108

3% 3%

IFOSFAMIDE, EPIRUBICIN AND CISPLATIN (IEP)- PHASE I TRIAL OF CHLOROQUINOXU~NE SU~ONMIDE AIWII-IER ACTIVE COMBINATION FOR SMALL CELL LUNG CANCER (SCLC).

(CQS): A UNIQUE AQENT WITH ACTIVIIV IN NSCLC SELECTED FOR STUDY BASED ON Acnvin IN AN IN Vrnso

Sumitra Thonqprasert, Krienqsak Jiemsriponqes, Chaicharn Phothiratana, Budsaba Atikachai Department of Medicine, Faculty of Medicine, Chianq Mai University, Chianq Mai, Thailand.

STEM CELLA~~AY. JR Rigas, MG Krii, WTong,CW Young, RP Warrell,Jr. MemorialSloan-Kettering Cancer Center, NewYork, NY

Fourty-five SCLC patients (30 males and 15 females, median aqe 58 yrs, median PS 60%) were treated with IEP r&men. Fourty-two cases were evaluable, 30 cases were limited disease (LD) and 12 cases were extensive djsease (ED). Treatment consisted of Ifosfamide 1.5 qm/m IV infusion 4 hrs on2day 1 & 2 with mesna uroprotectiqn. Epribucin 60 mq/m IV day 1 and Cis-platin 60 mq/m IV infusion over 2 hrs on day 3; repeated every 3-4 weeks.

Response No. of Pts. %CR%CR+PR median survival

LD 30 30 86.7 8 mos. ED 12 16.7 81.7 6 mos.

Treatment toxicity was moderate. Most co-n toxic effects included alopecia, leukopenia (28.5% qrade 3), nausea and vomitinq (50% qrade 2, 15% qrade 3), and anemia (40% qrade 2).

These results suqqest that IEP reqimen is one of the active combination for SCLC. The result previously reported usinq CAV or P/VP-16 was limited due to its majorhematoloqic side effect. The dosaqe of IEP in this study caused moderate toxicity. Increasinq the dosaqe of IEP is still possible. Further study aim to improve survival by usinq hiaher dose of IEP should be considered.

The in vitro human tumor colony forming assay (HTCFA) identified CQS as highly actiie in lung tumors. Preclinical studies also suggested that CQS concentrations used in the HTCFA (10 Pg/mL) could be achieved in man. In this trial, CQS was given as a 1 hr infusion every 28 days to determine the maximum tolerated dose (MTD) and verify the preclinical results. 88 patients (pts) received 172 courses of CQS from 184,870 mg/m2. Pts: median age 58 yrs (range,22-85); 44 men; median KPS 7096. The MTD was 4,080 mg/m2. Hypoglycemia, requiring glucose infusion, lasting 2-38 hours was dose limiting. Alopecia, phlebitis, perloral numbness, nausea, vomiting and diarrhea were seen. No cumulative toxicii occurred. Antitumor activfty was seen in 9 pts overall. 52 pts had NSCLC, all previously treated with chemotherapy. One had a major objective response lasting 12 months and 8 others had minor responses (median duration 8 months). Plasma levels >lO PglmL were seen in all pts given doses %rOmg/m? The TX, was 31 hrs (range 24-49). Area under the concentration-time curve at the MTD varied from lO- 15,000 kg/hr/mL. Conclusions: 1) When given every 28 days, the MTD of CQS was 4080 mg/m* 2) Hypoglycemia was dose-limiting; no myelosuppression occurred 3) Serum levels exceeded those required for activity in the HTCFA 4) As predicted, CQS produced responses in NSCLC pts with plasma levels > 10 Pg/mL 5) Testing of weekly CQS and Phase II trials in untreated pts with individualized dosing are planned. Supported by CA-05828.

397

Immunohistochemical Detection of CEA and P-glycoprotein (P-gp) in Small Cell Lung Cancer (SCLC): With Special Reference to the Tissue Expression of CEA and Response to Chemotherapy

Yoshihiko SEGAWA, Taisuke OHNOSHI, Shunkichi HIRAKI, Hiroshi UEOKA, Kazuyo MIYATAKE and Ikuro KIMURA Department of Medicine, Okayama University Medical School, Okayama 700, Japan

Mechanism of druq resistance in SCLC still remains obscure although it has been studied in a various point of view. Based on the clinical observations that a significant proportion of pts with relapsing tumor showed a elevated serum CEA level while serum NSE remained normal, we planned to determine whether the tissue expression of.CEA is a reoresentable findinq for a clonal chance in SCLC contrasting with the expression of NSE and P-gp. We examined 22 pts with SCLC whose tumor specimens were available for both at diagnosis and at relapse. Of those, there were two with CEA expression at diagnosis, and additional three pts showed CEA expression at relapse. It is of note that there were two pts whose tumors expressed NSE alane at diagnosis but CEA alone at relapse. Tumors with CEA expression at relapse were generally resistant to salvage chemotherapy, while there was no relationship between the tissue expression of P-gp and refractoriness to drugs at relapse. These findinqs indicate that the expression of CEA would be a mark of a clonal change,'and the change would play a role, in part, in the emergence of drug resistance in SCLC.

398

Potentially synergic effWt of combined treatment (chemotherapy+lonidamina+radiotherapy) in inope-

rable NSCLC. R.Felletti,A Cotella,L. Moretti,L Calcagno e Siragusa: AIPO Ligure l'boracic Cancer Cooperative Group: Chest Depts S.Martino,Sampiardarena and Galliera Rad& therapy - Genova, Italy. It seems potentially interesting that Lonidamine(LND) increases the cytotoxic effect of physical treatment (TCT hypertermia).Same in vitro and in viva experimen- tal works indicate that a very high cytotoxicity is observed when LND is combined with adrianycin(ADM): particulary a synergistic cell kill was produced when ADM precedes LND.In order to confirm these in vitro results we choose to treat a small number of stage III NSCLC pts with 3 cycles of chemotherapy (CDDP SOmg/Mq+ +ADMhOmg/Mq+CTX5OOmg/Mq) every 21 days followed by LND 600mg full dose orally given for 15 days+OOgy on pri- mary site.All pts were evaluable for response and to- xicity:lPT had CR,8 pts achieved PR>50 and 4C50%. 'I'he median survival after response was 6 mth but the pt in CR died after 9 mth for brain methaatasis.All cttherpta arc still alive.Haematologic and gaatrointestinsl taxi_ city were no more than l-2 ECQG scale, and the compli- ante was accettable,but there were 2 pneumonitis rela- ted.Tnis high response rate may auggeat trials with the sequency:CT containingADM*~~+R4di~tbe~py;mcry be adding prophilactic brain irradiation in CR.