110

417

CHEMOTHERAPY/NON-SMALL CELL

418

CLINICAL AND PHARMACOLOGICAL PHASE II STUDY OF PROLONGED ORAL ETOPOSIDE IN COMBINATION WlTH INTRAVENOUS CISPLATIN IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC). A.A. Miller, H.B. Niell, J.P. Griffin, E.A. Tolley. University of Tennessee, Memphis, Tennessee, USA.

The objectives of the study were to evaluatethe combination of cisplatin and prolonged oral etoposide for response rate and survival as well as for correlations between etoposide concentrations and nadir blood counts. The treatment regimen consisted of etoposide 50 mg/m2/day p.o. for 21 consecutive days and cisplatin 100 mg/m2 i.v. on day 1 every 28 days for up to 6 courses. Patients were followed weekly for CBC, etoposide concentration, and toxicity. Samples for etoposide were obtained before the daily dose and plasma concentrations measured by high performance liquid chromatography. Patients with stage IIIB or IV NSCLC who had not received prior chemotherapy and had a performance status of O-2 were eligible if they had normal bone marrow, liver and renal function. The total number of patients entered on study was 60 of whom 56 were male and 4 female, 40 white and 20 African Americans. Median age was 64 years (range, 39-77). Performance status 0, 1, and 2 was present in 5, 39, and 16 patients, respectively. Fourteen patients had stage IIIB and 46 stage IV disease. A total of 142 treatment courses was administered (median 2, range l-6). Three patients had a complete response and 19 patients had a partial response for an objective response rate of 37% (95% confidence interval, 31% to 43%). Median survival was 5 months (range, l-39+). Toxicity was assessable in 55 patients (no nadir counts in 5). Neutropenia was the major toxicity with grade 4 occurring in 25 patients after the first course. If analyzed for all courses, 44 patients had grade 3 or 4 neutropenia, and 3 patients died of neutropenic sepsis. Correlations between etoposide concentrations and logarithmic transformations of nadir counts after the first course were available for 49 patients: WBC (Spearman correlation coefficient =-0.72, p<O.OOOl), neutrophils (-0.79, p<O.oOOl), platelets (-0.52, p<O.O002), and hemoglobin (-0.43, p<O.o025). This regimen of prolonged etoposide with cisplatin is active in advanced NSCLC and etoposide levels are significantly correlated with the hematologic toxicity.

419

MANAGEMENT OF CHEMOTHERAPY IN ELDERLY PATIENTS WITH ADVANCED NON SMALL CELL LUNG CANCER (NSCLC): A PHASE III RANDOMIZED TRIAL. L. Portalone, M. D’Aprile, E De Marinis, A. Conm, F. Giordano, M. Rinaldi, F. Romano, M. Belli, G. Altavilla, G. De Cataldis, G.F. Addamo, M.R. Migliorino, S. Orto, P. Bruzzi, F. Salvati, R. Rosso, for the Italian Lung Cancer Task Force.

Patients older than 70 years with advanced NSCLC arc usually excluded from prospective randomized trials because are thought to bad tolerate standard chemotheray. In order to evaluate feasibility (toxicity and protocol adhesion) and efficacy (in terms of overall survival, OS and objective response, OR) of “mild” chemotherapy regimen in elderly patients (pts) (age 2 70 years) with advanced NSCLC, a cooperative phase III randomized trial, with factorial design, was performed: arm A: best supportive care (BSC); arm B: Lonidamine (LND) 450 mglday p.o.; arm C: Vindesine (VDS) 3 mglsqm I.V. weekly for one month and then every two weeks; arm D: LND plus VDS at the same schedule. 1.53 pts were enrolled: 60.8% stage III and 39.2% stage IV, age < 75 years: 48%; age > 75 years: 52%; median P.S. 1 (range O-3); male/female = 134119. Pts characteristics were well balanced. 82/116 pts (excluding 37 pts in BSC arm) were evaluable for toxicity: g. III-IV testicular pain 6.9% (B), 9.4% (D); myalgias 13.7% (B), 12.6% (D); fatigue 13.7% (B), 3.1% (C), 15.6% (D); abdominal pain 3.4% (B), 9.4 (D); leukopenia 9.4% (C), 12.5% (D); nausea 3.4% (B). No g. III-IV thrombocytopenia or anemia was observed. Overall, 100/153 pts were evaluable for response (drop-out 34.6%); 3 PR (1 ARMB, 2 ARMD) (2.7%). 45 (41.3) SD, 52 (52.0) failures were observed. A factorial analysis was performed in order to evaluate the efficacy of the regimens. Neither LND (LND f VDS vs BSC f VDS) 6 vs 6 months, nor VDS (VDS f LND vs BSC f LND) 5 vs 6 months, prolonged OS. In conclusion: 1) The management of randomized clinical studies in elderly NSCLC pts may results problematic because of low protocol adhesion even using mild CT. 2) VDS and LND have negligible antitumor efficacy both in terms of OS and OR. The optimal treatment of NSCLC in elderly pts require specifically designed clinical trials.

PHASE I STUDY OF ETOPOSIDE IN COMBINATION WITH CISPLATIN AND GRANULOCYTE COLONY STIMULATING FACTOR G-CSF IN PATIENTS WITH NON SMALL CELL LUNG CARCER (BSCLC). T Nakabayashi’ ,3 M. Harada' $., Sagaki', H.

lrnlZU Tamura’

Miyamotoa, F. Kisi

s. Fi.Tic[yjikane . T.

Hospital' Y. Kawaiamis s

, H. Akita6, H. apporo National

Hokkaido Kinhjkyo Chuou Hospital*, National bohoku Hospital minami Hospital& "5~h~~~~~~~"ag~~~,E~~~~~~~, Hokkaido University6

A phase I trial wa& carried'out to'determine the maximum tolerated dose(M L‘) of etoposide

ICDDP) VP 16) together with a fixed dose of cisplatin

and G-CSF in previously untreated and ;;zperable patlents(pts),w+th NSCLC, as well as

dose llmltlng toxlcltles(DLT) of this combination. 1-5(X5)

Pts were trfated with VP-16 on days lus CDDP(f30mg/m ,dl)

SC., d6-dP9). Wh en the legkoc increased above lOOOO/mm , t h

and G-CSF zl;glkg, tes after 6

5

e use of G-CSF was ~;;p ed. The starting dose of VP-16 was 60mg/m

days. Twenty eight pt? have been evaluated.

F;lT;;;oglc toxlcltles (WHO Grade 3, 4) were as

E;;e letel of VP-16(mg/m2) 6t 7: "9 ":

100

Leukopenia : : : ;

4' Neutropenia ~~~;~;ocytopenia

8 : s ':

in combination with CDDP and

etoposide.

420

PHASE II STUDY WITH THYMOSIN orI (TAl), INTERFERON a2a (IFN), CISPLA- TIN (DDP) AND ETOPOSIDE (VPl6) IN THE TREATMENT OF ADVANCED NON SMALL CELL LUNG CANCER (NSCLS). *M.P.iualdi, *E.Garaci. ‘G.Bousignore, ““M.D’Aprile, *M.Della Giulia, **C.Favalli, *I.Veuturo. *M.Lopez. *lstimro Regina Elena, “k Regina Elena 291, 00161 Roma, **Cart&a di Microbiologia. Uuiventi di

Roma “Tor Vergata”. ‘lstituto di Pneumologia, Universiti di Palenno, O’Centro Oucologi- co “G.Porfm” Ospedale Civile. Lad@&

TAl, a synthetic polipepdde of thymic origin, and 1FN are able to restore NK activity in

both cyclophosphamide (CTX) treated and tumor-beanng immunosuppressed mice. Morec- VW, treatment with CTX and TA1 plus IFN was s@icauUy more effective than CTX alone or in combination with TAI or IFN against Lewis lung carcinoma in mice.

To verify whether TAl and low dose IFNolZa could potentiate the activity of “conventio- nal” chemotherapy in patients with advanced NSCLC, we undertook this phase II trial. All patients received DDP 100 mgism on day 1, VP16 120 mgism on days l-3. TAl 1 mg S.C. ou days S-11 and 15-18. and dFN 2a 3~10~ IU S.C. on days 11 and 18, 1 h. after TAl (recycle every 4 weeks). 60 patients entered the study, 55 are w&able for response and toxicity. 5 patients were not evaluable for response because of loss to follow-up (I pt.). treatment refusal (3 pts.), excessive toxicity (1 pt.). The predominant ixstologies were squamous cell carcinomas (41%) and adenocarcinoma (34%) 55% had Mo and 45% Ml disease. Among the 55 patients evaluable for response 2 had CR, 22 PR with an OR of 43.6% (95% CL; 30.5-61.5). 24 were NC and 7 PD No statistical difference regarding the stage was found. The follow-up median duration was 12.3 months (0.033. -28.5+). At the time of this analysis 75% of patients had died. The overall median duration of response was 7.9 months. Median survival was 12.6 months (non responden 10. responders 15.7 months: P=O.OS) There were no treatment r&red deaths. Myelosuppression was the most common observed toxicity: in 41% of the patients leukopenia G3-4 was found, but no in- stances of infections were recorded. A part from moderate fever and minimal flu-l&e symptoms, no other loxic effects were related to IFN administration. TAl is apparently devoid of toxicity. NK activity was depressed by chemotherapy, but recovery was signifi- tautly showned in patients treated by chemoimmunotherapy in comparison to a concomi- tant group treasted with DDP and VP16 alone. The overall response rate is encouraging and the role of these BRMs is now investigated in a phase III multicenter randomized trial.