Abstracts/Lung Cancer I2 (1995) 113-160 151

An ongoing randomized study of q eoadjuvant cbemotberapy in reseetable non- small cell lung cancer Depierre A, Milleron B, Lebeau B, Moro D, Chastang C, Jacoulet P et al. Service de Pneumologie, CHU, 25000 Besancon. &mitt Chtcol 1994;2l:Suppl4:16-9. The purpose of this trial is to assess the possible benefit of neoadjuvant chemotherapy before. surgery in patients with operable non-small cell lung cancer. Patients with operable stages I (except TINO), II, or IIIA disease are eligible for this ongoing trial, Patients are randomized into two arms. Surgery is performed first in group I; patients found to have T3 hunors or N2 lymph nodes are given postoperative radiotherapy. Group 2 patients start with two cycles of chemotherapy; following surgery, two more cycles are administered in responder patients and, as in group I. patients with T3 tumors or N2 lymph nodes are given radiotherapy. Chemotherapy is the MlP protocol: mitomycin 6 mg/m* day 1, ifosfamide 1.5 p/m’ days 1 to 3, cisplatin 30 mg/m* days 1 to 3, and mesna 1,200 mglmr days 1 to 3. One hundred tlfty patients were enrolled between June 1991 and September 1993. By the time this report was prepared, 117 patients had completed all assigned treatment, 63 in group 1 and 54 in group 2. There were two ineligible patients, one in each group. Forty-nine patients underwent thoracotomy in the chemotherapy-surgery group and 62 in the surgery-only group. There was only one progression after two cycles of chemotherapy. Rates of exploratory and incomplete surgery were 17% in group 1 and 12% in group 2. The trial is ongoing.

Combination cbemotberapy with viaorelbine, ifosfamide, and cisplatbu A phase II study in stage IDEIV non-small cell lung cancer Baldini E, Tibaldi C, Chella A, Angeletti CA, Romanini A, Andrei A et al. Department ofMedical Oncology S. Chiara Hospital, Ma Roma, 67, 56100 Pisa. Semin Gncol 1994;2l:Suppl4:12-5. Forty-five stage IIIB-IV non-small cell lung cancer (NSCLC) patients entered a phase II study designed to evahtate the toxicity and the activity of a combination chemotherapy regimen consisting of vinorelbine (25 mg/m’ days 1 and 8). if&amide (3 g/m’ day 1 with uropmtective mesaa), and cisplatin (80 mg/m’ day 1). The regimen, VJP, was administered on an outpatient basis every 3 weeks. White blood cell counts were checked weekly, and granulocyte colony-stimulating factor was administered in case of grade 4 neutropenia lasting for more than 48 hours. Leukopenia was the most frequent toxicity, with grades 3 and 4 neutropenia reported in 25% of cycles and 11 episodes of febrile neutropenia recorded in 175 evaluable courses. The combination of vinorelbine and cisplatin did not result in additive neurotoxicity: only five patients experienced grade 2 neurotoxicity after six courses of treatment. Thirty-five patients were evaluable for response. Twenty partial responses (57%) and one complete response (2.8%) were observed, for an overall response rate of 60% (95% confidence interval, 42% to 76%). The median time to progression, measured from the start of treatment, was 7 months (range, 1 to IS+), and median survival for the whole group was 12 months (range, 1 to IS+). VIP is a well-tolerated regimen and shows interesting activity in advanced NSCLC.

Dose-intensive ifosfamidekarhoplatbuetoposide plus granulocyte- macropbage colony-stimulatbtg factor for non-small cell lung cancer Palackdhany CS, Krigel FZ. Department ofMedicine, Medical College of Ohio, PO Box 10008, Toledo. OH 43699-0008. Semin Oncol 1994;2l:Suppl 4:6-11. Whereas non-small cell lung cancer (NSCLC) comprises 80% of all lung cancer cases, effective prolongation of survival in NSCLC patients using currently available combination chemotherapy has been problematic. Use of dose-intensive chemotherapy along with hematopoietic growth factor support is an attractive, albeit experimental,

alternative. We have conducted a phase I study to determine the maximum tolerated dose of etoposide in the ifosfamide&rboplatin/ etoposide (ICE) regimen when used with granulocyte- macrophage colony-stimulating factor (GMCSF) support. lwenty-three patients with solid tumors refmctory to standard treatment who had not received previous platinum~ontaining chemotherapy or for whom there was no generally accepted curative therapy were treated. We present results obtained in 11 patients with previously untreated stage IV NSCLC. The use of ICE plus GM- CSF demonstrated promising activity in this group of patients; the overall response rate was 64% and median survival was 10.0 months. The maximum tolerated dose of this regimen is 900 mg/m’ etoposide in combination with 5 g/m2 ifosfamide, 400 mg/mZ carboplatin, and 5 ig/kg/d GM-CSF.

Etoposide/ifosfamide/cisplatin tvghuens in metastatic non-small cell lung cancer Perez EA, Gandara DR. Division ofHematologv and Oncologv Davis Cancer Centec Universib of Cabfirnia, 4501 X St, Sacramento, CA 95827. Semin Gncol 1994;21:Suppl4:2-5. Although non-small cell lung cancer has long been considered poorly responsive to chemotherapy, there are now a number of chemotherapeutic agents with reproducible activity in this disease, including cisplatin and ifosfamide. Another agent, etoposide, has been rationally in- corporated into combination regimens for this disease based on demon- strated pmclinical synergy. We review recent studies combining these three agents in the treatment of metastatic non-small cell lung cancer as well as prospects for further development.

lkgetlng the cytotoxicity of topoisomerase II-directed epipodu pbyllotoxins to tumor cells in acidic environments Jensen PB, Sorensen BS, Sehested M, Grue P, Demant EJF, Hansen HH. Department of Oncology, The Finsen Institute, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen. Cancer Res 1994;54:2959-63. The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes signilicant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF- 187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II- mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular PH. Chlotoquine, in contrast to etoposide, is a weak base and therefore does not enter the cell ifthe extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pHdependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH @H(e)) from neutral @H(e) = 7.4) to acidic @H(e) = 6.0) [‘H]cNoroquine accumulation was decreased 5- fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia Ll210 cells. In parallel. the antagonism exhibited by chlorcquine on etoposide cytotoxicity was pH(e) dependent. Thus, no protection by chloroquine was observed at pH(e) = 6.5, whereas at pH(e) = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.