BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin's disease. The German Hodgkin's Lymphoma Study Group. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: a preliminary report. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. Intermediate stage Hodgkin's disease: preliminary results on 210 patients treated with four ABVD chemotherapy cycles plus extended versus involved field radiotherapy. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). Treatment selection and outcomes in early-stage classical Hodgkin lymphoma: analysis of the National Cancer Data Base. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP 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). Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma. ABVD versus modified stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. POG 8625: A Randomized Trial Comparing Chemotherapy With Chemoradiotherapy for Children and Adolescents With Stages I, IIA, IIIA1 Hodgkin Disease: A Report from the Children's Oncology Group Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial. Competing risks analysis of patients with osteosarcoma: a comparison of four different approaches. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need? Involved-field radiotherapy for advanced Hodgkin's lymphoma. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advance Hodgkin's disease. German Hodgkins' Study Group (GHSG). Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
PURPOSE At present , treatment results for patients with advanced-stage Hodgkin 's disease remain unsatisfactory . St and ard chemotherapy M(C)OPP ( nitrogen mustard ( cyclophosphamide ) . vincristine , procabazine , and prednisone ) . ABVD ( adriamycine , bleomycine , vinblastine , and dacarbacine ) or M(C)OPP/ABVD + /- radiotherapy fail to achieve long-term complete remission in 35 % to 50 % of these patients . The BEACOPP ( bleomycin , etoposide , adriamycine , cyclophosphamide , vincristine , procarbazine , and prednisone ) regimen was developed to improve treatment results by dose intensification achieved by reduced duration of treatment ( time intensification ) and addition of etoposide . PATIENTS AND METHODS Thirty untreated patients with advanced Hodgkin 's disease stage IIB IV according to the Ann Arbor classification were treated with the time intensified BEACOPP regimen . Each patient was scheduled to receive eight cycles of chemotherapy with consolidating radiotherapy to sites of initial bulk disease and to residual tumor remaining after chemotherapy . RESULTS All patients were evaluable for assessment of toxicity , treatment response , freedom from treatment failure ( FFTF ) and survival ( SV ) . Of 30 treated patients , 29 patients received the intended eight cycles of BEACOPP . One patient in clinical CR , terminated the chemotherapy at his own request after six cycles and is at this time , 48 months after the end of treatment , in complete remission . Toxicity was tolerable with WHO grade 3/4 leucopenia in 28 % of chemotherapy cycles and one severe ( WHO grade 3 ) infection . No treatment-related death occurred . Cycles could generally be given on schedule . Complete remission ( CR ) was achieved in all but two patients ( 93 % ) . At present , only one patient has relapsed . At a median follow-up of 40 months , FFTF-rate is 89 % ( lower confidence limit : 80 % ) . One patient died due to progressive disease . CONCLUSION The BEACOPP regimen is feasible at moderate hematopoeitic toxicity . With a FFTF-rate of 89 % at a median follow-up of 40 months , the treatment results are very encouraging . A prospect i ve r and omised trial has been initiated to compare the BEACOPP regimen with the st and ard COPP/ABVD regimen in advanced-stage Hodgkin 's disease PURPOSE Current st and ard therapy for children and adolescents with Hodgkin 's disease includes combination chemotherapy and low-dose involved-field radiation ( LD-IFRT ) . Because radiation may be associated with adverse late effects , the Children 's Cancer Group ( CCG ) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy . PATIENTS AND METHODS Between January 1995 and December 1998 , 829 eligible patients were enrolled onto CCG 5942 . A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were r and omized to receive LD-IFRT or no further treatment .  Event-free survival ( EFS ) and overall survival were assessed from the date of study entry or the date of r and omization , as appropriate . RESULTS The projected 3-year EFS from study entry for the entire cohort was 87 % + /- 1.2 % . Among patients who achieved a complete response to initial chemotherapy , 92 % + /- 1.9 % of those r and omized to receive LD-IFRT were alive and disease free 3 years after r and omization , versus 87 % + /- 2.2 % for patients r and omized to receive no further therapy ( stratified log-rank test ; P = .057 ) . With an " as-treated " analysis , 3-year EFS after r and omization for the radiation cohort was 93 % + /- 1.7 % versus 85 % + /- 2.3 % for patients receiving no further therapy ( stratified log-rank test ; P = .0024 ) . Three-year survival estimates for patients treated with and without LD-IFRT were 98 % + /- 1.1 % for patients who received radiation and 99 % + /- 0.5 % for patients who did not receive radiation . CONCLUSION LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS . At this time , there is no survival advantage for LD-IFRT , but follow-up remains short BACKGROUND It is unclear whether patients with early-stage Hodgkin 's lymphoma and negative findings on positron-emission tomography ( PET ) after three cycles of chemotherapy with doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) require radiotherapy . METHODS Patients with newly diagnosed stage IA or stage IIA Hodgkin 's lymphoma received three cycles of ABVD and then underwent PET scanning . Patients with negative PET findings were r and omly assigned to receive involved-field radiotherapy or no further treatment ; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy . This trial assessing the noninferiority of no further treatment was design ed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95 % progression-free survival rate in the radiotherapy group . RESULTS A total of 602 patients ( 53.3 % male ; median age , 34 years ) were recruited , and 571 patients underwent PET scanning .  The PET findings were negative in 426 of these patients ( 74.6 % ) , 420 of whom were r and omly assigned to a study group ( 209 to the radiotherapy group and 211 to no further therapy ) . At a median of 60 months of follow-up , there had been 8 instances of disease progression in the radiotherapy group , and 8 patients had died ( 3 with disease progression , 1 of whom died from Hodgkin 's lymphoma ) ; there had been 20 instances of disease progression in the group with no further therapy , and 4 patients had died ( 2 with disease progression and none from Hodgkin 's lymphoma ) . In the radiotherapy group , 5 of the deaths occurred in patients who received no radiotherapy . The 3-year progression-free survival rate was 94.6 % ( 95 % confidence interval [ CI ] , 91.5 to 97.7 ) in the radiotherapy group and 90.8 % ( 95 % CI , 86.9 to 94.8 ) in the group that received no further therapy , with an absolute risk difference of -3.8 percentage points ( 95 % CI , -8.8 to 1.3 ) . CONCLUSIONS The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival . Nevertheless , patients in this study with early-stage Hodgkin 's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy . ( Funded by Leukaemia and Lymphoma Research and others ; RAPID Clinical Trials.gov number , NCT00943423 . ) The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers , reporting the results in the medical literature . One unreported result which deserves such publication is the development of the expertise to design and analyse such trials . This report was prepared by a group of British and American statisticians , but it is intended for people without any statistical expertise . Part I , which appears in this issue , discusses the design of such trials ; Part II , which will appear separately in the January 1977 issue of the Journal , gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test , including a worked example , and discusses the interpretation of trial results , including brief reports of 2 particular trials . Both parts of this report are relevant to all clinical trials which study time to death , and wound be equally relevant to clinical trials which study time to other particular classes of untoward event : first stroke , perhaps , or first relapse , metastasis , disease recurrence , thrombosis , transplant rejection , or death from a particular cause . Part I , in this issue , collects together ideas that have mostly already appeared in the medical literature , but Part II , next month , is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration . Such trials include the majority of all clinical trials of cancer therapy ; in cancer trials , however , it may be preferable to use these statistical methods to study time to local recurrence of tumour , or to study time to detectable metastatic spread , in addition to study ing total survival . Solid tumours can be staged at diagnosis ; if this , or any other available information in some other disease is an important determinant of outcome , it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive , and more intuitively satisfactory , for it will then only be necessary to compare like with like , and not , by chance , Stage I with Stage III PURPOSE Although survival rates have improved for patients with bulky and advanced-stage Hodgkin 's disease ( HD ) , current treatments entail substantial acute morbidity and risks for late effects such as infertility , second malignancies , and cardiopulmonary toxicities . A novel , brief chemotherapy regimen ( doxorubicin , vinblastine , mechlorethamine , vincristine , bleomycin , etoposide , and prednisone [ Stanford V ] ) was design ed to shorten the duration of treatment , significantly reduce cumulative doses of alkylating agents , doxorubicin , and bleomycin , and maintain dose-intensity ( DI ) . This brief chemotherapy was combined with radiation therapy ( RT ) to bulky disease sites . METHODS Since May 1989 , 65 previously untreated patients were treated for stage II HD with bulky mediastinal involvement ( n = 21 ) or for stage III or IV HD ( n = 44 ) . Patients received weekly chemotherapy for 12 weeks . Consolidative RT was given to the first 25 patients to sites of initial bulky disease or radiographic abnormalities that persisted after chemotherapy ; in the remaining 40 patients , RT was limited to bulky disease ( adenopathy > or = 5 cm and /or macroscopic splenic nodules defined by computed tomography [ CT ] ) . RESULTS With a median follow-up period of 2 years , actuarial 3-year survival rate is 96 % and failure-free survival ( FFS ) rate is 87 % . The 3-year FFS rate is 100 % for stage II patients with bulky mediastinal disease and 82 % for patients with stage III to IV disease . There were no treatment-related deaths . In a preliminary analysis on a subset of patients , female and male fertility appears to be preserved . CONCLUSION These preliminary results indicate that the Stanford V chemotherapy regimen with or without RT is well-tolerated and effective therapy for bulky , limited-stage , and advanced-stage HD . Less cumulative exposure to alkylating agents , doxorubicin , and bleomycin and limited use of radiation is expected to decrease risks for second neoplasms and late cardiopulmonary toxicity . Based on these results , the Stanford V chemotherapy with or without RT regimen deserves further study in the context of a r and omized clinical trial BACKGROUND BEACOPP , an intensified regimen consisting of bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone , has been advocated as the new st and ard of treatment for advanced Hodgkin 's lymphoma , in place of the combination of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) . METHODS We r and omly assigned 331 patients with previously untreated and unfavorable Hodgkin 's lymphoma ( stage IIB , III , or IV , or an international prognostic score of ≥3 on a scale of 0 to 7 , with higher scores indicating increased risk ) , to receive either BEACOPP or ABVD  , each followed by local radiotherapy  when indicated . Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program . The median follow-up period was 61 months . RESULTS The 7-year rate of freedom from first progression was 85 % among patients who had received initial treatment with BEACOPP and 73 % among those who had received initial treatment with ABVD ( P=0.004 ) , and the 7-year rate of event-free survival was 78 % and 71 % , respectively ( P=0.15 ) . A total of 65 patients ( 20 in the BEACOPP group , and 45 in the ABVD group ) went on to receive the intended high-dose salvage regimen . As of the cutoff date , 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease . After completion of the overall planned treatment , including salvage therapy , the 7-year rate of freedom from a second progression was 88 % in the BEACOPP group and 82 % in the ABVD group ( P=0.12 ) , and the 7-year rate of overall survival was 89 % and 84 % , respectively ( P=0.39 ) . Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group . CONCLUSIONS Treatment with BEACOPP , as compared with ABVD , result ed in better initial tumor control , but the long-term clinical outcome did not differ significantly between the two regimens . ( Funded by Fondazione Michelangelo ; Clinical Trials.gov number , NCT01251107 . ) PURPOSE Combined-modality treatment is st and ard treatment for patients with clinical stage I/II Hodgkin lymphoma ( HL ) . We hypothesized that an early positron emission tomography ( PET ) scan could be used to adapt treatment . Therefore , we started the r and omized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy ( IN-RT ) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD ( doxorubicin , bleomycin , vinblastine , and dacarbazine ) as compared with st and ard combined-modality treatment . PATIENTS AND METHODS Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible . Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group . Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference , a one-sided superiority test was conducted . RESULTS The analysis included 1,137 patients . In the favorable subgroup , 85.8 % had a negative early PET scan  ( st and ard arm , one event v experimental arm , nine events ) . In the unfavorable subgroup , 74.8 % had a negative early PET scan  ( st and ard arm , seven events v experimental arm , 16 events ) . The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping r and om assignment for early PET-negative patients . CONCLUSION On the basis of this analysis , combined-modality treatment result ed in fewer early progressions in clinical stage I/II HL , although early outcome was excellent in both arms . The final analysis will reveal whether this finding is maintained over time BACKGROUND Faced with unsatisfactory results of treatment for advanced Hodgkin 's disease , we investigated three combinations of chemotherapy . METHODS From 1993 to 1998 , 1201 eligible patients 15 to 65 years of age who had newly diagnosed Hodgkin 's disease in unfavorable stage IIB or IIIA or stage IIIB or IV were r and omly assigned to receive eight cycles of cyclophosphamide , vincristine , procarbazine , and prednisone alternating with doxorubicin , bleomycin , vinblastine , and dacarbazine ( COPP-ABVD ) ; bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) ; or increased-dose BEACOPP , each followed by local radiotherapy when indicated . Enrollment in the COPP-ABVD group was stopped in 1996 owing to inferior results . RESULTS For the final analysis , 1195 of 1201 patients could be evaluated : 260 in the COPP-ABVD group , 469 in the BEACOPP group , and 466 in the increased-dose BEACOPP group ; the median follow-up was 72 , 54 , and 51 months , respectively . The rate of freedom from treatment failure at five years was 69 percent in the COPP-ABVD group , 76 percent in the BEACOPP group , and 87 percent in the increased-dose BEACOPP group ( P=0.04 for the comparison of the COPP-ABVD group with the BEACOPP group and P<0.001 for the comparison of the increased-dose BEACOPP group with the COPP-ABVD group and with the BEACOPP group ) , and the five-year rates of overall survival were 83 percent , 88 percent , and 91 percent , respectively ( P=0.16 for the comparison of the COPP-ABVD group with the BEACOPP group , P=0.06 for the comparison of the BEACOPP group with the increased-dose BEACOPP group , and P=0.002 for the comparison of the COPP-ABVD group with the increased-dose BEACOPP group ) . Rates of early progression were significantly lower with increased-dose BEACOPP than with COPP-ABVD or st and ard BEACOPP . CONCLUSIONS Increased-dose BEACOPP result ed in better tumor control and overall survival than did COPP-ABVD BACKGROUND To improve long-term survival by reducing toxicity in intermediate stage Hodgkin 's disease patients , we compared the effects of involved field ( IF ) versus extended field ( EF ) irradiation administered after four cycles of ABVD regimen . MATERIAL S AND METHODS Two hundred and ten Hodgkin 's disease patients , at clinical stage II with risk factors and III without risk factors , were enrolled in the r and omized study HD94 . After four courses of ABVD regimen , patients who achieved complete remission ( CR ) or partial remission ( PR ) were r and omly assigned to the IF or EF arm . The Kaplan-Meier method was adopted to estimate overall survival ( OS ) and relapse-free survival ( RFS ) . RESULTS After a median follow-up of 78 months ( range 13 - 111 months ) , OS was 98 % and 96 % , respectively , in the EF and IF arms ; RFS was 94 % and 91 % , respectively , in the EF and IF arms . CONCLUSION We confirm the efficacy of four cycles of ABVD regimen , with suitable dose intensity , and radiotherapy as consolidation therapy , in intermediate stage Hodgkin 's disease patients ( CR = 99.5 % and OS = 95 % ) . We also found that involved field radiotherapy results were as effective as extended field , without acute toxicity BACKGROUND Whether it is possible to reduce the intensity of treatment in early ( stage I or II ) Hodgkin 's lymphoma with a favorable prognosis remains unclear . We therefore conducted a multicenter , r and omized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels . METHODS We r and omly assigned 1370 patients with newly diagnosed early-stage Hodgkin 's lymphoma with a favorable prognosis to one of four treatment groups : four cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) followed by 30 Gy of radiation therapy ( group 1 ) , four cycles of ABVD followed by 20 Gy of radiation therapy ( group 2 ) , two cycles of ABVD followed by 30 Gy of radiation therapy ( group 3 ) , or two cycles of ABVD followed by 20 Gy of radiation therapy ( group 4 ) . The primary end point was freedom from treatment failure ; secondary end points included efficacy and toxicity of treatment . RESULTS The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure ( P=0.39 ) or overall survival ( P=0.61 ) . At 5 years , the rates of freedom from treatment failure were 93.0 % ( 95 % confidence interval [ CI ] , 90.5 to 94.8 ) with the four-cycle ABVD regimen and 91.1 % ( 95 % CI , 88.3 to 93.2 ) with the two-cycle regimen . When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared , there were also no significant differences in freedom from treatment failure ( P=1.00 ) or overall survival ( P=0.61 ) . Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy ( group 1 ) . CONCLUSIONS In patients with early-stage Hodgkin 's lymphoma and a favorable prognosis , treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as , and less toxic than , four cycles of ABVD followed by 30 Gy of involved-field radiation therapy . Long-term effects of these treatments have not yet been fully assessed . ( Funded by the Deutsche Krebshilfe and the Swiss Federal Government ; Clinical Trials.gov number , NCT00265018 . PURPOSE Although ABVD ( doxorubicin , bleomycin , vinblastine , and dacarbazine ) has been established as the st and ard of care in patients with advanced Hodgkin lymphoma , newer regimens have been investigated , which have appeared superior in early phase II studies . Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD . PATIENTS AND METHODS The Eastern Cooperative Oncology Group , along with the Cancer and Leukemia Group B , the Southwest Oncology Group , and the Canadian NCIC Clinical Trials Group , conducted this r and omized phase III trial in patients with advanced Hodgkin lymphoma . Stratification factors included extent of disease ( localized v extensive ) and International Prognostic Factors Project Score ( 0 to 2 v 3 to 7 ) . The primary end point was failure-free survival ( FFS ) , defined as the time from r and om assignment to progression , relapse , or death , whichever occurred first . Overall survival , a secondary end point , was measured from r and om assignment to death as a result of any cause . This design provided 87 % power to detect a 33 % reduction in FFS hazard rate , or a difference in 5-year FFS of 64 % versus 74 % at two-sided .05 significance level . RESULTS There was no significant difference in the overall response rate between the two arms , with complete remission and clinical complete remission rates of 73 % for ABVD and 69 % for Stanford V. At a median follow-up of 6.4 years , there was no difference in FFS : 74 % for ABVD and 71 % for Stanford V at 5 years ( P = .32 ) . CONCLUSION ABVD remains the st and ard of care for patients with advanced Hodgkin lymphoma PURPOSE The choice between combined-modality therapy ( CMT ) and chemotherapy alone for early-stage Hodgkin lymphoma ( HL ) remains controversial . Our objective was to define factors affecting treatment selection and result ing survival outcomes in the United States . PATIENTS AND METHODS We identified 20,600 patients treated with CMT or chemotherapy between 2003 and 2011 from the National Cancer Data Base . Factors affecting treatment selection were studied in a mixed-effects logistic model . Survival outcomes were compared using a propensity score analysis to account for indication bias . RESULTS Only 49.5 % of patients received CMT , and this proportion steadily declined between 2003 ( 59.4 % ) and 2011 ( 45.2 % ) , particularly in younger patients . Apart from classical prognostic factors ( age , stage , tumor location , histology , comorbidities ) , treatment selection was significantly influenced by sex , black race , distance to facility , and type of insurance . Uninsured patients had the lowest odds of receiving CMT . A significant r and om effect related to facility-specific treatment preference was also evident . Estimated 5-year overall survival ( OS ) was 89.6 % , and relative survival ( RS ) was 94.3 % . After adjustment for guarantee-time and indication biases , CMT was associated with better OS ( hazard ratio [ HR ] , 0.61 ; 95 % CI , 0.53 to 0.70 ) and RS ( excess HR , 0.42 ; 95 % CI , 0.33 to 0.54 ) than chemotherapy alone . This effect was without significant heterogeneity in subset analysis and was not sensitive to unobserved confounding . CONCLUSION Socioeconomic factors affect selection of curative treatments in HL . Widespread ab and onment of CMT beyond circumstances sanctioned by guidelines may affect survival . Further research should focus on developing strategies that minimize toxicity and access disparities without compromising survival This paper reports the preliminary results of a controlled study r and omizing MOPP vs. a  new four‐drug combination ( ABVD ) in advanced Hodgkin 's disease .  ABVD consists of 6 cycles of adriamycin , bleomycin , vinblastine , and imidazole carboxamide . The purpose for design ing this new combination was two‐fold : to compare the efficacy of ABVD with MOPP , and to demonstrate absence of cross‐resistance between the two regimens . Of 60 patients entered into the study , 45 ( MOPP 25 , ABVD 20 ) are presently evaluable for the analysis of remission induction . No patient was previously treated with chemotherapy ; 20 % had relapsed after primary radiotherapy . Whenever possible , complete remission was defined also through rebiopsy of known organ involvement . Complete remission occurred in 76 % of patients treated with MOPP and in 75 % of those given ABVD , with no difference between the two regimens as far as stage ( IIIB – IIIs and IV ) , histologic type , and prior irradiation were concerned . Crossover carried out for progressive disease or for relapse after initial remission showed absence of cross‐resistance between MOPP and ABVD . Toxic manifestations after ABVD were in general well tolerated and reversible . The percent of optimal dose for each drug was as follows : adriamycin 87 % , vinblastine 87 % , bleomycin 96 % , and imidazole carboxamide 96 % . These preliminary results indicate that in terms of complete remission , ABVD could represent a successful alternative to MOPP to be used either in MOPP failures or in sequential combination with MOPP . However , the lack of long‐term followup limits at the present time an adequate comparison between the two treatments PURPOSE To perform an open-label , r and omized , 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 r and omly assigned between ABVD and MDR specified before r and omization 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 st and ard for treatment of advanced HL BACKGROUND We tested interim positron-emission tomography-computed tomography ( PET-CT ) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin 's lymphoma . METHODS Patients with newly diagnosed advanced classic Hodgkin 's lymphoma underwent a baseline PET-CT scan , received two cycles of ABVD ( doxorubicin , bleomycin , vinblastine , and dacarbazine ) chemotherapy , and then underwent an interim PET-CT scan . Images were central ly review ed with the use of a 5-point scale for PET findings . Patients with negative PET findings after two cycles were r and omly assigned to continue ABVD ( ABVD group ) or omit bleomycin ( AVD group ) in cycles 3 through 6 . Those with positive PET findings after two cycles received BEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ) . Radiotherapy was not recommended for patients with negative findings on interim scans . The primary outcome was the difference in the 3-year progression-free survival rate between r and omized groups , a noninferiority comparison to exclude a difference of 5 or more percentage points . RESULTS A total of 1214 patients were registered ; 937 of the 1119 patients ( 83.7 % ) who underwent an interim PET-CT scan according to protocol had negative findings . With a median follow-up of 41 months , the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7 % ( 95 % confidence interval [ CI ] , 82.1 to 88.6 ) and 97.2 % ( 95 % CI , 95.1 to 98.4 ) , respectively ; the corresponding rates in the AVD group were 84.4 % ( 95 % CI , 80.7 to 87.5 ) and 97.6 % ( 95 % CI , 95.6 to 98.7 ) . The absolute difference in the 3-year progression-free survival rate ( ABVD minus AVD ) was 1.6 percentage points ( 95 % CI , -3.2 to 5.3 ) . Respiratory adverse events were more severe in the ABVD group than in the AVD group . BEACOPP was given to the 172 patients with positive findings on the interim scan , and 74.4 % had negative findings on a third PET-CT scan ; the 3-year progression-free survival rate was 67.5 % and the overall survival rate 87.8 % . A total of 62 patients died during the trial ( 24 from Hodgkin 's lymphoma ) , for a 3-year progression-free survival rate of 82.6 % and an overall survival rate of 95.8 % . CONCLUSIONS Although the results fall just short of the specified noninferiority margin , the omission of bleomycin from the ABVD regimen after negative findings on interim PET result ed in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy . ( Funded by Cancer Research UK and Others ; Clinical Trials.gov number , NCT00678327 . ) PURPOSE In this multicenter , prospect i ve , r and omized clinical trial on advanced Hodgkin 's lymphoma ( HL ) , the efficacy and toxicity of two chemotherapy regimens , doxorubicin , vinblastine , mechlorethamine , vincristine , bleomycin , etoposide , and prednisone ( Stanford V ) and mechlorethamine , vincristine , procarbazine , prednisone , epidoxirubicin , bleomycin , vinblastine , lomustine , doxorubicin , and vindesine ( MOPPEBVCAD ) , were compared with doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) as st and ard therapy to select which regimen would best support a reduced radiotherapy program , which was limited to < or = two sites of either previous bulky or partially remitting disease ( a modification of the original Stanford program ) . PATIENTS AND METHODS Three hundred fifty-five patients with stage IIB , III , or IV HL were r and omly assigned . Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD ( n = 122 ) , three cycles of Stanford V ( n = 107 ) , or six cycles of MOPPEBVCAD ( n = 106 ) ; radiotherapy was administered to 76 , 71 , and 50 patients in these three arms , respectively . RESULTS The complete response rates for ABVD , Stanford V , and MOPPEBVCAD were 89 % , 76 % and 94 % , respectively ; 5-year failure-free survival ( FFS ) and progression-free survival rates were 78 % , 54 % , 81 % and 85 % , 73 % , and 94 % , respectively ( P < .01 for comparison of Stanford V with the other two regimens ) . Corresponding 5-year overall survival rates were 90 % , 82 % , and 89 % for ABVD , Stanford V , and MOPPEBVCAD , respectively . Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD , which had larger reductions in the prescribed drug doses . CONCLUSION When associated with conditioned and limited ( not adjuvant ) radiotherapy , ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival . Patients were irradiated less often after MOPPEBVCAD , but this regimen was more toxic .  ABVD is still the best choice when it is combined with optional , limited irradiation PURPOSE Radiation therapy ( RT ) alone can cure more than 80 % of all patients with pathologic stage IA , IB , and IIA Hodgkin 's disease , but some prognostic factors unfavorably affect treatment outcome . Combined-modality approaches improved results compared with RT , but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation . PATIENTS AND METHODS In February 1990 , we activated a prospect i ve trial in patients with early , clinical ly staged Hodgkin 's disease to assess efficacy and tolerability of four cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) followed by either subtotal nodal plus spleen irradiation ( STNI ) or involved-field radiotherapy ( IFRT ) . RESULTS Main patient characteristics were fairly well balanced between the two arms . Complete remission was achieved in 100 % and in 97 % of patients , respectively . The 12-year freedom from progression rates were 93 % ( 95 % CI , 83 % to 100 % ) after ABVD and STNI , and 94 % ( 95 % CI , 88 % to 100 % ) after ABVD and IFRT , whereas the figures for overall survival were 96 % ( 95 % CI , 91 % to 100 % ) and 94 % ( 95 % CI , 89 % to 100 % ) , respectively . Apart from three patients who developed second malignancies in the STNI arm , treatment-related morbidities were mild . CONCLUSION Present long-term findings suggest that , after four cycles of ABVD , IFRT can achieve a worthwhile outcome . The limited size of our patient sample , however , had no adequate statistical power to test for noninferiority of IFRT versus STNI . Despite this , ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin 's disease with both favorable and unfavorable presentation PURPOSE To investigate whether radiotherapy can be reduced without loss of efficacy from extended field ( EF ) to involved field ( IF ) after four cycles of chemotherapy . PATIENTS AND METHODS Between 1993 and 1998 , patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study . Patients were r and omly assigned to receive cyclophosphamide , vincristine , procarbazine , and prednisone ( COPP ) + doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease ( arm A ) or 30 Gy IF + 10 Gy to bulky disease ( arm B ) . RESULTS Of 1,204 patients r and omly assigned to treatment , 1,064 patients were informative and eligible for the arm comparison ( 532 patients in arm A ; 532 patients in arm B ) . The median observation time was 54 months . Five years after r and om assignment , the overall survival ( OSran ) for all eligible patients was 91 % and freedom from treatment failure ( FFTFran ) was 83 % . Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B , respectively , in terms of FFTF ( 85.8 % and 84.2 % ) and OS at 5 years ( 90.8 % and 92.4 % ) . There also were no differences between arms A and B , respectively , in terms of complete remission ( 98.5 % and 97.2 % ) , progressive disease ( 0.8 % and 1.9 % ) , relapse ( 6.4 % and 7.7 % ) , death ( 8.1 % and 6.4 % ) , and secondary neoplasia ( 4.5 % and 2.8 % ) . In contrast , acute side effects including leukopenia , thrombocytopenia , nausea , gastrointestinal toxicity , and pharyngeal toxicity were more frequent in the EF arm . CONCLUSION Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD PURPOSE This multicenter , prospect i ve , r and omized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkin 's lymphoma ( HL ) : the weekly alternating Stanford V and the st and ard , twice-weekly regimen of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) . PATIENTS AND METHODS Patients had stage IIB , III , or IV disease or had stages I to IIA disease with bulky disease or other adverse features .  Radiotherapy was administered in both arms to sites of previous bulk ( > 5 cm ) and to splenic deposits , although this was omitted in the latter part of the trial for patients achieving complete remission ( CR ) in the ABVD arm . A total of 520 patients were r and omly assigned and were assessed for the primary outcome measure of progression-free survival ( PFS ) .  Five hundred patients received protocol treatment , and radiotherapy was administered to 73 % in the Stanford V arm and to 53 % in the ABVD arm . RESULTS The overall response rates after completion of all treatment were 91 % for Stanford V and 92 % for ABVD . During a median follow-up of 4.3 years , there was no evidence of a difference in projected 5-year PFS and overall survival ( OS ) rates ( 76 % and 90 % , respectively , for ABVD ; 74 % and 92 % , respectively , for Stanford V ) . More pulmonary toxicity was reported for ABVD , whereas other toxicities were more frequent with Stanford V. CONCLUSION In a large , r and omized trial , the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy PURPOSE To compare doxorubicin , bleomycin , vinblastine , dacarbazine ( ABVD ) versus bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) versus cyclophosphamide , lomustine , vindesine , melphalan , prednisone , epidoxirubicin , vincristine , procarbazine , vinblastine , and bleomycin ( COPPEBVCAD ; CEC ) for advanced Hodgkin 's lymphoma ( HL ) . PATIENTS AND METHODS Three hundred seven patients with advanced HL ( stage IIB , III , and IV ) were r and omly assigned to receive six courses of ABVD , four escalated plus two st and ard courses of BEACOPP , or six courses of CEC , plus a limited radiation therapy program . RESULTS After a median follow-up of 41 months , BEACOPP result ed in a superior progression-free survival ( PFS ) , with a significant reduction in risk of progression ( hazard ratio [ HR ] = 0.50 ) compared with ABVD . No differences between BEACOPP and CEC , or CEC and ABVD were observed . The 5-year PFS was 68 % ( 95 % CI , 56 % to 78 % ) , 81 % ( 95 % CI , 70 % to 89 % ) , and 78 % ( 95 % CI , 68 % to 86 % ) , for ABVD , BEACOPP , and CEC , respectively ( BEACOPP v ABVD , P = .038 ; CEC v ABVD and BEACOPP v CEC , P = not significant [ NS ] ) . The 5-year overall survival was 84 % ( 95 % CI , 69 % to 92 % ) , 92 % ( 95 % CI , 84 % to 96 % ) , and 91 % ( 95 % CI , 81 % to 96 % ) for ABVD , BEACOPP , and CEC , respectively ( P = NS ) . BEACOPP and CEC  result ed in higher rates of grade 3 - 4 neutropenia than ABVD ( P = .016 ) ; BEACOPP was associated with higher rates of severe infections than ABVD and CEC ( P = .003 ) . CONCLUSION As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD , with a predictable higher acute toxicity To determine if 6 courses of chemotherapy alone could achieve the same or better outcome than 4 courses of chemotherapy followed by radiation therapy ( chemoradiotherapy ) in pediatric and adolescent patients with Hodgkin disease . Children ≤21 years old with biopsy-proven , pathologically staged I , IIA , or IIIA1 Hodgkin disease were r and omly assigned 6 courses of alternating nitrogen mustard , oncovin , prednisone , and procarbazine/doxorubicin , bleomycin , vinblastine , and dacarbazine ( treatment 1 ) or 4 courses of alternating nitrogen mustard , oncovin , prednisone , and procarbazine/doxorubicin , bleomycin , vinblastine , and dacarbazine + 2550 cGy involved-field radiotherapy ( treatment 2 ) . The complete response rate was 89 % , with a complete response and partial response rate of 99.4 % . There was no statistically significant difference in event-free survival ( EFS ) or overall survival between arms . The EFS for those who achieved an early complete response was significantly higher than for those who did not . For pediatric patients with asymptomatic low-stage and intermediate-stage Hodgkin disease  , chemotherapy and chemoradiotherapy both result ed in 3-year EFS of approximately 90 % and statistically indistinguishable 8-year EFS and overall survival , without significant long-term toxicity . Early response to therapy was associated with higher EFS , a concept that has led to the Children 's Oncology Group paradigm of response-based risk-adapted therapy for pediatric Hodgkin disease BACKGROUND Malignant cells of classical Hodgkin 's lymphoma are characterised by genetic alterations at the 9p24.1 locus , leading to overexpression of PD-1 lig and s and evasion of immune surveillance . In a phase 1b study , nivolumab , a PD-1-blocking antibody , produced a high response in patients with relapsed and refractory classical Hodgkin 's lymphoma , with an acceptable safety profile . We aim ed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin 's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin . METHODS In this ongoing , single-arm phase 2 study , adult patients ( aged ≥18 years ) with recurrent classical Hodgkin 's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin , and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 , were enrolled from 34 hospitals and academic centres across Europe and North America . Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression , death , unacceptable toxicity , or withdrawal from study . The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months , assessed by an independent radiological review committee ( IRRC ) . All patients who received at least one dose of nivolumab were included in the primary and safety analyses . This trial is registered with Clinical Trials.gov , number NCT02181738 . FINDINGS Among 80 treated patients recruited between Aug 26 , 2014 , and Feb 20 , 2015 , the median number of previous therapies was four ( IQR 4 - 7 ) . At a median follow-up of 8·9 months ( IQR 7·8 - 9·9 ) , 53 ( 66·3 % , 95 % CI 54·8 - 76·4 ) of 80 patients achieved an IRRC-assessed objective response . The most common drug-related adverse events ( those that occurred in ≥15 % of patients ) included fatigue ( 20 [ 25 % ] patients ) , infusion-related reaction ( 16 [ 20 % ] ) , and rash ( 13 [ 16 % ] ) . The most common drug-related grade 3 or 4 adverse events were neutropenia ( four [ 5 % ] patients ) and increased lipase concentrations ( four [ 5 % ] ) . The most common serious adverse event ( any grade ) was pyrexia ( three [ 4 % ] patients ) . Three patients died during the study ; none of these deaths were judged to be treatment related . INTERPRETATION Nivolumab result ed in frequent responses with an acceptable safety profile in patients with classical Hodgkin 's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin . Therefore , nivolumab might be a new treatment option for a patient population with a high unmet need . Ongoing follow-up will help to assess the durability of response . FUNDING Bristol-Myers Squibb Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma ( HL ) have an excellent outcome . Early response evaluation with positron emission tomography ( PET ) scan may improve selection of patients who need reduced or more intensive treatments . Methods We performed a r and omized trial to evaluate treatment adaptation on the basis of early PET ( ePET ) after two cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable ( F ) and unfavorable (U)-stage I and II HL . The st and ard arm consisted of ABVD followed by involved-node radiotherapy ( INRT ) , regardless of ePET result . In the experimental arm , ePET-negative patients received ABVD only ( noninferiority design ) , whereas ePET-positive patients switched to two cycles of bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPPesc ) and INRT ( superiority design ) . Primary end point was progression-free survival ( PFS ) . Results Of 1,950 r and omly assigned patients , 1,925 received an ePET-361 patients ( 18.8 % ) were positive . In ePET-positive patients , 5-year PFS improved from 77.4 % for st and ard ABVD + INRT to 90.6 % for intensification to BEACOPPesc + INRT ( hazard ratio [ HR ] , 0.42 ; 95 % CI , 0.23 to 0.74 ; P = .002 ) . In ePET-negative patients , 5-year PFS rates in the F group were 99.0 % versus 87.1 % ( HR , 15.8 ; 95 % CI , 3.8 to 66.1 ) in favor of ABVD + INRT ; the U group , 92.1 % versus 89.6 % ( HR , 1.45 ; 95 % CI , 0.8 to 2.5 ) in favor of ABVD + INRT . For both F and U groups , noninferiority of ABVD only compared with combined modality treatment could not be demonstrated . Conclusion In stage I and II HL , PET response after two cycles of ABVD allows for early treatment adaptation . When ePET is positive after two cycles of ABVD , switching to BEACOPPesc + INRT significantly improved 5-year PFS . In ePET-negative patients , noninferiority of ABVD only could not be demonstrated : risk of relapse is increased when INRT is omitted , especially in patients in the F group In failure time studies involving a chronic disease such as cancer , several competing causes of mortality may be operating . Commonly , the conventional statistical technique of Kaplan-Meier , which is only meaningfully interpreted by assuming independence of failure types and the censoring mechanism , is employed in clinical research involving competing risks data . Some authors have advocated the use of a cause-specific cumulative incidence function which takes into account the existence of other events within a competing risks framework , without making any assumption about independence . Lunn and McNeil have proposed an approach based on an extension of the Cox proportional hazards regression , which enables direct comparisons between failure types . We have extended this approach to estimate cause-specific cumulative incidence . As it is often not easy to follow competing risks methodology in the literature , this paper sets out systematic ally the assumptions made and the steps taken to implement four different methods of analysing competing risks data using cumulative incidence rates or the Kaplan-Meier estimates of cause-specific failure probabilities .  The data obtained from a r and omized trial of patients with osteosarcoma were used to compare these four approaches . As illustrated using the osteosarcoma data , the estimates of the classical Kaplan-Meier methods have larger numerical values than the cause-specific cumulative incidence . On the other h and , estimates of the cause-specific cumulative incidence rates from the conventional method and the modified Cox method are highly comparable BACKGROUND The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin 's lymphoma has been unclear . We did a prospect i ve r and omised clinical trial comparing two reduced-intensity chemotherapy variants with our previous st and ard regimen . Chemotherapy was followed by PET-guided radiotherapy . METHODS In this parallel group , open-label , multicentre , non-inferiority trial ( HD15 ) , 2182 patients with newly diagnosed advanced stage Hodgkin 's lymphoma aged 18 - 60 years were r and omly assigned to receive either eight cycles of BEACOPP(escalated ) ( 8 × B(esc ) group ) , six cycles of BEACOPP(escalated ) ( 6 × B(esc ) group ) , or eight cycles of BEACOPP(14 ) ( 8 × B(14 ) group ) . R and omisation ( 1:1:1 ) was done central ly by stratified minimisation . Non-inferiority of the primary endpoint , freedom from treatment failure , was assessed using repeated CIs for the hazard ratio ( HR ) according to the intention-to-treat principle . Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy ; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint . This trial is registered with Current Controlled Trials , number IS RCT N32443041 . FINDINGS Of the 2182 patients enrolled in the study , 2126 patients were included in the intention-to-treat analysis set , 705 in the 8 × B(esc ) group , 711 in the 6 × B(esc ) group , and 710 in the 8 × B(14 ) group . Freedom from treatment failure was sequentially non-inferior for the 6 × B(esc ) and 8 × B(14 ) groups as compared with 8 × B(esc ) . 5-year freedom from treatment failure rates were 84·4 % ( 97·5 % CI 81·0 - 87·7 ) for the 8 × B(esc ) group , 89·3 % ( 86·5 - 92·1 ) for 6 × B(esc ) group , and 85·4 % ( 82·1 - 88·7 ) for the 8 × B(14 ) group ( 97·5 % CI for difference between 6 × B(esc ) and 8 × B(esc ) was 0·5 - 9·3 ) . Overall survival in the three groups was 91·9 % , 95·3 % , and 94·5 % respectively , and was significantly better with 6 × B(esc ) than with 8 × B(esc ) ( 97·5 % CI 0·2 - 6·5 ) . The 8 × B(esc ) group showed a higher mortality ( 7·5 % ) than the 6 × B(esc ) ( 4·6 % ) and 8 × B(14 ) ( 5·2 % ) groups , mainly due to differences in treatment-related events ( 2·1 % , 0·8 % , and 0·8 % , respectively ) and secondary malignancies ( 1·8 % , 0·7 % , and 1·1 % , respectively ) . The negative predictive value  for PET  at 12 months was 94·1 % ( 95 % CI 92·1 - 96·1 ) ; and 225 ( 11 % ) of 2126 patients received additional  radiotherapy . INTERPRETATION Treatment with six cycles of BEACOPP(escalated ) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen . Thus , six cycles of BEACOPP(escalated ) should be the treatment of choice for advanced stage Hodgkin 's lymphoma . PET done after chemotherapy can guide the need for additional radiotherapy in this setting . FUNDING Deutsche Krebshilfe and the Swiss Federal Government PURPOSE Combined modality treatment using multidrug chemotherapy ( CTh ) and radiotherapy ( RT ) is currently considered the st and ard of care in early stage Hodgkin 's disease . Its role in advanced stages , however , continues to be debated . This study was aim ed at evaluating the role of consolidation radiation in patients achieving a complete remission after six cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy  using event-free survival ( EFS ) and overall survival ( OS ) as primary end points . PATIENTS AND METHODS Two hundred and fifty-one patients with Hodgkin 's disease attending the lymphoma clinic at the Tata Memorial Hospital ( Mumbai , India ) from 1993 to 1996 received induction chemotherapy with six cycles of ABVD after initial staging evaluation . A total of 179 of 251 patients ( 71 % ) achieved a complete remission after six cycles of ABVD chemotherapy and constituted the r and omized population . Patients were r and omly assigned to receive either consolidation radiation or no further therapy . RESULTS With a median follow-up of 63 months , the 8-year EFS and OS in the CTh-alone arm were 76 % and 89 % , respectively , as compared with 88 % and 100 % in the CTh+RT arm ( P = .01 ; P = .002 ) . Addition of RT improved EFS and OS in patients with age < 15 years ( P = .02 ; P = .04 ) , B symptoms ( P = .03 ; P = .006 ) , advanced stage ( P = .03 ; P = .006 ) , and bulky disease ( P = .04 ; P = .19 ) . CONCLUSION Our study suggests that the addition of consolidation radiation helps improve the EFS and OS in patients achieving a complete remission after six cycles of ABVD chemotherapy , particularly in the younger age group and in patients with B symptoms and bulky and advanced disease BACKGROUND The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin 's lymphoma is controversial . METHODS We r and omly assigned patients with previously untreated stage III or IV Hodgkin 's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine , vincristine , procarbazine , prednisone , doxorubicin , bleomycin , and vinblastine ( MOPP-ABV )  to receive either no further treatment or involved-field radiotherapy . Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites . Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites . RESULTS Of 739 patients , 421 had a complete remission ; 161 of these patients were assigned to no further treatment , and 172 to involved-field radiotherapy . The median follow-up was 79 months . The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that received involved-field radiotherapy ( P=0.35 ) . The five-year overall survival rates were 91 and 85 percent , respectively ( P=0.07 ) . Among the 250 patients in partial remission after chemotherapy , the five-year event-free and overall survival rates were 79 and 87 percent , respectively . CONCLUSIONS Involved-field radiotherapy did not improve the outcome in patients with advanced-stage Hodgkin 's lymphoma who had a complete remission after MOPP-ABV chemotherapy . Radiotherapy may benefit patients with a partial response after chemotherapy PURPOSE Brentuximab vedotin is an antibody-drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into CD30-expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas . PATIENTS AND METHODS In this multinational , open-label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin 's lymphoma ( HL ) after autologous stem-cell transplantation ( auto-SCT ) . Patients had histologically documented CD30-positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression-free survival time for all patients was 5.6 months , and the median duration of response for those in CR was 20.5 months . After a median observation time of more than 1.5 years , 31 patients were alive and free of documented progressive disease . The most common treatment-related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto-SCT . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy OBJECTIVE It was the aim of this prospect i ve r and omized multicenter study to compare chemotherapy and radiotherapy as consolidation treatments in patients achieving complete remission ( CR ) after 6 cycles of doxorubicin-containing chemotherapy in advanced-stage Hodgkin 's disease ( HD ) . METHODS A total of 288 previously untreated patients aged 18 - 60 years with stage IIIB or IV HD received induction chemotherapy with 3 X ( COPP + ABVD ) . Patients achieving CR were eligible for r and omisation to either 20 Gy radiotherapy to initially involved fields ( RT-arm ) or to an additional 1 X ( Copp + ABVD ) ( CT-arm ) . Patients with nodal PR were allocated to more intense radiotherapy ( IRT-arm : 20 Gy IF , 40 Gy to persisting tumor ) . Four patients with persisting organ involvement after induction received salvage chemotherapy . RESULTS Of 288 patients , 171 ( 59 % ) achieved CR after induction chemotherapy . Of these , 100 patients were successfully r and omized to RT or CT . In the CT arm relapses were observed on 10 of 49 patients compared with 13 of 51 patients in the RT arm ( p = n.s . ) . Fifty patients refused r and omisation and for them a treatment was chosen , and 21 patients refused any further treatment . Of these 21 patients with no consolidation therapy , 9 relapsed , indicating an approximately 3-fold increased relapse risk compared with those receiving either of the consolidation therapies . No relapse was observed in initially involved lung or liver sites . Adverse prognostic factors for freedom from treatment failure and survival were low hemoglobin and large mediastinal mass at initial presentation . CONCLUSIONS No statistically significant differences in treatment efficacy were detected between 20 Gy IF radiotherapy and 1X ( COPP + ABVD ) chemotherapy following CR after six cycles of alternating chemotherapy in patients with advanced-stage HD . However , limited observations in a non-r and omized cohort indicate that patients without consolidation treatment of CR after 6 cycles of chemotherapy may have an elevated risk of relapse Part I of this report appeared in the previous issue ( Br . J. Cancer ( 1976 ) 34,585 ) , and discussed the design of r and omized clinical trials . Part II now describes efficient methods of analysis of r and omized clinical trials in which we wish to compare the duration of survival ( or the time until some other untoward event first occurs ) among different groups of patients . It is intended to enable physicians without statistical training either to analyse such data themselves using life tables , the logrank test and retrospective stratification , or , when such analyses are presented , to appreciate them more critically , but the discussion may also be of interest to statisticians who have not yet specialized in clinical trial analyses PURPOSE Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy ( IFRT ) is the st and ard of care for patients with early unfavorable Hodgkin 's lymphoma ( HL ) . It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied . PATIENTS AND METHODS Patients age 16 to 75 years with newly diagnosed early unfavorable HL were r and omly assigned in a 2 × 2 factorial design to one of the following treatment arms : four cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) + 30 Gy of IFRT ; four cycles of ABVD + 20 Gy of IFRT ; four cycles of bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP(baseline ) ) + 30 Gy of IFRT ; or four cycles of BEACOPP(baseline ) + 20 Gy of IFRT . RESULTS With a total of 1,395 patients included  , the freedom from treatment failure ( FFTF ) at 5 years was 85.0 % , overall survival was 94.5 % , and progression-free survival was 86.0 % .  BEACOPP(baseline  ) was more effective than ABVD when followed by 20 Gy of IFRT ( 5-year FFTF difference , 5.7 % ; 95 % CI , 0.1 % to 11.3 % ) . However , there was no difference between BEACOPP(baseline ) and ABVD when followed by 30 Gy of IFRT ( 5-year FFTF difference , 1.6 % ; 95 % CI , -3.6 % to 6.9 % ) . Similar results were observed for the radiotherapy question ; after four cycles of BEACOPP(baseline ) , 20 Gy was not inferior to 30 Gy ( 5-year FFTF difference , -0.8 % ; 95 % CI , -5.8 % to 4.2 % ) , whereas inferiority of 20 Gy can not be excluded after four cycles of ABVD ( 5-year FFTF difference , -4.7 % ; 95 % CI , -10.3 % to 0.8 % ) . Treatment-related toxicity occurred more often in the arms with more intensive therapy . CONCLUSION Moderate dose escalation using BEACOPP(baseline ) did not significantly improve outcome in early unfavorable HL . Four cycles of ABVD should be followed by 30 Gy of IFRT
Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma .