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Early (EAC) versus late (LAC) alternating chemotherapy in small cell lung cancer (SCLC)
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chemothera _ AC) versus late &AC1 -tina pv in smg(i ceil IUna (;BI1EBrfSCLC) R. Joss, M. Bacchi, C. HOmy, J. Bernhard, Th. Cerny, F. Cavalii, S. Leyvraz, H.J. Senn, R. Stahei, P. Aiberto, C. Ludwia. P. Sieaenthaler for the Swiss Group for Clinical Cancer Research (SAKk). Bern, Switzerland 407 eligible patients (pts) with SCLC have been entered into a randomised phase iii trial comparing the value of EAC versus IAC. Regimen A was .I?&4 : cisriatin 30 mg/m2 d 1-3, Adriamycin 40 mglm2 d 1, YP 16-213 120 mglm2 dl-3. Regimen B was CvMOc: &ciophosphamide 1000 mg/m2 d 1, Methotrexate 20 mglm2 p.o. d 14 +17, Qncovin 1.4 mglm2 d 1, GCNU 40 mglm2 p.o. d 1. Cycles were repeated as soon as possible. Pts were randomized to receive either ABABAB (EAC) or AAABBB (LAC). After six cycles pts with limited disease in CR or PR and pts with extensive disease in CR were irradiated to the primaty (45 Gy) and the CNS (36 Gy). 69 % of the pts were classified as extensive disease. The overall remission rate was 87 % with 31 % CRs. The median survival of ail 407 eligible pts was 348 days. The overall remission rate, the rate of CRs, the median survival and the rate of iongterm survivors were no different in the two treatment arms. However extensive disease pts survived significantly longer with LAC compared to EAC (338 days versus 301 days, p = 0.02). Three toxic deaths due to ieukopenia were observed. Myelosuppression was more pronounced in pts treated with EAC. More pts treated with LAC experienced severe nausea and vomiting (20 % versus 11 %, p = 0.0014) We conclude that alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is an effective treatment for SCLC with acceptable toxicity. Whether LAC is advantageous in patients with a high tumor mass awaits the results of further studies.
PHASE II STUDY ON SEQUENTIAL CHEMOTHERAPY WITH HIGH-DOSE EPIRUBICIN (HD EPI) AND CISPLATINUM + ETOPOSIDE (CP+E) IN SMALL CELL LUNG CANCER.
M. Casadio, A. Martoni, B. Melotti, V. Pajetta, *L. Busutti, F. Pannuti. Medical Oncology Division, *Radiotherapy Division - S. OrsolaMalpighi Hospital, Bologna Italy. HD EPI has proven to be active ln advanced small cell lung cancer. A phase II study on the use of HD EPI followed by a standard combination CP + E in the treatment of patients with small cell lung cancer was designed. EPI was administerd at the dose of 135 mg/m2 iv for 2 courses on day 1 and 21 and was followed by CP and E at the respective doses of 30 mg/m2 and 120 mg/mz daily for 3 consecutive days on day 42 and subsequently every 21 days. Patients (Pts) with limited disease (LD) received chest radiation therapy (TCT 48 Gy) after 2 courses of CP + E. Pts with extended disease (ED) continued the treatment with CP+E until progression or to a maximum of 10 courses. Pts aged > 70 years or with PS ~70% or with active cardiac disease were excluded. From July 1989, 30 consecutive pts were admitted to the study 13 had LD and 17 ED. After the 2 courses of HD EPI objective partial remission was observed in 20130 (67%). The overall objective response rate was 73% ( 22130) (3 CR t 19 PR). The remission rate was 85% in LD and 65% in ED. Duration of response was 41.5 (6-83.5) weeks. Median survival was 35.5 (5.5 -117.5+) weeks. Side effects included: leukopenia 86% (43% grade 3-4), thrombocycopenia 27.5% (10% grade 3-4), nausea-vomiting 72%, alopecia 93%, mucositis 17% and dlarrhoea 10%. No case of clinical cardiotoxicicty was observed. In conclusion, this study confirms that HD EPI has high antitumor activity in small cell lung cancer and further studies on its inclusion in the treatment of this disease are warranted.
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Phese II study of Topotecrn (TC) in petlents (pts) with pretreeted small-cell lung cancer (SCLC). K Tvede, A. Ardiuoni, P. Dombemowsky, P. Postmus, M. Buitenhuis, J. Wenclers, N. van Zandwijk, J.B. Krebs, J. Verweij. On behalf of the EORTC Early Clinical Trials Group and the EORTC Lung Cancer Cooperative Group. There is a great need for new active agents in SCLC pts. TC is a semisynthetic camptothecin(CT) analogue. Response rates with CT were disappointingand toxicity, especially hemorrhagic cystitii was severe. TC has increased hydrophilic&ydue to a basic side chain and is at acidic pH water soluble compared to camptothecin.TC and CT appear to functionthrough interaction with toposomerase I. The dose limitingtoxicitiesin phase I studiesof TC were mainlvneutrooenia and diarrhea. There has been no evidence of hemorrhaaic cystitk ’ In phase I studies the most impressiveevidence of anti-tumoractivii occurred on the dailv x 5 schedule in eiaht out of 53 ots treated with this schedule. ’ Antitumor&tivity was demonstrsed. A phase II multicenter study of TC of 1.5 mg/m’ daily x 5 every 3 weeks is ongoing in pts with SCLC. At present 29 pts have entered with one-line of pretreatmem, 3 pts are not eligible. 14 pts were previously sensitive to chemotherapy and 15 refractory. Pts characteristics were: median age 61, median performance status 1, male/female 19/9. mean courses 7. 14 pts are off-study.Survival status: 3 pts are dead due to progression (2 cases) and toxicity(1 case). 22 pts have teen evaluated for toxicity. Hematoloaic toxicitv consists of leucooenia in 99% of 85 cci#sss wkh NCI Common foxicity Cheria (CTC) gr. 4 in‘s/65 courses. Neutropeniain 93% with or. 4 in 36185. ThrombonRooeniein 69% with or. 4 in 9185. and anemia in 93% >nh gr. 4 in 4/65 course; Bieedingin 1 pt, inf&tion w&s observed in 5 pts end 2 of them died. Non-hematologictoxicity was only moderate and consisted mainlyof alopecia (9 pts), nausea (i 5 pts), astenia (16 pts), liver(4 pts), grade 1-2 vomiting (7 pts). Hemorrhagic cystitishas not been observed. 20 pts are &&able for respon&. Preliminaryresponse for refractory/sensitive ots were: CR 111, PR 2/3. in conclusion:TC.is a new drug wkh tolerabletoxicityand some actMy against SCLC.
of life in the trealfnent of ad_ (SCLC). A randomlred phase iii ComParLson of weekiv CariwWiigW TaniDosidevcin. Etonoslde aiterwith CvBide. Methotrwxte. Vincristlne and m. R. Joss, P. Aiberto, C. Hiirny. M. v versus ~UI,WV
I ceil u
cancer
Bacchi, S. Leyvraz, B. Thiiriimann, T. Cerny, F. Cavalii, C. Sauter, C. Ludwig for the Swiss Group for Clinical Cancer Research (SAKK). Bern, Switzerland 59 eligible patients (pts) with advanced SCLC have been entered into a prematurely closed randomised phase iii trial comparing a weekly regimen of carboplatin 80 mg/m2 and teniposide 80 mg/m2 (CBDCANM) to our standard regimen of cispiatin, adriamycin, etoposide alternating with cyciophosphamide, methotrexate, vincristine and lomustine (PAV-CyMOC. i.e. cisplatin 30 mglm2 d l-3, Adrfamycin 40 mglm2 d 1, YP 16-213 120 mglm2 dl-3 alternating as fast as possible with uclophosphamide 1000 mg/m2 d 1, Methotrexate 20 mg/m2 p.o. d 14 +17, Qncovin 1.4 mg/m2 d 1, GCNU 40 mg/m2 p.o. d 1). The results achieved with PAV-CyMOC were significantly better than those observed in pts treated with weekly CBDCANM (remission rate of 85 % vs 29 %, p = 0.006; median survival of 260 days vs 147 days, p = 0.0035; l-year - survival rate of 30 % compared to 4 %). As expected side effects including myelosuppression, alopecia and mucositis were more pronounced in ps treated with the PAVCyMOC - regimen. Contraty to our initial hope that we could achieve similar therapeutic results with less subjective toxicity, this randomised prospective trial showed, that CBDCA/VM achieved significantly inferior results compared to PAV-CyMOC. Whether pts are willing to accept a significant trade off between quantity and quality of life remains to be evaluated.
402
403
chemothera _ AC) versus late &AC1 -tina pv in smg(i ceil IUna (;BI1EBrfSCLC) R. Joss, M. Bacchi, C. HOmy, J. Bernhard, Th. Cerny, F. Cavalii, S. Leyvraz, H.J. Senn, R. Stahei, P. Aiberto, C. Ludwia. P. Sieaenthaler for the Swiss Group for Clinical Cancer Research (SAKk). Bern, Switzerland 407 eligible patients (pts) with SCLC have been entered into a randomised phase iii trial comparing the value of EAC versus IAC. Regimen A was .I?&4 : cisriatin 30 mg/m2 d 1-3, Adriamycin 40 mglm2 d 1, YP 16-213 120 mglm2 dl-3. Regimen B was CvMOc: &ciophosphamide 1000 mg/m2 d 1, Methotrexate 20 mglm2 p.o. d 14 +17, Qncovin 1.4 mglm2 d 1, GCNU 40 mglm2 p.o. d 1. Cycles were repeated as soon as possible. Pts were randomized to receive either ABABAB (EAC) or AAABBB (LAC). After six cycles pts with limited disease in CR or PR and pts with extensive disease in CR were irradiated to the primaty (45 Gy) and the CNS (36 Gy). 69 % of the pts were classified as extensive disease. The overall remission rate was 87 % with 31 % CRs. The median survival of ail 407 eligible pts was 348 days. The overall remission rate, the rate of CRs, the median survival and the rate of iongterm survivors were no different in the two treatment arms. However extensive disease pts survived significantly longer with LAC compared to EAC (338 days versus 301 days, p = 0.02). Three toxic deaths due to ieukopenia were observed. Myelosuppression was more pronounced in pts treated with EAC. More pts treated with LAC experienced severe nausea and vomiting (20 % versus 11 %, p = 0.0014) We conclude that alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is an effective treatment for SCLC with acceptable toxicity. Whether LAC is advantageous in patients with a high tumor mass awaits the results of further studies.
PHASE II STUDY ON SEQUENTIAL CHEMOTHERAPY WITH HIGH-DOSE EPIRUBICIN (HD EPI) AND CISPLATINUM + ETOPOSIDE (CP+E) IN SMALL CELL LUNG CANCER.
M. Casadio, A. Martoni, B. Melotti, V. Pajetta, *L. Busutti, F. Pannuti. Medical Oncology Division, *Radiotherapy Division - S. OrsolaMalpighi Hospital, Bologna Italy. HD EPI has proven to be active ln advanced small cell lung cancer. A phase II study on the use of HD EPI followed by a standard combination CP + E in the treatment of patients with small cell lung cancer was designed. EPI was administerd at the dose of 135 mg/m2 iv for 2 courses on day 1 and 21 and was followed by CP and E at the respective doses of 30 mg/m2 and 120 mg/mz daily for 3 consecutive days on day 42 and subsequently every 21 days. Patients (Pts) with limited disease (LD) received chest radiation therapy (TCT 48 Gy) after 2 courses of CP + E. Pts with extended disease (ED) continued the treatment with CP+E until progression or to a maximum of 10 courses. Pts aged > 70 years or with PS ~70% or with active cardiac disease were excluded. From July 1989, 30 consecutive pts were admitted to the study 13 had LD and 17 ED. After the 2 courses of HD EPI objective partial remission was observed in 20130 (67%). The overall objective response rate was 73% ( 22130) (3 CR t 19 PR). The remission rate was 85% in LD and 65% in ED. Duration of response was 41.5 (6-83.5) weeks. Median survival was 35.5 (5.5 -117.5+) weeks. Side effects included: leukopenia 86% (43% grade 3-4), thrombocycopenia 27.5% (10% grade 3-4), nausea-vomiting 72%, alopecia 93%, mucositis 17% and dlarrhoea 10%. No case of clinical cardiotoxicicty was observed. In conclusion, this study confirms that HD EPI has high antitumor activity in small cell lung cancer and further studies on its inclusion in the treatment of this disease are warranted.
404
405
Phese II study of Topotecrn (TC) in petlents (pts) with pretreeted small-cell lung cancer (SCLC). K Tvede, A. Ardiuoni, P. Dombemowsky, P. Postmus, M. Buitenhuis, J. Wenclers, N. van Zandwijk, J.B. Krebs, J. Verweij. On behalf of the EORTC Early Clinical Trials Group and the EORTC Lung Cancer Cooperative Group. There is a great need for new active agents in SCLC pts. TC is a semisynthetic camptothecin(CT) analogue. Response rates with CT were disappointingand toxicity, especially hemorrhagic cystitii was severe. TC has increased hydrophilic&ydue to a basic side chain and is at acidic pH water soluble compared to camptothecin.TC and CT appear to functionthrough interaction with toposomerase I. The dose limitingtoxicitiesin phase I studiesof TC were mainlvneutrooenia and diarrhea. There has been no evidence of hemorrhaaic cystitk ’ In phase I studies the most impressiveevidence of anti-tumoractivii occurred on the dailv x 5 schedule in eiaht out of 53 ots treated with this schedule. ’ Antitumor&tivity was demonstrsed. A phase II multicenter study of TC of 1.5 mg/m’ daily x 5 every 3 weeks is ongoing in pts with SCLC. At present 29 pts have entered with one-line of pretreatmem, 3 pts are not eligible. 14 pts were previously sensitive to chemotherapy and 15 refractory. Pts characteristics were: median age 61, median performance status 1, male/female 19/9. mean courses 7. 14 pts are off-study.Survival status: 3 pts are dead due to progression (2 cases) and toxicity(1 case). 22 pts have teen evaluated for toxicity. Hematoloaic toxicitv consists of leucooenia in 99% of 85 cci#sss wkh NCI Common foxicity Cheria (CTC) gr. 4 in‘s/65 courses. Neutropeniain 93% with or. 4 in 36185. ThrombonRooeniein 69% with or. 4 in 9185. and anemia in 93% >nh gr. 4 in 4/65 course; Bieedingin 1 pt, inf&tion w&s observed in 5 pts end 2 of them died. Non-hematologictoxicity was only moderate and consisted mainlyof alopecia (9 pts), nausea (i 5 pts), astenia (16 pts), liver(4 pts), grade 1-2 vomiting (7 pts). Hemorrhagic cystitishas not been observed. 20 pts are &&able for respon&. Preliminaryresponse for refractory/sensitive ots were: CR 111, PR 2/3. in conclusion:TC.is a new drug wkh tolerabletoxicityand some actMy against SCLC.
of life in the trealfnent of ad_ (SCLC). A randomlred phase iii ComParLson of weekiv CariwWiigW TaniDosidevcin. Etonoslde aiterwith CvBide. Methotrwxte. Vincristlne and m. R. Joss, P. Aiberto, C. Hiirny. M. v versus ~UI,WV
I ceil u
cancer
Bacchi, S. Leyvraz, B. Thiiriimann, T. Cerny, F. Cavalii, C. Sauter, C. Ludwig for the Swiss Group for Clinical Cancer Research (SAKK). Bern, Switzerland 59 eligible patients (pts) with advanced SCLC have been entered into a prematurely closed randomised phase iii trial comparing a weekly regimen of carboplatin 80 mg/m2 and teniposide 80 mg/m2 (CBDCANM) to our standard regimen of cispiatin, adriamycin, etoposide alternating with cyciophosphamide, methotrexate, vincristine and lomustine (PAV-CyMOC. i.e. cisplatin 30 mglm2 d l-3, Adrfamycin 40 mglm2 d 1, YP 16-213 120 mglm2 dl-3 alternating as fast as possible with uclophosphamide 1000 mg/m2 d 1, Methotrexate 20 mg/m2 p.o. d 14 +17, Qncovin 1.4 mg/m2 d 1, GCNU 40 mg/m2 p.o. d 1). The results achieved with PAV-CyMOC were significantly better than those observed in pts treated with weekly CBDCANM (remission rate of 85 % vs 29 %, p = 0.006; median survival of 260 days vs 147 days, p = 0.0035; l-year - survival rate of 30 % compared to 4 %). As expected side effects including myelosuppression, alopecia and mucositis were more pronounced in ps treated with the PAVCyMOC - regimen. Contraty to our initial hope that we could achieve similar therapeutic results with less subjective toxicity, this randomised prospective trial showed, that CBDCA/VM achieved significantly inferior results compared to PAV-CyMOC. Whether pts are willing to accept a significant trade off between quantity and quality of life remains to be evaluated.