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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00005584

Collaborator

Lymphoma Study Association (Other), UNICANCER (Other)

1,649

Enrollment

121

Locations

13.6

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: bleomycin sulfate Drug: ABVD regimen Drug: BEACOPP regimen Drug: epirubicin hydrochloride Drug: prednisone Drug: vinblastine sulfate Radiation: radiation therapy	Phase 3

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

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.)

Study Design

Study Type:

Interventional

Actual Enrollment :

1649 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Prospective Controlled Trial in Clinical Stages I-II Supradiaphragmatic Hodgkin's Disease: Evaluation of Treatment Efficacy, (Long Term) Toxicity and Quality of Life in Two Different Prognostic Subgroups

Actual Study Start Date :

Oct 1, 1998

Actual Primary Completion Date :

May 1, 2004

Outcome Measures

Primary Outcome Measures

Relapse-free rate [5 years]
with events defined as lack of CR/CRu at the end of treatment or relapse

Secondary Outcome Measures

Overall Survival [Till withdrawal criteria met]
Failure Free Survival [Till withdrawal criteria met]
Relapse Free Survival [Till withdrawal criteria met]

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Sint Augustinus Ziekenhuis	Antwerpen	Belgium	2610
2	A.Z. St. Jan	Brugge	Belgium	8000
3	C.H.U. Saint-Pierre	Brussels	Belgium	1000
4	Institut Jules Bordet	Brussels	Belgium	1000
5	Cliniques Universitaires Saint-Luc	Brussels	Belgium	1200
6	Centre Hospitalier Universitaire Brugmann	Brussels	Belgium	B 1020
7	Universitair Ziekenhuis Antwerpen	Edegem	Belgium	B-2650
8	U.Z. Gasthuisberg	Leuven	Belgium	B-3000
9	Clinique Universitaire De Mont-Godinne	Mont-Godinne Yvoir	Belgium	5530
10	Clinique Saint-Pierre	Ottignies	Belgium	B-1340
11	Centre Hospitalier Annemasse Bonneville	Ambilly	France	74100
12	Centre Hospitalier d'Annecy	Annecy	France	74011 Cedex
13	Centre Hospital General Robert Ballanger	Aulnay Sous Bois	France	93602
14	Hopital Duffaut	Avignon	France	84902
15	Centre Hospitalier de la Cote Basque	Bayonne	France	64109
16	CHR de Besancon - Hopital Jean Minjoz	Besancon	France	25030
17	Hopital de Beziers	Beziers	France	34500
18	Hopital Saint Andre	Bordeaux	France	33075
19	Institut Bergonie	Bordeaux	France	33076
20	C.H. Bourg En Bresse	Bourg En Bresse	France	01012
21	CMC Bligny	Briis Sous Forges	France	91640
22	CHU de Caen	Caen	France	14033
23	Centre Regional Francois Baclesse	Caen	France	14076
24	Centre Hospitalier Regional de Chambery	Chambery	France	73011
25	Hopital Fontenoy	Chartres	France	28018
26	Centre d'Oncologie et de Radiotherapie de Chaumont le Bois	Chaumont	France	52000
27	Hopital d'Instruction des Armees Percy	Clamart	France	92140
28	Hopital Antoine Beclere	Clamart	France	92141
29	Hopital Beaujon	Clichy	France	92110
30	Hopital Louis Pasteur	Colmar	France	68024
31	Centre Hospitalier Compiegne	Compiegne	France	60321
32	Centre Hospitalier Sud Francilien - Site Corbeil	Corbeil	France	91100
33	Centre Hospitalier Universitaire Henri Mondor	Creteil	France	94010
34	Hopital Du Bocage	Dijon	France	21034
35	Centre de Lutte Contre le Cancer, Georges-Francois Leclerc	Dijon	France	21079
36	Institut Prive de Cancerologie	Grenoble	France	38100
37	Centre Hospitalier	Juvisy sur Orge	France	91260
38	Hopital Andre Mignot	Le Chesnay	France	78157
39	C.H.G. Du Havre - Hopital J. Monod	Le Havre	France	76083
40	Centre Hospitalier Universitaire de Bicetre	Le Kremlin Bicetre	France	94275
41	Clinique Victor Hugo	Le Mans	France	F-72000
42	Centre Hospitalier Lens	Lens	France	Cedex 62307
43	Centre Hospital Universitaire Hop Huriez	Lille	France	59037
44	Centre Hospitalier Regional et Universitaire de Lille	Lille	France	59037
45	Centre Hospital Regional Universitaire de Limoges	Limoges	France	87042
46	Centre Hospitalier General	Lons le Saunier	France	39000
47	Clinique Saint Jean	Lyon	France	69008
48	Centre Leon Berard	Lyon	France	69373
49	Hopital Edouard Herriot	Lyon	France	69437
50	Institut J. Paoli and I. Calmettes	Marseille	France	13273
51	Centre Hospitalier de Meaux	Meaux	France	77104
52	Hopital Notre-Dame de Bon Secours	Metz	France	55038
53	Intercommunal Hospital	Montfermeil	France	93370
54	Clinique Gui de Chauliac	Montpellier	France	34295
55	Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle	Montpellier	France	34298
56	Centre Hospitalier de Mulhouse	Mulhouse	France	68051
57	Hopital Pasteur	Nice	France	06002
58	Centre Antoine Lacassagne	Nice	France	06189
59	C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau	Nimes	France	30000
60	Hopital Saint Antoine	Paris	France	75012
61	Hopital de la Croix Rouge Francaise des Peupliers	Paris	France	75013
62	Hotel Dieu de Paris	Paris	France	75181
63	Institut Curie - Section Medicale	Paris	France	75248
64	Hopital Lariboisiere	Paris	France	75475
65	Hopital Saint-Louis	Paris	France	75475
66	CHU Pitie-Salpetriere	Paris	France	75651
67	Hopital Cochin	Paris	France	75674
68	Hopital Necker	Paris	France	75743
69	C.H.G. De Pau	Pau	France	64046 Universite Cedex
70	Hopital Haut Leveque	Pessac	France	33604
71	Centre Hospitalier Lyon Sud	Pierre Benite	France	69310
72	Centre Hospitalier Intercommunal de Poissy	Poissy	France	78498
73	Hopital Rene Dubos	Pontoise	France	95300
74	Polyclinique De Courlancy	Reims	France	F-51100
75	CHG Roanne	Roanne	France	F-42300
76	Centre Henri Becquerel	Rouen	France	76038
77	Centre Rene Huguenin	Saint Cloud	France	92211
78	C.H.U. Saint Etienne Hospital Nord	Saint Etienne	France	42055
79	Hopital de Saint Germain-en-Laye	Saint Germain-en-Laye	France	78104
80	Centre Medico-Chirurgical Foch	Suresnes	France	92151
81	Centre Hospitalier Regional de Purpan	Toulouse	France	31059
82	Centre Hospitalier Valence	Valence	France	26000
83	Centre Hospitalier de Valenciennes	Valenciennes	France	59300
84	Centre Alexis Vautrin	Vandoeuvre-les-Nancy	France	54511
85	CHU de Nancy - Hopitaux de Brabois	Vandoeuvre-Les-Nancy	France	54511
86	Hopital Paul Brousse	Villejuif	France	94804
87	Institut Gustave Roussy	Villejuif	France	F-94805
88	Centro di Riferimento Oncologico - Aviano	Aviano	Italy	33081
89	Ospedale Sta. Maria Delle Croci	Ravenna	Italy	48100
90	Ospedale S. Giovanni A.S. Dipartimente di Oncologia di Turin	Turin	Italy	10123
91	Leyenburg Ziekenhuis	's-Gravenhage	Netherlands	2545 CH
92	Groot Ziekengasthuis 's-Hertogenbosch	's-Hertogenbosch	Netherlands	5211 NL
93	Medisch Centrum Alkmaar	Alkmaar	Netherlands	1815 JD
94	Meander Medisch Centrum	Amersfoort	Netherlands	3816 CP
95	Comprehensive Cancer Center Amsterdam	Amsterdam	Netherlands	1006 CX
96	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam	Netherlands	1066 CX
97	Onze Lieve Vrouwe Gasthuis	Amsterdam	Netherlands	1091 HA
98	Academisch Medisch Centrum	Amsterdam	Netherlands	1105 AZ
99	Streekziekenhuizen Gooi-Noord	Blaricum	Netherlands	1261 AN
100	Amphia Ziekenhuis - locatie Molengracht	Breda	Netherlands	4818 CK
101	Atrium Medisch Centrum - Brunssum	Brunssum	Netherlands	6442 BE
102	Reinier de Graaf Group	Delft	Netherlands	NL 2600 GA
103	Catharina Ziekenhuis	Eindhoven	Netherlands	5602 ZA
104	Medisch Spectrum Twente	Enschede	Netherlands	7500 KA
105	Academisch Ziekenhuis Groningen	Groningen	Netherlands	9713 EZ
106	Atrium Medical Centre	Heerlen	Netherlands	6419 PC
107	Radiotherapeutisch Instituut	Leeuwarden	Netherlands	8934 AD
108	Diaconessenhuis Leiden	Leiden	Netherlands	2300 RD
109	Academisch Ziekenhuis Maastricht	Maastricht	Netherlands	6202 AZ
110	Sint Antonius Ziekenhuis	Nieuwegein	Netherlands	3435 CM
111	University Medical Center Nijmegen	Nijmegen	Netherlands	NL-6500 HB
112	Daniel Den Hoed Cancer Center at Erasmus Medical Center	Rotterdam	Netherlands	3008 AE
113	Maasland Hospital	Sittard	Netherlands	6131 BK
114	Academisch Ziekenhuis Utrecht	Utrecht	Netherlands	3584 CX
115	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology	Warsaw	Poland	02-781
116	Instituto Portugues de Oncologia Centro do Porto, SA	Porto	Portugal	4200
117	National Cancer Institute - Bratislava	Bratislava	Slovakia	833 10
118	Institute of Oncology, Ljubljana	Ljubljana	Slovenia	Sl-1000
119	Hospital Universitario 12 de Octubre	Madrid	Spain	28041
120	Hopital Cantonal Universitaire de Geneve	Geneva	Switzerland	CH-1211
121	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011