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COMBINED ANTIPROLIFERATIVE EFFECTS of TAXOL AND HIGH DOSE WXORUBICIN PLUS HIGH DOSE CISPLATIN FOR ARGININE BUTYRATE ON HUMAN MESOTHELIOMA CELLS

MESOTHELIOMAS. D.J. Stewart, S.Z. Gertler, R. Goal, F. Shamji,

S. Ehxi, Y. Koq, MC O’brien, D. Sanders, S. Tansan, F. Foss A. Tomiak, W.K. Evans. Ottawa Regional Cancer Centre, Ottawa, Ontario, KlY 4K7, Canada.

Boston University Medical Center, Martin Semler Memorial Laboratory of the Section of Medical Oncology, Boston, Massachusetts

Malignant mesothelioma is a disease for which there are no effective chemotherapeutic options. Tax01 (Paclitaxel) is a chemotherapeutic agent that promotes microtubule assembly and stabilizes tubulin polymer formation. Arginine Butyrate is a butyric acid derivative which has demonstrated antiproliferative and differentiating effects of various human cancer cell lines. Alpha interferon has been used as a modulator in combination with multiple chemotherapy agents. Little is known about the effects of taxol alone or combined use of taxol with butyrates or interferon on mesothelioma cells.

We herein report the in vitro effects of taxol at clinically relevant concentrations (10-250 nM) in combination with fixed concentrations of Arginine butyrate (0.5 mM) and Interferon&h (JFN-A) (100 U/ml) on the growth of a human mesothelioma cell lime (APlIA-257). Cells were incubated for 96 hours with and without drugs and inhibition of cell growth or cell kill was assessed by using MTT assay. When used alone, taxol and butyrate both inhibited cell growth whereas IFN-A was ineffective. At a concentration of 0.5 mM, butyrate resulted in 26% growth inhibition. At concentrations of lo-250 nM taxol resulted in 12- 48% growth inhibition. The combination of taxol and butyrate was additive. At tax01 concentration of 50 nM addition of butyrate (0.5 mM) resulted in the same degree of antiproliferative effect as that seen at 250 nM. Addition of IFN-A to taxol or to the combination of taxol and arginine butyrate did not effect the degree of antipmliferative effect seen.

We conclude that both taxol and arginine butyrate exerts in vitro inhibition of cell growth against APIIA-257 mesothelioma cell line and the combination results in additive antiproliferative effects at clinically achievable tax01 concentrations.

Four patients (age 39-57) with unresectable mesotheliomas were treated with high dose doxorubicin plus cisplatin since: a) this regimen at lower doses has a 25% response rate; b) the dmgs have a steep dose-response effect vs some tumor types; c) they have. non-overlapping dose-limiting toxicity; d) they are synergistic in vitro. Cisplatin 105-120 mg/m* was given iv in 500 ml saline over l-2 hr on day 1, or in divided doses over 2-3 days of each 3 week course. Hydration with 250 ml dextrose 5% in 0.45% saline was given iv over 0.5-I hr before cisplatin, and 20% mannitol 250 ml was given iv concurrently with cisplatin. Doxorubicin 90 mg/m* was given iv in 50 ml D5W Prior to the first day of cisplatin in one patient, and right after the last day of each cisplatin course for the other 3 Patients. All Patients developed febrile neutropenia. Other toxicity included nausea/vomiting (4 patients), stomathis (2), neuqathy (2), ototoxicity (2), and reversible nephrotoxicity (1). Two patients had complete remissions, one lasting one year and one persisting at llloTe than 4 years, respectively. The third ptient had >95% tuma regression that lasted 10 months. The fourth and eldest Patient had marked decrease in Pain and dyspnea, but needed substantial dose reductions due to toxicity, and objectively had only stable disease. He survived 9 months from first treatment and 5 months from his last treatment. Hence: This high dose outpatient combination is toxic, but warrants further study in good performance status Patients with unresectable mesotheliomas. Long term complete remission has been observed in one of 4 patients.

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OUTCOME OF DIFFUSE MALIGNANT PLEURAL MESOTHELIOMA. M. Ogiwara, K. Kaneko, M. Hatanaka, Y. Shimamura, M. Sukigara, R. Omoto, Department of Surgery, Saitama Medical School, Saitama, Japan An analysis was made from the results of diagnosis, treatment and prognosis of diffuse malignant pleural mesothelioma in 11 patients. The mean age of the patients was 56.8h9.7 years old, 7 were male. All patients had the pathological diagnosis of mesothelioma and they were classified into histological and Butchart clinicopathological classification before treatment. There were 6 patients in Stage I, 3 in II, 1 in III and 1 in Stage IV Six pateints in Stage I were all classified as pure epitherial type before

treatment, 3 of them by open chest biopsy and 3 by needle biopsy. Five patients underwent pleuropneumonectomy. Four of them had their histological diagnosis changed to a mixed type in a review of the surgical specimens and they died within 3 months after operation, 2 from recurrence of the disease and 2 from pneumonia. Only one patient classified as pure epithelial type in the review had a long term survival (72months) with adjuvant chemotherapy and irradiation. The patient, excluded from pleuropeumonectomy due to her advanced age (77 years old), was treated with chemotherapy alone and died of mesothelioma after 18 months. The 5 patients in Stage 11,111 and IV (2 pure epithelial and 3 mixed typ) were not operated and 3 of them were submitted to chemotherapy and died after 1,2 and 7 months later, respectively. The other 2 patients died soon after diagnosis. <Conclusion> l.Patients with pure epithelial histological type mesothelioma and in clinicopathological Stage I seemed to have better prognosis. 2. Histological classification based on the results of open chest and needle biopsies are not reliable, because mixed type mesothelioma can be misdiagnosed as epithelial type.

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A PHASE II TRIAL OF TAXOL IN MALIGNANT PLEURAL MESOTHELIOMA Van Meerbeeck, J.P., Postmus, P.E., Oliva, C., van Zandwijk N., Giaccone, G. on behalf of the EORTC- LCCG.

From April to October 1993, 25 chemotherapy-naive patients with biopsy proven malignant pleural mesothelioma were treated with taxol (200 mg/mz, 3 hours infusion, q3 weeks). Before treatment, standard premeditation with steroids, antihistamines Hl and H2 was administered. Toxicity was assessed during and after every cycle, re- sponses every 4th cycle, unless otherwise needed. CT scans were mandatory for response evaluation and were extramurally reviewed, as well as the pathologic slides of all responding patients. Patient characteristics: Male 21, female 4; median age: 62.4 y (36-73). all PS s WHO 2. Subtypes: epithelial 12; sarcomatous 2; mixed 6; 3 still unknown. TNM stages: I, II: 12; Ill, IV: 10; 3 still unknown. Median number of courses: 4 (I-6 + 1. Responses: NC: 8; PD 3; too early for evaluation: 13. Toxicity (CTC): alopecia gr. 2: 13; myalgia L gr. 2: 7; paresthesias 2 gr. 2: 5; HSR: 6 (mild). Based on these preliminary results we cannot establish any activity of taxol in this highly chemo-resistant neoplasm. An updated analysis will be presented including the data from the 13 patients still on study.