eight cycles of abvd versus four cycles of ... · less toxic than non-cross-resistant alternating...

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

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article.

Published online ahead of print at

www.jco.org on April 25, 2016.

Supported by Fonds Cancer of Belgium

and a grant from Amgen.

Written on behalf of the European

Organisation for Research and Treatment

of Cancer Lymphoma Group, the

Lymphoma Study Association, the

Australasian Leukaemia and Lymphoma

Group, the National Cancer Research

Institute Lymphoma Group, Grup per

l’Estudi dels Limfomes de Catalunya i

Balears, the National Cancer Institute of

Canada Clinical Trials Group, and the

Nordic Lymphoma Group.

Presented at the 48th Annual Meeting of

the American Society of Clinical

Oncology, Chicago, IL, June 1-5, 2012.

Author’s disclosures of potential conflicts

of interest are found in the article online at

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found at the end of this article.

Clinical trial information: NCT00049595.

Corresponding author: Patrice Carde, MD,

Department ofMedicine, Gustave Roussy

Cancer Campus, 114 rue Edouard Vaillant,

Villejuif 94805, France; e-mail: dr.pcarde@

gmail.com

© 2016 by American Society of Clinical

Oncology

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DOI: 10.1200/JCO.2015.64.5648

Eight Cycles of ABVDVersus Four Cycles of BEACOPPescalatedPlus Four Cycles of BEACOPPbaseline in Stage III to IV,International Prognostic Score $ 3, High-Risk HodgkinLymphoma: First Results of the Phase III EORTC 20012Intergroup TrialPatrice Carde, Matthias Karrasch, Catherine Fortpied, Pauline Brice, Hussein Khaled, Olivier Casasnovas, Denis Caillot,Isabelle Gaillard, Serge Bologna, Christophe Ferme, Pieternella Johanna Lugtenburg, Frank Morschhauser, Igor Aurer,Bertrand Coiffier, Ralph Meyer, Matthew Seftel, Max Wolf, Bengt Glimelius, Anna Sureda, and Nicolas Mounier

See accompanying editorial doi:10.1200/JCO.2015.66.3823

A B S T R A C T

PurposeTo compare patients with high-risk stage III to IV Hodgkin lymphoma (HL) in the phase III EuropeanOrganisation for Research and Treatment of Cancer 20012 Intergroup trial (Comparison of TwoCombinationChemotherapy Regimens in Treating Patients With Stage III or Stage IV Hodgkin’s Lymphoma) who wererandomly assigned to either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or to bleomycin,etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).Patients and MethodsPatients with clinical stage III or IV HL, International Prognostic Score of 3 or higher, and age 60 years oryounger received ABVD for eight cycles (ABVD8) or escalated-dose BEACOPP (BEACOPPescalated) for fourcycles followed by baseline BEACOPP (BEACOPPbaseline) for four cycles (BEACOPP4+4) without radio-therapy. Primary end points were event-free survival (EFS), treatment discontinuation, no completeresponse (CR) or unconfirmed complete response (CRu) after eight cycles, progression, relapse, or death.Secondary end points were CR rate, overall survival (OS), quality of life, secondary malignancies, anddisease-free survival in CR/CRu patients.ResultsBetween 2002 and 2010, 549 patients were randomly assigned to ABVD8 (n = 275) or BEACOPP4+4(n = 274). Other characteristics includedmedian age, 35 years; male, 75%; stage IV, 74%; “B” symptoms,81%; and International Prognostic Score $ 4, 59%. WHO performance status was 0 (34%), 1 (48%), or2 (17%).Median follow-upwas 3.6 years. CR/CRuwas 82.5% in both arms. At 4 years, EFSwas 63.7% forABVD8 versus 69.3% for BEACOPP4+4 (hazard ratio [HR], 0.86; 95%CI, 0.64 to 1.15;P= .312); disease-freesurvival was 85.8% versus 91.0% (HR, 0.59; 95% CI, 0.33 to 1.06; P = .076), and OS was 86.7% versus90.3%(HR,0.71; 95%CI, 0.42 to1.21;P= .208).Death asa result of toxicity occurred in six andfivepatients,early discontinuation (before cycle 5) in 12 and 26 patients, treatment crossovers in five and 10 patients, andsecondary malignancies in eight and 10 patients in the ABVD8 and BEACOPP4+4 arms, respectively.ConclusionABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stageHL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio comparedwith ABVD8, treatment burden, immediate and late toxicities, and associated costs must beconsidered before selecting one of these regimens on which to build future treatment strategies.

J Clin Oncol 34. © 2016 by American Society of Clinical Oncology

INTRODUCTION

Doxorubicin, bleomycin, vinblastine, and dacarbazine(ABVD) is standard for advanced Hodgkin lym-phoma (HL).1,2 ABVD proved to be superior to or

less toxic than non-cross-resistant alternating regi-mens (mechlorethamine, vincristine, procarbazine,and prednisone/doxorubicin, bleomycin, vinblastine,and dacarbazine [MOPP/ABVD] and MOPP/ABV),multidrug regimens (MOPP/epirubicin, bleomycin,and vinblastine/cyclophosphamide, doxorubicin,

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dacarbazine, cytarabine, and daunorubicin [MOPP/EBV/CAD];methotrexate, etoposide, and lomustine [MEC]; chlorambucil,vinblastine, procarbazine, and prednisone/prednisolone, doxorubicin,bleomycin, vincristine, and etoposide [ChlVPP/PABlOE]; hybridChlVPP/etoposide, vinblastine, and doxorubicin [ChlVPP/EVA]), andchemoradiotherapy (mechlorethamine, doxorubicin, vinblastine,vincristine, bleomycin, etoposide, and prednisone [Stanford V]).3-8

Increased cumulative and intensity dosing have improvedcomplete response (CR) rates and event-free survival (EFS) inHL.9,10 This relationship with the response warranted dose esca-lation from standard cyclophosphamide, vincristine, procarbazine,and prednisone [COPP]/ABVD to bleomycin, etoposide, doxo-rubicin, cyclophosphamide, vincristine, procarbazine, and pred-nisone (BEACOPP) at baseline (BEACOPPbaseline) and escalatedBEACOPP (BEACOPPescalated; HD9 trial).11-13 BEACOPPescalatedcompared with BEACOPPbaseline provided fewer early progressionsand higher 3-year freedom from treatment failure (FFTF) and EFSat 40 months (89% v 79%) and 70% with standard COPP/ABVD(P , .05 each comparison). This higher FFTF translated into ahigher overall survival (OS): 92% for BEACOPPescalated and 91%for BEACOPPbaseline versus 86% for COPP/ABVD. Deaths were 32of 463 versus 41 of 457 versus 46 of 263, respectively.14 However,no FFTF advantage was observed in patients older than age 60years. Immediate toxicity was severe: grade 3 to 4 anemia occurredin 25% of the cycles and 69% of the patients. More occurrences oftherapy-related acute myeloid leukemia and myelodysplasticsyndromes were observed in the BEACOPPescalated arm (1.8%[SE, 0.8%] after 3 years).

The HD12 trial confirmed the HD9 results: it compared eightcycles of BEACOPPescalated with BEACOPP4+4 (with or withoutinvolved field radiotherapy), which was meant to reduce latehematologic and gonadal toxicity in young patients while main-taining disease control, mainly through a 25% reduction of thecumulative dose of etoposide (4.8 g/m2 reduced to 3.6 g/m2).15

This reinforced the hypothesis that a dose increment was impor-tant primarily during the first part of the treatment.16 Indeed, inaccordance with the effective dose model, similar results wereobserved in the HD12 trial: FFTF was 86.4% and 84.8% (differ-ence, –1.6%; 95% CI, –5.2% to 1.9%), progression-free survival(PFS) was 87.5% and 85% (difference, –2.5%; 95% CI, –6% to1%), and 5-year OS was 92% versus 90.3% (difference, –1.7%;95% CI, –4.6% to 1.1%), respectively.13,15 Similarly, eight cycles ofBEACOPPescalated was tested against six cycles of BEACOPPescalatedin the HD15 trial: the 5-year FFTF rates were 84.4% for eight cycles ofBEACOPPescalated versus 89.3% for six cycles of BEACOPPescalated(97.5% CI, 0.5% to 9.3% for difference), thus promoting thestandard of care. OS was 91.9% versus 95.3%, respectively (97.5%CI, 0.36 to 0.98).17 The cumulative drug doses in the BEACOPP4+4regimen and in six cycles of BEACOPPescalated are almost identical, arelevant criterion in the effective dose model (doxorubicin, 240 v210 mg/m2; cyclophosphamide, 7,600 v 7,500 mg/m2; etoposide,3,600 v 3,600 mg/m2; and procarbazine, 560 v 420 mg/m2,respectively).

The contribution of radiotherapy was unclear in the HD9trial; it was marginal and restricted to the 10% of the patients withresidual disease of 2.5 cm or more who were still positive bypositron emission tomography after chemotherapy in the HD12trial.14,15,17 Conversely, a large randomized trial showed that

consolidation radiotherapy was detrimental for OS in CR and CRunconfirmed (CRu) patients after chemotherapy.18 First-lineirradiation was not allowed in the EORTC 20012 Intergroupprotocol.

Considering that standard dose regimens are suboptimal inpoor-prognosis advanced-stage HL, we selected the patients withInternational Prognostic Score (IPS) $ 3 as the most likely tobenefit from increased chemotherapy dosing.19 We aimed to clarifywhether BEACOPPescalated, provides a better EFS and leads to alonger OS than ABVD, especially because COPP/ABVD was not astandard therapy regimen.16,20-23 Meanwhile, two trials com-pared ABVD and BEACOPP4+4 and failed to show a survivaldifference.24,25 These randomized trials contradict the results of arecent and contested German Hodgkin Study Group meta-analysisthat addressed the effect of initial treatment strategy on the survivalof patients with advanced-stage HL, which increased interest in theEORTC 20012 Intergroup study, the largest one to target patientswith high-risk stage III or IV HL.26,27

PATIENTS AND METHODS

The European Organisation for Research and Treatment of CancerLymphoma Group led this phase III intergroup trial, in collaboration withthe Lymphoma Study Association, Groupe d’Etude des Lymphomes del’Adulte, the Australasian Leukaemia and Lymphoma Group, the NationalCancer Research Institute Lymphoma Group, Grup per l’Estudi delsLimfomes de Catalunya i Balears, the National Cancer Institute of CanadaClinical Trials Group, and the Nordic Lymphoma Group.

PatientsInclusion criteria included untreated histologic classic HL, age 16 to

60 years, clinical stage III or IV, at least one bidimensionally measurabletarget lesion, performance status (PS) of 0 to 2, IPS $ 3, and no othermalignancies except basal cell skin and in situ uterine cervix carcinomas.Exclusion criteria included no measurable disease; fertile patients whowere not using contraception; pregnant or lactating patients; activeinfection; severe cardiopulmonary, neurologic, or metabolic disease;inadequate liver function (bilirubin $ 2.5 3 upper limit of normal) orrenal function (creatinine$ 150 mmol/L or$ 2.0 mg/dL) unless they werea result of HL. Written informed consent per the local ethics committeewas mandatory before enrollment. The study was conducted according tothe Declaration of Helsinki.

TreatmentRandom assignments were stratified by institution and IPS (3 v$ 4).

The standard treatment was eight cycles of ABVD (ABVD8) given every4 weeks. The experimental treatment was four cycles of BEACOPPescalatedfollowed by four cycles of BEACOPPbaseline (BEACOPP4+4) given every3 weeks. Prophylactic granulocyte colony-stimulating factor was man-datory with BEACOPPescalated. Planned regimens are listed in AppendixTable A1 (online only).

Assessments and End PointsDisease assessment was planned after cycles 4, 6, and 8 by using

clinical and computed tomography examinations according to theResponse Evaluation Criteria in Solid Tumors (RECIST) for HL.28

The central study coordinators (CSCs) blindly reviewed the responses of thelocal investigator (LI). An extension of the definition for CRu (as defined inthe HD12 trial) was used for central review: patients who, on the basis ofdisease status evaluation at 4 to 6 weeks after treatment completion, were in

2 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Carde et al


partial response without additional treatment and progression of diseasewithin 6 months.15 EFS was the primary end point, defined as the timefrom random assignment to early discontinuation of protocol treatmentand no CR or CRu after eight cycles of chemotherapy, relapse, progression,or death. Secondary end points were CR or CRu, disease-free survival(DFS) in patients with CR, OS, quality of life, second malignancies, andcost effectiveness. As a result of the composite nature of the primary endpoint (including both treatment efficacy and feasibility), PFS was definedas time from random assignment to progression, relapse, or death and wasalso analyzed after the study was closed. Toxicities were graded according toCommon Toxicity Criteria version 2.0.

Statistical Design and Planned AnalysisThe study was designed to detect a 10% increase in the 3-year EFS rate

from 70% (ABVD8) to 80% (BEACOPP4+4; hazard ratio [HR], 0.62) byusing a two-sided log-rank test with type I error of 0.05. With one interimanalysis, 152 events were required to yield a power of 80% with 550patients randomly assigned over 5.5 years and observed for 8 months afterlast random assignment. An interim analysis of EFS was planned after 50events to stop the trial in case of superiority of the experimental arm. Analpha-spending function with a boundary parameter equal to 0.2 based onthe Wang-Tsiatis method was used as a compromise between the O’Brien-Fleming and the Pocock approaches.29 The Independent Data MonitoringCommittee was to be consulted if the lower limit of the 95% CI for thedeath-as-a-result-of-toxicity rate was $ 3% in any arm. All randomlyassigned patients were to be included in the analysis of efficacy end points

per intention to treat. The Kaplan-Meier method was used to analyze time-to-event end points, and the log-rank test was used to compare the twoarms.30,31 All inferential tests were performed at the two-sided a = .05level, and estimates were provided with their 95% CIs. Adverse events(AEs) were analyzed for all patients who started protocol therapy. Theworst grade for each Common Toxicity Criteria toxicity item recordedduring the entire treatment period was tabulated. For the most frequentevents, the proportions of grade 4 hematologic toxicities and of grade 3 or 4nonhematologic toxicities were computed with 95% CIs. Relative doseintensity (RDI) was the ratio (%) of the average 1-day dose administered orplanned during the treatment period. This article is based on data for 549patients with 233 events for the primary end point up to the clinical cutoffdate of November 19, 2010, 2 months after all patients stopped protocoltreatment (Fig 1, CONSORT diagram). Median follow-up was 3.6 years.

RESULTS

Between October 2002 and January 2010, 550 patients wererandomly assigned. One patient who lacked informed consent wasnot included, leaving 275 (ABVD8) and 274 (BEACOPP4+4)intention-to-treat patients. Three (ABVD8) and five (BEACOPP4+4)patients who did not start treatment were excluded from safetyanalyses (Fig 1). Eighteen patients (3%), nine in each arm, amongwhom 15 started treatment, were ineligible because of the absence of

Randomly assigned(N = 550)

No IC(n = 1)

ITT population (n = 275)

Safety population (n = 272)

Assigned to ABVD8 Did not receive ABVD8 because of ineligibility

Started ABVD8 (n = 272)

(n = 275)

(n = 3)

Discontinued treatment (n = 43)

(n = 8)Relapse/progression

Less than PR at cycle 4 or less than CR/CRu at cycle 6Toxicity (n = 7)

Death not as a result of HL (n = 2)

Other reasons (n = 10)

Refused treatment (n = 7)

Toxicity (n = 24)

Discontinued treatment (n = 49)

Relapse/progression (n = 1)

Less than PR at cycle 4 or less than CR/CRuat cycle 6 (n = 11)

Deaths not as a result of HL (n = 2)

Refused treatment (n = 6)

Other reasons (n = 5)Treatment administration unknown (n = 2)

(n = 2)

Assigned to BEACOPP4+4

Did not receive BEACOPP4+4 (n = 5) Refused treatment (n = 2) Ineligible Site-specific exclusion respiratory function (n = 1)

Started BEACOPP4+4 (n = 267) Treatment administration unknown (n = 2)

ITT population (n = 274)

Safety population (n = 269)

Randomly assigned with IC(n = 549)

Fig 1. CONSORT diagram. ABVD8, doxo-rubicin, bleomycin, vinblastine, and dacarba-zine (eight cycles); BEACOPP4+4, bleomycin,etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (fourcycles of BEACOPPescalated followed by fourcycles of BEACOPPbaseline); CR, completeresponse; CRu, unconfirmed CR; HL, Hodgkinlymphoma; IC, informed consent; ITT, inten-tion to treat; PR, partial response.

www.jco.org © 2016 by American Society of Clinical Oncology 3

ABVD Versus BEACOPP in Hodgkin Lymphoma: EORTC Intergroup 20012


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bidimensionally measurable target lesion (3), concomitant activediseases (2), IPS , 3 (2), age older than 60 years (1), inappropriatestage (4), histology (4), prior treatment (1), and inadequate organfunction (1). There were 531 eligible patients, 266 in the ABVD8 armand 265 in the BEACOPP4+4 arm (per protocol population). No datawere available at the time of database lock for two BEACOPP4+4patients (Fig 1).

Patient CharacteristicsBaseline characteristics are provided in Table 1 and include stage

IV disease, 74%; WHO PS 0 to 1, 82%; and “B” symptoms, 81%.Median age was 35 years, 75%were males, and IPS was$ 4 in 59% ofpatients. Baseline characteristics were balanced across the two groups.

Flow of Patients and Adherence to Protocol TreatmentIn the ABVD8 arm, three patients did not start treatment,

229 (84%) completed treatment, and 43 discontinued treatment,compared with the BEACOPP4+4 arm in which five patients didnot start treatment, 218 (81%) completed treatment, and 49discontinued treatment. Reasons for treatment discontinuationin the ABVD8 and BEACOPP4+4 arms were progressive disease(eight v one), inability to achieve partial response after cycle 4 orCRu after cycle 6 (nine v 11), toxicity (seven v 24), patient refusal(seven v six), and death not as a result of HL (two v two),respectively (Fig 1).

Main protocol treatment violations were the absence of fullydocumented restaging at cycle 6 contrary to protocol requirements:54% (ABVD8) and 48% (BEACOPP4+4) of the patients continuedchemotherapy beyond cycle 6 without restaging. Incorrect responseassessment was observed for 5.1% and 3.6% of the patients in theABVD8 and BEACOPP4+4 arms, respectively.

RDI for ABVD8 was 97.5% for doxorubicin, 92.6% forbleomycin, 95.7% for vinblastine, and 97.0% for dacarbazine. RDIfor the four cycles of BEACOPPescalated was 100.9% for doxo-rubicin, 99.7% for cyclophosphamide, 96.3% for etoposide, and99.6% for procarbazine; vincristine was the only drug with an RDIbelow 90%. Treatment was delayed, reduced, or both less often inthe ABVD8 arm than in the BEACOPP4+4 arm (16.7% v 30.6% ofcycles), usually from hematologic toxicity.

ResponseA total of 227 patients (83%; 95% CI, 78% to 87%) achieved a

CR or CRu, which was the same in both arms after centralizedreview, a higher number than that from the LI. According to the LI,CR was achieved by 202 patients (73.5%; 95% CI, 68.2% to 78.7%)in the ABVD8 arm and by 189 patients (69.0%; 95% CI, 63.5% to74.5%) in the BEACOPP4+4 arm.

EFS (primary end point)EFS at 4 years was 63.7% in the ABVD8 arm and 69.3% in the

BEACOPP4+4 arm (HR, 0.86; 95% CI, 0.64 to 1.15; P = .313 by

Table 1. Patient Baseline Characteristics

Characteristic

ABVD8(n = 275)

BEACOPP4+4(n = 274)

Total(n = 549)

No. % No. % No. %

Median age, years (range) 34.9 (16.1-67.4) 35.3 (16.8-60.9) 35.2 (16.1-67.4)No. of patients 275 272 547

SexMale 209 76.0 202 73.7 411 74.9Female 66 24.0 70 25.5 136 24.8Missing 0 0.0 2 0.7 2 0.4

Median weight, kg (range) 69.5 (40-118) 68 (44-125) 69 (40-125)No. of patients 273 272 545

Histologically documented HLNo 2 0.7 1 0.4 3 0.5Yes 273 99.3 271 98.9 544 99.1Missing 0 0.0 2 0.7 2 0.4

Clinical stageII 1 0.4 1 0.4 2 0.4III 65 23.6 76 27.7 141 25.7IV 209 76.0 195 71.2 404 73.6Missing 0 0.0 2 0.7 2 0.4

WHO performance status0 96 34.9 93 33.9 189 34.41 133 48.4 129 47.1 262 47.72 45 16.4 50 18.2 95 17.33 1 0.4 0 0.0 1 0.2Missing 0 0.0 2 0.7 2 0.4

B symptomsNo 55 20.0 47 17.2 102 18.6Yes 219 79.6 225 82.1 444 80.9Missing 1 0.4 2 0.7 3 0.5

Abbreviations: ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline; HL, Hodgkin lymphoma.


Carde et al


centralized review; Table 2 and Fig 2). The events that defined EFSwere premature discontinuation (10.5% v 13.9%), no CR or CRu atcycle 8 (9.1% v 4.7%), progression or relapse (12.7% v 7.7%), anddeath (3.3% v 3.3%), respectively. In the BEACOPP4+4 arm, morepatients ended protocol treatment prematurely as a result ofimmediate hematologic and infectious complications, includingseptic shock (one [ABVD8] v 18 [BEACOPP4+4]). Indeed, com-pared with the ABVD8 arm, grade 4 hematologic toxicity wasmore frequent in the BEACOPP4+4 arm for neutropenia (31.6%v 64.7%), febrile neutropenia (5.9% v 33.8%), severe AEs, andsevere adverse reactions, which were sevenfold more frequent (101v 708). Respiratory-related treatment discontinuations were morefrequent and severe in the ABVD8 arm (7 v 5), including two deathsas a result of toxicity. An amendment for additional lung functiontests prevented additional respiratory severe AEs. No difference forEFS was observed per LI in either arm (Appendix Table A2 [onlineonly] and Appendix Fig A1 [online only]).

DFS in CR and CRu PatientsDFS rates in CR and CRu patients at 4 years were 85.8% in the

ABVD8 arm and 91.0% in the BEACOPP4+4 arm (HR, 0.59; 95%CI, 0.33 to 1.06; P = .076; by centralized review: Table 2 and Fig 3).

PFSPFS rates at 4 years were 72.8% in the ABVD8 arm and 83.4%

in the BEACOPP4+4 arm (HR, 0.58; 95% CI, 0.39 to 0.85; P = .005by centralized review [Table 2 and Appendix Fig A2, online only]and by LI [Appendix Table A2 and Appendix Fig A2]).

OS and Causes of DeathOS rates at 4 years were 86.7% in the ABVD8 arm and 90.3%

in the BEACOPP4+4 arm (HR, 0.71; 95% CI, 0.42 to 1.21; P = .208;Table 2 and Fig 4). We observed 56 deaths (Tables 2 and 3): 33(12.0%) in the ABVD8 arm and 23 (8.4%) in the BEACOPP4+4arm. The main causes were HL (15 and seven patients) and toxicity(nine and six patients), respectively (Table 3). Only one death as aresult of HL (BEACOPP4+4) occurred early (ie, within 3 months ofthe end of treatment). There were 11 early deaths as a result oftoxicity (six in the ABVD8 arm and five in the BEACOPP4+4 arm),including five (two and three) on treatment as a result of

bleomycin-induced acute respiratory distress syndrome, acutehepatitis (ABVD8 [one in each arm]), septic shock during aplasia,including one case of enterocolitis (BEACOPP4+4 [three]). Deathas a result of a secondary malignancy occurred in two and fourpatients, respectively.

AEs and Toxicity During TreatmentGrade 4 hematologic toxicities in the ABVD8 and BEACOPP4+4

arms were a result of febrile neutropenia in 0.0% and 6.3%,leucopenia in 4.8% and 70.6%, granulocytopenia in 31.6% and64.7%, and thrombocytopenia in 0% and 7.8% of the patients,respectively. Main nonhematologic toxicities (grade 3 to 4 in$ 5%of patients) were cardiovascular other than edema, hypertension,or hypotension (4.8% and 7.4%); fatigue (2.6% and 10.4%); GIother than anorexia, constipation, diarrhea, nausea, or vomiting(1.8% and 9.7%); infection in non-neutropenic patients (4.4% and9.7%); neurologic other than dizziness or neuropathy (2.6% and5.2%); and pulmonary other than cough, dyspnea, or pleuraleffusion (4.0% and 7.1%).

Table 2. EFS, DFS, PFS (centralized review data), and OS

Survival

ABVD8 BEACOPP4+4

HR(BEACOPP4+4 v

ABVD8)

Log-Rank PNo. ofPatients

No. of ObservedEvents

%(at 4 years) 95% CI

No. ofPatients

No. of ObservedEvents

%(at 4 years) 95% CI HR 95% CI

EFS 275 98 63.67 57.45 to 69.24 274 81 69.30 63.17 to 74.61 0.86 0.64 to 1.15 .3129DFS* 227 29 85.8 80.1 to 89.9 227 18 91.0 85.9 to 94.3 0.59 0.33 to 1.06 .076PFS 275 69 72.80 66.63 to 78.02 274 41 83.38 77.89 to 87.61 0.58 0.39 to 0.85 .0052OS 275 33 86.69 81.23 to 90.65 274 23 90.33 85.49 to 93.61 0.71 0.42 to 1.21 .2081

NOTE. Median was not reached for any type of survival.Abbreviations: ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline; DFS, disease-free survival; EFS, event-freesurvival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.*Analysis conducted on the subset of patients who reached complete response or unconfirmed complete response.

Time (years)0 1 2 3 4 5 6 7 8

102030405060708090

100

Overall log-rank test P = .313

No. at risk 186 147 113 84 58 26 8

196 161 118 87 55 29 7

Treatment

ABVD8 (N = 275; O = 98)

BEACOPP4+4 (N = 274; O = 81)

Even

t-Fre

e Su

rviv

al (%

)

Fig 2. Event-free survival according to data from a centralized review. ABVD8,doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4,bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,and prednisone (four cycles of BEACOPPescalated followed by four cycles ofBEACOPPbaseline); N, No. at risk; O, observed events.




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Deaths in the ABVD8 and BEACOPP4+4 arms that were not aresult of HL were, respectively, bleomycin-induced pulmonarytoxicity (six and zero), septic shock or severe intercurrent infection(four and eight), liver failure (one and two), cardiomyopathy (twoand one), and death after a second tumor (two and four), includingnon-Hodgkin lymphoma (NHL; two and one), bronchogenic andunknown primary carcinoma (zero and two), and acute mono-blastic leukemia (zero and one).

Late AEs and Second MalignanciesSecond malignancies were observed in eight patients in the

ABVD8 arm (two lung, three NHL, twomyeloproliferative diseases,one other) and in 10 patients in the BEACOPP4+4 arm (one lung,two NHL, four myeloproliferative disease, three other). Cumu-lative incidence rates (Appendix Fig A3, online only) did not differsignificantly (3.4% and 4.7% at 4 years, respectively).

DISCUSSION

This randomized phase III trial compared ABVD8 and BEACOPP4+4to assess chemotherapy dose density and dose intensity in thehighest-risk patients (IPS $ 3) with stage III or IV HL (n = 550).Patients with poor-prognosis stage II disease (13% of theadvanced-stage HL series) who were potentially curable with lesstreatment, were excluded. Our patient population accountedfor 42%, 43%, 54%, and 59% of the advanced-stage HL popu-lation of the initial IPS project, HD9, EORTC 20804, andGroupe d’Etude des Lymphomes de l’Adulte H89 studies,respectively.18,19,32,33 The corresponding FFTF rates were 55%,64%, and 84% at 3 years and 72% at 5 years, respectively, althoughOS rates were 78%, 86%, and 89% at 3 years and 80% at 5 years, asuboptimal result. The EORTC 20012 Intergroup study inves-tigated whether patients age 60 years or younger with stages III to

IV HL at the highest-risk IPS ($ 3) would most benefit from dose-dense and dose-intense treatment, in keeping with the Kairoshypothesis.16

EFS was chosen as the main end point to account fortreatment efficacy and feasibility. Positron emission tomographyimaging, not standard when the trial started, was excluded fromthe initial response assessment plan. To secure patient manage-ment, response evaluations were scheduled after cycles 4 and 6 inboth arms. However, protocol time point evaluations were oftenomitted by the LI (primary analysis), particularly after cycle 6.Nevertheless, a retrospective central evaluation of responses(sensitivity analysis) was performed in all cases by the CSC (M.D.,N.M., P.C.). No statistically significant difference was observed inEFS between the ABVD8 and BEACOPP4+4 arms by either local orcentral assessment.

Despite similar CR and EFS rates, causes of treatment failurediverged between the ABVD8 and BEACOPP4+4 arms. Morepatients progressed or relapsed in the ABVD8 arm than in theBEACOPP4+4 arm; however, the resulting DFS and PFS were muchcloser than anticipated from the results of the HD9 trial. DFS wasa better parameter for expressing dose-response, as reported inthe Standardized Response Criteria (revision 2007). The sameobservation applies to PFS. ABVD8 turned out to be more effectivethan COPP/ABVD, contrary to the prediction of the equivalenteffective doses model, simply because “doxorubicin is confirmed asmost important drug in [HL],” as acknowledged by Hasencleverhimself.13

Central reviewers noted that many deaths as a result of toxicitycould have been avoided considering the poor initial condition ofpatients: indeed, numbers were similar in both arms (six v fivepatients; 2% overall), in keeping with observations of the GermanHodgkin Study Group.34

OS rate was similarly high. Remarkably, OS in the BEACOPP4+4arm of the EORTC 20012 Intergroup trial was the same (90.3%)

Time (years)No. at risk 174 140 105 79 48 23 1

195 155 117 81 50 22 5

Overall score test: P = .076

1 2 3 4 5 6 7 80

10

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100

Treatment

BEACOPP4+4 (N = 227; O = 18)

AVBD8 (N = 227; O = 29)

Dise

ase-

Free

Sur

viva

l (%

)

Fig 3. Disease-free survival in patients with complete response or unconfirmedcomplete response according to data from a centralized review. ABVD8, doxo-rubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4,bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,and prednisone (four cycles of BEACOPPescalated followed by four cycles ofBEACOPPbaseline); N, No. at risk; O, observed events.

Time (years)0 1 2 3 4 5 6 7 8

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No. at risk 246 200 150 107 72 34 9

241 198 149 108 65 34 7

Treatment

ABVD8 (N = 275; O = 33)

BEACOPP4+4 (N = 274; O = 23)

Over

all S

urvi

val (

%)

Fig 4. Overall survival in the intent-to-treat population (randomly assignedpatients with informed consent). ABVD8, doxorubicin, bleomycin, vinblastine, anddacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone (four cycles ofBEACOPPescalated followed by four cycles of BEACOPPbaseline); N, No. at risk; O,observed events.


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as in the BEACOPP4+4 arm of the HD12 trial for patients withstandard-risk stages II, III, or IV disease who received radiotherapy.15

Some questions were not answered. Late morbidity will bereported later, hopefully decreased by the omission of irradiation.35,36

However, BEACOPP4+4 induced 3.5-fold more secondary hemato-logic malignancies than other regimens.37 Furthermore, in theHD2000 randomized trial, second malignancy risk—mostlysolid tumors—at 10 years was 6.7 for BEACOPP4+4 versus 0.9for ABVD (P = .027).38 Although ABVD is known to preservefertility, BEACOPP is associated with testicular and ovariandamage.39-43 This is a significant drawback in a young population(median age, 35 years; 67% of patients were younger than age 44years). Feasibility and the results of stem-cell harvest for salvagetherapy for our progressing or relapsing patients after ABVD8 andBEACOPP4+4 will be reported.

The large EORTC 20012 Intergroup trial compared ABVD8

and BEACOPP4+4 administered with excellent compliance inpatients in the highest-risk group of advanced-stage HL. Ascompared with ABVD, BEACOPP4+4 produced an identical CR/CRu rate (82%) and no significant increase in 4-year EFS and OS.Themarginal effect seen on DFS in favor of BEACOPP4+4 (P = .001[per LI]; P = .076 [per CSC]) did not translate into a difference inOS. A higher PFS for BEACOPP4+4 (centralized review) also didnot translate into higher OS, contrary to the result of the com-panion Lymphoma Study Association trial in patients with IPS 0 to2.44 One explanation may be a better efficacy of salvage therapyafter ABVD8. Another explanation might be a poorer tolerance ofBEACOPP4+4 in the population of patients with more severe initialcharacteristics than in the other studies: age 35 versus 28 years; sexratio of males to females, 3:1 versus 1:1; WHO PS of 1 or higher,66% versus 36%; stage IV, 74% versus 57%; and B symptoms, 81%versus 54%.45,46 Our results confirm the results of two studies thatrandomly assigned patients with advanced-stage HL to ABVDor BEACOPP4+4, which resulted in identical OS, with fewer

BEACOPP4+4 patients requiring salvage therapy.24,25 The dis-appointing yield from dose increment in the high-risk group, thesevere early and late morbidities, and associated costs, all raisequestions about the benefits of BEACOPP. Pooling the results of thethree randomized studies that compared ABVD and BEACOPP4+4(manuscript in preparation) should reinforce their similar con-clusions, assess potential differences, and may identify a group ofpatients that benefit from initial increment of dose intensity anddose density while minimizing immediate and late toxicities.Meanwhile, new agents should be tested with both regimens.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Patrice Carde, Pauline Brice, Christophe Ferme,Pieternella Johanna Lugtenburg, Ralph MeyerAdministrative support: Patrice Carde, Matthias Karrasch, CatherineFortpied, Olivier Casasnovas, Bertrand Coiffier, Ralph Meyer, Max Wolf,Bengt Glimelius, Anna Sureda, Nicolas MounierProvision of study materials or patients: Patrice Carde, Hussein Khaled,Olivier Casasnovas, Denis Caillot, Isabelle Gaillard, Serge Bologna,Christophe Ferme, Pieternella Johanna Lugtenburg, Frank Morschhauser,Igor Aurer, Bertrand Coiffier, Ralph Meyer, Matthew Seftel, Max Wolf,Bengt Glimelius, Anna Sureda, Nicolas MounierCollection and assembly of data: All authorsData analysis and interpretation: Patrice Carde, Matthias Karrasch,Catherine Fortpied, Matthew Seftel, Nicolas MounierManuscript writing: All authorsFinal approval of manuscript: All authors

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Table 3. Causes of Death

Cause of Death

ABVD8(n = 275)

BEACOPP4+4(n = 274)

No. % No. %

Hodgkin lymphoma 15 5.5 7 2.6Secondary hematologic or solid tumor 2 0.7 4 1.5Toxicity including death as a result of toxicity 9 3.3 6 2.2Intercurrent infectious disease 2 0.7 3 1.1Intercurrent cardiovascular disease 1 0.4 1 0.4Other 2 0.7 2 0.7Unknown 2 0.7 0 0.0

Abbreviations: ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline.




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12. Diehl V, Franklin J, Pfreundschuh M, et al:Standard and increased-dose BEACOPP chemo-therapy compared with COPP-ABVD for advancedHodgkin’s disease. N Engl J Med 348:2386-2395,2003

13. Hasenclever D, Brosteanu O, Gerike T, et al:Modelling of chemotherapy: The effective doseapproach. Ann Hematol 80:B89-B94, 2001

14. Engert A, Diehl V, Franklin J, et al: Escalated-dose BEACOPP in the treatment of patients withadvanced-stage Hodgkin’s lymphoma: 10 years offollow-up of the GHSG HD9 study. J Clin Oncol 27:4548-4554, 2009

15. Borchmann P, Haverkamp H, Diehl V, et al:Eight cycles of escalated-dose BEACOPP comparedwith four cycles of escalated-dose BEACOPP fol-lowed by four cycles of baseline-dose BEACOPPwith or without radiotherapy in patients withadvanced-stage Hodgkin’s lymphoma: Final analysisof the HD12 trial of the German Hodgkin StudyGroup. J Clin Oncol 29:4234-4242, 2011

16. Diehl V: Advanced Hodgkin’s disease: ABVDis better, yet is not good enough! J Clin Oncol 21:583-585, 2003

17. Engert A, Haverkamp H, Kobe C, et al:Reduced-intensity chemotherapy and PET-guidedradiotherapy in patients with advanced stage Hodg-kin’s lymphoma (HD15 trial): A randomised, open-label, phase 3 non-inferiority trial. Lancet 379:1791-1799, 2012

18. Aleman BM, Raemaekers JM, Tirelli U, et al:Involved-field radiotherapy for advanced Hodgkin’slymphoma. N Engl J Med 348:2396-2406, 2003

19. Hasenclever D, Diehl V: A prognostic score foradvanced Hodgkin’s disease: International Prog-nostic Factors Project on Advanced Hodgkin’s Dis-ease. N Engl J Med 339:1506-1514, 1998

20. Carde P: The chemotherapy/radiation balancein advanced Hodgkin’s lymphoma: Overweightwhich side? J Clin Oncol 23:9058-9062, 2005

21. Horning SJ: Risk, cure and complications inadvanced Hodgkin disease. Hematology Am SocHematol Educ Program 197-203, 2007

22. Carde P, Cavalli F, Diehl V: Is escalatedBEACOPP a standard therapy for advanced Hodg-kin’s disease? Hematol J 1:282-290, 2000

23. Cheson BD: Is BEACOPP better than ABVD?Curr Hematol Malig Rep 2:161-166, 2007

24. Federico M, Luminari S, Iannitto E, et al: ABVDcompared with BEACOPP compared with CEC forthe initial treatment of patients with advancedHodgkin’s lymphoma: Results from the HD2000Gruppo Italiano per lo Studio dei Linfomi Trial. J ClinOncol 27:805-811, 2009

25. Viviani S, Zinzani PL, Rambaldi A, et al: ABVDversus BEACOPP for Hodgkin’s lymphoma whenhigh-dose salvage is planned. N Engl J Med 365:203-212, 2011

26. Skoetz N, Trelle S, Rancea M, et al: Effect ofinitial treatment strategy on survival of patients withadvanced-stage Hodgkin’s lymphoma: A systematicreview and network meta-analysis. Lancet Oncol 14:943-952, 2013

27. Federico M, Bellei M, Cheson BD: BEACOPPor no BEACOPP? Lancet Oncol 14:e487-e488, 2013

28. Cheson BD, Horning SJ, Coiffier B, et al:Report of an international workshop to standardizeresponse criteria for non-Hodgkin’s lymphomas.J Clin Oncol 17:1244, 1999

29. Wang SK, Tsiatis AA: Approximately optimalone-parameter boundaries for group sequential trials.Biometrics 43:193-199, 1987

30. Kaplan EL, Meier P: Nonparametric estimationfrom incomplete observations. J Am Stat Assoc 53:457-481, 1958

31. Mantel N: Evaluation of survival data and twonew rank order statistics arising in its consideration.Cancer Chemother Rep 50:163-170, 1966

32. Ferme C, Mounier N, Casasnovas O, et al:Long-term results and competing risk analysis ofthe H89 trial in patients with advanced-stage Hodg-kin lymphoma: A study by the Groupe d’Etudedes Lymphomes de l’Adulte (GELA). Blood 107:4636-4642, 2006

33. Dose escalated BEACOPP chemotherapyimproves failure-free survival in advanced Hodgkin’sdisease: Updated results of the German Hodgkin’sLymphoma Study Group. Presented at the 42nd ASHAnnual Meeting and Exposition, San Francisco, CA,December 1-5, 2000

34. Wongso D, Fuchs M, Plutschow A, et al:Treatment-related mortality in patients with advanced-stage Hodgkin lymphoma: An analysis of the GermanHodgkin Study Group. J Clin Oncol 31:2819-2824,2013

35. Aleman BM, van den Belt-Dusebout AW, DeBruin ML, et al: Late cardiotoxicity after treatment forHodgkin lymphoma. Blood 109:1878-1886, 2007

36. Ghalibafian M, Beaudre A, Girinsky T: Heartand coronary artery protection in patients withmediastinal Hodgkin lymphoma treated with intensity-modulated radiotherapy: Dose constraints to virtualvolumes or to organs at risk? Radiother Oncol 87:82-88, 2008

37. Eichenauer DA, Thielen I, Haverkamp H, et al:Therapy-related acute myeloid leukemia and myelo-dysplastic syndromes in patients with Hodgkinlymphoma: A report from the German Hodgkin StudyGroup. Blood 123:1658-1664, 2014

38. Merli F, Luminari S, Mammi C, et al: Long-term follow-up analysis of HD2000 trial comparingABVD versus BEACOPP versus COPP/EBV/CAD inpatients with newly diagnosed advanced-stageHodgkin lymphoma: A study from the Fonda-zione Italiana Linfomi. 56th ASH Annual Meetingand Exposition, San Francisco, CA, December 6-9,2014 (abstr 499)

39. Behringer K, Breuer K, Reineke T, et al: Sec-ondary amenorrhea after Hodgkin’s lymphoma isinfluenced by age at treatment, stage of disease,chemotherapy regimen, and the use of oral contra-ceptives during therapy: A report from the GermanHodgkin’s Lymphoma Study Group. J Clin Oncol 23:7555-7564, 2005

40. Carde P: Risks of infertility and early meno-pause from anticancer and immunosuppressiveprograms: Methods of fertility preservation and pal-liation. Am Soc Clin Oncol Ed Book, 400-417, 2004

41. Jurczak W, Krochmalczyk D, Pabian W, et al:Quality of life and fertility in Hodgkin disease patientstreatedwith escalated BEACOPP. Haematologica 94,2009 (abstr 89)

42. Santoro A, Bonadonna G, Valagussa P, et al:Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: Superi-ority of ABVD plus radiotherapy versus MOPP plusradiotherapy. J Clin Oncol 5:27-37, 1987

43. Sieniawski M, Reineke T, Nogova L, et al:Fertility in male patients with advanced Hodgkinlymphoma treated with BEACOPP: A report of theGerman Hodgkin Study Group (GHSG). Blood 111:71-76, 2008

44. Mounier N, Brice P, Bologna S, et al: ABVD(8 cycles) versus BEACOPP (4 escalated cycles $ 4baseline): Final results in stage III-IV low-risk Hodgkinlymphoma (IPS 0-2) of the LYSA H34 randomizedtrial. Ann Oncol 25:1622-1628, 2014

45. Schmitz N, Pfistner B, Sextro M, et al:Aggressive conventional chemotherapy comparedwith high-dose chemotherapy with autologoushaemopoietic stem-cell transplantation for relapsedchemosensitive Hodgkin’s disease: A randomisedtrial. Lancet 359:2065-2071, 2002

46. Sureda A, Robinson S, Canals C, et al:Reduced-intensity conditioning compared with con-ventional allogeneic stem-cell transplantation in relapsedor refractory Hodgkin’s lymphoma: An analysis from theLymphoma Working Party of the European Group forBlood and Marrow Transplantation. J Clin Oncol 26:455-462, 2008

AffiliationsPatrice Carde and Christophe Ferme, Gustave Roussy Cancer Campus, Villejuif; Pauline Brice, Hopital St. Louis, Paris; Olivier

Casasnovas and Denis Caillot, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon; Isabelle Gaillard, CHU Henri Mondor, Creteil;Serge Bologna, Centre Hospitalier Regional Universitaire (CHR) de Nancy, Nancy; Frank Morschhauser, CHR de Lille, Lille; BertrandCoiffier, CHU de Lyon, Lyon; Nicolas Mounier, Hopital de L’Archet, Nice, France; Matthias Karrasch and Catherine Fortpied, EuropeanOrganisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Hussein Khaled, National Cancer Institute, Cairo,


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Egypt; Pieternella Johanna Lugtenburg, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Igor Aurer, UniversityHospital Centre Zagreb, Zagreb, Croatia; Ralph Meyer, Juravinski Cancer Centre, Hamilton, Ontario; Matthew Seftel, Cancer CareManitoba, Winnipeg, Manitoba, Canada; Max Wolf, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia; BengtGlimelius, Uppsala University, Uppsala, Sweden; and Anna Sureda, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International PrognosticScore ‡ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Patrice CardeNo relationship to disclose

Matthias KarraschTravel, Accommodations, Expenses: Abbott, MSD, Seegene

Catherine FortpiedNo relationship to disclose

Pauline BriceNo relationship to disclose

Hussein KhaledNo relationship to disclose

Olivier CasasnovasHonoraria: Genentech, Takeda Pharmaceuticals, Gilead Sciences, SanofiConsulting or Advisory Role:Genentech, Takeda Pharmaceuticals, GileadSciencesResearch Funding: Genentech (Inst)Travel, Accommodations, Expenses:Genentech, Takeda Pharmaceuticals,Gilead Sciences

Denis CaillotNo relationship to disclose

Isabelle GaillardEmployment: AmgenHonoraria: AmgenResearch Funding: AmgenTravel, Accommodations, Expenses: Amgen

Serge BolognaNo relationship to disclose

Christophe FermeNo relationship to disclose

Pieternella Johanna LugtenburgConsulting or Advisory Role: Takeda Pharmaceuticals

Frank MorschhauserConsulting or Advisory Role: Gilead Sciences, ServierExpert Testimony: Genentech, Janssen OncologyTravel, Accommodations, Expenses: Sanofi Pasteur, Celgene, GileadSciences

Igor AurerNo relationship to disclose

Bertrand CoiffierNo relationship to disclose

Ralph MeyerNo relationship to disclose

Matthew SeftelConsulting or Advisory Role: LundbeckResearch Funding: Lundbeck

Max WolfNo relationship to disclose

Bengt GlimeliusNo relationship to disclose

Anna SuredaNo relationship to disclose

Nicolas MounierNo relationship to disclose

© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Acknowledgment

We thank Marine Divine, MD, our previous co-coordinator, and the European Organisation for Research and Treatment of CancerHeadquarters team, in particular Bart Meulemans, Livia Giurgea, Tiana Raveloarivahy, StevenMortier, Niels Goetschalcks, Hilde Bressens,Emad Shash, Safaa Ramadan, Sarah Nuyens, and Alice Preumont.

Appendix

Table A1. Treatment Regimen

Drug

ABVD8 BEACOPPescalated BEACOPPbaseline

Daily Dose Days Given Daily Dose Days Given Daily Dose Days Given

Bleomycin 10 mg/m2 1, 15 10 mg/m2 8 10 mg/m2 8Etoposide* 200 mg/m2/d 1-3 100 mg/m2/d 1-3Doxorubicin 25 mg/m2 1, 15 35 mg/m2 1 25 mg/m2 1Cyclophosphamide 1,250 mg/m2 1 650 mg/m2 1Vincristine 1.4 mg/m2

(maximum, 2 mg)8 1.4 mg/m2

(maximum, 2 mg)8

Procarbazine 100 mg/m2/d 1-7 100 mg/m2/d 1-7Prednisone† 40 mg/m2/d 1-14 40 mg/m2/d 1-14Vinblastine 6 mg/m2 1, 15Dacarbazine 375 mg/m2 1, 15

NOTE. Protocol treatment was to be discontinued in case of insufficient response (ie, less than partial response after four cycles, less than unconfirmed completeresponse after six cycles, progression, or relapse), excessive toxicity, patient refusal, or investigator’s decision. Radiotherapy was not part of the protocol treatment.Abbreviations: ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vin-cristine, procarbazine, and prednisone.*A dose of etoposide phosphate 113 mg is equivalent to etoposide 100 mg.†Prednisone could be replaced by an equivalent dose of dexamethasone (5 mg/m2/d).

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Time (years)0 1 2 3 4 5 6 7 8

102030405060708090

100


No. at risk 169 136 100 73 51 20 5

164 137 102 75 48 23 6

Treatment

ABVD8 (N = 275; O = 121)

BEACOPP4+4 (N = 274; O = 112)

Even

t-Fre

e Su

rviv

al (%

)

Fig A1. Event-free survival according to local assessment. ABVD8, doxorubicin,bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4, bleomycin,etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone(four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline); N, No.at risk; O, observed events.

Table A2. EFS, DFS in CR Patients, and PFS

Treatment No. of Patients OEs HR 95% CI PMedian(years)

%(at 4 years) 95% CI

EFSABVD8 275 121 1.00 .8980* NR 54.01 47.57 to 60.01BEACOPP4+4 274 112 1.02 0.79 to 1.32 NR 58.08 51.78 to 63.86

DFS (LI, CSC)†ABVD8 202 35 1.00 .001‡ NR 79.7 72.7 to 85.1BEACOPP4+4 189 13 0.36 0.19 to 0.68 .001* NR 92.0 86.4 to 95.3

PFS (LI)§ABVD8 275 75 1.00 , .001 NR 69.36 62.88 to 74.93BEACOPP4+4 274 39 0.50 0.34 to 0.73 NR 84.02 78.56 to 88.20

Abbreviations: ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline; CR, complete response; CSC, central studycoordinator; DFS, disease-free survival; EFS, event-free survival; HR, hazard ratio; LI, local investigator; NR, not reached; OE, observed events; PFS, progression-freesurvival.*Log-rank P value.†For DFS, HR, 95% CI, and P values were determined according to the Cox model; median, percent (at 4 years), and 95% CI were determined according to anonparametric model.‡Score text P value.§From initial Case Report Form.


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227 184 137 100 62 32 7

Treatment

ABVD8 (N = 275; O = 69)

BEACOPP4+4 (N = 274; O = 41)

1 2 3 4 5 6 7 80

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229 184 137 99 61 32 7

Overall log-rank test P < .001

1 2 3 4 5 6 7 80

10

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B

A

Treatment

BEACOPP4+4 (N = 274; O = 39)

ABVD8 (N = 275; O = 75)

Prog

ress

ion-

Free

Sur

viva

l (%

)Pr

ogre

ssio

n-Fr

ee S

urvi

val (

%)

Fig A2. Progression-free survival according to data from (A) a centralized reviewand (B) local assessment. ABVD8, doxorubicin, bleomycin, vinblastine, anddacarbazine (eight cycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone (four cycles ofBEACOPPescalated followed by four cycles of BEACOPPbaseline); N, No. at risk; O,observed events.

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Time (years)No. at risk

1 2 3 4 5 6 7 80

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245 197 147 105 71 33 8

241 195 145 104 63 34 7

Treatment

ABVD8 (N = 275; O = 8)

BEACOPP4+4 (N = 274; O = 10)

Cum

ulat

ive

Inci

denc

e (%

)

Fig A3. Cumulative incidence for second malignancies with death as a com-peting event. ABVD8, doxorubicin, bleomycin, vinblastine, and dacarbazine (eightcycles); BEACOPP4+4, bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone (four cycles of BEACOPPescalated fol-lowed by four cycles of BEACOPPbaseline); N, No. at risk; O, observed events.


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eight cycles of abvd versus four cycles of ... · less toxic than non-cross-resistant alternating...

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