Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma

NCT ID: NCT00005584

Last Updated: 2025-08-05

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1649 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1998-10-31

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy with radiation therapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is most effective in treating Hodgkin's lymphoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy with or without radiation therapy in treating patients who have Hodgkin's lymphoma.

Detailed Description

OBJECTIVES:

• Compare the late toxicity of 6 courses of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by involved-field radiotherapy (IF-RT) (36 Gy) vs IF-RT (20 Gy), vs no IF-RT (closed to accrual as of 6/2002) in patients with supradiaphragmatic Hodgkin's lymphoma, favorable prognosis, and complete remission (CR) or CR unconfirmed after completion of chemotherapy. (Favorable prognosis group [group 1] closed to accrual as of 4/28/04.)
• Compare 6 courses of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) vs 4 courses of ABVD vs 4 courses of cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, and prednisone (BEACOPP) followed by IF-RT, with respect to overall survival and late treatment-related toxicity, in patients with supradiaphragmatic Hodgkin's lymphoma and unfavorable prognosis. (Unfavorable prognosis group [group 2] closed to accrual as of 9/2002.) (Favorable prognosis group [group 1] closed to accrual as of 4/28/04.)
• Maintain the failure-free survival and relapse-free survival rates that were reached in the previous EORTC studies (H5 to H8), with a reduction in acute and delayed side effects of the treatment, in particular that of severe late radiotherapy and chemotherapy-related toxicity.
• Compare the quality of life, overall survival, treatment quality control, and duration of treatment in patients with favorable (closed to accrual as of 4/28/04) or unfavorable (closed to accrual as of 9/2002) prognoses treated with these regimens.
• Determine the efficacy of conservative therapy comprised of observation until disease progression (DP) and administration of IF-RT at the time of DP in patients with lymphocyte-predominant Hodgkin's lymphoma, nodular subtype (nodular paragranuloma).

OUTLINE: This is a randomized, multicenter study.

Patients with classical Hodgkin's lymphoma are assigned to 1 of 2 randomized groups. (Group 2 [unfavorable prognosis] closed to accrual as of 9/2002.) (Group 1 [favorable prognosis] closed to accrual as of 4/28/04.) Patients with lymphocyte-predominant Hodgkin's lymphoma are assigned to the nonrandomized group.

Randomized groups

• Patients are stratified by prognosis (favorable vs unfavorable). Patients are assigned to 1 of 2 treatment groups based on prognosis. (Group 2 [unfavorable prognosis] closed to accrual as of 9/2002.) (Group 1 [favorable prognosis] closed to accrual as of 4/28/04.)

• Group 1 (favorable prognosis) (closed to accrual as of 4/28/04): Patients receive epirubicin IV over 5 minutes, bleomycin intramuscularly (IM) (or IV if necessary), and vinblastine IV on day 1 and oral prednisone on days 1-5. Treatment repeats every 3 weeks for 6 courses. Patients are then assigned to 1 of 3 involved-field radiotherapy (IF-RT) groups based on response to chemotherapy:

• Group A (complete remission (CR) or CR unconfirmed [CRu]) Patients are randomized to 1 of 3 radiotherapy arms. (Arm III closed to accrual as of 6/2002.)

• Arm I (36 Gy): Patients undergo IF-RT 5 days a week for 3.5 weeks.
• Arm II (20 Gy): Patients undergo IF-RT 5 days a week for 2 weeks.
• Arm III (closed to accrual as of 6/2002): Patients undergo no IF-RT.
• Group B (partial remission [PR]): Patients undergo IF-RT 5 days a week for 3.5 weeks and boost radiotherapy.
• Group C (stable disease or disease progression [DP]): Patients receive no IF-RT and are taken off study.
• Group 2 (unfavorable prognosis) (closed to accrual as of 9/2002): Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive doxorubicin IV over 5 minutes, bleomycin IM (or IV if necessary), vinblastine IV, and dacarbazine IV over 5-10 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses.
• Arm II: Patients receive chemotherapy as in arm I. Treatment repeats every 4 weeks for 4 courses.
• Arm III: Patients receive cyclophosphamide IV and doxorubicin IV over 5 minutes on day 1, vincristine IV and bleomycin IM (or IV if necessary) on day 8, etoposide IV over a minimum of 30 minutes on days 1-3, oral procarbazine on days 1-7, and oral prednisone on days 1-14. Treatment repeats every 3 weeks for 4 courses.

Patients on all arms who achieve CR or CRu undergo IF-RT 5 days a week for 3 weeks. Patients who achieve PR undergo IF-RT 5 days a week for 3.5 weeks and boost radiotherapy.

• Groups 1 and 2 (group 2 closed to accrual as of 9/2002) (group 1 closed to accrual as of 4/28/04): IF-RT begins within 3-4 weeks after completion of the last course of chemotherapy.

Nonrandomized group

• Patients with completely resected stage I disease undergo observation until DP and undergo IF-RT after documentation of DP. Patients with stage II or incompletely resected stage I disease undergo IF-RT immediately.

Quality of life is assessed before starting study therapy, immediately after completion of study, and then annually for 10 years.

Patients are followed at 2, 4, 6, 9, and 12 months; every 4 months for 1 year; every 6 months for 3 years; and then annually thereafter.

PROJECTED ACCRUAL: A total of 903 patients (group 1) will be accrued for this study within 7.7 years. A total of 723 patients (group 2) will be accrued for this study within 3.8 years. (Group 2 [unfavorable prognosis] closed to accrual as of 9/2002.) (Group 1 [favorable prognosis] closed to accrual as of 4/28/04.)

Conditions

Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

bleomycin sulfate

Intervention Type: BIOLOGICAL

ABVD regimen

Intervention Type: DRUG

BEACOPP regimen

Intervention Type: DRUG

epirubicin hydrochloride

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vinblastine sulfate

Intervention Type: DRUG

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Randomized groups: Histologically proven previously untreated stage I or II supradiaphragmatic Hodgkin's lymphoma

• No prior staging laparotomy
• Favorable (closed to accrual as of 4/28/04) or unfavorable (closed to accrual as of 9/2002) prognosis
• Nonrandomized group: Histologically proven lymphocyte-predominant Hodgkin's lymphoma, nodular subtype (nodular paragranuloma)

• Stage I with complete or incomplete resection OR
• Stage II

PATIENT CHARACTERISTICS:

Age:

• 15 to 70

Performance status:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Cardiovascular:

• No severe cardiac disease that would interfere with normal life expectancy or study treatment

Pulmonary:

• No severe pulmonary disease that would interfere with normal life expectancy or study treatment

Other:

• No other prior or concurrent malignancy except basal cell skin cancer or carcinoma in situ of the cervix
• No severe neurologic or metabolic disease that would interfere with normal life expectancy or study treatment
• No psychologic, familial, socioeconomic, or geographic circumstances that would preclude proper staging or compliance
• HIV negative
• Not pregnant
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior biologic therapy for this malignancy

Chemotherapy

• No prior chemotherapy for this malignancy

Endocrine therapy

• No prior endocrine therapy for this malignancy

Radiotherapy

• No prior radiotherapy for this malignancy

Surgery

• No prior surgery for this malignancy

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lymphoma Study Association

OTHER

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jose Thomas, MD

Role: STUDY_CHAIR

University Hospital, Gasthuisberg

H. Eghbali, MD

Role: STUDY_CHAIR

Institut Bergonié

E.M. Noordijk, MD

Role: STUDY_CHAIR

Leiden University Medical Center

Christophe Ferme

Role: STUDY_CHAIR

Centre Medical de Bligny

Christian Gisselbrecht, MD

Role: STUDY_CHAIR

Hopital Saint-Louis

Thierry O. Philip, MD

Role: STUDY_CHAIR

Centre Leon Berard

Locations

Sint Augustinus Ziekenhuis

Antwerp, , Belgium

A.Z. St. Jan

Bruges, , Belgium

C.H.U. Saint-Pierre

Brussels, , Belgium

Institut Jules Bordet

Brussels, , Belgium

Cliniques Universitaires Saint-Luc

Brussels, , Belgium

Centre Hospitalier Universitaire Brugmann

Brussels, , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

U.Z. Gasthuisberg

Leuven, , Belgium

Clinique Universitaire De Mont-Godinne

Mont-Godinne Yvoir, , Belgium

Clinique Saint-Pierre

Ottignies, , Belgium

Centre Hospitalier Annemasse Bonneville

Ambilly, , France

Centre Hospitalier d'Annecy

Annecy, , France

Centre Hospital General Robert Ballanger

Aulnay-sous-Bois, , France

Hopital Duffaut

Avignon, , France

Centre Hospitalier de la Cote Basque

Bayonne, , France

CHR de Besancon - Hopital Jean Minjoz

Besançon, , France

Hopital de Beziers

Béziers, , France

Hopital Saint Andre

Bordeaux, , France

Institut Bergonie

Bordeaux, , France

C.H. Bourg En Bresse

Bourg-en-Bresse, , France

CMC Bligny

Briis-sous-Forges, , France

CHU de Caen

Caen, , France

Centre Regional Francois Baclesse

Caen, , France

Centre Hospitalier Regional de Chambery

Chambéry, , France

Hopital Fontenoy

Chartres, , France

Centre d'Oncologie et de Radiotherapie de Chaumont le Bois

Chaumont, , France

Hopital d'Instruction des Armees Percy

Clamart, , France

Hopital Antoine Beclere

Clamart, , France

Hopital Beaujon

Clichy, , France

Hopital Louis Pasteur

Colmar, , France

Centre Hospitalier Compiegne

Compiègne, , France

Centre Hospitalier Sud Francilien - Site Corbeil

Corbeil, , France

Centre Hospitalier Universitaire Henri Mondor

Créteil, , France

Hopital Du Bocage

Dijon, , France

Centre de Lutte Contre le Cancer, Georges-Francois Leclerc

Dijon, , France

Institut Prive de Cancerologie

Grenoble, , France

Centre Hospitalier

Juvisy-sur-Orge, , France

Hopital Andre Mignot

Le Chesnay, , France

C.H.G. Du Havre - Hopital J. Monod

Le Havre, , France

Centre Hospitalier Universitaire de Bicetre

Le Kremlin-Bicêtre, , France

Clinique Victor Hugo

Le Mans, , France

Centre Hospitalier Lens

Lens, , France

Centre Hospital Universitaire Hop Huriez

Lille, , France

Centre Hospitalier Regional et Universitaire de Lille

Lille, , France

Centre Hospital Regional Universitaire de Limoges

Limoges, , France

Centre Hospitalier General

Lons-le-Saunier, , France

Clinique Saint Jean

Lyon, , France

Centre Leon Berard

Lyon, , France

Hopital Edouard Herriot

Lyon, , France

Institut J. Paoli and I. Calmettes

Marseille, , France

Centre Hospitalier de Meaux

Meaux, , France

Hopital Notre-Dame de Bon Secours

Metz, , France

Intercommunal Hospital

Montfermeil, , France

Clinique Gui de Chauliac

Montpellier, , France

Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle

Montpellier, , France

Centre Hospitalier de Mulhouse

Mulhouse, , France

Hopital Pasteur

Nice, , France

Centre Antoine Lacassagne

Nice, , France

C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau

Nîmes, , France

Hopital Saint Antoine

Paris, , France

Hopital de la Croix Rouge Francaise des Peupliers

Paris, , France

Hotel Dieu de Paris

Paris, , France

Institut Curie - Section Medicale

Paris, , France

Hopital Lariboisiere

Paris, , France

Hopital Saint-Louis

Paris, , France

CHU Pitie-Salpetriere

Paris, , France

Hopital Cochin

Paris, , France

Hopital Necker

Paris, , France

C.H.G. De Pau

Pau, , France

Hopital Haut Leveque

Pessac, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Centre Hospitalier Intercommunal de Poissy

Poissy, , France

Hopital Rene Dubos

Pontoise, , France

Polyclinique De Courlancy

Reims, , France

CHG Roanne

Roanne, , France

Centre Henri Becquerel

Rouen, , France

Centre Rene Huguenin

Saint-Cloud, , France

C.H.U. Saint Etienne Hospital Nord

Saint-Etienne, , France

Hopital de Saint Germain-en-Laye

Saint-Germain-en-Laye, , France

Centre Medico-Chirurgical Foch

Suresnes, , France

Centre Hospitalier Regional de Purpan

Toulouse, , France

Centre Hospitalier Valence

Valence, , France

Centre Hospitalier de Valenciennes

Valenciennes, , France

Centre Alexis Vautrin

Vandœuvre-lès-Nancy, , France

CHU de Nancy - Hopitaux de Brabois

Vandœuvre-lès-Nancy, , France

Hopital Paul Brousse

Villejuif, , France

Institut Gustave Roussy

Villejuif, , France

Centro di Riferimento Oncologico - Aviano

Aviano, , Italy

Ospedale Sta. Maria Delle Croci

Ravenna, , Italy

Ospedale S. Giovanni A.S. Dipartimente di Oncologia di Turin

Turin, , Italy

Groot Ziekengasthuis 's-Hertogenbosch

's-Hertogenbosch, , Netherlands

Medisch Centrum Alkmaar

Alkmaar, , Netherlands

Meander Medisch Centrum

Amersfoort, , Netherlands

Comprehensive Cancer Center Amsterdam

Amsterdam, , Netherlands

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, , Netherlands

Onze Lieve Vrouwe Gasthuis

Amsterdam, , Netherlands

Academisch Medisch Centrum

Amsterdam, , Netherlands

Streekziekenhuizen Gooi-Noord

Blaricum, , Netherlands

Amphia Ziekenhuis - locatie Molengracht

Breda, , Netherlands

Atrium Medisch Centrum - Brunssum

Brunssum, , Netherlands

Reinier de Graaf Group

Delft, , Netherlands

Catharina Ziekenhuis

Eindhoven, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Academisch Ziekenhuis Groningen

Groningen, , Netherlands

Atrium Medical Centre

Heerlen, , Netherlands

Radiotherapeutisch Instituut

Leeuwarden, , Netherlands

Diaconessenhuis Leiden

Leiden, , Netherlands

Academisch Ziekenhuis Maastricht

Maastricht, , Netherlands

Sint Antonius Ziekenhuis

Nieuwegein, , Netherlands

University Medical Center Nijmegen

Nijmegen, , Netherlands

Daniel Den Hoed Cancer Center at Erasmus Medical Center

Rotterdam, , Netherlands

Maasland Hospital

Sittard, , Netherlands

Leyenburg Ziekenhuis

The Hague, , Netherlands

Academisch Ziekenhuis Utrecht

Utrecht, , Netherlands

Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology

Warsaw, , Poland

Instituto Portugues de Oncologia Centro do Porto, SA

Porto, , Portugal

National Cancer Institute - Bratislava

Bratislava, , Slovakia

Institute of Oncology, Ljubljana

Ljubljana, , Slovenia

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hopital Cantonal Universitaire de Geneve

Geneva, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Countries

Belgium; France; Italy; Netherlands; Poland; Portugal; Slovakia; Slovenia; Spain; Switzerland

References

van der Kaaij MA, Heutte N, van Echten-Arends J, Raemaekers JM, Carde P, Noordijk EM, Ferme C, Thomas J, Eghbali H, Brice P, Bonmati C, Henry-Amar M, Kluin-Nelemans HC. Sperm quality before treatment in patients with early stage Hodgkin's lymphoma enrolled in EORTC-GELA Lymphoma Group trials. Haematologica. 2009 Dec;94(12):1691-7. doi: 10.3324/haematol.2009.009696. Epub 2009 Oct 22.

Reference Type: BACKGROUND

PMID: 19850901 (View on PubMed)

van der Kaaij MA, Heutte N, Le Stang N, Raemaekers JM, Simons AH, Carde P, Noordijk EM, Ferme C, Thomas J, Eghbali H, Kluin-Nelemans HC, Henry-Amar M; European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group; Groupe d'Etude des Lymphomes de l'Adulte. Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007 Jul 1;25(19):2825-32. doi: 10.1200/JCO.2006.10.2020. Epub 2007 May 21.

Reference Type: BACKGROUND

PMID: 17515571 (View on PubMed)

Eghbali H, Brice P, Creemers GY, et al.: Comparison of three radiation dose levels after EBVP regimen in favorable supradiaphragmatic clinical stages (CS) I-II Hodgkin's lymphoma (HL): preliminary results of the EORTC-GELA H9-F trial. [Abstract] Blood 106 (11): A-814, 2005.

Reference Type: RESULT

Ferme C, Diviné M, Vranovsky A, et al.: 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. [Abstract] Blood 106 (11): A-813, 2005.

Reference Type: RESULT

Girinsky T, Gargi T, Carrie C, et al.: Quality assurance program in the EORTC-GELA H9 randomized study results on 282 patients. [Abstract] Int J Radiat Oncol Biol Phys 63 (2 Suppl 1): A77, S47, 2005.

Reference Type: RESULT

Noordijk EM, Thomas J, Fermé C, et al.: First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL) . [Abstract] J Clin Oncol 23 (Suppl 16): A-6505, 561s, 2005.

Reference Type: RESULT

Thomas J, Ferme C, Noordijk EM, et al.: Six cycles of EBVP followed by 36 Gy involved-field irradiation vs. no irradiation in favourable supradiaphragmatic clinical stages I-II Hodgkin's lymphoma: the EORTC-GELA strategy in 771 patients (H9-F trial-20982). [Abstract] Eur J Haematol 75 (Suppl 65): A-E11a, 40, 2004.

Reference Type: RESULT

Thomas J, Ferme C, Noordijk EM, et al.: Six cycles of ABVD + IF-RT vs. four cycles of ABVD + IF-RT vs. four cycles of BEACOPP + IF-RT in unfavourable supradiaphragmatic clinical stages I-II Hodgkin's lymphoma: the EORTC-GELA H9-U randomized clinical trial (20982) in 808 patients. [Abstract] Eur J Haematol 73 (Supp 65): A-E12, 40, 2004.

Reference Type: RESULT

Thomas J, Ferme C, Noordijk EM, Morschhauser F, Girinsky T, Gaillard I, Lugtenburg PJ, Andre M, Lybeert MLM, Stamatoullas A, Beijert M, Helias P, Eghbali H, Gabarre J, van der Maazen RWM, Jaubert J, Bouabdallah K, Boulat O, Roesink JM, Christian B, Ong F, Bordessoule D, Tertian G, Gonzalez H, Vranovsky A, Quittet P, Tirelli U, de Jong D, Audouin J, Aleman BMP, Henry-Amar M. Comparison of 36 Gy, 20 Gy, or No Radiation Therapy After 6 Cycles of EBVP Chemotherapy and Complete Remission in Early-Stage Hodgkin Lymphoma Without Risk Factors: Results of the EORT-GELA H9-F Intergroup Randomized Trial. Int J Radiat Oncol Biol Phys. 2018 Apr 1;100(5):1133-1145. doi: 10.1016/j.ijrobp.2017.10.015. Epub 2017 Oct 27.

Reference Type: DERIVED

PMID: 29229324 (View on PubMed)

Ferme C, Thomas J, Brice P, Casasnovas O, Vranovsky A, Bologna S, Lugtenburg PJ, Bouabdallah R, Carde P, Sebban C, Eghbali H, Salles G, van Imhoff GW, Thyss A, Noordijk EM, Reman O, Lybeert MLM, Janvier M, Spina M, Audhuy B, Raemaekers JMM, Delarue R, Anglaret B, de Weerdt O, Marjanovic Z, Tersteeg RJHA, de Jong D, Briere J, Henry-Amar M; European Organisation for Research and Treatment of Cancer Lymphoma Group, and; Groupe d'Etude des Lymphomes de l'Adulte. ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)-Groupe d'Etude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial. Eur J Cancer. 2017 Aug;81:45-55. doi: 10.1016/j.ejca.2017.05.005. Epub 2017 Jun 8.

Reference Type: DERIVED

PMID: 28601705 (View on PubMed)

Other Identifiers

FRE-FNCLCC-98014

Identifier Type: OTHER

Identifier Source: secondary_id

GELA-H9

Identifier Type: OTHER

Identifier Source: secondary_id

EORTC-20982

Identifier Type: -

Identifier Source: org_study_id