Clinical trial NCT00005584: Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Lymphoma
Keywords: stage I adult Hodgkin lymphoma
stage II adult Hodgkin lymphoma
adult lymphocyte predominant Hodgkin lymphoma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Lymphoma Study Association
name: UNICANCER
First posted: 2003-01-27
Enrollment: 1649
Sex: ALL
Minimum age (years): 15
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.)

Eligibility 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

Primary outcomes:
measure: Relapse-free rate
timeFrame: 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Till withdrawal criteria met
measure: Failure Free Survival
timeFrame: Till withdrawal criteria met
measure: Relapse Free Survival
timeFrame: Till withdrawal criteria met
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Sint Augustinus Ziekenhuis
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels
country: Belgium
facility: C.H.U. Saint-Pierre
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Centre Hospitalier Universitaire Brugmann
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Mont-Godinne Yvoir
country: Belgium
facility: Clinique Universitaire De Mont-Godinne
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre
city: Ambilly
country: France
facility: Centre Hospitalier Annemasse Bonneville
city: Annecy
country: France
facility: Centre Hospitalier d'Annecy
city: Aulnay Sous Bois
country: France
facility: Centre Hospital General Robert Ballanger
city: Avignon
country: France
facility: Hopital Duffaut
city: Bayonne
country: France
facility: Centre Hospitalier de la Cote Basque
city: Besancon
country: France
facility: CHR de Besancon - Hopital Jean Minjoz
city: Beziers
country: France
facility: Hopital de Beziers
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Bordeaux
country: France
facility: Institut Bergonie
city: Bourg En Bresse
country: France
facility: C.H. Bourg En Bresse
city: Briis Sous Forges
country: France
facility: CMC Bligny
city: Caen
country: France
facility: CHU de Caen
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Chambery
country: France
facility: Centre Hospitalier Regional de Chambery
city: Chartres
country: France
facility: Hopital Fontenoy
city: Chaumont
country: France
facility: Centre d'Oncologie et de Radiotherapie de Chaumont le Bois
city: Clamart
country: France
facility: Hopital d'Instruction des Armees Percy
city: Clamart
country: France
facility: Hopital Antoine Beclere
city: Clichy
country: France
facility: Hopital Beaujon
city: Colmar
country: France
facility: Hopital Louis Pasteur
city: Compiegne
country: France
facility: Centre Hospitalier Compiegne
city: Corbeil
country: France
facility: Centre Hospitalier Sud Francilien - Site Corbeil
city: Creteil
country: France
facility: Centre Hospitalier Universitaire Henri Mondor
city: Dijon
country: France
facility: Hopital Du Bocage
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer, Georges-Francois Leclerc
city: Grenoble
country: France
facility: Institut Prive de Cancerologie
city: Juvisy sur Orge
country: France
facility: Centre Hospitalier
city: Le Chesnay
country: France
facility: Hopital Andre Mignot
city: Le Havre
country: France
facility: C.H.G. Du Havre - Hopital J. Monod
city: Le Kremlin Bicetre
country: France
facility: Centre Hospitalier Universitaire de Bicetre
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lens
country: France
facility: Centre Hospitalier Lens
city: Lille
country: France
facility: Centre Hospital Universitaire Hop Huriez
city: Lille
country: France
facility: Centre Hospitalier Regional et Universitaire de Lille
city: Limoges
country: France
facility: Centre Hospital Regional Universitaire de Limoges
city: Lons le Saunier
country: France
facility: Centre Hospitalier General
city: Lyon
country: France
facility: Clinique Saint Jean
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Institut J. Paoli and I. Calmettes
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Metz
country: France
facility: Hopital Notre-Dame de Bon Secours
city: Montfermeil
country: France
facility: Intercommunal Hospital
city: Montpellier
country: France
facility: Clinique Gui de Chauliac
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Mulhouse
country: France
facility: Centre Hospitalier de Mulhouse
city: Nice
country: France
facility: Hopital Pasteur
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nimes
country: France
facility: C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hopital de la Croix Rouge Francaise des Peupliers
city: Paris
country: France
facility: Hotel Dieu de Paris
city: Paris
country: France
facility: Institut Curie - Section Medicale
city: Paris
country: France
facility: Hopital Lariboisiere
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: CHU Pitie-Salpetriere
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Necker
city: Pau
country: France
facility: C.H.G. De Pau
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poissy
country: France
facility: Centre Hospitalier Intercommunal de Poissy
city: Pontoise
country: France
facility: Hopital Rene Dubos
city: Reims
country: France
facility: Polyclinique De Courlancy
city: Roanne
country: France
facility: CHG Roanne
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Saint Etienne
country: France
facility: C.H.U. Saint Etienne Hospital Nord
city: Saint Germain-en-Laye
country: France
facility: Hopital de Saint Germain-en-Laye
city: Suresnes
country: France
facility: Centre Medico-Chirurgical Foch
city: Toulouse
country: France
facility: Centre Hospitalier Regional de Purpan
city: Valence
country: France
facility: Centre Hospitalier Valence
city: Valenciennes
country: France
facility: Centre Hospitalier de Valenciennes
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Vandoeuvre-Les-Nancy
country: France
facility: CHU de Nancy - Hopitaux de Brabois
city: Villejuif
country: France
facility: Hopital Paul Brousse
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico - Aviano
city: Ravenna
country: Italy
facility: Ospedale Sta. Maria Delle Croci
city: Turin
country: Italy
facility: Ospedale S. Giovanni A.S. Dipartimente di Oncologia di Turin
city: 's-Gravenhage
country: Netherlands
facility: Leyenburg Ziekenhuis
city: 's-Hertogenbosch
country: Netherlands
facility: Groot Ziekengasthuis 's-Hertogenbosch
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Comprehensive Cancer Center Amsterdam
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Blaricum
country: Netherlands
facility: Streekziekenhuizen Gooi-Noord
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis - locatie Molengracht
city: Brunssum
country: Netherlands
facility: Atrium Medisch Centrum - Brunssum
city: Delft
country: Netherlands
facility: Reinier de Graaf Group
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Academisch Ziekenhuis Groningen
city: Heerlen
country: Netherlands
facility: Atrium Medical Centre
city: Leeuwarden
country: Netherlands
facility: Radiotherapeutisch Instituut
city: Leiden
country: Netherlands
facility: Diaconessenhuis Leiden
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Daniel Den Hoed Cancer Center at Erasmus Medical Center
city: Sittard
country: Netherlands
facility: Maasland Hospital
city: Utrecht
country: Netherlands
facility: Academisch Ziekenhuis Utrecht
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Centro do Porto, SA
city: Bratislava
country: Slovakia
facility: National Cancer Institute - Bratislava
city: Ljubljana
country: Slovenia
facility: Institute of Oncology, Ljubljana
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
Study officials:
affiliation: University Hospital, Gasthuisberg
name: Jose Thomas, MD
role: STUDY_CHAIR
affiliation: Institut Bergonié
name: H. Eghbali, MD
role: STUDY_CHAIR
affiliation: Leiden University Medical Center
name: E.M. Noordijk, MD
role: STUDY_CHAIR
affiliation: Centre Medical de Bligny
name: Christophe Ferme
role: STUDY_CHAIR
affiliation: Hopital Saint-Louis
name: Christian Gisselbrecht, MD
role: STUDY_CHAIR
affiliation: Centre Leon Berard
name: Thierry O. Philip, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.