MALIGNANT MESOTHELIOMA is an aggressive

Cisplatin and Gemcitabine Treatment for Malignant Mesothelioma: A Phase II Study By M.J. Byrne, J.A. Davidson, A.W. Musk, J. Dewar, G. van Hazel, M. Buck, N.H. de Klerk, and B.W.S. Robinson Purpose: We performed a phase II study of combined cisplatin 100 mg/m 2, given intravenously on day 1, and gemcitabine 1,000 mg/m 2, given intravenously on days 1, 8, and 15 of a 28-day cycle for six cycles among patients with advanced measurable pleural mesothelioma. Patients and Methods: Pleural tumor was measured at three levels on computed tomographic scans at study entry and before the second, fourth, and sixth cycles and every 2 months thereafter to disease progression. Of the 21 patients treated, 19 were male; the median age was 62 years (range, 46 to 74 years); 62% had epithelial tumors; and 18 were classified as tumor-nodemetastasis system stage III or IV. Ninety-four cycles were given (median, six; mean, 4.5 per patient), with a mean relative dose intensity of cisplatin 96.7% and gemcitabine 82.5%. Results: Best objective responses achieved were as follows: complete response, no patients; partial response, 10 patients (complete response partial re- MALIGNANT MESOTHELIOMA is an aggressive tumor of the pleura and peritoneum. It is uncommon but is increasing in incidence, particularly in regions where occupational exposure to asbestos has been prominent. 1 Although it has been the subject of intensive clinical and laboratory research, case fatality for the disease remains high and conventional treatments are inadequate. 2,3 A wide range of chemotherapeutic agents used singly and in combination have been evaluated in the treatment of mesothelioma, but no drugs have consistently induced a response rate of greater than 20%. 3 We have previously reported a phase II evaluation of doxorubicin and interferon alfa-2a in the treatment of patients with mesothelioma and measurable lesions. This regimen yielded a response rate of 16% among 25 patients, with significant toxicity in all patients and no evidence of sustained benefit even among responders. 4 As part of a continuing program to develop and evaluate novel therapies for mesothelioma, we have assessed the antitumor effect of the pyrimidine analog gemcitabine using mesothelioma cell lines of human and murine origin. In a murine mesothelioma model, gemcitabine shows additive antitumor effects when administered in combination with cisplatin and, at clinically achievable concentrations, causes significant tumor regressions. 5 Reports of phase II studies of the use of combined cisplatin and gemcitabine in the treatment of non small-cell lung cancer have been published. 6-8 These indicate an sponse, 47.6% [95% confidence interval, 26.2% to 69.0%]); no change, nine patients; and progressive disease, two patients. Median response duration was 25 weeks, progression-free survival was 25 weeks, and overall survival was 41 weeks. Nine of the 10 responders (90%) and three of nine patients with no change had significant symptom improvement. Serial measurements of vital capacity were performed on three of the responders; all showed a significant increase during the time of remission. Toxicity was mainly gastroenterologic and hematologic. Grade 3 nausea and vomiting occurred in 33% of patients, grade 3 leukopenia in 38%, grade 3 thrombocytopenia in 14%, and grade 4 thrombocytopenia in 19%. Conclusion: Combined cisplatin and gemcitabine is an active combination in malignant mesothelioma and produces symptomatic benefit in responding patients. J Clin Oncol 17:25-30. 1999 by American Society of Clinical Oncology. acceptable toxicity profile when gemcitabine 1,000 mg/m 2 is administered at weekly intervals on days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m 2 administered as a single dose on day 1, 2, or 15. We report here the results of a phase II study of the efficacy of combined cisplatin and gemcitabine in the treatment of patients with advanced malignant mesothelioma. PATIENTS AND METHODS Patients and Chemotherapy Patients with histologically or cytologically confirmed malignant mesothelioma of the pleura were eligible for entry onto the study. Those included were less than 75 years of age and had measurable disease on thoracic computed tomographic (CT) scans, no prior chemotherapy either systemically or intrapleurally, an Eastern Cooperative Oncology Group performance status of 0 to 2, and a life expectancy of at least 12 weeks. When the disease was confined to the pleural cavity, we demanded that the pleural rind be at least 1.5 cm in thickness, at one From the Departments of Medical Oncology and Respiratory Medicine, Sir Charles Gairdner Hospital; and Departments of Medicine and Public Health, University of Western Australia, Nedlands, Western Australia, Australia. Submitted June 1, 1998; accepted September 28, 1998. Address reprint requests to Dr Michael J. Byrne, Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia. 1999 by American Society of Clinical Oncology. 0732-183X/99/1701-0025$3.00/0 Journal of Clinical Oncology, Vol 17, No 1 (January), 1999: pp 25-30 25

26 BYRNE ET AL level of the thorax or more, for the disease to be considered measurable. All patients had an adequate bone marrow function (defined as hemoglobin concentration 10 g/dl, total leukocyte count 3.0 10 9 /L, granulocyte count 1.5 10 9 /L, and platelet count 100 10 9 /L); adequate renal function (defined as serum creatinine level 120 µmol/l); and adequate hepatic function (defined as total bilirubin level 1.5 times the upper limit of normal and serum ALT and alkaline phosphatase levels 3 times the upper normal limit for the laboratory). Patients were staged using the tumor-node-metastasis system of the International Union Against Cancer. 9 Written informed consent was obtained from each patient before entry. The protocol was approved by the Committee for Human Rights of the University of Western Australia and the Sir Charles Gairdner Hospital Clinical Drug Trials Committee. All patients received cisplatin 100 mg/m 2 intravenously over 1 hour on day 1 and gemcitabine 1,000 mg/m 2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. On day 1, cisplatin was administered before gemcitabine. Intensive prophylactic antiemetic therapy with 5-hydroxytryptamine (5-HT 3 ) antagonists and dexamethasone was given intravenously on day 1. Oral 5-HT 3 antagonists and/or phenothiazine antiemetics orally or by suppository were continued over the succeeding 3 to 5 days. On days 8 and 15, gemcitabine was given with 5-HT 3 antagonist cover. In the absence of objective evidence of disease progression, patients were scheduled to receive six cycles of chemotherapy. Dose Adjustments No dose escalations were permitted. A complete blood cell count and differential, serum electrolytes, creatinine, bilirubin, ALT, and alkaline phosphatase levels were assessed on days 1, 8, and 15 of each cycle. The cisplatin dose was reduced to 50% and the gemcitabine dose to 75% if the creatinine level increased to more than 120 µmol/l, and the drugs were delayed or omitted if the creatinine level reached 150 µmol/l. Cisplatin dosage was not adjusted for hematologic toxicity but was delayed on day 1 if gemcitabine was delayed. Gemcitabine dosage was reduced to 75% for a leukocyte count of less than 3 10 9 /L or a platelet count of less than 100 10 9 /L on day 1, 8, or 15 and was omitted on day 8 or 15 if the leukocyte count was lower than 2 10 9 /L or the platelet count lower than 75 10 9 /L. Tumor Assessment Clinical history, physical examination, a CT scan of the chest and abdomen, and a chest x-ray were required for all patients before entry. Patients were examined and the chest x-ray was repeated on day 1 of each cycle. A thoracic CT scan was repeated just before day 1 of the second, fourth, and sixth cycles. Patients whose disease was stable or who had achieved a complete or partial response to treatment at the end of six cycles of chemotherapy were observed clinically and given repeat CT scans every 2 months. In all patients with pleural mesothelioma, the thickness of the pleural tumor was measured at three separate levels on transverse sections on the thoracic CT scan at study entry. The sum of the measurements of tumor thickness at the three levels defined a unidimensional measure. Repeat measurements were taken at the same levels at the time of repeat CT scans, and response was assessed by the criteria outlined below. All bidimensionally measurable lesions were measured and used in assessing response. Tumor Response Tumor response was assessed as follows: complete response: complete disappearance of all clinically detectable malignant disease on two occasions at least 4 weeks apart. Partial response: bidimensionally measurable lesions: greater than or equal to a 50% decrease in the sum of the products of the perpendicular diameters of measurable lesions on two occasions at least 4 weeks apart; or unidimensionally measurable lesions: greater than or equal to a 30% decrease in the sum of linear tumor measurements on two occasions at least 4 weeks apart. No change: decrease in size of bidimensionally measurable lesions by less than 50%, or decrease in the size of unidimensionally measurable lesions by less than 30%, or increase in the size of malignant lesions at any site by less than 25%. Progressive disease: bidimensionally or unidimensionally measurable: greater than or equal to a 25% increase in the size of lesions or the appearance of any new lesions. Patients who died of mesothelioma in whom there was no change or a response were regarded as having disease progression at the time of death. Time to disease progression was measured from time of first chemotherapy dose to first date of progression or death. Duration of remission was measured from the first date of best response to date of progression or death. Treatment toxicity was assessed according to World Health Organization criteria. 10 The study was designed to use the one-sample multiple testing procedure of Fleming. 11 The aim was to recruit a maximum of 35 patients with an analysis of the interim results after 15 patients were fully assessable. This plan allowed early termination of the study as soon as possible should it become evident that the true rate of response (complete plus partial responses) was less than 20% or greater than 40%. RESULTS Patient Characteristics The characteristics of the 21 patients entered onto the study are listed in Table 1. Twenty patients had pleural mesothelioma. One patient was ineligible, having peritoneal mesothelioma with no pleural disease, and another had a performance status of 3 at study entry. Because of the requirement for patients to have measurable disease, 18 had stage III or IV disease at the time of entry, and all were symptomatic. Four patients had extrathoracic bidimension- Table 1. Patient and Tumor Characteristics Characteristic No. of Patients Sex Male 19 Female 2 Age, years Median 62 Range 46-74 Performance status 1 15 2 5 3 1 Tumor-node-metastasis system stage I-II 2 III-IV 18 Unstageable (peritoneal) 1 Histologic subtype Epithelial 13 Mixed/biphasic 8 Sarcomatous 0 Prior talc pleurodesis 8

CISPLATIN AND GEMCITABINE FOR MESOTHELIOMA 27 ally measurable lesions (supraclavicular nodes and subcutaneous nodules), and four others had similarly measurable intrathoracic lesions. Of the remaining 13 patients, 12 had pleural lesions that were unidimensionally measurable but had no bidimensionally measurable lesions, and one had a peritoneal mesothelioma, which was not measurable. Response to Treatment A total of 94 cycles of treatment were delivered to the 21 patients. The median number of cycles per patient was six (mean, 4.5 cycles). The relative dose intensity of treatment delivered was high for both cisplatin (median, 100%; mean, 96.7%) and gemcitabine (median, 91%; mean, 82.5%) and was similar for responders and for the group as a whole. Eleven patients completed the scheduled six cycles of treatment. Of those who did not complete six cycles, seven patients had disease progression while on treatment, and two refused further therapy after the first cycle of treatment because of gastrointestinal toxicity. Another patient, who had stable disease after three cycles of treatment, ceased chemotherapy because of an unrelated intercurrent illness. His disease progressed 7 months later, and he then received a further three cycles. The data on treatment response are listed in Table 2. No patient had a complete remission of disease. Ten patients had a partial response, and in nine, the best response achieved was no change. In two patients, the disease progressed without a period of prior stabilization. The overall response rate was 47.6% (95% confidence interval [CI], 26.2% to 69%). For those with pleural mesothelioma, the overall response rate was 50%. In nine of the 10 responding patients, the mesothelioma was of the epithelial subtype; one patient had a mixed or biphasic tumor. A response was observed among nine (69%) of 13 patients with measurable disease and epithelial mesothelioma and among one (14%) of seven with biphasic mesotheliomas. The patient with peritoneal mesothelioma (not measurable) had a biphasic tumor. Among those achieving a partial remission, the median duration of response was 25 weeks (range, 8 to 33 weeks). Symptom Control Formal quality-of-life assessment was not performed in this study; however, serial changes in symptoms were noted after chemotherapy administration. No patient was asymptomatic at the time of treatment. Seventeen complained of shortness of breath, 13 of chest wall, shoulder, or arm pain, three of lethargy, two of cough, two of anorexia, and one each of night sweats and nausea. Nine of the 10 responding patients had substantial or complete relief of symptoms. The remaining patient had been dyspneic on study entry and remained so. Three other patients, who had stable disease on objective assessment, gained significant symptomatic benefit from treatment. Serial measurements of vital capacity were recorded for three of the responding patients and showed significant improvement correlating with the objective changes on CT scans. Re-treatment Five patients were retreated after progression had occurred after cessation of the initial therapy. Four patients had had a partial remission of disease with the initial six cycles of treatment, and one patient, whose disease was stable after three cycles, progressed after a treatment break due to an unrelated intercurrent illness. None of these patients achieved a partial response on retreatment; five had stable disease accompanied by transient symptomatic improvement lasting 4 to 12 weeks. Disease Progression and Relapse Mesothelioma progressed in 19 of the 21 patients after treatment. The median progression-free survival for the total group was 25 weeks (95% CI, 17 to 33 weeks). For the 10 patients who achieved a partial remission of disease, the median time to progression was 36 weeks (95% CI, 28 to 44 weeks). For those in whom the disease stabilized on treatment, the median time to progression was 22 weeks (95% CI, 5 to 39 weeks). Response Category Table 2. Response to Treatment No. of Patients Complete response 0 Partial response 10 No change 9 Progressive disease 2 Total response* (%) 10 (47.6) Total 21 *Complete response partial response. Survival The estimated median survival for the whole group was 41 weeks (95% CI, 24 to 59 weeks), with an estimated 1-year survival of 41%. The distribution of progression-free survival times and survival are shown in Fig 1. Survival from the time of initial diagnosis of malignant mesothelioma for the group as a whole was 56 weeks (95% CI, 13 to 99 weeks).

28 BYRNE ET AL Fig 1. Progression-free survival (PFS) and overall survival (OS) for all patients from start of cisplatin-gemcitabine treatment. Toxicity The major toxicities observed were gastrointestinal and hematologic (Tables 3 and 4). Severe nausea and vomiting was experienced on at least one occasion by one third of patients and was worst after day 1 of treatment. Approximately 50% vomited with at least one cycle. Day 8 and 15 gemcitabine treatment rarely caused vomiting. Thrombocytopenia on day 8 or 15 was the major cause of dose modification. No patient had bruising or bleeding. One patient required treatment for febrile neutropenia. Significant cumulative hematologic toxicity was not demonstrated. Hospitalization was required on three occasions for control of nausea and vomiting, once for febrile neutropenia, and once for unexplained abdominal pain. Table 3. Treatment Toxicity Among 21 Patients Worst Toxicity Grade (% of patients) 0 1 2 3 4 Leukopenia 29 10 24 38 0 Thrombocytopenia 24 14 29 14 19 Anemia 14 29 57 0 0 Nausea/vomiting 0 14 52 33 0 Diarrhea 67 38 10 0 0 Stomatitis 62 38 0 0 0 Alopecia 71 24 5 0 0 Hearing loss 57 33 5 5 0 Neurologic 90 10 0 0 0 DISCUSSION The cisplatin and gemcitabine regimen used in this trial produced a 47% objective response rate in patients with advanced malignant mesothelioma. This exceeds the response seen in our previous trial of adriamycin and interferon alfa in similar patients. The high response rate observed in this study suggests that the combination of cisplatin and gemcitabine may have greater efficacy than most other single agents or combinations. In a recent review of studies that accrued more than 15 patients, Ong and Vogelzang 3 found no drug that consistently induced a response in greater than 20% of patients with mesothelioma. Higher response rates to detorubicin (26%), high-dose methotrexate (37%), and edatrexate (25%), reported in single phase II studies, have yet to be confirmed. 12-14 Neither cisplatin, 15,16 with a response rate of 13% to 14%, nor gemcitabine, 17-19 with a response rate of 0% to 31%, has shown great promise as a single agent, although the response rate to the latter has been variable. Table 4. Risk of Developing Grade 3 or 4 Hematologic Toxicity by Cycle Cycle (no. of patients) Patients 1 2 3 4 5 6 At risk 21 19 18 16 13 11 With leukopenia 3 2 3 2 1 4 With thrombocytopenia 3 0 3 1 0 1

CISPLATIN AND GEMCITABINE FOR MESOTHELIOMA 29 Regimens involving combinations of agents have been similarly disappointing with three exceptions. Breau et al 20 reported a response rate of 44% among patients with stage II and III mesothelioma given a combination of cisplatin, adriamycin, bleomycin, and mitomycin C plus systemic and intrapleural hyaluronidase. This study apparently has yet to be published in full. Trandafir et al 21 observed a response rate of 36% among 22 patients with predominantly stage II and III mesothelioma to a combination of cisplatin and low-dose interferon alfa. Middleton et al, 22 using a combination of mitomycin C, vinblastine, and cisplatin, achieved a 32% objective response rate among 22 patients, 59% of whom gained significant symptomatic relief with the treatment. Our data indicate that cisplatin and gemcitabine, used in the dose and schedule described, are clearly an active combination in the treatment of patients with advanced mesothelioma. Although quality of life was not formally measured in this patient group, all patients were symptomatic at the time of entry into the study. Significant symptomatic improvement occurred in approximately 90% of those in whom the disease showed an objective response and in a number in whom a no-change status was achieved. Decrease or cessation of chest pain was frequently reported and often accompanied by an increase in exercise tolerance and a decrease in dyspnea. Subjective improvement was also reported in a number of patients who were retreated after a further disease progression, although objective improvement was less clear. The symptomatic improvement seen in patients on this regimen is in sharp contrast to the results experienced by patients receiving adriamycin and interferon alfa in our earlier trial. In that study, we found little evidence of overall subjective benefit, even among those who achieved an objective response. Even with the use of serial CT scans, malignant mesothelioma is difficult to measure. When the disease was confined to the pleural cavity, we demanded that the pleural rind be at least 1.5 cm in thickness, at one level of the thorax or more, for the disease to be considered measurable. We assessed thickness at three levels on the CT scan and used the sum of the measurements of thickness at reproducible points to compute a unidimensional measurement. A decrease of 30% in this measurement, sustained for at least 4 weeks, was required to confirm a partial tumor response. If patients had bidimensionally measurable lesions, these were measured and a 50% decrease in the sum of the products of the diameters of the lesions was used to define a partial response. Although these criteria have not been validated in mesothelioma, and there are no validated response criteria for the disease, three of our patients who achieved a response showed a measured and significant increase in vital capacity. In addition, responding patients lived longer than nonresponding patients. These observations suggest that the response criteria used define tumor regression of sufficient magnitude to be of practical benefit to the patient. A larger experience will be necessary to confirm these observations and to validate the criteria. Malignant mesothelioma is a disease in which there is no standard treatment. Criteria for the assessment of objective response are not standardized and have not been correlated with functional or symptomatic benefit. The combination of cisplatin and gemcitabine seems promising. If the results obtained in this single-institution study can be repeated and reproduced in a multicenter setting, the combination may constitute an advance over best supportive care, but this would need evaluation in a randomized comparison with quality-of-life end points. 1. Musk AW, Dolin PJ, Armstrong BK, et al: The incidence of malignant mesothelioma in Australia, 1947-1980. Med J Aust 150:242-246, 1989 2. Musk AW, Woodward SD: Conventional treatment and its effect on survival of malignant pleural mesothelioma in Western Australia. Aust N Z J Med 12:229-232, 1982 3. Ong ST, Vogelzang NJ: Chemotherapy in malignant pleural mesothelioma: A review. J Clin Oncol 14:1007-1017, 1996 4. Upham J, Musk AW, van Hazel G, et al: Interferon alfa and doxorubicin in malignant mesothelioma: A phase II study. Aust N Z J Med 23:683-687, 1993 5. Davidson JA, Robinson BWS: Gemcitabine activity on murine and human malignant mesothelioma cell lines show additive activity in combination with cisplatin. Aust N Z J Med 27:213, 1997 6. Sandler A, Ansari R, McClean J, et al: Gemcitabine plus cisplatin in non-small cell lung cancer: A phase II study. Eur J Cancer 31A:S225, 1995 (suppl 5, abstr 1079) REFERENCES 7. Abratt RP, Bezwoda WR, Goedhals L, et al: Weekly gemcitabine with monthly cisplatin: Effective chemotherapy for advanced non-smallcell lung cancer. J Clin Oncol 15:744-749, 1997 8. Crino L, Seagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non-small cell lung cancer: A phase II study. J Clin Oncol 15: 297-303, 1997 9. Hermanek P, Sobin LH (eds): TNM Classification of Malignant Tumours (ed 4, revision 2). Berlin, Germany, Springer-Verlag, 1992 10. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981 11. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982 12. Colbert N, Vannetzel JM, Izrael V, et al: A prospective study of detorubicin in malignant mesothelioma. Cancer 56:2170-2174, 1985 13. Solheim OP, Saeter G, Finnanger AM, et al: High dose methotrexate in the treatment of malignant mesothelioma of the pleura: A phase II study. Br J Cancer 65:956-960, 1992

30 BYRNE ET AL 14. Belani CP, Herdon J, Vogelzang NJ, et al: Edatrexate for malignant mesothelioma: A phase II study of the Cancer and Leukemia Group B (CALGB 9131). Proc Am Soc Clin Oncol 13:329, 1994 (abstr) 15. Mintzer DM, Kelsen D, Frimmer D: Phase II trial of high dose cisplatin in patients with malignant mesothelioma. Cancer Treat Rep 69:711-718, 1985 16. Zidar BL, Green S, Pierce HI, et al: A phase II evaluation of cisplatin in unresectable diffuse malignant mesothelioma: A Southwest Oncology Group study. Invest New Drugs 6:223-226, 1988 17. Van Meerbeeck JP, Baas P, Debruyne C, et al: Gemcitabine (G) in malignant pleural mesothelioma (MPM): A phase II study. Lung Cancer 18:17, 1997 (suppl 1) 18. Millard FE, Herndon J, Vogelzang MR, et al: Gemcitabine for malignant mesothelioma: A phase II study of the Cancer and Leukemia Group B (CALGB 9530). Proc Am Soc Clin Oncol 16:1710, 1997 19. Bischoff HG, Manegold C, Knopp M, et al: Gemcitabine (Gemzar) may reduce tumor load and tumor associated symptoms in malignant pleural mesothelioma. Proc Am Soc Clin Oncol 17:1784, 1998 20. Breau JL, Boaziz C, Morere JJF, et al: Combination chemotherapy with cisplatinum, adriamycin, bleomycin and mitomycin C plus systemic and intrapleural hyaluronidase in 25 consecutive cases of stages II, III pleural mesothelioma. First International Mesothelioma Conference, Paris, France, 1991 (abstr 15) 21. Trandafir L, Borel C, Ruffie P, et al: Combined systemic CDDP-interferon alfa (IFN) in advanced pleural malignant mesothelioma. Proc Am Soc Clin Oncol 13:405, 1994 22. Middleton GW, Verrill MW, Priest K, et al: Good symptom relief with palliative MVP (mitomycin C, vinblastine, cisplatin) chemotherapy in malignant mesothelioma. Lung Cancer 18:22, 1997 (suppl 1)