Comparison of Three Radiation Dose Levels after EBVP Regimen in Favorable Supradiaphragmatic Clinical Stages I-II Hodgkin s Lymphoma (HL):

Transcription

1 Comparison of Three Radiation Dose Levels after EBVP Regimen in Favorable Supradiaphragmatic Clinical Stages I-II Hodgkin s Lymphoma (HL): Preliminary Results of the EORTC-GELA H9-F Trial H. Eghbali, P. Brice, G.Y. Creemers, M. van Marwijk Kooij, P. Carde, M. van t Veer, E. Lugtenburg, A. Sonnet, C. Sebban, M. Blanc, J.M. Raemaekers, L. Voillat, C. Rieux, E. Noordijk, and M. Henry-Amar

2 Objectives 1 To compare in a randomized fashion two dose levels for radiotherapy in favorable group HL in complete remission after chemotherapy 1 To demonstrate that in this subset of patients radiotherapy could be omitted 1 To reduce late toxicity and maintain the failurefree survival rate for these patients

3 Eligibility criteria! Favorable subgroup based on retrospective analysis of previous trials CS I-II supradiaphragmatic HL with no adverse factors: age < 50 years and A + ESR < 50 mm or B + ESR < 30 mm and 1 to 3 nodal areas involved and no mediastinal involvement or M/T ratio < 0.35! Age years! WHO performance status 0-2! Informed consent

4 EORTC GELA H9 Trial S T R A T I F I C A T I O N HLP nodular H9 U > 1 risk factor H9 - F No risk factors EBVP x 6 Registration CR + CRu PR R A N D O M IF-RT 36 Gy IF-RT 20 Gy No RT IF-RT 36 Gy + boost 4 Gy NC + PD off protocol

5 Design Equivalence trial with a one-sided test End point: 5-year cumulative proportion of relapses in patients who achieved a complete remission Hypothesis True 5-year cumulative proportion of failures = 10%, δ = 10% α = 0.05, β = 0.20, one final comparison, 20% lost to FU Total to be accrued: 139 x 3 x 3 x 1/0.80 = 903 H9-F stopping rules Proportion of CR/CRu rate after EBVP < 70% Proportion of early adverse effects 20%: early death, severe (Grade 3-4) treatment-related toxicity within 1.5 year after randomization, treatment discontinued for any reason

6 EORTC - GELA H9-F Trial Accrual period: 9/1998-5/ H9-F TRIAL ACCRUAL (EORTC # 20982) Patients enrolled: 783 in 10 countries Analysis on an intent-to-treat basis Update as of November 1, 2005 Observed Follow-up time since registration to last examination / death median: 37 months (7 to 78) Cumulative number Las t H9-F patie nt randomized to no-rt: May 3, Time since trial start patients enrolled Closure of trial May 14, 2004

7 Staging procedures At entry - Clinical staging - ESR, CBC, blood chemistry - Chest X-ray (MT ratio), CT scans thorax, abdomen - Bone marrow biopsy - Ann Arbor classification Evaluation of response - Restaging after 6 courses of EBVP

8 EBVP chemotherapy regimen Protocol derived from ABVD with epirubicin replacing doxorubicin and prednisone replacing dacarbazine 1 course 6 courses Epirubicin d1 60 mg/m² 360 mg/m² Bleomycin d1 10 mg/m² 60 mg/m² Vinblastin d1 6 mg/m² 36 mg/m² Prednisone d1-d5 40 mg/m² 1200 mg/m² Every 3 weeks, 6 courses

9 Response to EBVP chemotherapy CR / CRu N = % randomized for IF RX - 36 Gy 239 pts IF RX - 20 Gy 209 pts no radiotherapy 130 pts not randomized Refusal, violation, other 13 pts Toxicity 9 pts PR / Progression N = % (95% CI: 18-24%) No data N = 21 2% Total enrolled 783 pts

10 Patient characteristics IF-RT 36 Gy IF-RT 20 Gy No RT No Random. % n = 239 n = 209 n = 130 n = 205 Sex M/F 56 / / / / 44 Age, median (range) 31 (15-49) 30 (15-49) 31 (15-49) 32 (16-49) CS I II 2 II 3 * 42/38/20 37/43/20 44/40/16 28/48/24 A + ESR < B + ESR < Mediastinum involved * Bulky disease ** E lesion * No CR v. CR-CRu, P < 0.01; ** nodal masses 100 mm

11 Response to treatment after at the end of treatment EBVP Random. No random. CR 51% 76% 28% CRu 26% 22% 33% PR 18% 0% 23% NC, Prog. 3% 1% 15% Unspecified 2% 1% 1%

12 Progressions Relapses 36 Gy 20 Gy no RT no CR / no random. Number of events Prog. under treat Relapse Prog + Rel Prog + Rel Prog + Rel Prog + Rel Involved, unirrad Involved, irradiated Extra-nodal relapse Unspecified

13 EORTC-GELA H9-F trial relapse-free survival Proportion Relapse-Free yr rate P value 6 EBVP-IF RT 36Gy (239) 89% 6 EBVP-IF RT 20Gy (209) 86% 6 EBVP-no RT (130) 70% <0.001 final value 1-β' = 77% November Time since EBVP start, mo

14 EORTC-GELA H9-F trial treatment failure-free survival Proportion Failure-Free yr rate P value 6 EBVP-IF RT 36Gy (239) 89% 6 EBVP-IF RT 20Gy (209) 86% 6 EBVP-no RT (130) 70% 6 EBVP-no random. (205) 71% <0.001 November Time since EBVP start, mo

15 Deaths 36 Gy 20 Gy no RT no CR / no random. Total observed Progressive disease Treatment-related 2 Intercurrent disease 1 Second cancer 1 (AL) 1 (NHL)

16 EORTC-GELA H9-F trial overall survival Proportion Surviving yr rate P value 6 EBVP-IF RT 36Gy (239) 96% 6 EBVP-IF RT 20Gy (209) 100% 6 EBVP-no RT (130) 98% November Time since EBVP start, mo

17 EORTC-GELA H9-F trial overall survival Proportion Surviving yr rate P value 6 EBVP-IF RT 36Gy (239) 96% 6 EBVP-IF RT 20Gy (209) 100% 6 EBVP-no RT (130) 98% 6 EBVP-no random. (205) 91% November Time since EBVP start, mo

18 Conclusions (1) " With the chosen chemotherapy so far there has been no difference in clinical outcome between 20 and 36 Gy confirming the results of the GHSG HD10 trial (4 ABVD + IF RX, 30 Gy v. 20 Gy) " With the chosen chemotherapy the non-radiotherapy arm failed " Is this failure due to the nature of the chemotherapy regimen or lack of any radiotherapy? The discussion is open

19 Conclusions (2) " The next H10 trial addresses the same question using ABVD which is considered as the conventional chemotherapy regimen " PET-scan will be used to assess early complete remission (after 2 courses of ABVD)

20 Four ABVD and Involved-field Radiotherapy in Unfavorable Supradiaphragmatic Clinical Stages (CS) I-II Hodgkin s Lymphoma (HL): Preliminary Results of the EORTC-GELA H9-U Trial C. Fermé, M. Diviné,, A. Vranovsky,, F. Morschhauser, R. Bouabdallah,, J. Gabarre, A. Bastard-Stamatoullas Stamatoullas, R. Delarue, V. Zagonel,, J. Jaubert, A. Hagenbeek, M.H.H. Kramer,, C. Rieux, J. Thomas, and M. Henry-Amar

21 Objectives To compare in unfavorable patients 6 x ABVD v. 4 x ABVD v. 4 x BEACOPP baseline all followed by involved-field RT To maintain the failure-free survival rate with a reduction of the acute side effects and severe late toxicity

22 Eligibility criteria! Unfavorable subgroup CS I-II supradiaphragmatic HL with at least 1 adverse factor: age > 50 years or A + ESR > 50 mm or B + ESR > 30 mm or > 4 nodal areas involved or M/T ratio > 0.35! Age years! WHO performance status 0-2! Informed consent

23 EORTC GELA H9 Trial S T R A T I F I C A T I O N HLP - nodular H9 - F No risk factors ABVD x 6 H9 - U ABVD x 4 factor BEACOPP x 4 > 1 risk factor Registration CR-CRu / PR NC PD IF - RT BEACOPP baseline (Diehl V, GHSG 1997) arms 2 & 3 common with that of the GHSG HD11 trial Involved-field RT CR / CRu after 4-6 courses PR after 4-6 courses off protocol 30 Gy 36 Gy + 4 Gy boost in PR areas

24 Design Equivalence trial with a one-sided test End point: 5-year cumulative proportion of treatment failures during or after initial treatment Hypothesis True 5-year cumulative proportion of failures = 10%, δ = 10%, α = 0.05, β = 0.20, one final comparison Total number of patients to be accrued: 139 x 3 x 3 = 723 H9-U stopping rules Failure rate 20% in any arm: partial or no response, progressive disease after initial treatment, relapse after CR or CRu Proportion of early adverse effects 20%: early death, severe (Grade 3-4) treatment-related toxicity within 1.5 year after randomisation, treatment discontinued for any reason

25 EORTC - GELA H9-U Trial Accrual period: 10/1998-9/2002 Patients enrolled: 808 Analysis on an intent-to-treat basis Cumulative number EORTC-GELA H9-U TRIAL Total enrolled: 808 Update as of November 1, /98 09/99 09/00 09/01 09/02 09/03 09/04 Time since trial start Observed Follow-up time since registration to last examination / death median: 42 months (1 to 83)

26 Treatment groups 6 x ABVD - IF RT 276 pts 4 x ABVD - IF RT 277 pts 4 x BEACOPP - IF RT 255 pts Total enrolled 808 pts

27 Patient characteristics % 6 ABVD 4 ABVD 4 BEACOPP Age > 50 (median) 20 (31) 20 (30) 21 (31) CS I / II 2 -II 3 22 / / / 62 CS II 4 - II A & ESR > 50 or B & ESR > Mediastinum involved M/T ratio > Bulky disease * E lesion ** Histological type NS / MC 82 / / / 10 * M/T ratio 0.35 or nodal masses 100 mm ** P = 0.057

28 Response to treatment (1) At the end of chemotherapy 6 ABVD 4 ABVD 4 BEACOPP CR / CRu 74% 71% 60% PR 23% 28% 38% No change 1% 1% 1% Progression 2% < 1% - Early death - - < 1%

29 Response to treatment (2) At the end of treatment 6 ABVD 4 ABVD 4 BEACOPP IF-RT IF-RT IF-RT CR / CRu 87% 87% 86% PR 8% 10% 11% No change < 1% < 1% - Progression 4% 3% 3% Early death < 1% - < 1%

30 Progressions Relapses 6 ABVD 4 ABVD 4 BEACOPP IF-RT IF-RT IF-RT Number of events Prog. under treat Relapse Prog + Rel Prog + Rel Prog + Rel Involved, unirrad Involved, irradiated Extra-nodal relapse Unspecified

31 EORTC-GELA H9-U trial treatment failure-free survival Proportion Failure-Free yr rate P value 6 ABVD-IF RT (276) 92% 4 ABVD-IF RT (277) 89% 4 BEACOPP-IF RT (255) 91% 0.43 November Time since Randomization, mo

32 EORTC-GELA H9-U trial relapse-free survival 1.0 Proportion Relapse-Free yr rate P value 6 ABVD-IF RT (244) 96% 4 ABVD-IF RT (243) 91% 4 BEACOPP-IF RT (214) 95% November Time since Randomization, mo

33 Deaths Progressive disease 20 Treatment-related complication 14 pneumopathy (2), septicemia (4), bleeding (1) severe pulmonary fibrosis (7) Intercurrent disease 4 septicemia (2), pulmonary embolism (1) suicide (1) Second cancer MDS (1), NHL (1) 2 Unspecified 3 Total observed 43

34 EORTC-GELA H9-U trial overall survival Proportion Surviving yr rate P value 6 ABVD-IF RT (276) 91% 4 ABVD-IF RT (277) 92% 4 BEACOPP-IF RT (255) 91% 0.97 November Time since Randomization, mo

35 Conclusions (1) " 4 ABVD + IF-RT 30 Gy can cure most of patients with unfavorable early stage HL who achieve CR / CRu after 4 courses " BEACOPP baseline has no advantage over ABVD in these patients

36 Conclusions (2) " The next H10-U trial using 4 x ABVD + IF-RT as standard arm, addresses the question of chemotherapy alone " In this trial, early response to 2 courses of ABVD will be evaluated using PET-scan

37 Acknowledgements Participating investigators, physicians, radiotherapists, radiologists, data-managers, nurses Patients who participated in this European trial French Federation of Comprehensive Cancer Centers (sponsor of the French centers) Supported by a grant from the French Ministry of Health (PHRC 1998)