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A phase II trial of induction chemotherapy followed by concomitant chemo-radiotherapy in stage IIIb non small cell lung cancer (NSCLC)
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A PHASE I/II TRIAL OF NEOADJUVANT CHEMOTHERAPY (CT) WITH CISPLATIN AND VINORELBINE (NAVELBINEQ) FOLLOWED BY ACCELERATED THORACIC IRRADIATION (TRT) IN INOPERABLE NONEARLY SMALL CELL LUNG CANCER (NSCLC). TOXICITIES AND RESPONSES. ,I. Viallett, P. Rousseaui, L. Souhamir, H. Kreismant, J. Guerrat, J. Ayoub2, P. Del Vecchios, A. Langlebent, W. Kerbyt, M. Petrella4 and B. Leyland-Jonest. Depastments of Oncologyt, McGill University, of Medicine2 and Radiation Gncologya, Hopital Notre-Dame and Burroughs Wellcome In&, Montreal P.Q., CANADA.
PROGNOSTICSIGNIFICANCEOFHISTOLOGIC COMPLETEREMISSIONIN NEOADJWANT TRIALS IN STAGE III NON-SMALL CELL LDNG CANCER (NSCLC)
BACUROUND: Failure of local control and systemic metastascs contribute to the poor outcome of patients treated with standard TRT for inoperable NSCLC. Cisplatin based CT decreases the risk of metastases and may improve survival rates. Cisplatin and Navelbine is superior to other cisplati&inca combinations. Accelerated repopulation of clonogenie cells during TRT contributes to local failure and may be overcome by accelerating the delivery of TRT fractions. w: inoperable stages II, III-A and B NSCLC, staged with bone scan, brain CT and CI scan of chest and upper abdomen. Kamofsky index of 2 70, normal kidney, hepatic and hematological function. Prior weight loss allowed. Treatment: cisplatin 100 mg/m2 week 1 and 5, Navelbine 30 mg/m2 weekly X 5 with a 50% reduction planned for week 2 followed by TRT, 30 fractions of 2 Gy in four weeks, once daily during weeks 1 and 2, twice daily during weeks 3 and 4. 17 patients have entered in 11 months. MIJLTS: objective partial response in 3/17 (18%) after CT and in 8/17 (47%) 4 weeks after TRT. 3 patients died at weeks 17,17 and 39 from metastases with persistent local control. 4/17 grade III toxicities post TRT (2 lung, 1 skin, 1 pericardium) all resolved. No grade III oesophageal toxicities. Despite the planned dose reduction of Navelbine on week 2,7/17 (41%) patients had neutrophils < 1000 on week 3. CONCLUSIONS: this aggressive RT technique is welI tolerated when administered after CT. Accrual is continuing to better defme the toxicities and responses to this regimen.
702 A PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CONCOMITANT CHEMO-RADIOTHERAPY IN STAGE IIIb NON SMALL CELL LUNG CANCER (NSCLC). E. Bardet, E. Quoix, A. Riviere, D. Spaeth, A. Le Groumellec, B. Maury, B. Pellae-Cosset and J.Y. Douillard. Centre Rem? Gauducheau, 44805 NANTBS-ST HERBLAIN PRANCE. From October 1992 to june 1993, 43 patients with stage Illb NSCLC were entered in a phase II trial of induction chemotherapy followed by concomitant chemo-radiotherapy. The primary goal of this trial was to assess the local control rate obtained with concomitant treatment and to eventually initiate a randomized phase III trial to evaluate the contribution of concomitant chemotherapy over radiation therapy alone. Patient population included 4lmales and 2 females, mean age 59.8 y. (33 to 73 y.). Treatment consisted of VP16 (lOOmg/m2 IV, d. 1, 2, 3) and carboplatinum (350mg/m2 d. 1). two cycles were delivered d. 1 and 28. Radiation therapy started on d. 56 and was given once a day, 5 days-a-week, 2 Gy per fraction for a total dose of 66 Gy along with a daily dose of 15 mg/m* carboplatinum 2 to 4 hours before radiation. In patients responding to induction chemotherapy, two additional courses of VPlh-carboplatinum were delivered 4 weeks after the end of chemoI St 1993, 25 patients have been radiotherapy. As of decembcr analysed : 19/25 squamous cell-, 4/25 adeno- and 2/25 large cell carcinomas, 11 T4, 6 T3, 5 T2 and 2 Tl and 1 TX, lo/25 N3, S/25 N2, 6/25 NO and l/25 Nx, all staged Illb. Among 21/25 evaluable patients for induction chemotherapy, partial response rate is only 15%. stable 57% and progression 28%. Concomitant chemo-radiotherapy data are available for 11/25 patients. All received full dose-radiation with 1 grade IV mucositis and minor hematological toxicity (< grade 3). All included patients have now terminated the full treatment course and are being analysed for assessment of local control. Based on the initial result of the VP16 and carboplatinum combination however, it may already be concluded that a better drug combination should be used as induction treatment. Overall analysis will presented at the meeting.
Bonomi P, Faber LP, Reddy S, Recine D. Rartsell U, Warren w., Somers J, Gale n. Complete clearance of tumor (histologicCR) has been observed in 22 of 128 patients (17%) who were treated with preoperativechemoradiotherapyonthree consecutivephase II trials. The objective of the current study is to determine the prognostic significance of achieving histologic CR. Thoracotomy was attempted in 102 of 128 eligible patients and tumor resection was accomplishedin 99 patients (77%). Assessment of histologic response was not possible in 26 patients for the followingreasons: patient refused surgery - 14, disease progression - 8, death due to myocardial The infarct - 1, and treatment related deaths -3. pretreatment characteristicsof the 102 patients who were included in these analyses are as follows: males/famales70/32, performance status O-1/2-3 - 93/9, weight loss <5%/>5% - 69/31, stage IIIa/IIIb 06/14, NJNz - M/46, squamouscell/adeno-largecell carcinoma- 43/59, medianage - 57 years. The following histologic responses were observed: CR - 22, microscopic foci (If)- 18, and gross residual disease (G) - 62. Step - wise regression analyses fail to identify pretreatment cbaracteri‘tics which predicted tumor sterilisation. Survival for CR and X and G patients were determined by the l&plan-Meier method. The logrank statistic revealed that CR patients survived significantlylonger than lland G patients (p-.009). These result‘ suggest that histologic CR has prognostic significance with respect to survival, and that this parameter may be useful in selectingregimens to be studied in phase III trials testing preoperativetreatment in stage III NSCLC patients.
703 SURGICAL RFSECTION
OF STAGE III B NON-S-CRLL
LUNG CANCER (NSCLC!) AFTER CONCOMITANT INDUCTION CBBMO-BADIOTBBBAF’Y. PRELIMINARY ruz?uLTB. D. Grunenwald, Th. Le Chevalier, R. Arriagada, P. Baldeyrou, G. Dennewald, Ph. Girard, J.J. Bretel, P. RuffiB, M. Tarayre, A. Laplanche. Centre MBdieo-Chirurgical de la Porte de Choisy , Paris. Institut Gustave Roussy, Villejuif, France. Recent trials suggest that induction chemo-radiotherapy can improve both local and distant metastasis control, resectability and survival of patients with stage III NSCLC. This prospective phase II trial tests the feasibility of concomitant preoperative chemo-radiotherapy for stage IIIB NSCLC. Eligible patients had documented T4 (superior vena cava, trachea, aorta, carins) and/or N3 tumors. Induction therapy was 5 FU 1 g/m2, days 1, 2, 3, cisplatin 100 n&n2 day 1, vinblastine 4 mg/m2, plus concomitant accelerated thoracic radiotherapy (42 Gy, 2 x 1.5 Gy fractions/day, 5 days/week, week 1 and 3). Surgical resection is attempted at day 65, except in case of tumor progression. From January to December 1993, 13 patients were entered. Surgical data are available on 9 patients. Eight were eligible for surgery. Seven had a complete surgical resection. No patient died during or after the operation. From the histological point of view, we registered 2 complete responses, without detectable residual tumor, 2 rare microscopic foci of residual cancer, and 3 partial tumor responses. If the preliminary results are confirmed, we will conduct a phase III trial testing the role of surgical resection in stage IIIB NSCLC.
701
A PHASE I/II TRIAL OF NEOADJUVANT CHEMOTHERAPY (CT) WITH CISPLATIN AND VINORELBINE (NAVELBINEQ) FOLLOWED BY ACCELERATED THORACIC IRRADIATION (TRT) IN INOPERABLE NONEARLY SMALL CELL LUNG CANCER (NSCLC). TOXICITIES AND RESPONSES. ,I. Viallett, P. Rousseaui, L. Souhamir, H. Kreismant, J. Guerrat, J. Ayoub2, P. Del Vecchios, A. Langlebent, W. Kerbyt, M. Petrella4 and B. Leyland-Jonest. Depastments of Oncologyt, McGill University, of Medicine2 and Radiation Gncologya, Hopital Notre-Dame and Burroughs Wellcome In&, Montreal P.Q., CANADA.
PROGNOSTICSIGNIFICANCEOFHISTOLOGIC COMPLETEREMISSIONIN NEOADJWANT TRIALS IN STAGE III NON-SMALL CELL LDNG CANCER (NSCLC)
BACUROUND: Failure of local control and systemic metastascs contribute to the poor outcome of patients treated with standard TRT for inoperable NSCLC. Cisplatin based CT decreases the risk of metastases and may improve survival rates. Cisplatin and Navelbine is superior to other cisplati&inca combinations. Accelerated repopulation of clonogenie cells during TRT contributes to local failure and may be overcome by accelerating the delivery of TRT fractions. w: inoperable stages II, III-A and B NSCLC, staged with bone scan, brain CT and CI scan of chest and upper abdomen. Kamofsky index of 2 70, normal kidney, hepatic and hematological function. Prior weight loss allowed. Treatment: cisplatin 100 mg/m2 week 1 and 5, Navelbine 30 mg/m2 weekly X 5 with a 50% reduction planned for week 2 followed by TRT, 30 fractions of 2 Gy in four weeks, once daily during weeks 1 and 2, twice daily during weeks 3 and 4. 17 patients have entered in 11 months. MIJLTS: objective partial response in 3/17 (18%) after CT and in 8/17 (47%) 4 weeks after TRT. 3 patients died at weeks 17,17 and 39 from metastases with persistent local control. 4/17 grade III toxicities post TRT (2 lung, 1 skin, 1 pericardium) all resolved. No grade III oesophageal toxicities. Despite the planned dose reduction of Navelbine on week 2,7/17 (41%) patients had neutrophils < 1000 on week 3. CONCLUSIONS: this aggressive RT technique is welI tolerated when administered after CT. Accrual is continuing to better defme the toxicities and responses to this regimen.
702 A PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CONCOMITANT CHEMO-RADIOTHERAPY IN STAGE IIIb NON SMALL CELL LUNG CANCER (NSCLC). E. Bardet, E. Quoix, A. Riviere, D. Spaeth, A. Le Groumellec, B. Maury, B. Pellae-Cosset and J.Y. Douillard. Centre Rem? Gauducheau, 44805 NANTBS-ST HERBLAIN PRANCE. From October 1992 to june 1993, 43 patients with stage Illb NSCLC were entered in a phase II trial of induction chemotherapy followed by concomitant chemo-radiotherapy. The primary goal of this trial was to assess the local control rate obtained with concomitant treatment and to eventually initiate a randomized phase III trial to evaluate the contribution of concomitant chemotherapy over radiation therapy alone. Patient population included 4lmales and 2 females, mean age 59.8 y. (33 to 73 y.). Treatment consisted of VP16 (lOOmg/m2 IV, d. 1, 2, 3) and carboplatinum (350mg/m2 d. 1). two cycles were delivered d. 1 and 28. Radiation therapy started on d. 56 and was given once a day, 5 days-a-week, 2 Gy per fraction for a total dose of 66 Gy along with a daily dose of 15 mg/m* carboplatinum 2 to 4 hours before radiation. In patients responding to induction chemotherapy, two additional courses of VPlh-carboplatinum were delivered 4 weeks after the end of chemoI St 1993, 25 patients have been radiotherapy. As of decembcr analysed : 19/25 squamous cell-, 4/25 adeno- and 2/25 large cell carcinomas, 11 T4, 6 T3, 5 T2 and 2 Tl and 1 TX, lo/25 N3, S/25 N2, 6/25 NO and l/25 Nx, all staged Illb. Among 21/25 evaluable patients for induction chemotherapy, partial response rate is only 15%. stable 57% and progression 28%. Concomitant chemo-radiotherapy data are available for 11/25 patients. All received full dose-radiation with 1 grade IV mucositis and minor hematological toxicity (< grade 3). All included patients have now terminated the full treatment course and are being analysed for assessment of local control. Based on the initial result of the VP16 and carboplatinum combination however, it may already be concluded that a better drug combination should be used as induction treatment. Overall analysis will presented at the meeting.
Bonomi P, Faber LP, Reddy S, Recine D. Rartsell U, Warren w., Somers J, Gale n. Complete clearance of tumor (histologicCR) has been observed in 22 of 128 patients (17%) who were treated with preoperativechemoradiotherapyonthree consecutivephase II trials. The objective of the current study is to determine the prognostic significance of achieving histologic CR. Thoracotomy was attempted in 102 of 128 eligible patients and tumor resection was accomplishedin 99 patients (77%). Assessment of histologic response was not possible in 26 patients for the followingreasons: patient refused surgery - 14, disease progression - 8, death due to myocardial The infarct - 1, and treatment related deaths -3. pretreatment characteristicsof the 102 patients who were included in these analyses are as follows: males/famales70/32, performance status O-1/2-3 - 93/9, weight loss <5%/>5% - 69/31, stage IIIa/IIIb 06/14, NJNz - M/46, squamouscell/adeno-largecell carcinoma- 43/59, medianage - 57 years. The following histologic responses were observed: CR - 22, microscopic foci (If)- 18, and gross residual disease (G) - 62. Step - wise regression analyses fail to identify pretreatment cbaracteri‘tics which predicted tumor sterilisation. Survival for CR and X and G patients were determined by the l&plan-Meier method. The logrank statistic revealed that CR patients survived significantlylonger than lland G patients (p-.009). These result‘ suggest that histologic CR has prognostic significance with respect to survival, and that this parameter may be useful in selectingregimens to be studied in phase III trials testing preoperativetreatment in stage III NSCLC patients.
703 SURGICAL RFSECTION
OF STAGE III B NON-S-CRLL
LUNG CANCER (NSCLC!) AFTER CONCOMITANT INDUCTION CBBMO-BADIOTBBBAF’Y. PRELIMINARY ruz?uLTB. D. Grunenwald, Th. Le Chevalier, R. Arriagada, P. Baldeyrou, G. Dennewald, Ph. Girard, J.J. Bretel, P. RuffiB, M. Tarayre, A. Laplanche. Centre MBdieo-Chirurgical de la Porte de Choisy , Paris. Institut Gustave Roussy, Villejuif, France. Recent trials suggest that induction chemo-radiotherapy can improve both local and distant metastasis control, resectability and survival of patients with stage III NSCLC. This prospective phase II trial tests the feasibility of concomitant preoperative chemo-radiotherapy for stage IIIB NSCLC. Eligible patients had documented T4 (superior vena cava, trachea, aorta, carins) and/or N3 tumors. Induction therapy was 5 FU 1 g/m2, days 1, 2, 3, cisplatin 100 n&n2 day 1, vinblastine 4 mg/m2, plus concomitant accelerated thoracic radiotherapy (42 Gy, 2 x 1.5 Gy fractions/day, 5 days/week, week 1 and 3). Surgical resection is attempted at day 65, except in case of tumor progression. From January to December 1993, 13 patients were entered. Surgical data are available on 9 patients. Eight were eligible for surgery. Seven had a complete surgical resection. No patient died during or after the operation. From the histological point of view, we registered 2 complete responses, without detectable residual tumor, 2 rare microscopic foci of residual cancer, and 3 partial tumor responses. If the preliminary results are confirmed, we will conduct a phase III trial testing the role of surgical resection in stage IIIB NSCLC.