of growing importance. As predicted (25), its incidence is increasing (17) as a result of Mice were observed every weekday and weighed once weekly. Both lines BG and ES have retained their original histological, histochemical, the widespread use of asbestos, its major etiological agent. and ultrastructural features despite serial transplantation (6, 30). Kary- Results of various therapies for malignant mesothelioma have otypes have confirmed their human nature (6). Line BG is an epithelial been generally poor (5, 8). Neither surgery nor radiotherapy is malignant mesothelioma, and line ES is a mixed or biphasic, but predom curative. Very little information is available regarding the activity inantly epithelial malignant mesothelioma (6). After the growth of s.c. of chemotherapeutic agents (4, 8). implants was established, cohorts of mice transplanted with the same The availability in our laboratory of 2 distinct cell lines of human tumor specimen (one or 4 s.c. implants/mouse) were randomized be malignant mesothelioma serially transplanted into nude mice (6) tween chemotherapy (2 to 6 animals/group), and control with 0.9% NaCI allowed us to study systematically the activity of chemothera solution (2 animals/group). All injections were given i.p. peutic agents alone and in combination in this model. One Quantification of Antineoplastic Activity. Tumor volume was mea sured with calipers once or twice weekly, using the formula for a prolate combination, mitomycin C and cisplatin, exhibited efficacy ellipsoid against both lines in the nude mouse system (7). Based on this research, a clinical trial of this combination was initiated in 12 consecutive patients with malignant mesothelioma. where L is the greatest length and W is the perpendicular width of the MATERIALS AND METHODS tumor corrected for skin thickness (12, 19) (Fig. 1). Overall treatment effect was measured using the mean ratio T/C (expressed as a percent Nude Mouse Xenografts. Two lines of human malignant mesothe age) of the tumor volumes between Days 35 to 49 after tumor implan lioma (designated BG and ES) have been serially transplanted s.c. since tations for treated animals (T) over the tumor volumes of corresponding 1978 in nude mice, as previously described (6). For these experiments, controls (C) (12). A T/C ratio of 42% or less is considered to be an 8- to 10-week-old homozygous female nude (nu/nu) mice were obtained indication of activity (12). Life span was measured from the time of tumor from the Animal Genetics and Production Branch of the National Cancer implantation to death. Statistical comparison of means between treated animals and controls was carried out using Student's f test, with modi Institute, Bethesda, MD. Filtered air and sterilized bedding, cages, food, and water were used. Serial transplantation of tumors was carried out fication for small numbers. by excision of tumors under light anesthesia by inhalation with methox- In addition, a method of quantification of antineoplastic effect was yflurane (Penthrane; Abbott Laboratories, North Chicago, IL). The tumor designed which did not assume a preconceived pattern of growth but specimens were dissected under sterile conditions in a Petri dish con- which examined the efficacy of therapy as reflected in the shrinkage of tumor mass in each individual experiment. For individual tumors, re garded as independent, each tumor volume N(t) as a function of time f 1Supported in part by Cancer Center Grant CA-23102 from the National Cancer was fit by a polynomial spline technique (10, 23), and integrated analyti Institute, and by the T. J. Marteli Memorial Foundation for Leukemia and Cancer cally from the time of initiation of therapy at fâ€žto the time td of last Research. Presented in part at the 74th Annual Meeting of the American Association for Cancer Research, San Diego, May 25 to 28, 1983 (7). volume measurement prior to death. The parameter A, which can be 2 To whom requests for reprints should be addressed. conceptualized as an average tumor volume between fâ€žand td was Received September 13, 1983; accepted January 6, 1984. therefore calculated as

1688 CANCER RESEARCH VOL. 44

i.p. weekly for 3 weeks resulted in 4 of 22 acute deaths (18%), = (ta- N(t)dt r which is about equitoxic to each drug given as a single agent at these doses. In the experiments detailed below, treatment was Parameter A Â¡sfunctionally related to the ratio of growth rates in the started between Days 13 and 20 after tumor transplantation. perturbed (treated) versus unperturbed (control) situation, as previously The overall results of these experiments, summarized in Table described (18). Values for A for each tumor line and each therapeutic situation were transformed logarithmically to stabilize variances, com 1, revealed that this combination of mitomycin C and cisplatin pared by an analysis of variance, and then compared pairwise by was the most active regimen for both lines ES and BG in nude Student's f tests, one-tailed. mice. No difference was seen between mice bearing one or 4 Patients. Twelve consecutive patients with malignant mesothelioma xenografts each. were treated between the end of 1981 and the beginning of 1983 with Quantification of antineoplastic effect in a representative ex the best regimen found in the nude mouse system. Pretreatment evalu periment shown in Chart 1 and Table 2 (BG, 29th generation; ation procedures, performance status categories, and criteria of re ES, 31st generation) revealed that, for tumor line ES, there was sponse to chemotherapy using clinically palpable tumors, roentgeno- no significant difference between control tumors and those grams, and/or computed tomography, have been previously described treated wtih cisplatin. Mitomycin C caused tumors smaller than (8). All patients had advanced disease at the initiation of chemotherapy (Stages III and IV from a TNM (tumors-nodes-metastases) classification those of controls, but this did not achieve statistical significance (4) for patients with pleural mesothelioma). Ten patients had a history of in this particular experiment, where the number of tumors was small (p = 0.1). The combination of the ineffective drug cisplatin prior asbestos exposure. Cell type was epithelial, except for Patient 1, who had a biphasic or mixed type. All patients gave informed consent. with mitomycin C, however, produced a significant difference All patients had normal hematological and renal functions. The initial 5 between tumors so treated and controls (p < 0.005). In addition, patients had all been treated previously with doxorubicin-containing tumors treated with the combination were significantly different regimens and were in progression. In Patients 1 to 4, these regimens from those treated with mitomycin C alone (p < 0.01). Tumor included 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 to Table1 5, cycles being repeated every 4 weeks (8). After 7 cycles, doxorubicin Overall results of the effect of mitomycin C and cisplatin alone and in combination was discontinued and replaced by cyclophosphamide, 200 mg/sq m/day in nude mice with human malignant mesothelioma xenografts i.v. on Days 1 to 3. The total number of such cycles was 11 for Patient The mean volume ratio of treated tumors over control tumors was calculated 1, 22 for Patient 2, 21 for Patient 3, and 23 for Patient 4. Patient 5 was between Days 35 and 49 after tumor implantation. Treatments were started between Days 13 and 20 after tumor implantation. T/C of 42% or less indicates previously treated with a combination of doxorubicin (45 mg/sq m i.v.) activity (12). Statistical comparison of means was earned out using Student's f and cyclophosphamide (450 mg/sq m i.v.) once every 4 weeks for 10 test. cycles. ES6%T/C

%ILS70 AgentsMitomycin %ILS22 RESULTS Â±1417Â±10d 131 C, 1.5 mg/ Â±10 131 Â±43 Nude Mouse System. Initial results3 of single agent chemo kg/wk i.p. for 3 wk (p< 0.001) Cisplatin, 4 mg/kg/wk Â± 6 142 Â±17 77610 Â±10 116 Â± therapy in nude mice bearing human malignant mesothelioma Â¡.p.for 3 wk (p< 0.001) Â± 2 185 Â±18Â° xenografts revealed that 5-azacytidine, doxorubicin, 5-fluorou- Mitomycin C, 1.5 mg/ 10 Â± 3 120 Â±22 kg/wk i.p. for 3 wk, (p< 0.0001)Une (p< 0.0001) racil, methotrexate, vincristine, and vindesine were inactive for and cisplatin, 4 mg/ both lines ES and BG. Active single agents for ES (by decreasing kg/wk i.p. for 3 wkUneBG8%T/CÂ° order of activity) were mitomycin C, dacarbazine, 1,3-bis(2- Generations 28 and 29, 8 to 15 tumors/group. " Generations 31 and 32, 12 to 13 tumors/group. chloroethyl)-1-nitrosourea, bleomycin, and cyclophosphamide. c T/C, ratio of treated tumors to control tumors; ILS, increase in mean life span Only cisplatin and bleomycin (by decreasing order of activity) of treated animals compared to control animals. " Mean Â±S.E. were active in line BG. A combination of mitomycin C and 8 p < 0.01 by Student's i test. cisplatin, the most active single agents for line ES and BG, respectively, was then compared to mitomycin C alone and cisplatin alone. Experiments were carried out to determine the IO4 Line BG : Line ES Iâ€”*C acute toxicity of mitomycin C and cisplatin in these nude mice (29thgenerotion) ~ (3lstgenerotion)f bearing human mesothelioma xenografts. Mitomycin C alone at a dose of 3 mg/kg i.p. weekly for 3 weeks resulted in the acute io- death of 4 of 5 animals; a dose of 1.5 mg/kg i.p. weekly for 3 weeks was acceptable with an acute death rate of only 3 of 16 animals (19%). Cisplatin alone at a dose of 10 mg/kg i.p. weekly 5 io' for 3 weeks was lethal for 4 of 8 animals, and the surviving t t t animals developed cachexia and total body weight loss of 25 to f t t

39%. Cisplatin alone at a dose of 6 mg/kg i.p. weekly for 3 IO io' weeks still resulted in 3 of 5 acute deaths, whereas a dose of 4 IO 20 30 40 50 60 O IO 20 30 40 50 60 70 80 DAYS FROM IMPLANTATION mg/kg i.p. weekly for 3 weeks produced an acceptable level of Chart 1. Growth curves of human malignant mesothelioma xenografts in nude acute deaths (5 of 21 animals, or 24%). Therefore, unit doses of mice. Results of one experiment in lines BG and ES. Treatments were all given i.p. mitomycin C of 1.5 mg/kg and of cisplatin of 4 mg/kg were once a week for 3 weeks (arrows), starting on Day 13 for BG and on Day 20 for selected. These 2 agents given simultaneously at these doses ES. 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 the same doses as above. Each treatment group includes 2 mice with 4 s.c. xenografts each. Bars, S.E. of the mean tumor volume which were generated using Student's 3 A. P. Chahinian, unpublished results. t test distribution.

APRIL 1984 1689

line BG displayed an opposite pattern of sensitivity. While cispla- seen in Patient 1 (Fig. 2), it was decided to use this regimen for tin was ineffective against line ES, mitomycin C was ineffective previously untreated patients as well. Overall results showed against line BG. However, tumors of line BG treated with cisplatin objective response in 4 of 12 patients (one complete and 3 partial were significantly smaller than those of controls (p < 0.05). The responses), occurring in 1 of 5 previously treated and 3 of 7 combination of mitomycin C and cisplatin in line BG caused a previously untreated patients (Table 3). Responses were usually further effect, so that tumors so treated were significantly differ slow to occur, requiring an average of 3 cycles. Patient 10 ent from those treated with cisplatin alone (p < 0.01), and of relapsed after 7 cycles, and subsequently responded to a com course, from controls (p < 0.0005). Hence, for each tumor line, bination of doxorubicin and 5-azacytidine. the ineffective drug (cisplatin for ES and mitomycin C for BG) Toxicity was moderate. Thrombocytopenia (platelets significantly augmented the antineoplastic effect of the other <100,000/ÃÃl)occurred in 7 patients, with a median nadir at effective drug of this combination (Table 2). 45,000 (range, 24,000 to 73,000). Four of these patients had Clinical Investigations. Following these experiments in nude previously been treated with chemotherapy. Leukopenia (leuko mice, it was decided to evaluate the most active regimen, a cytes <3,000/ÃÂ¿l)occurred in 4 patients (range, 2,600 to 2,900), combination of mitomycin C and cisplatin, in patients with malig including 2 previously treated patients. Hematological toxicity nant mesothelioma. Treatment included mitomycin C, 10 mg/sq was usually reversible within 2 weeks, but dose adjustments m i.V., and cisplatin, 50 mg/sq m i.V., after adequate i.v. hydration. were made if necessary. Nausea and vomiting were expected Antiemetic agents usually included a combination of metoclo- with cisplatin but were tolerable with the use of antiemetics. pramide (1 mg/kg i.v. every 4 hr for 4 doses, then as needed, Serum blood urea nitrogen and creatinine, urinalysis, and creat- and started 4 hr before cisplatin) and lorazepam (0.04 mg/kg i.v. inine clearance were obtained before each cycle. Renal toxicity once, 1 hr before cisplatin). Cycles were repeated every 4 weeks occurred in only one patient with a serum blood urea nitrogen at in the absence of residual toxicity. Dose adjustments for mito 37 mg/100 ml and serum creatinine at 2.1 mg/100 ml after 6 mycin C in case of residual hematological toxicity were as cycles of therapy. Patient 7 developed acute shortness of breath follows: 100% if peripheral blood leukocytes were 4,000 or more and bilateral pulmonary infiltrates after the fourth cycle of chem per n\ and/or platelets were over 100,000/ÃÂ¿l;50%if leukocytes otherapy, while in complete remission. He responded quickly to were between 3,000 and 3,999, and/or platelets were between prednisone, but mitomycin C, the most probable responsible 80,000 and 99,000; 25% if leukocytes were between 2,000 and agent (3, 20), was discontinued. He relapsed within 3 months, 2,999, and/or platelets were between 70,000 and 79,000; and and subsequently failed to respond to doxorubicin and cisplatin. 0% if leukocytes were below 2,000, and/or platelets were below 70,000. Initial patients had failed prior chemotherapy with doxorubicin-containing combinations (Table 3). After the response DISCUSSION

Table 2 Malignant mesothelioma is notorious for its poor prognosis. Average tumor volumeA tor experimentsshown in Chart 1 Although some anecdotal cases of prolonged survival without See text for details on calculation and statistical analysis. treatment have been reported, median survival usually does not Av. tumor volume (cu mm) reach 1 year from diagnosis (4, 5, 8). Few chemotherapeutic Xenografts Controls Mitomycin C Cisplatin Combination agents have been clinically evaluated (4, 5, 8). Among them Â±606" Line ES Â±278 +443475 Â±121 doxorubicin, alone and in combination, has been the most widely Line BG2480 934 Â±1761510 920 Â±1791890 Â± 94706 163 Â± 29 used. Our own results with such therapy have been disappoint BMean Â±S.E. ing. A response rate of 21% was obtained in 14 patients with

Tables Mitomycin C and cisplatin in 12patients with malignantmesothelioma cyclesof fromfirst mitomy ofresponse mitomy ance sta chem cin C and tus8311341131002Priorotherapy*YesYesYesYesYesNoNoNoNoNoNoNoNo. cin C and cis Patient123456789101112SexMMMMMMMMMMMMAge(yr)635961635860525248617860SitePleura, cisplatin101172110444764Response0Partial"StableStable0ProgressionProgression0Partial0CompletePartial0Stable0StableStable0Progression0Duration(mos)9>158136>4367Survivalplatin(mos)12>15>942>1512>5>5>13>86 leftPleura, rightPeritoneumPleura,

rightPeritoneum andpleura, rightPleura, leftPleura, rightPleura, leftPleura, leftPleura, leftPleura, rightPleura, rightPerform 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 measurablelesions without appearanceof a new lesion elsewhere;stable disease, less than 50% regression of measurablelesions, or stabilization, or regression of Ã©valuablebutnot measurable lesions; progression, clinical and/or radiologicalprogression with more than 25% increase in measurable lesions. 0 Denotes presence of measurable lesion(s)

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1984 American Association for Cancer Research. Malignant Mesothelioma pleural malignant mesothelioma treated with high-dose doxorub- ACKNOWLEDGMENTS icin (90 mg/sq m over 3 days) combined with radiotherapy (8). We are indebted to Drs. Y. Suzuki and M. Kaneko for review of pathological Another trial of doxorubicin (60 mg/sq m every 3 weeks) com material; to Drs. L. Chusid. G. Hyman, E. Petrick. C. Rabin, and A. Teirstein for bined with radiotherapy yielded only one measurable response collaboration in treating patients; and to R. D'Agostino, R. Fleming,G. Green, and among 10 patients with pleural malignant mesothelioma (27). In P. Schwartz for technicalassistance. a cooperative group trial, objective response to doxorubicin was seen in only 7 of 51 patients (14%) with malignant mesothelioma (16). A more recent trial comparing 2 dose schedules of doxo REFERENCES rubicin alone (70 mg/sq m every 3 weeks, or 20 mg/sq m on 1. Arnold, W., Naundorf, H., Wildner, G. P., Nissen, E., and Tannenberger, S. Days 1 to 3 and 15 mg/sq m weekly) versus a combination of Biological characterization of a mesothelioma line in nude mice. Arch. Gesch- doxorubicin (60 mg/sq m on Day 1) and dacarbazine (250 mg/ wulstforsch., 49. 495-507. 1979. sq m on Days 1 to 3) every 3 weeks yielded a total of only 7 of 2. Bahr, G. F., Bloom. G., and Friberg, U. Volume changes of tissues in physio logical fluids during fixation in osmium tetroxide or formaldehyde and during 66 objective responses (11%), with no differences among the 3 subsequent treatment. Exp. Cell Res. 12: 342-355, 1957. treatment programs (15). The evaluation of other regimens of 3. Buzdar, A. U., Legha, S. S., Luna, M. A., Tashima, C. K., Hortobagyi, G. N., and Blumenschein,G. R. Pulmonarytoxicity of mitomycin. Cancer (Phila.),45: chemotherapy is therefore highly desirable. The small number of 236-244,1980. patients with malignant mesothelioma, however, precludes a 4. Chahinian, A. P. Malignant mesothelioma. In: E. Greenspan (ed.), Clinical systematic evaluation of these therapies. It is unlikely that em Interpretationand Practiceof Cancer Chemotherapy,pp. 599-606. New York; Raven Press, 1982. pirical clinical trials will lead to the discovery of active regimens 5. Chahinian,A. P. Malignantmesothelioma.In: J. F. Hollandand E. Frei III(eds.), for such a refractory disease. Cancer Medicine, pp. 1744-1751. Philadelphia:Lea & Febiger, 1982. Development of a predictive system as an experimental model 6. Chahinian, A. P., Beranek, J. T., Suzuki, Y., Bekesi, J. G., Wisniewski, L., Selikoff, I. J., and HollandJ. F. Transplantation of human malignant mesothe for malignant mesothelioma may circumvent this problem. A lioma into nude mice. Cancer Res., 40: 181-185, 1980. hamster mesothelioma obtained by i.p. injection of asbestos 7. Chahinian,A. P., Norton, L.. Szrajer, L., and Holland, J. F. Mitomycin C and fibers has been described (14), but such tumors are not of human cisplatin in human malignant mesothelioma xenografts in nude mice. Clinical correlations. Proc. Am. Assoc. Cancer Res., 24. 151, 1983. origin. In vitro clonogenic assays have met with limited success 8. Chahinian,A. P., Pajak, T. F., Holland,J. F., Norton, L., Ambinder, R. M., and in mesothelioma (31). The cloning efficiency of human malignant Mandel, E. M. Diffuse malignant mesothelioma. Prospective evaluation of 69 patients. Ann. Intern. Med., 96: 746-755,1982. mesothelioma in such a system seems to be low (28). Recently, 9. Chalkley, H. W., Cornfield, J., and Park H. A method for estimating volume- a number of human tumors have been successfully transplanted surface ratios. Science(Wash. D. 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Parts, 3: 1-103, 1972. mouse model for a rare tumor such as mesothelioma, for which 13. Giovanella,B. C., Stehlin, J. S.. Jr., Williams, L. J., Lee, S. S., and Shepard, fresh specimens are not routinely or repeatedly available, are R. C. Heterotransplantationof humancancers into nude mice.A model system obvious. The xenografts can be serially transplanted for pro for human cancer chemotherapy. Cancer (Phila.),42: 2269-2281,1978. 14. Holiat, S. M., Smith, W. E., Hubert, D. D., and Davis, S. Chemotherapeutic longed periods of time, they constitute a permanent source of trials with hamster mesothelioma 10-24. Responses to azacitidine,aziridinyl- fresh tissue, and they allow the screening of many agents alone benzoquinone,cisplatin and PCNU.CancerTreat. Rep.,65:1113-1115.1981. and in combination. Doxorubicin did not show activity against 15. Lemer, H., Amato, D., Shiraki, M., and Borden, E. A prospective study of Adriamycin programs in malignantmesothelioma.Proc. Am. Soc. Clin. Oncol., lines BG and ES in our nude mouse model. After exploratory 2:230, 1983. thoracotomy and transplantation of the tumor into nude mice, 16. Lemer, H., Schoenfeld, D., Martin, A., Falkson, G., and Borden, E. Malignant mesothelioma: The Eastern Cooperative Oncology Group (E.C.O.G.) experi Patient B. G. was treated with a combination of doxorubicin and ence. Proc. Am. Soc. Clin. Oncol., 22: 527,1981. 5-azacytidine without any response. Patient E. S. died shortly 17. Newhouse, M. Epidemiology of asbestos-related tumors. Semin. Oncol., 8: after surgery without receiving chemotherapy. 250-257,1981. 18. Norton, L., and Simon, R. Growth curve of an experimental solid tumor Our results with mitomycin C and cisplatin in 12 patients with following radiotherapy. J. Nati. Cancer Inst., 58: 1735-1741,1977. malignant mesothelioma seem to confirm the usefulness of the 19. Norton, L.. and Simon. R. New thoughts on the relationship of tumor growth characteristics to sensitivity to treatment. Methods Cancer Res., 17: 63-90, nude mouse model for this disease. Some clinical data are 1979. available for cisplatin alone in malignant mesothelioma, including 20. Orwoll, E. S., Kiessling, P. J., and Patterson, J. R. Interstitial pneumoniafrom one complete response from 9 patients with pleural mesothe mitomycin. Ann. Intern. Med., 89: 352-355, 1978. 21. Ovejera, A. A., Houchens, D. P., and Barker, A. D. Chemotherapy of human lioma in one trial (11), and one complete response out of 6 tumor xenografts in genetically athymic mice. Ann. Clin. Lab. Sci., 8: 50-56, patients in another (24). No meaningful information is available 1978. regarding the activity of mitomycin C as a single agent. Our 22. Povlsen, C. 0. Status of chemotherapy, radiotherapy, endocrine therapy and immunotherapy studies of human cancer in the nude mouse. In: J. Fogh, B. decision to evaluate clinically the combination of mitomycin C C. Giovanella,(eds.),The Nude Mouse in Experimentaland ClinicalResearch, and cisplatin was entirely based on the nude mouse model, pp. 437-456. New York: Academic Press, Inc., 1978. 23. Reinsch, C. H. Smoothing by spline functions. Numer. Math., 10: 177-183, where this combination was the most active for both lines. The 1967. limited number of patients with malignant mesothelioma did not 24. Samson, M. K., Baker, L. H., Benjamin, R. S., Lane, M., and Plager, C. C/s- allow exploration of multiple dose schedules, nor random com dichlorodiammineplatinum(II) in advanced soft tissue and bony sarcomas. A Southwest Oncology Group study. Cancer Treat. Rep., 63: 2027-2029,1979. parison with either drug given alone in an attempt to fully verify 25. Selikoff, I. J., Bader, R. A., Bader, M. E., Churg, J., and Hammond. E. C. the experimental results obtained in the nude mouse model. Asbestosis and neoplasia.Am. J. Med., 42: 487-495, 1967.

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26. Shorthouse, A. J., Peckham, M. J., Smyth, J. F., and Steel, G. G. The 29. Steel, G. G., Courtenay, V. D., and Peckham, M. J. The response to chemo therapeutic response of bronchial carcinoma xenografts. A direct patient- therapy of a variety of human tumor xenografts. Br. J. Cancer, 47: 1-13, xenografts comparison. Br. J. Cancer, (Suppl. IV), 41: 142-145, 1980. 1983. 27. Sinoff, C., Falkson, G., Sandison, A. G., and De Muelenaere, G. Combined 30. Suzuki, Y., Chahinian, A. P., and Ohnuma, T. Malignant mesothelioma in vivo, doxorubicin and radiation therapy in malignant pleural mesothelioma. Cancer in vitro, and under heterotransplanted conditions. Fed. Proc., 42: 782, 1983. Treat. Rep.. 66: 1605-1607, 1982. 31. Von Hoff, D. D., Casper, J., Bradley, E., Sanbach, J., Jones, D., and Makuch, 28. Sridhar, K. S., Piasse, T., Ohnuma, T., Chahinian, A. P., and Holland, J. F. R. Association between human tumor colony-forming assay results and re sponse of an individual patient's tumor to chemotherapy. Am. J. Med., 70: Soft agar cloning and in vitro chemosensitivity of lung cancer and mesothe lioma. Ann. R. Coll. Physicians Surg. Can., 75: 326, 1982. 1027-1032,1981.

Fig. 1. Nude mouse with 4 human malignant mesothelioma xenografts. Line ES, first generation, Day 68 after tumor implantation. The s.c. tumors are easily measurable 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, during progression after 11 cycles of doxorubicin and 5-azacytidine; ÃŸ,January 1982, after 5 cycles of mitomycin C and cisplatin.

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1984 American Association for Cancer Research. Experimental and Clinical Activity of Mitomycin C and cis -Diamminedichloroplatinum in Malignant Mesothelioma

A. Philippe Chahinian, Larry Norton, James F. Holland, et al.

Cancer Res 1984;44:1688-1692.

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