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Originally published as JCO Early Release 10.1200/JCO.2005.03.2151 on November 28 2005 © 2005 American Society of Clinical Oncology. Comparison of ABVD and Alternating or Hybrid Multidrug Regimens for the Treatment of Advanced Hodgkin's Lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519)From the Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton; Cancer Research UK Department of Medical Oncology, Christie Hospital, Manchester; Department of Medical Oncology, Queen Elizabeth Hospital, Birmingham; Medical Research Council Clinical Trials Unit; Lymphoma Trials Office, Cancer Research UK/University College London Trials Unit, London; Hematologic Malignancy Diagnosis Service, The General Infirmary, Leeds; Yorkshire Cancer Research Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom; and Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; on behalf of the UKLG LY09 Collaborators Address reprint requests to Peter W.M. Johnson, MD, FRCP, Cancer Research UK Clinical Centre, Somers Cancer Research Building, MP824, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; e-mail: johnsonp{at}soton.ac.uk
PURPOSE: To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. RESULTS: At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). CONCLUSION: There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.
Treatment for advanced Hodgkin's lymphoma (HL) has steadily improved since the introduction of combination chemotherapy; cure rates have increased during the last 30 years. The early four-drug regimens based on alkylating agents (such as mustine, vincristine, procarbazine, and prednisolone [MOPP]), have been superseded by anthracycline-containing regimens, particularly doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), after trials that proved ABVD was superior in terms of disease-free and overall survival (OS).1 Attempts were made to increase the efficacy of treatment further using multidrug regimens (MDRs) containing seven or eight cytotoxic agents.2,3 These used similar drugs as those in MOPP and ABVD, as alternating regimens for which one cycle of each type is given every 3 to 4 weeks, or as hybrid regimens for which each drug is given in every cycle, usually at attenuated doses. These approaches have the potential advantage of circumventing resistance to some agents, and for hybrid regimens, the dose-intensity of treatment is increased. Comparisons with MOPP-like treatments showed superior results for the more complex regimens,4-7 but it was not clear whether they would also prove superior to ABVD. The study that established the superiority of ABVD over MOPP also compared alternating MOPP/ABVD, which gave similar results to those for ABVD in terms of failure-free survival (FFS; 64% at 3 years in both arms, compared with 48% for MOPP).4 Additional studies suggested the equivalence of alternating and hybrid regimens,8,9 and a recently reported Intergroup trial suggests that the MOPP/doxorubicin, bleomycin, vinblastine (ABV) hybrid is equivalent to ABVD for FFS and OS at 5 years (66% v 63% and 81% v 82%, respectively), but with greater acute toxicity and excess myelodysplasia/acute leukemia in the hybrid arm.10 The risk of long-term treatment-related toxicity is important.11 High cure rates and young age at onset for most patients result in a significant number of individuals alive and disease free more than 20 years after treatment. Predisposition to cardiac disease from anthracyclines and mediastinal irradiation, to pulmonary disease from bleomycin, to secondary malignancy from cytotoxic drugs and radiotherapy, and to infertility from alkylating agents are significant considerations in selecting appropriate therapy.12,13 None of the chemotherapy regimens currently used avoids all of these problems, and the balance of risk varies according to the agents used. Thus ABVD does not seem to result in either secondary leukemia or infertility,1 whereas the more intensive hybrid bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen has both of these problems.14 A marginally less intense hybrid regimen comprising chlorambucil, vinblastine, procarbazine, and prednisolone with etoposide, vincristine, and doxorubicin (ChlVPP/EVA) has been used in United Kingdom. It seems to provide similar levels of disease control to BEACOPP but without the same leukemia incidence.15 However, it does result in permanent azoospermia in a high proportion of men.16 Finally, an alternating regimen may offer the advantage that the total dose of each drug is lower than might be the case for a four-drug or hybrid scheme, with the expectation that pulmonary and cardiac toxicity might thereby be mitigated. An alternating regimen that has been tested extensively in the United Kingdom comprises ChlVPP alternating with a modification of ABVD whereby etoposide is substituted for dacarbazine and vincristine for vinblastine, with the addition of prednisolone (PABlOE).3 This regimen (ChlVPP/PABlOE) has already been shown superior to the PABlOE regimen in a previous trial.17 LY09 was undertaken to compare the results of treatment with the two seven-/eight-drug regimens (MDRs) versus standard ABVD. Because previous comparisons of alternating and hybrid regimens have yielded similar results, this study was designed with a common control arm, ABVD, and the choice for investigators to assign treatment randomly against either the hybrid or the alternating regimen.
Ethical Issues The trial was conducted in compliance with the Declaration of Helsinki, was accepted by the appropriate Research Ethics Committees, and required each patient to give written informed consent to participation.
Eligibility Patients were excluded if they had received prior therapy for HL, had inadequate renal or hepatic function (creatinine > 100 µmol/L and bilirubin > 20 µmol/L, respectively, unless values were abnormal due to lymphoma), were pregnant or lactating, had a history of previous malignancy, or were otherwise unfit for a full chemotherapy course.
Staging
Treatment Allocation and Administration Drug regimens were administered, open label, according to schedules in published literature (Tables 1 and 2). Hematopoietic growth factors were not prescribed routinely, but patients repeatedly experiencing delayed blood count recovery were recommended for secondary prophylaxis using granulocyte colony-stimulating factor subsequently. Toxicity was recorded at each cycle using standard National Cancer Institute of Canada expanded Common Toxicity Criteria (December 1994 revision).
Patients responding clinically received six cycles of treatment before formal reassessment of disease. Patients showing continuing response could continue to eight cycles total; those judged to have reached maximum response were considered for consolidation radiotherapy (usually 30 to 35 Gy) to residual masses or sites of original bulk disease. Responses were graded using the Cotswolds Committee modification of Ann Arbor criteria. A standard follow-up schedule (every 3 months to 2 years, every 6 months to 5 years, then annually) was used with scheduled clinical examinations and radiology. Patients with disease unresponsive to initial therapy or recurrent disease were recommended for standard salvage chemotherapy, if possible, followed by high-dose consolidation chemotherapy with autologous hematopoietic progenitor-cell rescue.
Statistical Considerations
Assuming 5-year EFS of 65% for patients allocated ABVD and 75% for patients allocated MDR (hazard ratio [HR] = 0.67), 800 patients recruited during 4 years were required to report 240 EFS events (2 An independent Data Monitoring and Ethics Committee (DMEC) reviewed interim analyses on three occasions. No formal stopping rules were prespecified but the DMEC considered recommending stopping the trial only if the results were sufficiently convincing to a broad range of clinicians. The DMEC recommended continuation of trial recruitment at each review.
All analyses were performed on an intention-to-treat basis. Categoric data are compared with Relative doses (total dose administered/total dose planned) and relative dose-intensity [(total dose administered/duration of cycles administered)/(expected total dose for cycles administered/expected duration of cycles administered)], were calculated for the first six cycles. The expected doses and durations assumed that cycles were given at full dose without delays. Analyses were performed using Stata 8 (Stata Corp, College Station, TX).
Source Data Verification
Between February 1998 and September 2001, 807 patients were randomly assigned from 104 centers (95% in the United Kingdom), with 406 patients allocated to ABVD and 401 patients allocated to MDR (Fig 1). Of these, 582 entered the comparison of ABVD versus alternating, whereas 225 entered the comparison of ABVD versus hybrid. Independent central pathology review was possible in 715 patients (89%) and ruled 19 patients ineligible. These confirmed ineligible patients are excluded from the main analyses. The baseline characteristics of patients in each of the treatment groups were well balanced, and are listed in Table 3.
Treatment Delivery Protocol compliance was high, with all drugs other than the vinca alkaloids given at more than 80% of the intended total dose (Table 4) and relative dose-intensity. Dose reductions were most often used with vinca alkaloids, mainly due to nonprotocol capping of doses or in response to neurotoxicity. For doxorubicin, relative dose-intensity was at least 80% for 85%, 89%, and 86% of patients allocated ABVD, alternating, and hybrid groups, respectively (Fig A1, Appendix). Use of growth factor support varied according to randomized arm and choice of MDR (Table 5), with 44% of patients allocated ABVD receiving granulocyte colony-stimulating factor in at least one cycle, versus 29% in the alternating group and 53% in the hybrid group. The percentage of patients completing at least six cycles of allocated chemotherapy was 86% for ABVD patients, 86% alternating, and 80% hybrid (Table 5).
Chemotherapy was continued beyond six cycles in 27 patients (12%) in the ABVD/hybrid comparison and 162 patients (27%) in the ABVD/alternating comparison. The use of prolonged chemotherapy was similar between the randomly assigned ABVD and MDR arms in both randomizations (Table 5). Radiotherapy use followed the converse pattern: patients in the ABVD/hybrid comparison received consolidation treatment more often (n = 166; 56%) than patients in the ABVD/alternating comparison (n = 182; 32%). Again, this was balanced between the randomly assigned treatment arms. The main reported reasons for administering radiotherapy were prior bulk disease (n = 191; 62%), incomplete response (n = 48; 16%), and consolidation of complete remission in the absence of prior bulk (n = 58; 19%). Radiotherapy doses were balanced between the arms: 30 to 35 Gy was administered in 213 patients (70%), more than 35 Gy was administered in 76 patients (25%), and less than 30 Gy was administered in only 15 patients (5%).
Toxicity
Outcomes The response rates were similar between the ABVD and MDR arms. Overall, 262 patients (68%) allocated to ABVD and 257 patients (67%) allocated to MDRs reached complete response or unconfirmed complete response by the end of chemotherapy. The overall response rate (complete response + partial response) was 354 (92%) for ABVD and 352 (92%) for the MDRs. With reverse Kaplan-Meier censoring of survival data, the overall median follow-up time was 52 months (range, 6 to 80 months). There were 212 events (27%) in the analysis of EFS, including 111 deaths (14%). The HRs and Kaplan-Meier plots for comparisons of ABVD with MDR, and for ABVD with each MDR separately are shown in Figures 2A to 2F. Table 7 shows the estimated 3-year event rates. Causes of death are shown in Table 8.
A total of 169 patients (21%) developed progressive disease. Of these, 101 (60%) have gone on to receive high-dose therapy as part of their additional treatment. The survival rate 2 years from progression was 80% (95% CI, 67% to 88%) for those originally allocated ABVD and 85% (95% CI, 70% to 93%) for those allocated an MDR.
In planned exploratory subgroup analyses, baseline Hasenclever International Prognostic Index score (Fig 3), center size (in approximate tertiles), age, WHO performance status, and Ann Arbor disease stage showed no good evidence of differently sized treatment effects based on the
Twelve second malignancies are reported (four other lymphomas, seven epithelial malignancies, one myelodysplastic syndrome). Three (1%) occurred in patients allocated ABVD, nine (3%) occurred in patients allocated to the alternating group, and none occurred in patients allocated to the hybrid group. No occurrences of secondary acute leukemia have been reported.
This trial compared ABVD and the two MDRs in common use in the United Kingdom, alternating ChlVPP/PABlOE and hybrid ChlVPP/EVA. No significant difference in OS or EFS was seen between the arms for the study as a whole, or when the two different MDRs were compared with ABVD individually. With a median follow-up of more than 4 years, these conclusions are unlikely to change substantially with longer observation. With current data, the upper 95% CIs for the treatment difference in 3-year EFS and OS exclude absolute increases of more than 4% for MDRs compared with ABVD. This result is in keeping with two other studies that addressed a similar question in patients with advanced HL: the Cancer and Leukemia Group B trial in which ABVD and alternating MOPP/ABVD were compared,4 and the North American Intergroup trial in which ABVD and hybrid MOPP/ABV were compared.10 In neither trial was a clear difference in survival seen. Despite theoretical reasons for preferring MDRs, based on dose-intensity and the circumvention of resistance, these potential advantages do not seem to influence the outcome in practice. This may be explained by a degree of cross resistance between chemotherapy agents, and that the most active drugs (eg, doxorubicin) are delivered at lower initial intensity in the MDRs (particularly in the alternating therapy) than in ABVD. The outcomes in this trial are broadly similar to those reported previously. This trial included patients with stage I and II disease in the presence of systemic symptoms, multiple sites of involvement, or bulky disease, unlike the two trials that are most comparable. We have therefore derived survival data for those patients with Ann Arbor stage III or IV disease to make a more direct comparison. Thus, in the Cancer and Leukemia Group B trial, the 3-year FFS for such patients was 64% for ABVD, whereas in this trial EFS was 67% (and 71% in the MDR arm). Similarly, the 5-year EFS and OS rates in this trial (65% and 81%, respectively, for ABVD) are comparable to figures of 63% (FFS) and 82% (OS) for ABVD in the Intergroup trial. Treatment compliance was good, and overall activity of ABVD and MDRs seems consistent with other series. This makes it unlikely that inadequate application of chemotherapy might have biased the outcome, despite the large number of participating hospitals. The choice of MDR before random assignment was designed to address the main comparison of ABVD versus MDRs while optimizing participation in the trial and also permitting separate, exploratory, analysis of the two MDRs with ABVD. The size of the subgroups, particularly the ABVD/hybrid comparison, provides low power to detect differential treatment effects. However, there does not seem to be a substantial difference in outcomes between ABVD and either the hybrid or the alternating regimen individually. There is a nonsignificant trend toward worse freedom from progression in the ABVD arm compared with the hybrid arm, primarily because the patients receiving ABVD apparently had a small excess of early progressions. The results with ABVD in the hybrid comparison seem worse in this respect than do those with ABVD in the alternating comparison. There is no clear reason for this difference in the ABVD results, although the ABVD versus hybrid group patients did include 10% more with mediastinal bulk and B symptoms. The initial delivery of treatment was similar in both arms, with the same levels of protocol compliance over six cycles of treatment. Patients in the ABVD versus hybrid group random assignment were more likely to receive consolidation radiotherapy and less likely to undergo more than six cycles of chemotherapy than those in the alternating group random assignment. However, in both substudies the use of radiotherapy or extended chemotherapy was balanced between the randomly assigned arms. Prolonged chemotherapy seems to have been used by many centers as an alternative to radiotherapy, where availability and access to radiotherapy were limited. Indirect (nonrandomized) comparison of EFS in the two ABVD arms suggests that the more restricted use of radiotherapy in the ABVD versus alternating comparison did not have an adverse effect on the results; if anything, EFS seems better than for ABVD patients in the hybrid comparison. However, this may relate to the lower number of patients with bulky disease or B symptoms. Given that control of HL is similar in both arms, relative toxicity is an important consideration. It is clear in this trial, as in previous trials, that MDRs have more adverse effects than ABVD. Thus, both the MDRs were responsible for higher incidence of neuropathy (both peripheral and autonomic), and hybrid treatment carries the particular risk of severe mucositis. There was a small excess of deaths in the MDR patients during the treatment period, mainly from infective and cardiorespiratory causes in patients receiving hybrid treatment, but also because of some early HL progression in the alternating group. Although these MDRs were developed with the intention of avoiding the more severe effects of regimens such as MOPP/ABV and MOPP/ABVD, it is clear that they too carry a greater burden of morbidity than ABVD. From previous studies it is likely that the hybrid regimen will result in premature gonadal failure in a high proportion of patients, whereas ABVD probably will not. Long-term collection of sex hormone data, as well as cardiac and pulmonary function, is ongoing in a subset of patients. The analysis of second malignancies requires longer follow-up, but it is encouraging that the numbers so far seem lower than previous trials using regimens such as MOPP/ABV10 or BEACOPP.14 The absence of secondary leukemia in the hybrid arm is notable, given the incidence of this problem in the German study and the similarity between ChlVPP/EVA and the BEACOPP regimen. These data are consistent with those previously reported19 and may reflect the nonescalated design of the ChlVPP/EVA schedule and less use of growth factor support. Preplanned subgroup analysis did not identify any particular population for whom one or other regimen is demonstrably superior, with the exception of patients older than age 45, in whom ABVD is associated with better survival, mainly because of a lower rate of treatment-related deaths and second malignancies. In conclusion, ABVD remains the standard treatment for advanced HL, given the EFS and survival results, and the better toxicity profile, including late effects. The borderline advantage for the hybrid regimen in freedom from progression and the excellent results of the German BEACOPP studies leave open the possibility that risk-stratified use of hybrid therapy may be of future potential benefit, although it is not possible here to identify the group in which such intensification would be beneficial. The results of the ongoing European study comparing ABVD versus BEACOPP directly will be critical in this respect. For patients in whom preservation of fertility is important, this intensification is unattractive; trials comparing ABVD with the mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) regimen20 may be an alternative.
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version. The following groups participated in this study: Trial Management Group: Michael Cullen, Birmingham; Barry Hancock, Sheffield; Peter Johnson, Southampton; John Radford, Manchester; Sally Stenning, London; Matthew Sydes, London; Simon Clawson, London; Paul Smith, London; Ken McLennan, Leeds (to June 2000); Andrew Jack, Leeds (from June 2000); David Ryder, Manchester. Participating clinicians and centers (number of patients): J. Radford, Manchester (69); B.W. Hancock, Sheffield (46); J.A. Walewski, Warsaw (22); M. Danilova, Obninsk (15); A. Haynes, Nottingham (15); D. Deakin, Manchester (14); R. Marcus, Cambridge (13); J.K. Wood, Leicester (13); D.W. Milligan, Birmingham (12); J.S. Morgan, Ipswich (12); M. Cullen, Birmingham (11); M.L. Shields, Hull (10); N. Akhtar, Redbridge (4); A.M. Brunt, Stoke-on-Trent (4); M. Deane, Norwich (4); J. Duguid, Wrexham (4); S. Elyan, Cheltenham (4); D.S. Gillett, Tunbridge Wells (4); D.I. Gozzard, Rhyl (4); M.S. Hamilton, Sutton Coldfield (4); M. Hill, Maidstone (4); S. Jalihal, Scunthorpe (4); R.J. Johnson, Birmingham (4); P. Kettle, Belfast (4); D.C. Mitchell, Derby (4); P. Murray, Colchester (4); J.P. Ng, Barnsley (4); L.A. Parapia, Bradford (4); D.H. Parry, Bangor (4); M. Rowlands, Manchester (4); M. Ryan, Waterford (4); P.A. Stevenson, Aintree (4); T.A.S. Amos, Stafford (3); H. Barker, Rotherham (3); A. Biswas, Preston (3); S. Bolam, Taunton (3); L.R. Bond, York (3); C. Carter, Huddersfield (3); M. Dyer, Leicester (3); J.G. Erskine, Kilmarnock (3); D. Gilson, Leeds (3); P. Harrison, Dudley (3); J. Houghton, Salford (3); R.M. Hutchinson, Leicester (3); C.J Irwin, Coventry (3); M.T. Jeha, Great Yarmouth (3); P. Johnson, Leeds (3); S.A.N. Johnson, Yeovil (3); M. Leahy, Canterbury (3); N.P. Lucie, Glasgow (3); M. Lyttelton, Kettering (3); H. Myint, Bournemouth (3); A.M. O'Hea, Aylesbury (3); N. Parker, London (3); A.G. Prentice, Plymouth (3); D. Rea, Birmingham (3); P. Revell, Stafford (3); M. Robertson, Paisley (3); A. Rohatiner, London (3); G. Satchi, Liverpool (3); V.M. Tringham, Grantham (3); J. Tucker, Sutton Coldfield (3); S.G. Weston-Smith, St Leonards-on-Sea (3); S. Ali, Hull (2); C.C. Anderson, London (2); M. Auger, Sutton-in-Ashfield (2); D. Bareford, Birmingham (2); D.I. Berney, Barnet (2); P.C. Bevan, Chichester (2); N.E. Blesing, Swindon (2); T. Bogatyreva, Obninsk (2); D. Chan-Lam, Barnsley (2); C. Chapman, Leicester (2); P. Clark, Wirral (2); J.V. Clough, Chester (2); P. Coates, Kings Lynn (2); R Cuthbert, Londonderry (2); AC Cuthbert, Keighley (2); A Eden, Southend (2); S Falk, Bristol (2); EJ Fitzsimons, Glasgow (2); EJ Gaminara, Hemel Hempstead (2); S Green, Swindon (2); D Hull, Portadown (2); AE Hunter, Leicester (2); T. Kataria Sethi, New Delhi (2); S.M. Lee, London (2); M.L. Lewis, Kidderminster (2); F. Matthey, Redhill (2); M. McEvoy, Harrogate (2); P.K. Mehrotra, Bury St. Edmonds (2); E. Miller, Milton Keynes (2); T.R. Mitchell, Great Yarmouth (2); D. Moir, Milton Keynes (2); A.E. Morrison, Glasgow (2); A. Olujohungbe, Aintree (2); S. O'Reilly, Wirral (2); B. Paul, Worksop (2); C. Reid, Harrow (2); S. Sadullah, Great Yarmouth (2); S.M. Sherrin, Aylesbury (2); G. Smith, Leeds (2); M. Soukop, Glasgow (2); P.J. Stableforth, West Bromwich (2); B.E. Woodcock, Southport (2); H.M. Yosef, Glasgow (2); O.O. Ajose-Coker, London (1); D.M. Alderson, Urmston (1); S. Al-Ismail, Swansea (1); F. Booth, Torquay (1); D. Bowen, Dundee (1); H.K. Boyd, Portadown (1); A.G. Bynoe, Harrogate (1); P Cachia, Dundee (1); P. Carrington, Salford (1); J.D. Cavenagh, London (1); T. Clarke, Alexandria (1); R.J.G. Cuthbert, Belfast (1); C. De Silva, London (1); N.J. Dodd, Ipswich (1); Edwards, Rhyl (1); M. Galvin, Wakefield (1); I.R. Grant, Ilford (1); A. Gray, Swindon (1); H.W. Habboush, Abergavenny (1); T.J. Hamblin, Bournemouth (1); Hanley, Dundee (1); R.I. Harris, Coventry (1); J. Harrison, Hemel Hempstead (1); D.M. Harvey, Barnet (1); R. Jan-Mohammed, Uxbridge (1); J.B. Krzyzanowski, Warsaw (1); D.C. Linch, London (1); J. Littler, Wirral (1); A.T. Macheta, Barrow-in-Furness (1); P. Mahendra, Birmingham (1); E. Marshall, Wirral (1); M.F. McMullin, Belfast (1); M. Moody, Bury St Edmund's (1); T. Mughal, Preston (1); D. Obeid, Redditch (1); D.G.L. Pickering, Maidstone (1); M.J. Pippard, Dundee (1); C. Price, Bristol (1); J.K. Rees, Cambridge (1); S. Rule, Taunton (1); W. Sadik, Aintree (1); A.H. Sawers, Worcester (1); J.S. Seale, Bangor (1); T. Simoyi, Huddersfield (1); J.A. Snowdon, Leicester (1); R.J. Stockley, Worcester (1); W.P. Stross, Chichester (1); P.J. Tansey, Glasgow (1); G. Thomas, Derby (1); C.W. Trask, Southend (1); M. Treacy, Enfield (1); G. Turner, Norwich (1); J.S. Whelan, London (1); D.A. Winfield, Sheffield (1). Data Monitoring Committee: G. McVie, London, UK (Chair); J. Armitage, Omaha, NE; A Hagenbeek, Utrecht, Netherlands; J. Imeson, Leicester, UK. MRC CTU statisticians: D. Machin (to June 1997); M.K.B. Parmar (June 1997-March 1998); P.M. Fayers (March 1998-December 1998); S.P. Stenning (January 1999 onwards); M.R. Sydes (March 2001 onward). MRC CTU Trial Managers: S. Simnett (to June 1997); M.R. Sydes (June 1997-March 2001); D. Andrews (March 2001-June 2001); H. Brooks (June 2001-September 2001); S. Clawson (September 2001 onward). Reference Pathologists: K. McLennan, Leeds (to June 2000); A. Jack, Leeds (June 2000 onward).
The authors indicated no potential conflicts of interest.
Supported by a research grant from the UK Cancer Research Campaign (now Cancer Research UK). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
16 years of age, with biopsy-proven HL of any subtype requiring systemic chemotherapy, namely those with "B" symptoms, Ann Arbor stage I or II disease with bulky masses or more than three sites of involvement, or stage III or IV disease. Bulky disease was defined by a maximum mediastinal width more than one third of the internal thoracic diameter at D5/6 (mid-dorsal spine), or any node mass more than 10 cm in diameter. Histopathology was reviewed centrally. 
= .05; 87% power). On completing accrual, review of event rates indicated better than expected EFS and consequently 240 events were unlikely to be reported in the original trial timescale. This analysis was therefore planned for when approximately 90% of the expected events had been seen, giving more than 80% power to detect the same HR. 
2 tests for heterogeneity of treatment effect between patients randomly assigned to receive ABVD versus alternating and those randomly assigned to receive ABVD versus hybrid were planned; we acknowledge that there was limited power for these analyses. 
45 and older than 45 years were 0.86 (95% CI, 0.62 to 1.21) and 1.52 (95% CI, 0.97 to 2.36), respectively (
