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447 Combination chemotherapy with Cisplatin, Ifosf- amide and Etoposide for small cell lung cancer K. Ohta, N. Kurihara, T. Kamimori, H. Kanazawa, K. Wakayama, N. Adachi, K. Hirata, T. Takeda, The First Department of Internal Medicine, Osaka City University Medical School, l-5-7 Asahi-machi, Abeno-ku, Osaka, Japan Cisplatin, Ifosfamide and Etoposideare three of the most active single agents in small cell lung cancer (SCLC), and we are being evaluatingthe activity of their combinationin SCLC. The therapeutic regimen consisted of; Cisplatin 80 mg/m' day 1, Ifosfamide 1 g/m? day 1-5, Etoposide 80 mg/m' day l-3 every 4 weeks (3-5 courses). Patient (Pts) characteristics: male 23, female 7; age 64 yrs (38-79); PS (ECDG) O-l 14 pts, 2-3 16 pts; ED 15 pts, LD 15 pts. Results: Response is as follows Pts CR PR CR + PR MST (M) 3YS* LD 15 6 (40%) 9 (60%) 15 (100%) 15.4 13% ED 15 1 ( 7%) 10 (67%) 11 (74%) 6.3 0% (*3YS: three years survival rate) Toxicity was primarily myelosuppression with leu- kopenia WHO grade 3-4 in 80%, and thrombocytopenia grade 2-4 in 57% of the patients, with 15 manageable infections. These adverse reactions were reversible. Neutrotoxity was seen in 7% (grade 1). Alopecia was grade 2 or less in all pts and nausea/vomiting in 29 pts. Conclusion: The results of this trial demonstrate that this regimen is very effective and tolerable therapy for SCLC. 449 EMPOSIDE AND TENIPOSIDE IN UNTREATED SMALL CELL LUNG CANCER (SCLC). E.Bork,T.Sigsgaard, K.M.Nissen, T.Randlev, B.Bergman, P.Dombemowsky,M.Hansenand H.H.Hansen.: Herlev-, Bispebjerg-,Hillered-,Renstromska- Hospitals and Rigshospitalet, DK-2100Copenhagen, Denmark. In a previousstudy using etoposide(VP-16) 90 mg/m* and teniposide(VM-26) 80 mg/m2 we found no differences in activity(J Clin Oncol,inpress).Becauseof diffe- rences in hematologic toxicity we have randomized fur- ther 130 untreatedpatientsabove 70 years in good per- formancestatus (PSI=O-2. The supposed equietoxic do- ses were 100 mg/m2 for VP-16 and 75 mg/m2 for VM-26 i. v. daily x 5 q.3wks.At present103 pts. are evaluable. RESULTS: No. of pts. Age,median(range) PS (O/1/2) Local/Extensive PR + CR CR WPC (nadirs x 10v/l) VP-16 VM-26 74:1;0-84) 741;:0-81) 14127113 7125117 32122 29120 65% 79% 23% 2.7 23% 1.8 Survival(median) mths. 10.6+ 9.5+ These resultsconfirmsthat both drugs are highly activeas singleagents in SCLC. There was still a slightlower median leucocyte nadir of VM-26, but no significant differences in activitybetween the two analogswere found in this trial.The treatments were well tolerated. 121 448 PHASEIISTUDYOFGEMCITABINEINNON SMALLCELLLUNGCANCER(NSCLC). B. Lund, H. Anderson, J. Walling, N. Thatcher, H.H.Hansen Dept. ofOncology,Rigshospitalet, Copenhagen, Denmark,and Wythenshawe Hospital, Manchester, England. Gemcitabine (difluorodeoxycytidine) 800 mg/m’ i.v. q W x 3 followed by one weeks rest was given to 56 previously untreated patients (pts) with measurable NSCLC. Another 3 pts were treated with 1000 mg/mz. Patient characteristics were: males 38, females 21; median age 59 years (range 23-71); PS 0: 23,l: 23,2: 13; stage II 1, IIIa 17, IIIb 20, IV 21. Histologic type: adenocarcinoma 37, squamous 20, mixed 1, unclassified 1. A total of 197 courses has been given. Preliminary response rate (PR) in 47 evaluable pts: 12/ 47=26% (95% CI 1440%). Median response duration 6 months (2.lo+). Even though leucopenia grade 3 and thrombocytopenia grade 2 was seen in ~1% of 566 injections given, the myelosup- pression was the main reason for the 26 of 58 dose reductions or delays performed (45%). Grades 2-3 rises in transaminases were seen in 7%. Non-hematologic toxicity consisted of: grades 2-3 vomiting 33% of courses, lethargy 26%, flu-like symptoms 21%, peripheral oedema 18%, grades l-2 proteinuria 7%, grade 1 hematuria 5%, grade 2 cutaneous 5%, grade 2 fever 58, and > grade 1 alopecia 4%. Two responders developed acute renal failure at 4 and 6 weeks following completion of Gemcitabine. In conclu- sion, Gemcitabine is active in NSCLC and the toxicity modest. 450 A THREE-ARMED RANDOMIZED TRIAL IN SMALL CELL LUNG CANCER (SCLC) OFTWO INDUCTION REGIMENS WlTH TENIPOSIDE AND CISPLATIN OR CARBOPLATIN FOLLOWED BY ALTERNATING CHEMOTHERAPY VER- SUS ALTERNATING CHEMOTHERAPY. PEG Kktjaasen, K QkterIind, P Dombernowsky, M Hansen, OP Hansen, B Bergman, HH Hansen. The Finsen Institute. Herlev, Bis- pebjerg, Hillergd, and [email protected] Hospitals, Sweden and Denmark. 48dpatientst70 years with confmed SCLC in both stages (LD/ED) were entered. The aim was (1) to compare two induction regimens contain- ing teniposide (VM-26). vincristine (VCR), and either cisplatin (PI) or car- boplatin (JM-8).followed by alternatingchemotherapy,and (2) to compare these regimens with alternatingchemotherapy alone. S&&&&n, following staging: Arm 1 : D,-D,-D, -evaluate- A-B-C-D-A-B-C-D -evaluate. Randomize Arm 2 : DiDiD, evaluate- A-B-C-D-A-B-C-D -evaluate Arm 3 : A-B-C evaluate A-B-C-A-B-C-A-B evaluate. -:A: cyclophosphamide lg dl; CCNU 7Omgdl; etoposide7Omgd3-6;VCRl.3mg(max2.0mg)dl(+d8,15,22in lstcycle). B: doxombicine 60mg dl; VCR 1.3mg. C: PI 75mg dl; hexamethyl- melamine 200mg d8-22; vindesine 3mg d1.15. D,: P13Smg d2,3; VM-26 5Omgdl-5; VCR 1.3mgdl(+ d&15,22 in lstcycle). D,: JM-8 15Omgd2.3: VM-26 SOmg dl-5; VCR 1.3mg dl(+ d8.15.22 in 1st cycle). m an survival &.&year survival; Censored LD ED AI1 May91 AllIll S8w 20% 36~ 10% 48~ 18% 13% Arm2 61~ 18% 38~ 13% 49w 15% 13% Arm3 48~ 15% 3Ow SW 42~ 10% 16% Patientchamctezistics and hematological toxicity were comparable in the 3 amts. No strikingly differenttoxicity patternswere observed. There was no difference. in the survival of pxtients treatedwith the 2 platinum containing induction atms, while the survival was better in the 2 induction arms wO.05) than in the alternatingcontrol arm.

Phase II study of gemcitabine in non small cell lung cancer (NSCLC)

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447

Combination chemotherapy with Cisplatin, Ifosf- amide and Etoposide for small cell lung cancer K. Ohta, N. Kurihara, T. Kamimori, H. Kanazawa, K. Wakayama, N. Adachi, K. Hirata, T. Takeda, The First Department of Internal Medicine, Osaka City University Medical School, l-5-7 Asahi-machi, Abeno-ku, Osaka, Japan

Cisplatin, Ifosfamide and Etoposide are three of the most active single agents in small cell lung cancer (SCLC), and we are being evaluating the activity of their combination in SCLC. The therapeutic regimen consisted of; Cisplatin 80 mg/m' day 1, Ifosfamide 1 g/m? day 1-5, Etoposide 80 mg/m' day l-3 every 4 weeks (3-5 courses). Patient (Pts) characteristics: male 23, female 7; age 64 yrs (38-79); PS (ECDG) O-l 14 pts, 2-3 16 pts; ED 15 pts, LD 15 pts. Results: Response is as follows

Pts CR PR CR + PR MST (M) 3YS* LD 15 6 (40%) 9 (60%) 15 (100%) 15.4 13% ED 15 1 ( 7%) 10 (67%) 11 (74%) 6.3 0%

(*3YS: three years survival rate) Toxicity was primarily myelosuppression with leu- kopenia WHO grade 3-4 in 80%, and thrombocytopenia grade 2-4 in 57% of the patients, with 15 manageable infections. These adverse reactions were reversible. Neutrotoxity was seen in 7% (grade 1). Alopecia was grade 2 or less in all pts and nausea/vomiting in 29 pts. Conclusion: The results of this trial demonstrate that this regimen is very effective and tolerable therapy for SCLC.

449

EMPOSIDE AND TENIPOSIDE IN UNTREATED SMALL CELL LUNG CANCER (SCLC).

E.Bork, T.Sigsgaard, K.M.Nissen, T.Randlev, B.Bergman, P.Dombemowsky, M.Hansen and H.H.Hansen.: Herlev-, Bispebjerg-,Hillered-,Renstromska- Hospitals and Rigshospitalet, DK-2100 Copenhagen, Denmark.

In a previous study using etoposide(VP-16) 90 mg/m* and teniposide(VM-26) 80 mg/m2 we found no differences in activity (J Clin Oncol,in press). Because of diffe- rences in hematologic toxicity we have randomized fur- ther 130 untreated patients above 70 years in good per- formance status (PSI= O-2. The supposed equietoxic do- ses were 100 mg/m2 for VP-16 and 75 mg/m2 for VM-26 i. v. daily x 5 q.3wks. At present 103 pts. are evaluable. RESULTS: No. of pts. Age,median(range) PS (O/1/2) Local/Extensive PR + CR CR WPC (nadirs x 10v/l)

VP-16 VM-26

74:1;0-84) 741;:0-81) 14127113 7125117 32122 29120 65% 79% 23% 2.7

23% 1.8

Survival (median) mths. 10.6+ 9.5+

These results confirms that both drugs are highly active as single agents in SCLC. There was still a slight lower median leucocyte nadir of VM-26, but no significant differences in activity between the two analogs were found in this trial. The treatments were well tolerated.

121

448

PHASEIISTUDYOFGEMCITABINEINNON SMALLCELLLUNGCANCER(NSCLC).

B. Lund, H. Anderson, J. Walling, N. Thatcher, H.H.Hansen Dept. ofOncology,Rigshospitalet, Copenhagen, Denmark,and Wythenshawe Hospital, Manchester, England.

Gemcitabine (difluorodeoxycytidine) 800 mg/m’ i.v. q W x 3 followed by one weeks rest was given to 56 previously untreated patients (pts) with measurable NSCLC. Another 3 pts were treated with 1000 mg/mz. Patient characteristics were: males 38, females 21; median age 59 years (range 23-71); PS 0: 23,l: 23,2: 13; stage II 1, IIIa 17, IIIb 20, IV 21. Histologic type: adenocarcinoma 37, squamous 20, mixed 1, unclassified 1. A total of 197 courses has been given. Preliminary response rate (PR) in 47 evaluable pts: 12/ 47=26% (95% CI 1440%). Median response duration 6 months (2.lo+). Even though leucopenia grade 3 and thrombocytopenia grade 2 was seen in ~1% of 566 injections given, the myelosup- pression was the main reason for the 26 of 58 dose reductions or delays performed (45%). Grades 2-3 rises in transaminases were seen in 7%. Non-hematologic toxicity consisted of: grades 2-3 vomiting 33% of courses, lethargy 26%, flu-like symptoms 21%, peripheral oedema 18%, grades l-2 proteinuria 7%, grade 1 hematuria 5%, grade 2 cutaneous 5%, grade 2 fever 58, and > grade 1 alopecia 4%. Two responders developed acute renal failure at 4 and 6 weeks following completion of Gemcitabine. In conclu- sion, Gemcitabine is active in NSCLC and the toxicity modest.

450

A THREE-ARMED RANDOMIZED TRIAL IN SMALL CELL LUNG CANCER (SCLC) OFTWO INDUCTION REGIMENS WlTH TENIPOSIDE AND CISPLATIN OR CARBOPLATIN FOLLOWED BY ALTERNATING CHEMOTHERAPY VER- SUS ALTERNATING CHEMOTHERAPY.

PEG Kktjaasen, K QkterIind, P Dombernowsky, M Hansen, OP Hansen, B Bergman, HH Hansen. The Finsen Institute. Herlev, Bis- pebjerg, Hillergd, and [email protected] Hospitals, Sweden and Denmark.

48dpatientst70 years with confmed SCLC in both stages (LD/ED) were entered. The aim was (1) to compare two induction regimens contain- ing teniposide (VM-26). vincristine (VCR), and either cisplatin (PI) or car- boplatin (JM-8). followed by alternating chemotherapy, and (2) to compare these regimens with alternating chemotherapy alone. S&&&&n, following staging:

Arm 1 : D,-D,-D, -evaluate- A-B-C-D-A-B-C-D -evaluate. Randomize Arm 2 : DiDiD, evaluate- A-B-C-D-A-B-C-D -evaluate

Arm 3 : A-B-C evaluate A-B-C-A-B-C-A-B evaluate. -:A: cyclophosphamide lg dl; CCNU 7Omg dl; etoposide7Omgd3-6;VCRl.3mg(max2.0mg)dl(+d8,15,22in lstcycle). B: doxombicine 60mg dl; VCR 1.3mg. C: PI 75mg dl; hexamethyl- melamine 200mg d8-22; vindesine 3mg d1.15. D,: P13Smg d2,3; VM-26 5Omgdl-5; VCR 1.3mgdl(+ d&15,22 in lstcycle). D,: JM-8 15Omgd2.3: VM-26 SOmg dl-5; VCR 1.3mg dl(+ d8.15.22 in 1st cycle). m an survival &.&year survival; Censored

LD ED AI1 May91 AllIll S8w 20% 36~ 10% 48~ 18% 13% Arm2 61~ 18% 38~ 13% 49w 15% 13% Arm3 48~ 15% 3Ow SW 42~ 10% 16%

Patient chamctezistics and hematological toxicity were comparable in the 3 amts. No strikingly different toxicity patterns were observed. There was no difference. in the survival of pxtients treated with the 2 platinum containing induction atms, while the survival was better in the 2 induction arms wO.05) than in the alternating control arm.