Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. The efficiency of different combined treatment programs (combination chemotherapy-radiotherapy) used for stage I-II Hodgkin's disease. A randomised study of adjuvant chemotherapy after mantle radiotherapy in supradiaphragmatic Hodgkin's disease PS IA-IIB: a report from the Manchester lymphoma group. Hodgkin's disease in childhood and adolescence: results of chemotherapy-radiotherapy in clinical stages IA-IIB. [Multiple chemotherapy (MOPP) followed by either focal or selective radiotherapy in clinical stages IA and II2A of Hodgkin's disease: results after four years of the use of prospective schedule (H 7701) in 79 patients (author's transl)]. Treatment of stages I and II Hodgkin's disease with three different therapeutic modalities. The management of stages I, II, and III Hodgkin's disease with combined radiotherapy and chemotherapy Combined modality therapy of Hodgkin's disease: 10-year results of National Cancer Institute of Canada Clinical Trials Group multicenter clinical trial. Long term follow‐up of combination chemotherapy‐radiotherapy of stage III Hodgkin's disease. A cancer and acute leukemia group B study The intergroup Hodgkin's disease in children. A study of stages I and II Evaluation of therapeutic modalities in the control of Hodgkin's disease. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Combined modality (ABVD plus radiotherapy) versus radiotherapy in the management of early stage (IIA) Hodgkin's disease with mediastinal involvement. Vinblastine, bleomycin, and methotrexate: an effective adjuvant in favorable Hodgkin's disease. Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease. Leukemia following Hodgkin's disease. A combined modality approach to the treatment of Hodgkin's disease. Preliminary results of a prospectively randomized clinical trial Extended versus involved fields irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin's disease. MOPP chemotherapy versus extended-field radiotherapy in the management of pathological stages I-IIA Hodgkin's disease. Radiotherapy versus radiotherapy plus chemotherapy in stages I and II Hodgkin's disease. A prospective, randomized study by the Danish National Hodgkin Study Group, LYGRA. Chemotherapy of Hodgkin’s lymphoma with alternating cycles of COPP (cyclophosphamide, vincristin, procarbazine, prednisone) and ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Results of the HD1 and HD3 trials of the German Hodgkin Study Group Radiotherapy or chemotherapy as the initial treatment for stage IIIA Hodgkin's disease (Report no 13). Conclusions from clinical trials of the Southwest Oncology Group. Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease. EORTC Lymphoma Cooperative Group. Groupe Pierre-et-Marie-Curie. Results of involved field and extended field radiotherapy in patients with pathologic state I and II Hodgkin's disease. Low-Dose Involved Field Radiation after Chemotherapy in Advanced Hodgkin Disease: A Southwest Oncology Group Randomized Study The risk of non-Hodgkin's lymphoma after Hodgkin's disease, with special reference to splenic treatment. REVIEW OF BRITISH NATIONAL LYMPHOMA INVESTIGATION STUDIES OF HODGKIN'S DISEASE AND DEVELOPMENT OF PROGNOSTIC INDEX Treatment of stage I and II mediastinal Hodgkin disease. A comparison of involved fields, extended fields, and involved fields followed by MOPP in patients staged by laparotomy. A prospective clinical trial comparing chemotherapy, radiotherapy and combined therapy in the treatment of early stage Hodgkin's disease with bulky disease. Intergroup Hodgkin's disease in children study of stages I and II: a preliminary report. Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin's disease. Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study. Treatment of advanced Hodgkin's disease: 10-year experience in the Eastern Cooperative Oncology group. A randomised study of adjuvant MVPP chemotherapy after mantle radiotherapy in pathologically staged IA-IIB Hodgkin's disease: 10-year follow-up. Chemotherapy and combined modality therapy for Hodgkin's disease: a progress report on Cancer and Leukemia Group B studies. Stanford-Kaiser Permanente G1 study for clinical stage I to IIA Hodgkin's disease: subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation. 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. Augmented therapy of extensive Hodgkin's disease: radiation to known disease or prolongation of induction chemotherapy did not improve survival--results of a Cancer and Leukemia Group B study. Occurrence of acute nonlymphocytic leukemia in a prospective randomized study of treatment for Hodgkin's disease. Extended-field radical radiotherapy in advanced Hodgkin's disease: short-term results of 2 randomized clinical trials. The EORTC treatment of early stages of Hodgkin's disease: the role of radiotherapy. EORTC Lymphoma Cooperative Group studies in clinical stage I-II Hodgkin's disease 1963-1987. Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy for patients with advanced Hodgkin's disease: results of the groupe d'études des lymphomes de l'Adulte H89 trial. Pathologic stages IA and IIA Hodgkin's disease: results of treatment with radiotherapy alone (1968-1980). Large mediastinal mass in Hodgkin's disease: Results of two treatment modalities Competing risks analysis of patients with osteosarcoma: a comparison of four different approaches. The EORTC trials for limited stage Hodgkin's disease. The EORTC Lymphoma Cooperative Group. The treatment of stage IIIA Hodgkin's disease. Sequential radiotherapy and chemotherapy in the treatment of Hodgkin's disease. A progress report. A randomized study comparing chemotherapy alone with chemotherapy followed by radiotherapy in patients with pathologically staged IIIA Hodgkin's disease. Combination chemotherapy-radiotherapy for stage 3 Hodgkin's disease. An acute leukemia group B study. Patients with stage III/IV Hodgkin's disease in partial remission after MOPP/ABV chemotherapy have excellent prognosis after additional involved-field radiotherapy: interim results from the ongoing EORTC-LCG and GPMC phase III trial. The EORTC Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Cu Involved-field radiotherapy for advanced Hodgkin's lymphoma. Radiotherapy of stage I and II Hodgkin's disease. A collaborative study Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial. MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial. Combination chemotherapy and radiotherapy for Hodgkin's disease Comparison of total nodal irradiation versus combined sequence of mantle irradiation with mechlorethamine, vincristine, procarbazine, and prednisone in clinical stages I and II Hodgkin's disease: experience of the European Organization for Research and Treatment of Cancer. Combined modality treatment of Hodgkin's disease confined to lymph nodes. Results eight years later. Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease. Adjuvant Radiotherapy to Initial Bulky Disease in Patients with 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 This study presents the analysis of results obtained in 237 Hodgkin 's disease patients , stages I and II , treated with combined modality therapy .  The overall and disease-free survival rates at 5 years were 96.6 and 85.2 % , respectively . The study has demonstrated the superiority of the following treatment program : one cycle of combination chemotherapy + radiation therapy + 5 cycles of combination chemotherapy . It has been found possible to reduce the number of radiation fields in combined modality therapy : for patients with stage IA-IIA lymphocyte predominant or nodular sclerosing Hodgkin 's disease it was sufficient only to treat clinical ly involved sites . Short- and long-term consequences of combined modality therapy have been analysed One hundred and fourteen untreated patients with pathological stage ( PS ) IA-IIB supradiaphragmatic Hodgkin 's Disease were r and omised to mantle radiotherapy alone ( 55 ) or mantle radiotherapy followed by 6 courses of adjuvant chemotherapy with mustine , vinblastine , prednisolone and procarbazine- MVPP ( 59 ) . Patients excluded were those outside the age range 16 - 65 years and those with massive mediastinal disease precluding laparotomy . Bulk disease was defined as a mass of lymph nodes measuring five centimetres or more in any axis . Mediastinal bulk was present if the ratio of the maximum width of mediastinal disease to the maximal chest diameter was more than one third . All patients achieved a complete remission . Median duration of follow-up was 62 months ( range 16 - 97 ) . The relapse free survival ( RFS ) was 81 % ; 69 % for radiotherapy alone and 93 % for adjuvant chemotherapy ( P = 0.002 ) . RFS was also shown to be adversely affected by B symptoms ( P = 0.0003 ) , bulk disease ( P = 0.018 ) , abnormal CXR ( P = 0.037 ) , and increasing stage ( P = 0.039 ) . Age , sex , histology , and number of sites involved had no significant effect upon RFS . A Cox multivariate analysis showed that only three variables had a significant adverse effect on RFS - radiotherapy alone , the presence of bulk disease , and B symptoms . The overall 5 year survival was 93 % with no statistically significant difference between the two treatment groups ( P = 0.54 ) . Survival was adversely affected by three variables - B symptoms ( P = 0.02 ) , the presence of bulk disease ( P = 0.002 ) , and pathological stage ( P = 0.05 ) . High risk groups for relapse are those with bulk and B symptoms . This analysis has shown that RFS was significantly improved by adjuvant chemotherapy , but that overall survival was not From April 1972 to May 1980 , 72 children and adolescents ( aged 5 to 19 years old , median 16 ) with Hodgkin 's disease , clinical stages IA-IIB ( IA , 18 ; II2A , two areas involved on the same side of the diaphragm , 23 ; II3+A , three areas or more , 16 ; IIB , 15 ) were prospect ively treated in two successive clinical trials ( H 72 and H 77 ) . Clinical stages IA and II2A received three courses of mechlorethamine , Oncovin , procarbazine , and prednisone ( MOPP ) and supradiaphragmatic radiotherapy ( 40 Gy ) , and no laparotomy was performed . Clinical stages II3+A and IIB received either six cycles of MOPP ( H 72 ) , three cycles of MOPP , or three cycles of CCNU , vinblastine , procarbazine , and prednisone ( CVPP ) ( H 77 ) and subsequently had a laparotomy followed by supradiaphragmatic radiotherapy and a lumboaortic field if results of laparotomy were positive . Patients without evidence of mediastinal involvement did not have mediastinal radiotherapy . At the completion of therapy , the disease in 70 of 72 patients was in complete remission ( one failure , one death during treatment ) . Eight patients relapsed ( in situ , 1 ; marginal , 1 ; nonirradiated subdiaphragmatic area , 6 ) after three to 57 months of complete remission ( median 20 months ) ; one patient died after relapse . There were three deaths after complete remission of the disease ( infection , two ; acute nonlymphocytic leukemia [ ANLL ] , one ) . As of June 1984 the median follow-up was 82 months ( range , 49 to 145 months ) , the actuarial probabilities for survival and freedom from relapse for all patients being 91.6 % and 87.6 % , respectively . There was no statistical difference according to clinical stage , age ( greater than 15 or less than 15 years ) , sex , or number of cycles of chemotherapy ( six or three ) . Bone growth defects related to radiotherapy were reduced particularly in the 29 patients who did not receive mediastinal radiotherapy . None of these patients had a mediastinal relapse . Azoospermia was the rule for the male patients studied , but young girls and young women retained reproductive integrity Seventy-nine patients with clinical stages IA , or II2A of Hodgkin 's disease were treated from January 1977 to April 1980 by a multiple therapy schedule , H 7701 . Three courses of MOPP chemotherapy were first given to all patients . They were then r and omly allocated to two groups : group 7701 S ( 38 patients ) was treated by mantle irradiation , excluding the mediastinum when this was not initially involved , or inverted Y radiotherapy ;  group 7701 F ( 41 patients ) was treated by focal irradiation only . After follow-up for 9 - 48 months ( median : 26 months ) , overall survival was 98,6 p. cent and relapse-free duration 94,9 p cent . No statistical difference exists between the two r and omized groups . Four patients relapsed ; three are now free of disease after further treatment , while one patient has since died . With this chemotherapy-radiotherapy selective of focal sequence , staging laparotomy is not indicated . Results and side effects of this treatment schedule are compared with those of other treatment strategies Since 1969 , 184 previously untreated and evaluable adult patients with Hodgkin 's disease , staged as I ( 43 ) or II ( 141 ) , have been treated . Eighty patients were part of the National Hodgkin 's Disease Study , r and omly assigned to receive  radiotherapy  to either an involved ( 39 ) or extended field ( 41 ) . In a subsequent single-arm study , 104 patients were treated with involved-field radiotherapy preceded and followed by three cycles of MOPP chemotherapy . Median duration s of follow-up have been 172 , 172 , and 92 months , for the involved-field radiotherapy , extended-field radiotherapy , and MOPP plus involved-field radiotherapy treatment groups , respectively . Although significant differences among the three treatment groups were observed with respect to disease-free survival ( p less than 0.001 ) , only the group of patients treated with involved-field radiotherapy had a statistically significant decline in overall survival as compared with the two other treatment groups ( p less than 0.001 ) . Moreover , patients who underwent clinical staging and were treated with MOPP plus involved-field radiotherapy had significantly prolonged disease-free survival compared with those who underwent surgical staging and were treated with extended-field radiotherapy ( p less than 0.001 ) . One of the patients who received MOPP plus involved-field radiotherapy had subsequent development of acute monocytic leukemia , and another had refractory anemia with excess blasts . One instance of diffuse poorly differentiated lymphocytic lymphoma was also observed . Acute monocytic leukemia developed in another patient treated with involved-field radiotherapy . The rates of amenorrhea in the group treated with MOPP plus involved-field radio-therapy were 9.6 percent and 78.5 percent for female patients younger and older than 30 years of age , respectively . Despite the universal azoospermia ensuing after MOPP plus involved-field radiotherapy , in three patients whose sperm counts were checked sequentially for 26 to 53 months after treatment , evidence of spermatogenesis was observed . Three patients with remission of Hodgkin 's disease after involved-field ( two ) and extended-field ( one ) radiotherapy died from cardiovascular disease that could only be attributed to the prior radiotherapy . Although further follow-up evaluation will be required to determine the impact of the three different treatment modalities on survival and long-term toxicity , MOPP plus involved-field radiotherapy appears to be superior to involved-field or extended-field radiotherapy alone in achieving prolonged disease-free survival without significant leukemogenic potential An analysis and progress report is presented of the r and omized clinical trials testing the value of adjuvant MOPP chemotherapy with irradiation in the management of Hodgkin 's disease . The 213 patients with Stages IA through IIIB have been followed for periods of up to 64 months . The chemotherapy controls the occult disease , result ing in significant improvement in disease‐free survival ( p = .002 ) . Over‐all survival is not yet affected , however , with combined 5‐year survival results of 92 % and 88 % in the two groups . The treatment program is difficult but feasible . No increased incidence of second malignancies has been observed in this study group . It is premature to conclude that adjuvant MOPP chemotherapy is indicated in the radiation management of Hodgkin 's disease The purpose of this study was to compare four methods of treatment for stage III-IV Hodgkin 's disease . Between January 1972 and September 1976 , 266 patients with stage IIIB , IVA , and IVB Hodgkin 's disease from 21 cancer treatment centers across Canada were registered as eligible ; 40 were found to be ineligible . Of the 226 remaining patients , only seven were followed for less than 10 years . All patients received three courses of mechlorethamine , vincristine , procarbazine , and prednisone ( MOPP ) chemotherapy , which induced a complete response ( CR ) in 36 % ; an additional 42 % obtained adequate disease control . Patients were r and omly assigned to ( 1 ) treatment with radiation to the abdomen and mantle ( group AX3 , 62 patients ) or ( 2 ) continue their treatment with an additional three courses of MOPP ( group A , 105 patients ) . For the A group , a second r and omization took place 3 months later ( regardless of status at that time ) to ( 1 ) no further treatment ( AC6 , 23 patients ) , ( 2 ) radiotherapy to the abdomen and mantle ( AX6 , 48 patients ) , or ( 3 ) maintenance chemotherapy at 3-month intervals for 1 year ( AC10 , 26 patients ) . The survival of AX3 patients was somewhat better than for the A group , but the difference was not significant ( P = .0565 ) . However , there was a significant interaction ( P = .0029 ) between age and treatment , so that among patients less than 30 years of age , the survival of the A group was better , whereas for older patients , treatment with AX3 result ed in improved survival . Age itself remained a significant prognostic factor for survival after controlling for the amount of radiotherapy delivered to the abdomen and the dose intensity of vincristine for the first three courses of chemotherapy . The addition of radiation therapy to MOPP significantly reduced the frequency of nodal relapses . These results suggest that combined modality therapy may be beneficial for some patients with Hodgkin 's disease and that age must be carefully considered in interpreting the results of clinical trials in Hodgkin 's disease The Cancer and Acute Leukemia Group B studied the effect of combination chemotherapy‐radiotherapy on Stage III Hodgkin 's disease .  Chemotherapy consisting of 4 weekly doses of vinblastine and one dose of mechlorethamine hydrochloride was followed by no therapy ( CT ) , radiation to involved fields ( CTIF ) or total nodal radiation ( CTTN ) . Two other treatment arms included total nodal radiation alone ( TN ) or total nodal radiation followed by chemotherapy ( TNCT ) . Maximum follow‐up is ten years . Complete remission percentages were 36 ( 8/22 ) for CT , 71 ( 17/24 ) for CTIF , 100 ( 21/21 ) for CTTN , 86 ( 19/22 ) for TNCT and 89 ( 16/18 ) for TN . Disease‐free survival in patients receiving radiation ± chemotherapy is 23%(19/73 ) at 5 years , but even after 9 years relapses were observed in two patients . Forty‐one percent of all patients are alive and 32 % have survived for five years . Ability to administer adequate therapy was the main determinant for response duration and survival . Factors influencing the outcome of the disease include histology , age , splenectomy , initial white blood cell count and performance status , whereas symptomatology , initial absolute lymphocyte count and sex played no role on survival A total of 228 previously untreated and eligible children with pathologic Stage I or II Hodgkin 's disease were registered in the Intergroup Study of Hodgkin 's Disease in Children between February 1977 and April 1981 . Patients were r and omized in the Southwest Oncology Group ( later the Pediatric Oncology Group [ POG ] to involved‐field ( IF ) radiotherapy alone or IF radiotherapy followed by six courses of mechlorethamine , vincristine , prednisone , and procarbazine ( MOPP ) chemotherapy ;  patients in the Children 's Cancer Study Group ( CCSG ) and Cancer and Leukemia Group B ( CALGB ) were r and omized to receive extended‐field ( EF ) radiotherapy or IF radiotherapy followed by six courses of MOPP . An estimated 97 % of patients receiving IF + MOPP  were relapse‐free and surviving ( RFS ) at 5 years , which was significantly better than 41 % for patients receiving IF alone ; however there was essentially no overall difference in survival experience between groups . Patients in CCSG and CALGB receiving IF + MOPP had significantly superior RFS at 5 years than patients receiving EF . Survival rate was not different between these two groups , an estimated 93 % of patients surviving 5 years or longer . Although patients were not r and omized between IF or EF radiotherapy , they were similar with respect to patient characteristics . There was some statistical evidence that RFS was superior at 5 years for patients receiving EF than for IF ; however , there was no evidence of a difference in survival experience . The percentages of patients with late effects of therapy were not significantly different by treatment . The most common types of late effects were endocrine dysfunction and impaired resistance to infection . Overall , the response rate to therapy for relapse patients was good , being 83 % among all patients who relapsed . Patient characteristics related to poor prognosis were the presence of constitutional ( B ) symptoms ( fever , night sweats , and weight loss ) and poor performance status The results achieved in three different studies carried out on patients affected by Hodgkin 's disease are discussed . In study No. 1 , 58 patients with pathological Stage I-II were treated with only a " Mantle " field irradiation . The complete remission ( CR ) rate was 98 % with an actuarial overall survival of 90 % , and a median of follow-up of 80 months . Thirty-one percent of patients relapsed . In study No. 2 , 42 patients were r and omly allocated to receive only MOPP chemotherapy versus extended field irradiation ; CR rate was 68 and 95 % , respectively ( p less than 0.05 ) . The overall survival rate was 100 % in the radiotherapy group and 82 % in the MOPP group . No relapses have been observed in patients treated with MOPP . In study No. 3 , 218 patients affected by advanced Stage HD were r and omly treated with 6 cycles of MOPP chemotherapy versus 6 cycles of ABVD chemotherapy . In the MOPP group the CR rate , the relapse-free survival rate ( RFS ) , and overall survival ( OS ) rates at 60 months were 77 , 68 , and 76 % respectively , whereas , in the ABVD group the CR , the RFS , and OS rates at 60 months were 75 , 77 and 80 % respectively , ( p less than 0.05 ) . These data and statistical comparisons are analyzed To determine whether combined modality therapy ( CMT ) is superior to chemotherapy ( CT ) alone , 152 untreated Hodgkin disease patients with clinical stages ( CSs ) IA , IB , IIA , IIB , and IIIA without bulk disease were prospect ively r and omized to 6 cycles of doxorubicin , bleomycin , vinblastine , dacarbazine ( ABVD ) alone or 6 cycles of ABVD followed by radiation therapy ( RT ) ( 3600 cGy : involved field for 11 patients , modified extended field for the rest ) . Of 76 patients r and omized to receive RT , 65 actually received it , and 11 did not ( 4 progressed , 1 had bleomycin toxicity , 6 refused ) . For ABVD + RT , the complete remission ( CR ) percentage was 94 % and no major response , 6 % . For ABVD alone , 94 % achieved a CR ; 1.5 % , a partial response ( PR ) ; and 4.5 % , no major response . At 60 months CR duration , freedom from progression ( FFP ) , and overall survival ( OS ) for ABVD + RT versus ABVD alone are 91 % versus 87 % ( P = .61 ) , 86 % versus 81 % ( P = .61 ) , and 97 % versus 90 % ( P = .08 ) , respectively ( log-rank ) . The 95 % confidence intervals for CR duration , FFP , and OS differences at 5 years were -8 % to 15 % , -8 % to 18 % , and -4 % to 12 % , respectively . Although significant differences were not seen , it is possible that a benefit in outcome of less than 20 % for CMT might be seen in a larger trial The aim of this study was to establish whether combined modality treatment ( ABVD plus radiotherapy ) can reduce the risk of relapse in Hodgkin 's disease patients with mediastinal involvement , as compared to radiotherapy alone . The results obtained suggest that one course of ABVD before irradiation can reduce the incidence of relapse . These findings , however , should be considered preliminary and need to be confirmed in larger studies Sixty-seven patients with favorable pathologic stage ( PS ) I and IIA or B or IIIA Hodgkin 's disease were r and omized to receive subtotal or total lymphoid irradiation ( STLI/TLI ) alone or involved field irradiation ( IF ) plus six cycles of a novel adjuvant chemotherapy containing vinblastine , bleomycin , and methotrexate ( VBM ) . With a follow-up from 6 to 72 months ( median , 37 months ) , the actuarial freedom-from-progressive disease ( FFP ) at 5 years is 70 % after STLI/TLI and 95 % after IF plus VBM . One death has occurred in the irradiation-only treatment group . The data for IF plus VBM are significantly superior to previous actuarial results at 5 years using IF alone ( FFP = 35 % , P less than .00001 ) and compare favorably with prior results with IF plus nitrogen mustard , vincristine , procarbazine , + /- prednisone ( MOP[P ] ) chemotherapy ( FFP = 80 % at 5 years , P = .10 ) . VBM is well tolerated with greater than 90 % of calculated doses delivered . As anticipated , VBM has had relatively little adverse effect on male or female fertility . Selected pulmonary functions are reduced early after IF plus VBM to a greater degree than with irradiation of the mediastinum alone , but the differences are modest . Based upon our current numbers and follow-up , we can be 90 % confident that VBM as an adjuvant to irradiation in favorable Hodgkin 's disease is as effective , or even superior , to MOP(P ) chemotherapy . Because of its lesser toxicity , adjuvant VBM may have a broader role in the management of Hodgkin 's disease PURPOSE To evaluate the effect of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy alone and of ABVD with mantle or mediastinal irradiation ( RT ) on the pulmonary function of patients with early-stage Hodgkin 's disease . PATIENTS AND METHODS Between 1989 and 1993 , 60 patients with clinical stage I to IIIA HD enrolled onto r and omized trials at Memorial Sloan-Kettering Cancer Center ( MSKCC ) underwent prospect i ve evaluation of pulmonary function . All patients received six cycles of ABVD , and 30 patients received mantle or mediastinal RT .  Pulmonary function tests ( PFTs ) and symptom evaluation were conducted before , during , and after completion of chemotherapy and RT , and at various intervals thereafter . The median follow-up time was 30 months . RESULTS During chemotherapy , symptoms of cough and dyspnea on exertion developed in 32 of 60 patients ( 53 % ) and declines in pulmonary function occurred in 22 of 60 patients ( 37 % ) . Discontinuation of bleomycin was necessary in 14 of 60 patients ( 23 % ) . Following chemotherapy , there was a significant decline in median forced vital capacity ( FVC ) and diffusing capacity of carbon monoxide ( DLCO ) . In patients who received mantle or mediastinal RT , there was a further decline in FVC following radiation therapy . At the most recent follow-up evaluation , five of 29 patients ( 18 % ) who received ABVD alone and nine of 30 ( 30 % ) who received ABVD and RT reported persistent mild pulmonary symptoms ( P = .36 ) , which did not significantly affect normal daily activity . CONCLUSION ABVD chemotherapy induced acute pulmonary toxicity that required bleomycin dose modification in a substantial number of patients . The addition of RT result ed in a further decrease in FVC ; however , this did not significantly affect the functional status of patients To investigate the effect of different treatments for Hodgkin 's disease on the risk of leukemia , we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkin 's disease . For each case patient with leukemia , three matched controls were chosen who had been treated for Hodgkin 's disease but in whom leukemia did not develop . The use of chemotherapy alone to treat Hodgkin 's disease was associated with a relative risk of leukemia of 9.0 ( 95 percent confidence interval , 4.1 to 20 ) as compared with the use of radiotherapy alone . Patients treated with both had a relative risk of 7.7 ( 95 percent confidence interval , 3.9 to 15 ) . After treatment with more than six cycles of combinations including procarbazine and mechlorethamine , the risk of leukemia was 14-fold higher than after radiotherapy alone . The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone , but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone . The peak in the risk of leukemia came about five years after chemotherapy began , and a large excess persisted for at least eight years after it ended . After adjusting for drug regimen , we found that patients who had undergone splenectomy  had at least double the risk of leukemia of patients who had not , and an advanced stage of Hodgkin 's disease carried a somewhat higher risk of leukemia than Stage I disease . We conclude that chemotherapy for Hodgkin 's disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy . In addition , the risk is greater for patients with more advanced stages of Hodgkin 's disease and for those who undergo splenectomy Eighty‐seven previously untreated patients with pathologic Stage IA , II ( A or B ) , or IIIA Hodgkin 's disease were r and omized over a 48‐month period to receive either megavoltage extended field radiotherapy alone or megavoltage radiotherapy limited to involved lymph node sites ( including at least an upper mantle field ) followed by combination chemotherapy with nitrogen mustard , vincristine , prednisone , and procarbazine ( MOPP ) . Four patients ( 4.6 % ) failed to achieve remission with initial radiotherapy .  Seventy‐two evaluable patients have currently completed therapy . Ten of 41 patients achieving remission with radiation alone have relapsed , compared to only 1 of 31 receiving radiation plus chemotherapy . Seven patients have died , 3 of whom failed to achieve remission with initial radiotherapy . The other 4 had Stage IIIA disease treated with radiation  alone . Severe myelosuppression occurred infrequently during chemotherapy , and neither serious infections nor second neoplasms have been observed . Although these preliminary results are encouraging , longer followup is required to determine the ultimate effects of combined modality therapy on survival and long‐term complications From 1976 to 1981 , 335 patients with untreated Hodgkin 's disease , clinical stages I , II , and IIIA , have been treated by MOPP ( nitrogen mustard , vincristine , procarbazine , prednisone ) chemotherapy , three to six cycles according to the prognostic factors , combined with radiotherapy . Irradiation was always performed after the first three cycles of chemotherapy , and was r and omized between extensive radiotherapy , ie , mantle and paraaortic areas for supradiaphragmatic presentations , and radiotherapy restricted to the involved areas . No significant difference was observed between the two r and omized branches for the disease-free survival ( 86 % after six years in the involved field branch v 90 % in the extended field branch ) , and none for the overall survival . Most of the relapses occurred in nonirradiated areas in the first group , and in irradiated areas in the second . Relapses were especially frequent in the IIE stages with pulmonary extension ; extranodal relapses occurred with osseous and cutaneous localizations . Two cases of secondary leukemia were observed after three- or six-cycle MOPP plus radiotherapy limited to the involved areas In order to assess whether mechlorethamine , vincristine , procarbazine , and prednisone ( MOPP ) chemotherapy ( CT ) , which is less expensive and more easily available than radiotherapy ( RT ) , is at least as effective as RT in terms of cure rate and has less iatrogenic damage , 89 consecutive patients with Hodgkin 's disease ( HD ) ( pathological stage I-IIA ) were r and omly allocated to receive mantle plus lumbar bar RT ( 36 - 45 Gy ) or CT  ( six courses of MOPP ) . Forty-five patients were entered in the RT group and 44 in the CT group . The median follow-up was 60 months . Complete remission ( CR ) was obtained in all patients in the RT group and in 40 of 44 patients in the CT group . Overall survival ( OS ) and disease-free survival ( DFS ) were , respectively , 87.2 % and 72.7 % in the CT group and 93.5 % and 74 % in the RT group . Survival probability of relapsing patients was 76 % for the patients in the RT group and 45 % in the CT group . Treatment-related complications were more severe in the CT group as compared with the RT group In a multi-centre study in which data from all Danish Hodgkin patients have been registered since 1971 , all patients in supradiaphragmatic stages I or II , as confirmed by staging laparotomy , were r and omized to either radiotherapy ( RT ) to supra- and infradiaphragmatic lymph node regions ( total nodal irradiation , TNI ) , or RT to a mantle field followed by 6 cycles of MOPP combination chemotherapy ( RT+CT ) . Interim results up to July 1979 , when 237 patients had entered the study , showed a treatment failure rate of 19/117 in the TNI group and 4/120 in the RT+CT group ( P less than 0.05 ) . 19 of the 23 relapsing patients were under the age of 40 , and 14 in the TNI group and 3 in the RT+CT group belonged to stage II . 13 patients had nodular sclerosis , 9 had mixed cellularity and 1 had lymphocytic predominance histology . 12 of 19 relapsing patients in the TNI group had hilar or mediastinal involvement as against 51 of the 117 patients in the entire group . Most of the TNI failures could be retreated , and as yet there is no difference in the overall survival Untreated patients with Hodgkin ’s lymphoma in stages I-IIIA with risk factors ( large mediastinal mass , massive splenic involvement , extranodal disease ) were entered into the HD1 protocol and received a combined chemoradiotherapy [ 2 × ( COPP+ABVD ) + 40 Gy extended field irradiation ( EF ) vs 2 × ( COPP+ABVD ) + 20 Gy EF ] . Patients in stages IIIB/IV ( HD3 protocol ) received induction chemotherapy [ 3 × ( COPP+ABVD ) ] and were r and omized into consolidation by radiotherapy [ 20 Gy involved field irradiation ( IF ) ] vs chemotherapy [ 1 × ( COPP+ABVD ) ] . Seventy-three of 89 evaluable patients ( 82 % ) treated according to the HD1 protocol achieved a complete remission . Freedom from progression and survival of patients in stages I-IIIA with risk factors treated according to HD1 were no worse than those of patients in stages I and II without risk factors who received only radiotherapy . Eighty-six of 137 patients ( 63 % ) treated according to the HD3 protocol achieved complete remission  after induction chemotherapy with COPP+ABVD . This is significantly better than the 31 % complete remission rate observed in a previous pilot study with COPP alone ( P < 0.01 ) . Including salvage therapy ( radiotherapy in case of persisting nodal disease ; chemotherapy with 4 × CEVD in case of persisting disseminated disease ) , a total of 76 % complete remissions in stages IIIB/IVAB were achieved . A high erythrocyte sedimentation rate ( > 80 mm h−1 ) was the most significant risk factor for achieving freedom from progression This report describes three comparative studies of treatment methods in patients with Stage IIIA Hodgkin 's disease in whom the extent of disease had been confirmed by a diagnostic laparotomy . The first trial ( 1970 - 75 ) compared TNI with MOPP . The recurrence-free survival curve for patients treated with TNI was significantly better than that for those treated with MOPP at four years , but the survival rate of the two cohorts was identical , presumably because of good salvage treatment . The second study ( 1975 - 80 ) compared TNI with TNI followed by LOPP . Initially the addition of LOPP appeared to improve the disease-free survival rate but at three years no difference was apparent between the two treatment groups . The third ( 1980-present ) study divides patients into those with and those without splenic involvement . Retrospective analysis of all patients included in the BNLI with Stage IIIA Hodgkin 's disease confirmed by laparotomy and treated initially by TNI  shows that splenic involvement does not influence the survival but decreases the relapse-free survival rate , making additional treatment with MOPP necessary in 75 % of long-term survivors . In the current study , patients without splenic involvement are treated with TNI whereas those with splenic involvement are treated initially with chemotherapy , r and omising between MOPP and LOPP Mature data from four clinical trials conducted by the Southwest Oncology Group from 1971 to 1978 for patients with all stages of Hodgkin 's disease ( HD ) are review ed in this paper . In the RAC # 1 trial of stage I and II HD we demonstrated that involved-field radiotherapy plus six courses of MOPP chemotherapy improved relapse-free survival compared to st and ard radiotherapy alone ( P = 0.12 ) , especially in patients with B symptoms ( P less than 0.03 ) or mediastinal disease ( P = 0.08 ) . However , at present , there is no significant difference in overall survival . In the CAR # 1 study for patients with pathologic stage IIB , IIIA , and IIIB HD , we demonstrated that three or four courses of MOPP before radiotherapy produced a 90 % complete remission ( CR ) rate , with 70 % of the patients remaining free of disease at 5 years . In the CAR # 2 study for patients with pathologic stage IIIA or IIIB disease , we demonstrated that chemotherapy alone ( MOPP-bleomycin ) was as effective as combined modality treatment ( MOPP-bleomycin plus radiotherapy ) in terms of CR rate ( 85 % versus 89 % , respectively ) , relapse-free survival , and survival . For advanced stages of HD we added doxorubicin to our MOPP-bleomycin schedule and demonstrated that MOP-BAP produced a 77 % CR rate compared to 67 % for MOPP-bleomycin ( P = 0.10 ) . Moreover , MOP-BAP produced consistently superior CR rates and survival in patients with more prognostically favorable presentations of HD . Our new ongoing study ( MOPP # 6 ) incorporates many of the concepts derived from these earlier clinical investigations In this phase III trial , 770 patients with clinical stage I-II Hodgkin 's disease ( HD ) have been enrolled since November 1988 . Preliminary results are given for the 605 ( 79 % ) patients who have completed their initial therapy . Patients were grouped according to 6 pretreatment prognostic characteristics . In the very favourable ( VF ) group , treatment consisted of mantle field alone . In the favourable ( F ) group , patients were r and omized to either subtotal nodal irradiation ( STNI ) , or 6 cycles of EBVP ( epirubicin , bleomycin , vinblastine , prednisone ) followed by involved-field irradiation ( IF-RT ) . Unfavourable ( U ) patients were r and omized to either 6 cycles of EBVP plus IF-RT , or to 6 cycles of MOPP/ABV hybrid plus IF-RT . Of the 35 VF patients , none have progressed during radiotherapy . Four patients relapsed and were salvaged . Three-year failure-free survival ( FFS ) was 82 % ; overall survival ( OS ) was 100 % . Of the 254 F patients , 130 were treated with STNI and 124 with EBVP plus IF-RT . At 3 years , FFS rates were 81 % ( 1 progression , 14 relapses ) and 79 % ( 5 progressions , 8 relapses ) , respectively . Corresponding OS rates were 99 % and 100 % . Of the 316 U patients , 160 received EBVP and 156 MOPP/ABV . At 3 years , FFS rates were 72 % ( 18 progressions , 20 relapses ) and 88 % ( 7 progressions , 6 relapses ) , respectively ( p < 0.001 ) . Although OS rates were identical ( 92 % ) , the entry in the U-EBVP arm was stopped in November 1992 . We conclude that a treatment strategy based on prognostic factors allows the use of less aggressive treatment in favourable patients . ( ABSTRACT TRUNCATED AT 250 WORDS A series of 44 previously untreated patients was found to have stage I or II Hodgkin 's disease on the basis of a diagnostic workup which included laparotomy and splenectomy in 39 cases . The patients were r and omized to either involved field or extended field radiotherapy . No difference was found in overall survival rates between the two groups . Regional recurrences were seen in four patients in the involved field group and in none of the extended field group . Regional recurrences were seen in four patients in the involved field group and in none of the extended field group . Radiotherapy to the extended field treatment port ( generally an extended mantle ) can be given with acceptable side effects . Staging laparotomy was of definite value , changing the classification and result ing therapy of two groups : ( 1 ) patients with clinical stage ( CS ) I or II , pathologic stage ( PS ) III involvement , who were treated with appropriately larger radiotherapy fields ; and ( 2 ) patients with CS III , PS I or II , who were spared unnecessarily extensive radiotherapy Up to 40 % of patients with stage III or IV Hodgkin disease relapse within 5 years of entering complete remission with current chemotherapy regimens [ 1 - 4 ] . Only 20 % of patients who relapse enter a prolonged second complete remission after receiving chemotherapy , radiation , or bone marrow transplantation [ 5 - 14 ] . Thus , prevention of relapse remains an important issue . Factors associated with relapse after a complete response has occurred with chemotherapy include the following : nodular sclerosis histology , bulky disease , more than three cycles of chemotherapy required to achieve complete response , decreased chemotherapy doses , and B symptoms [ 15 - 22 ] . Eighty percent of relapses in patients with Hodgkin disease occur in sites of initial clinical involvement [ 22 , 23 ] . Because Hodgkin disease is a radiosensitive tumor , a logical step is to use radiation in an attempt to eradicate sub clinical disease after remission induction with chemotherapy . Kaplan [ 24 ] and others have shown that a radiation dose of 2000 to 2500 cGy is effective in preventing recurrence in all but 25 % to 30 % of patients with clinical disease when radiation is used as the sole treatment modality [ 24 ] . This relatively low dose of radiation might be even more effective if only sub clinical disease was being treated . Further , using low-dose radiation after chemotherapy might decrease some of the morbidity associated with the combined use of both modalities at full doses . Early nonr and omized studies by Prosnitz and colleagues [ 25 ] , in which the MVPP regimen ( nitrogen mustard , vincristine , prednisone , and procarbazine ) was administered with low-dose involved field radiation , showed only a 10 % relapse rate when stage III or IV patients had achieved complete response with chemotherapy before receiving radiation . In 1978 , we initiated a r and omized trial for patients with stage III or IV Hodgkin disease that was design ed to test the efficacy of low-dose involved field radiation after complete remission induction with chemotherapy . The MOP-BAP ( nitrogen mustard , vincristine , procarbazine , bleomycin , doxorubicin , and prednisone ) chemotherapy regimen was used as induction treatment because this regimen had been associated with a complete response rate of 77 % [ 2 ] . Complete responders to six cycles of MOP-BAP were r and omly assigned to a radiation dose of 2000 cGy to initially involved sites or to no further treatment . We determined the remission duration and relapse-free and overall survival rates for the entire group of patients with advanced Hodgkin disease as well as for several major subsets of patients . Methods Previously untreated patients ( n = 564 ) with clinical or pathologic evidence ( or both ) of stage III or IV Hodgkin disease were registered for induction with MOP-BAP chemotherapy between June 1978 and September 1988 . Pathology slides were review ed by the Southwest Oncology Group Pathology Review Committee . A final review was made by the Lymphoma Central Repository . Patients who were known to be positive for human immunodeficiency virus or who had a clinical diagnosis of the acquired immunodeficiency syndrome were excluded from analysis . The pathology review is now complete for 95 % of the patients who entered this study . Thirty-four patients ( 6 % ) were ineligible , primarily because they had non-Hodgkin lymphoma after pathology review . The Ann Arbor Staging Classification was used [ 26 ] . Staging requirements included bone marrow aspiration and biopsy ; renal , heart , and lung function studies ; and staging laparotomy or radiographic evaluation of the abdomen with either computerized tomography or lymphangiography or both . Patients with any mass 6 cm or more in size were design ated as having bulky disease . Flow sheets , pre study forms , and radiographic reports were review ed on all patients who achieved complete response to make the assessment of bulky disease . Liver biopsy was required in patients with stage IIIB or IV disease unless the patient had clinical liver involvement or it was medically contraindicated . Clinical liver involvement was defined as an enlarged liver on physical examination or computed tomography together with increased levels of at least one liver enzyme other than alkaline phosphatase or lactate dehydrogenase . Clinical spleen involvement was defined as a palpable spleen on physical examination or an enlarged spleen on computed tomography with or without filling defects . Response Definitions A partial response was defined as a 50 % or greater decrease in the sum of the products of the largest diameter and its perpendicular for 4 weeks or more . Patients with question able residual disease were classified as partial responders . For patients with minimal residual disease detected by computerized tomography scanning after six cycles of chemotherapy , design ation of partial or complete remission was left to the discretion of the individual investigator . In general , however , patients with minimal residual disease were classified as partial responders . If the residual mediastinal mass on the computerized tomographic scan was less than 3 cm or the residual peripheral nodal mass was 1.5 cm or less , partial responders were classified as having minimal residual disease . Complete response was defined as disappearance of all clinical evidence of disease for 4 or more weeks . Treatment Chemotherapy The MOP-BAP chemotherapeutic regimen consisted of nitrogen mustard ( 6 mg/m2 ) on day 1 , bleomycin ( 2 mg/m2 ) and vincristine ( 1 mg/m2 ; maximum dose , 2 mg ) on days 1 and 8 , doxorubicin ( 30 mg/m2 ) on day 8 , and prednisone ( 100 mg ) and procarbazine ( 100 mg/m2 ) on days 2 to 7 and 9 to 12 . Courses were repeated every 28 days if the absolute granulocyte count was 1500 cells/mm3 or more . A total of 6 cycles was administered . Prednisone was given only during the first and fourth cycles . Initial doses of MOP-BAP were 50 % of those listed above if the patient was older than 65 years or had bone marrow involvement with leukopenia . Dose escalation in subsequent courses was encouraged . Initial  doxorubicin doses were also decreased by 50 % to 75 % for serum bilirubin levels greater than 1.5 mg/dL or increases in liver enzyme levels of more than threefold the normal level or both . Subsequent drug doses were reduced for severe myelosuppression or delayed hematopoietic recovery as in previous Southwest Oncology Group studies [ 2 ] using this regimen . The ratio of actual/planned full-dose chemotherapy  for each of the 5 drugs ( nitrogen mustard , bleomycin , procarbazine , vincristine , and doxorubicin ) was calculated for the 530 eligible patients . The average percentage was used to describe the amount of chemotherapy given . The average for the 5 drugs was 85 % . The average number of courses was 5.6 . The average actual/planned ratio for each drug was 86 % for nitrogen mustard , 84 % for doxorubicin , 82 % for procarbazine , 91 % for bleomycin , and 81 % for vincristine . Sixty-six percent of patients achieving complete response received more than 85 % of the planned induction chemotherapy . Radiation Therapy for Complete Responders All patients were seen in consultation by a radiation oncologist before induction chemotherapy was started , and all clinical and pathologic sites of disease were mapped . If the patient was later given radiation , all initially involved areas were included in the treatment ports with the exception of bone marrow . Patients with previously involved nodal sites received 2000 cGy in 150-cGy fractions , those with previously involved liver sites received 1500 cGy in 150-cGy fractions , those with previously involved spleen sites received 1500 cGy in 125-cGy fractions , and those with previously involved lung sites received 1000 cGy in 100-cGy fractions . Kidney blocks were used when necessary , and a spinal cord block was used when the dose to the cord had reached 2000 cGy . Patients only received radiation to those areas identified as being clinical ly or pathologically involved with Hodgkin disease .  Radiation was started , 6 weeks after day 1 of the sixth MOP-BAP cycle , if the leukocyte count was more than 3000 cells/mm3 and if the platelet count was more than 100 000/mm3 . A 3-week rest was recommended between radiation of large volumes or major lymph node areas . Supervoltage radiation of at least 2 MV or cobalt-60 was required . Port films , dose calculations , and treatment records were review ed by the Quality Assurance Center , the Radiologic Physics Center , and the Medical and Radiation Oncology Coordinators . Failure to give any radiation to a previously involved site or concomitant administration of radiation and chemotherapy was considered a major radiation violation . Dose infractions and failure to complete radiation for any reason were considered minor radiation violations . Ninety-six percent of patients receiving radiation have had their records evaluated by the Radiologic Physics Center in Houston , Texas , and the Radiation and Medical Oncology Study Coordinators . All eligible patients who achieved complete response and were r and omized were included in comparisons of remission duration , relapse-free survival , and survival regardless of whether a major or minor radiation violation had occurred . Patients r and omized to no further treatment received no radiation or chemotherapy after six cycles of MOP-BAP until they relapsed . Planned follow-up intervals in patients r and omized to receive low-dose radiation were identical to those for patients r and omized to no further treatment . Treatment at the time of relapse was at the discretion of the individual investigator . Study Design When the study was initially opened , patients in complete response were r and omized after six cycles of MOP-BAP and restaging to one of three possible groups : no further therapy , levamisole for 2 years , or low-dose radiation to previously involved sites of disease . The study design was changed in 1982 because of lower-than-anticipated patient accrual . The levamisole arm was eliminated , and patients were r and omized BACKGROUND AND OBJECTIVE One of the consequences of the enormous improvement in survival rates of patients treated for Hodgkin 's disease ( HD ) is the emergence in the long term of treatment-related complications , particularly secondary cancers . This study was undertaken to observe the occurrence of non-Hodgkin 's lymphoma ( NHL ) in patients treated for HD and to identify the etiological role of various risk factors , especially spleen irradiation , in the pathogenesis of this illness . DESIGN AND METHODS From 1972 to 1996 , the Department of Radiation Oncology and the Hematology Section of " La Sapienza " University of Rome observed and analyzed the occurrence of NHL in 1,391 patients treated for HD . The average follow-up period was 84 months . For a more accurate calculation of the risk of the occurrence of NHL , the patients were first divided into 3 groups according to their initial treatment and also according to the total treatment they had received . Then , in order to establish the possible connection between NHL and splenic treatment the patients were also divided into 3 subgroups according to whether they had undergone splenectomy , splenic irradiation or neither of these . Two different methods of statistical analysis were used : ( a ) the cumulative risk ( confidence interval ) was evaluated in relation to treatment ( initial and at the time of salvage ) and ( b ) the Cox model was applied to identify the variables which play a role in the appearance of NHL . The cumulative risk of developing NHL was assessed using the Kaplan and Meier method . A multivariate analysis was performed using the Cox Proportional Hazard Model . RESULTS A total of 20 cases of NHL were observed , appearing between 17 and 206 months after initial treatment . The cumulative risk was 0.8 % , 1.8 % , 2.6 % and 3.5 % at 5 , 10 , 15 and 20 years respectively . According to the multivariate analysis , significant risk factors were splenic irradiation and age ( > 40 years ) . Splenic irradiation ( vs no splenectomy/no splenic irradiation ) showed a relative risk of 5.69 , p = 0.0280 , while age over 40 showed a relative risk of 3.05 , p = 0.0152 . INTERPRETATION AND CONCLUSIONS From the results of this study , if appears that there is a possibility that splenic irradiation and age over 40 increase the risk of NHL in HD patients . Further studies are needed to investigate in greater depth the role of spleen irradiation in the occurrence of this illness A review of data from the British National Lymphoma Investigation ( BNLI ) studies of Hodgkin 's disease ( HD ) done over the past 14 years shows ( i ) that systemic chemotherapy is appropriate for all clinical stages except I and IIA , and that MOPP ( mustine , vincristine , procarbazine , and prednisone ) courses are substantially more effective than MOP ( the same without prednisone ) but no better than the less toxic LOPP combinations ( where chlorambucil replaces mustine ) ; ( ii ) that local involved-field irradiation in stages I and IIA HD is as effective as wide-field in terms of both overall and recurrence-free survival ; and ( iii ) that , histologically , nodular sclerosing HD can be divided into grade s 1 and 2 , the latter containing areas of lymphocyte depletion or numerous pleomorphic Hodgkin 's cells . A multivariate analysis of factors influencing prognosis in clinical stages I and IIA disease shows that  laparotomy  has no significant effect but that age , sex , erythrocyte sedimentation ( ESR ) , the presence or absence of mediastinal involvement and , especially , pathological grade are the most important factors influencing overall survival , while ESR , pathological grade , and stage of disease ( I or II ) correlate with recurrence-free time . A prognostic " survival " index was developed ; an index of greater than 7.5 indicated a poor prognosis and that chemotherapy was perhaps more appropriate than local radiation . Laparotomy is no longer justified as a routine procedure in staging HD , although it may still be useful in special circumstances and in some research investigations Three treatment programs for Stage I and II mediastinal Hodgkin disease ( established by laparotomy ) were compared . Involved-field radiotherapy + MOPP gave a disease-free survival rate of 97 % , significantly different from 62 % and 55 % for involved and extended fields , respectively . Corresponding survival figures of 97 % , 88 % , and 84 % were not significantly different statistically due to salvage with radiotherapy and /or chemotherapy . Among patients given radiotherapy alone , the survival figure of 94 % for limited mediastinal disease was significantly better than 63 % for extensive mediastinal and hilar disease ; corresponding disease-free figures of 72 % and 35 % were also significantly different . Constitutional symptoms were an important prognostic factor in disease-free survival following the use of involved fields ; hilar disease was important only with large mediastinal masses . Most relapses were intrathoracic ; MOPP alone salvaged only 47 % . Treatment of Stage I and II Hodgkin disease should be based on symptoms , extent of mediastinal disease , and hilar involvement We performed a r and omized clinical trial to assess the usefulness and toxicity of combined therapy compared with chemotherapy and radiotherapy in the treatment of early stage Hodgkin 's disease with bulky disease as an adverse prognostic factor . Three-hundred and seven patients were enrolled into the study . They were r and omized to receive either radiotherapy ( extended field , generally mantle , 3500 cGy ) , or chemotherapy ( adriamycin , bleomicin , vinblastine and dacarbazine : ABVD , 6 monthly ) cycles or combined therapy ( three cycles of ABVD , followed by irradiation therapy and three more cycles of chemotherapy ) . The median follow-up duration from start of treatment was 11.4 years . Complete response rates were similar in the three arms : 83 % for radiotherapy ( 95 % confidence interval [ CI ] 67 - 92 % ) , 80 % for chemotherapy ( CI 69 - 88 % ) and 87 % for combined therapy ( CI 74 - 94 % ) . However , disease-free survival and overall survival were better in the patients treated with combined therapy . At 12 years 76 % ( CI 51 - 93 % ) of the patients treated with combined therapy remained alive in the first complete remission compared with 42 % ( CI 26 - 61 % ) in patients treated with radiotherapy and 48 % ( CI 31 - 57 % ) in patients who had received chemotherapy alone ( P < 0.01 ) . Improvement in overall survival was also evident at 12 years : 88 % ( CI 59 - 93 % ) in those who had received combined therapy , compared with 53 % ( CI 36 - 67 % ) in the radiotherapy arm and 59 % ( CI 35 - 67 % ) in the chemotherapy group . Acute toxicity was more frequent in patients treated with combined therapy , but no death related treatment was observed in the three groups . Late toxicity was similar in the three treatment groups . Combined therapy with extended field radiotherapy and six cycles of chemotherapy is an effective treatment of patients with early stage bulky Hodgkin 's disease compared with chemotherapy or radiotherapy alone The intergroup study of involved-field ( IF ) radiotherapy , IF radiotherapy plus MOPP chemotherapy , and extended-field ( EF ) radiotherapy for treatment of Hodgkin 's disease in children has assessed 305 patients . Of these , 279 were " not ineligible " ( no mediate cause for disqualification ) . Among 223 r and omized patients , 144 were evaluable , 131 had documentation of complete or partial remission , 20 of the remitters relapsed , and two died . Among 62 nonr and omized patients with favorable presentations ( unilateral upper neck , unilateral inguinal , or massive mediastinal disease ) , 29 had documented remission , two relapsed , and none died . Length of initial disease control ( LIDC ) was used to measure duration of response . LIDC was best in patients given IF plus MOPP , and 95 % are disease free . EF was better than IF radiotherapy ( P = 0.004 ) . Of the disease characteristics prognostic for response ( stage , histologic subtype , and presence of symptoms ) , only the last factor had a statistically significant effect on LIDC ( P = 0.004 ) . Ninety-six percent of the patients survive . Using criteria developed by the committee , 23 % of the staging procedures review ed were nonevaluable and 28 % of the radiotherapy treatments were nonevaluable . The necessity for criteria for evaluation of staging and treatment is certain . Length of followup is too short for correlations of treatment with significant late effects and for relevant therapeutic recommendations A total of 277 patients with untreated Hodgkin 's disease , clinical stages I-II , were r and omized to cyclophosphamide , vinblastine , procarbazine , and prednisone ( CVPP ) alone for 6 monthly cycles or to CVPP plus radiation therapy ( RT ) , 3,000 rad , to involved areas ( CVPP plus RT ) . One or more of the following factors were considered as unfavorable prognosis : age greater than 45 years , more than two lymph node areas involved , or bulky disease . In the favorable group , disease-free survival ( 77 % vs. 70 % ) or overall survival ( 92 % vs. 91 % ) at 84 months for CVPP versus RT plus CVPP was similar . Patients with unfavorable prognosis treated with RT plus CVPP had longer disease-free survival ( 75 % vs. 34 % ) ( P = .001 ) and overall survival ( 84 % vs. 66 % ) than patients treated with CVPP alone PURPOSE To compare the effectiveness of chemotherapy ( CHT ) with extended-field radiotherapy ( RT ) in the treatment of early-stage Hodgkin 's disease ( ESHD ) , we report an 8-year up date d analysis of a study in which treatment with six cycles of mechlorethamine , vincristine , procarbazine , and prednisone ( MOPP ) CHT was r and omly compared with extended-field RT . PATIENTS AND METHODS From August 1979 to December 1982 , 89 adult patients with pathologic stage I-IIA Hodgkin 's disease ( HD ) were r and omly allocated to receive either RT with mantle field followed by periaortic irradiation ( n = 45 ) or six monthly courses of MOPP CHT ( n = 44 ) . RESULTS All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission . Twelve relapses occurred in each group . Eight patients treated with MOPP and two of the RT arm died of HD . Three other patients of the CHT group died because of a second cancer . With a median follow-up greater than 8 years , the overall survival rate is significantly higher in the RT than in the CHT group ( 93 % v 56 % ; P less than .001 ) , whereas the rates of freedom from progression and relapse-free survival ( RFS ) were similar in the two groups ( 76 % v 64 % and 70 % v 71 % , respectively ) . Of the 12 patients relapsing after RT , 11 ( 92 % ) achieved a second CR , compared with only six of the 12 ( 50 % ) in the MOPP group . Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR , whereas in the RT group , a second CR was obtained regardless of the characteristics of the relapses . At 80 months , the probability of survival of relapsing patients calculated from time of relapse was 85 % and 15 % in the RT and CHT groups , respectively ( P = .02 ) . CONCLUSION We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors Between 1972 and 1981 , the Eastern Cooperative Oncology Group completed two major studies of advanced Hodgkin 's disease . The first trial EST 2472 , demonstrated that the five-drug combination of carmustine ( BCNU ) , cyclophosphamide , vinblastine , procarbazine , and prednisone ( BCVPP ) is an effective alternative to mechlorethamine , vincristine , prednisone , and procarbazine ( MOPP ) chemotherapy . Although the complete remission ( CR ) rate for BCVPP ( 77 % ) was similar to that for MOPP ( 73 % ) in this r and omized trial , the choice of induction chemotherapy significantly influenced CR duration . Patients achieving CR with BCVPP had a significantly greater disease-free survival than those who achieved CR with MOPP ( 65 % vs 50 % , respectively , at 5 years , P = 0.02 ) . Overall survival is not different at this time between patients who received BCVPP and those who received MOPP . BCVPP produced significantly less gastrointestinal toxicity and neurotoxicity than MOPP . There was no influence on CR duration or survival with maintenance chemotherapy or BCG immunotherapy when compared to no further treatment . In the second trial , EST 1476 , there was only a 58 % CR rate with six cycles of low-dose bleomycin-MOPP induction chemotherapy . Complete responders and continuing partial responders were then r and omized to receive either non-cross-resistant chemotherapy with doxorubicin , bleomycin , vinblastine , and DTIC ( dacarbazine ) ( ABVD ) or low-dose radiotherapy to all sites of pretreatment involvement except bone marrow . Fifty percent of the partial responses were converted to CR with either ABVD or radiotherapy consolidation . The overall CR rate at the end of consolidation was 68 % . At the present time , there is no significant difference in disease-free or overall survival between ABVD and radiotherapy One hundred fifteen untreated patients with supra-diaphragmatic , pathologically staged ( PS ) IA-IIB Hodgkin 's disease ( HD ) were entered into a r and omised study comparing treatment using mantle radiotherapy followed by adjuvant treatment with mustine , vinblastine , prednisolone , and procarbazine ( MVPP ) with mantle radiotherapy alone .  Fifty-six patients were r and omised to receive radiotherapy alone ( RT ) and 59 to radiotherapy followed by six cycles of adjuvant MVPP ( RT + MVPP ) . One hundred fourteen patients achieved a complete remission ( CR ) with radiotherapy . One patient achieved a partial remission . The overall 10-year survival after correction for intercurrent death was 92 % with no difference between the two treatment groups ( 90 % for RT alone and 95 % for RT + MVPP P = 0.66 ) . There were 9 ( 8 % ) deaths from HD ( 5 patients had received RT alone ) , and 10 ( 9 % ) intercurrent deaths . Eight ( 7 % ) patients have developed a second malignancy , and two of them are alive . No patient has developed secondary acute myelogenous leukaemia . The 10-year relapse-free survival ( RFS ) was 79 % overall , 67 % in the RT group , and 91 % in the RT + MVPP group ( P = 0.0004 ) . There were 25 relapses ; 20 patients had received RT alone and 5 had received adjuvant MVPP . Of the relapsed patients , 13 ( 52 % ) have received successful salvage therapy and are in CR . In the RT alone group , 45 ( 80 % ) patients are alive in CR , 5 ( 9 % ) died of HD , and 6 ( 11 % ) died of intercurrent causes . In the adjuvant MVPP group , 51 ( 86 % ) are alive in CR , 4 ( 7 % ) died of HD , and 4 ( 7 % ) died of intercurrent causes . ( ABSTRACT TRUNCATED AT 250 WORDS Between 1974 and 1977 , the Cancer and Leukemia Group B ( CALGB ) initiated four studies which address current major questions in the therapy for Hodgkin 's disease . The efficacy of chemotherapy alone as compared with combined modality therapy in patients with poor-prognostic stages I and II is evaluated in CALGB 7751 . Currently , both therapies produce very high complete remission rates in asymptomatic patients ; the remission rate is better with combined modality therapy in symptomatic patients . Single and combined modality therapies are compared for stage III patients in CALGB 7451 . Complete remission rates have been similar , but relapse-free survival is superior for patients treated with local nodal radiotherapy followed by chemotherapy ( P = 0.04 ) . In particular , stage IIIA patients with nodular sclerosis seem to benefit from the inclusion of radiotherapy in their initial treatment . In CALGB 7551 , the efficacy of chemotherapy alone versus chemotherapy plus radiotherapy to areas of bulky disease is under study in patients with stages IIIB and IV . Currently , a relapse rate of less than 10 % has been seen among sites irradiated , and survival is best for patients treated with radiotherapy bracketed by chemotherapy . Finally , the role of two alternating non-cross-resistant combination chemotherapy programs is being studied in CALGB 7552 . Relapse-free and overall survival is better with the doxorubicin-containing regimen than with either the alternating or alternate chemotherapy program . At present , the median followup for each of these studies is less than 5 years . Further observation is required to answer the critical questions relating to prolonged disease-free survival and cure PURPOSE We have demonstrated that a relatively mild chemotherapy regimen , vinblastine , methotrexate , and bleomycin ( VBM ) , and involved-field radiotherapy ( IFRT ) could substitute for extended-field radiotherapy in patients with favorable Hodgkin 's disease ( HD ) who have been laparotomy-staged . The purpose of this study is to determine if VBM and regional radiotherapy can substitute for extended-field radiotherapy in favorable clinical stage ( CS ) I and II HD . PATIENTS AND METHODS Seventy-eight patients with favorable CS I to II HD were r and omly assigned to subtotal lymphoid irradiation ( STLI ) or VBM chemotherapy and regional radiotherapy . R and omization was stratified on the basis of age , sex , number of Ann Arbor sites , histology , and institution . Patients were evaluated for freedom from progressive HD , survival , and toxicity . Results were compared with the predecessor trial in pathologically staged patients . RESULTS With a median follow-up period of 4 years , the rate of freedom from progressive HD was 92 % ( 95 % confidence interval [ CI ] , 88 % to 96 % ) for patients treated with STLI and 87 % ( 95 % CI , 81 % to 93 % ) for patients treated with VBM and regional radiotherapy . Six of seven patients who relapsed are alive and in remission following successful second-line therapy . CONCLUSION Given the caveat of a small number of patients , the results of extended-field radiotherapy and VBM and regional radiotherapy are comparable with a median follow-up period of 4 years . VBM serves as a paradigm to reduce late effects in favorable early-stage HD . We do not advocate its routine use in clinical practice , but instead encourage participation in clinical trials with the objective of maintaining efficacy while reducing toxicity in CS I and II HD 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 prospect i ve r and omized trial in extensive untreated Hodgkin 's disease was undertaken to assess the potential benefit of augmented therapy ( 12 months chemotherapy or radiation to known disease ) compared to st and ard 6 months chemotherapy . PATIENT AND METHODS A total of 258 patients , mostly Stage IV , were r and omized to four treatment regimens consisting of six cycles of CCNU , vinblastine , procarbazine , and prednisone ( CVPP ) ; 12 cycles of CVPP ; six cycles of CVPP followed by 25 Gy radiotherapy ; or three cycles CVPP , 25 Gy radiotherapy , and three cycles CVPP . RESULTS Complete remissions were achieved in 65 % of all patients . A 58 % overall 5-year survival rate was obtained . Relapses in irradiated areas of known disease occurred in only 6 % of responding patients . There was , however , no statistical difference in response frequency , disease-free survival , or overall survival among the four regimens . Elderly patients responded less frequently . CONCLUSION While radiotherapy provided control of local ( known ) disease , no impact on overall survival was apparent . Likewise , doubling the duration of chemotherapy did not improve response or survival . Augmentation of therapy with either radiotherapy or more chemotherapy in this study was of no benefit compared to the st and ard 6 months of treatment In a prospect i ve r and omized study of treatment with radiation therapy ( RT ) or RT followed by chemotherapy ( CT ) for patients with Hodgkin 's disease stages I-III , four patients developed acute nonlymphocytic leukemia ( ANLL )  during post-treatment follow-up . There was a significant relationship between the intensity of the treatment and the appearance of this complication : no cases of ANLL were observed among the 128 patients treated with involved field ( IF ) RT , IF RT followed by CT , total nodal RT alone ( TNR ) , or total lymphoid irradiation alone ( TLI ) after a follow-up from 21 to 126 + months ( median follow-up 76 months ) . In contrast , four of 36 patients treated with extensive RT followed by CT developed ANLL at 17 , 63 , 72 , and 91 months . Three of these patients had received TLI + CT , the fourth one TNR + CT The 2 clinical trials described herein were initiated in 1962 with the following objectives : ( a ) to determine whether intensive prophylactic irradiation of apparently uninvolved lymph node regions adjacent to clinical ly involved regions in patients with regionally localized Hodgkin 's disease increases the duration of remission and of survival ; ( b ) to determine whether potentially curative doses of radiation given to patients with generalized Hodgkin 's disease are more effective than palliative doses , as measured by length of remission and /or survival ; ( c ) to accumulate additional information on the natural history of Hodgkin 's disease in patients whose clinical stage was , in all instances , determined with the aid of lymphangiography and other special diagnostic procedures ; ( d ) to evaluate the tolerance of normal tissues in patients treated with extended-field , high-dose radiations . Patients who met the defined eligibility criteria were assigned to alternative treatment groups at r and om after an extensive diagnostic evealuation , which included lymphangiography , open bone marrow biopsy , and a battery of liver function tests , as well as other , more routine procedures in all cases . All patients were carefully examined at serial intervals , following completion of the defined radiotherapeutic program . Follow-up intervals are not yet long enough to permit evaluation of comparative survival in the various treatment groups . However , it is clear that extended-field megavoltage radiotherapy to doses in the range of 4000 rads , given at the rate of about 1000 rads/week , is surprisingly well tolerated ; there have been virtually no major complications , and most of the observed hematologic , respiratory , neurologic , and endocrine complications have been relatively mild and transient in nature Since 1964 , the European Organisation for Research and Treatment of Cancer has conducted three subsequent clinical trials on clinical Stages ( CS ) I + II Hodgkin 's disease ( HD ) in which 1059 patients have been entered . The first trial compared regional radiotherapy ( RT ) with mantle field or inverted Y , versus the same RT followed by a weekly injection of vinblastine for 2 years . The relapse free survival ( RFS ) and overall survival ( S ) were higher in patients treated by RT and chemotherapy ( CT ) . This benefit , however , was significant only in patients with a mixed cellularity histologic type . The second trial compared the therapeutic efficacy of splenic irradiation versus splenectomy and found that in both arms , RFS and S were identical . Moreover , it was found that splenic involvement was correlated with an increased incidence of relapse in extranodal sites and in non irradiated lymphatic areas . In this trial , CT was given only to patients with poor histologic types , mixed cellularity or lymphocytic depletion . In the third trial , staging laparotomy was performed only to further delineate a good prognostic group which could be treated by RT alone . In this limited treatment group , there was no difference in RFS and S between mantle field and mantle field + para-aortic RT . In the extensive treatment group , total nodal irradiation ( TNI ) was compared with RT + MOPP . The RFS was slightly lower in the TNI arm , but there was no significant difference in S. The data of the 3 trials underline the importance of prognostic factors in the choice of optimal treatment and show that their significance depends upon the type of treatment . Multivariate statistical analyses showed that the main prognostic factors , which can help to identify the subsets of patients who can be treated by RT alone , are ( 1 ) systemic symptoms and elevated erythrocyte sedimentation rate ( ESR ) , ( 2 ) the number of involved lymphatic areas , and ( 3 ) staging laparotomy .  Extended RT ( mantle + para-aortic + spleen treatment ) gives satisfactory results in patients without systemic symptoms and /or elevated ESR and one or two involved sites , whereas TNI or combined modality treatment becomes m and atory for patients with 3 or more involved sites or splenic involvement and /or systemic symptoms . With proper adjustment of the irradiated volume , a very large proportion of CS I + II patients can be best treated by RT alone The European Organization for Research and Treatment of Cancer ( EORTC ) Lymphoma Cooperative Group was founded in 1963 as the  Radiotherapy-Chemotherapy  Group . It changed its name in 1986 because the main study objects of the group were Hodgkin ’s disease and non-Hodgkin ’s lymphoma . Its aim is to organize multicenter trials between European hospitals , mainly Dutch , French , and Belgian , but recently extended with groups from Switzerl and The treatment of advanced Hodgkin 's disease ( HD ) with chemotherapy ( CTx ) alone or combined modality treatments has been controversial . In 1989 , we design ed a r and omized study to compare 2 cycles of CTx to (sub)total nodal irradiation ( RTx ) as consolidation treatments for patients with stage IIIB/IV HD in complete remission ( CR ) or good partial response after 6 cycles of CTx .  A total of 559 patients were r and omized to receive 6 cycles of MOPP/ABV ( mechlorethamine , vincristine , procarbazine , prednisone/Adriamycin [ doxorubicin ] , bleomycin , vinblastine ) hybrid ( n = 266 ) or ABVPP ( n = 267 ) . After induction treatment , 418 patients could be evaluated for the consolidation phase . With a median follow-up of 48 months , the 5-year disease-free survival estimates were 80 % for 8 cycles of MOPP/ABV , 82 % for 6 cycles of MOPP/ABV plus RTx , 68 % for 8 cycles of ABVPP , and 75 % for 6 cycles of ABVPP plus RTx ( P = .01 ) . The 5-year disease-free survival estimates did not differ between CTx and RTx , 74 % and 79 % , respectively ( P = .07 ) . After MOPP/ABV , the 5-year overall survival estimates did not differ between CTx and RTx , 85 % and 88 % , respectively ( P = .2 ) . After ABVPP , the 5-year survival estimates were 94 % for CTx and 78 % for RTx ( P = .002 ) . These results showed that RTx was not superior to CTx consolidation after doxorubicin-induced CR for patients with advanced HD . Because of the uncertainty of obtaining a prolonged second remission for patients relapsing after CTx and RTx and the possible long-term effects of RTx , we prefer 8 cycles of CTx as st and ard treatment when a CR has been achieved after 6 cycles Between Jan 1 , 1968 , and Dec 31 , 1980 , 108 previously untreated patients with Hodgkin 's disease pathologic stages ( PSs ) IA ( 29 patients ) and IIA ( 79 patients ) initially received radiotherapy alone . One postoperative death ( due to pulmonary embolus ) ( 0.9 % ) occurred , with one serious complication ( 0.9 % ) . Between 1968 and 1973 , patients were r and omized to receive either  involved field radiation treatment ( RTIF ) or extended field radiation treatment ( RTEF ) .  Since 1973 all patients have received RTEF , 4,000 cGy in four to five weeks , with a median follow-up of 7.4 years . Complete remission ( CR ) was achieved in 102 patients ( 94.4 % ) , with no significant difference according to treatment or stage . Of the complete responders , 25 patients relapsed : 5/15 RTIF and 20/87 RTEF ( P = .6 ) . Twenty-one of 25 relapsing patients achieved a second CR . Disease free survival rates at five and ten years constituted : PS IA , 78.6 % for both ; PS IIA , 74.8 % and 73.1 % ( P = .6 ) ; RTEF , 76.7 % for both ; RTIF , 73.3 % and 66.7 % ( P = .7 ) . Eighteen patients have died : eight of recurrent lymphoma , two of pulmonary embolus , one each of myocardial infa rct ion , pulmonary fibrosis , and acute nonlymphocytic leukemia ( ANLL ) ( following salvage chemotherapy ) , and one of diffuse histiocytic lymphoma ( DHL ) . Four patients died in remission of unrelated causes . Actuarial survival rates at five and ten years constituted : PS IA , 95.7 % and 72.4 % ; PS IIA , 89.6 % and 81.4 % ( P = .3 ) ; RTIF , 93.7 % for both ; RTEF , 90.7 % and 71.2 % ( P = .2 ) . Age , sex , number of sites , and mediastinal involvement did not influence the outcome . Acute toxicity was modest and more frequent among those receiving RTEF ( P = .08 ) . Chronic toxicity ( onset more than 30 days after completion of treatment ) was identified in 16 patients : 1/16 RTIF ; 15/92 RTEF ( P = .5 ) . Three patients developed a second malignancy : one carcinoma of the cervix in situ ; one ANLL ( following salvage chemotherapy ) ; and one DHL of the stomach . At least 75 % of patients with PS IA and IIA Hodgkin 's disease were cured by radiation alone , with a risk of secondary malignancy following radiation alone of 0.9 % . Since the majority of relapsing patients were successfully salvaged by chemotherapy , radiation alone appears to be the initial treatment of choice in this group of patients Sixty-eight untreated patients with Hodgkin 's disease ( HD ) , stages I-III , presenting with a large mediastinal mass were treated as follows : patients with " good-risk HD " ( lymphocyte predominant or nodular sclerosis and no " B " symptoms ) stages I and II were treated by r and omization with involved field radiotherapy ( IF RT ) or IF RT plus six cycles of combination chemotherapy ( CT ) .  Those with " poor-risk HD " ( presence of B symptoms or with other histologic types ) stages I and II and all patients with stage III were treated by r and omization with total nodal radiation ( TNR ) or TNR + CT .  Complete remission ( CR ) was achieved in 66/68 patients ( 97 % ) with the initial RT . A significantly longer duration of remission ( p = 0.001 ) , but not of survival ( p = 0.08 ) was observed in patients treated with RT + CT compared to RT alone . Significantly longer duration of remission ( p = 0.01 ) , but not of survival , was observed in patients with good-risk stages I-II treated with RT + CT . In this category , remission and survival was better with RT + CT than with RT alone in stage III , but these differences were not statistically significant . In poor-risk patients stages I-II , a trend for longer remission and survival ( not significant ) was observed in patients treated with RT + CT ; in stage III , both treatment modalities gave similar poor results . Both treatment modalities were well tolerated by most patients . One patients died with radiation pneumonitis shortly after completion of TNR . One patient developed a malignant schwannoma after treatment with IF RT , and another one developed acute nonlymphocytic leukemia after TNR + CT . Decrease in the transverse diameter of the heart without overt manifestations of cardiac disease was observed in 59 % of the patients evaluated for this parameter 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 SINCE 1964 , all the efforts of the Lymphoma Group of the EORTC ( European Organisation for Research and Treatment of Cancer ) have been devoted to the task of tailoring treatment to the presentation of Hodgkin ’s disease ( HD ) for any given patient [ l-12 ] . We will first briefly review the results of the four controlled studies conducted by the group from 1964 to 1988 for stages I and II HD . We will then present in detail the design s of the on-going H7 r and omised trials for these same subsets of Hodgkin ’s disease patients Sixty consecutive previously untreated adults with surgically confirmed stage IIIA Hodgkin 's disease ( 39 stage IIIA1 , 21 stage IIIA2 ) began therapy at St. Bartholomew 's Hospital between 1969 and 1981 . Prior to 1973 , treatment consisted of total nodal irradiation ( TNI ) . From 1973 until 1978 patients were r and omly allocated to receive either TNI or cyclic combination chemotherapy of mustine , vinblastine , prednisolone , and procarbazine ( MVPP ) as part of a Medical Research Council Trial . Since 1978 treatment has been allocated according to substage , those with stage IIIA1 receiving TNI and those with stage IIIA2 receiving MVPP . Seven patients received " non protocol " therapy ( extended mantle radiotherapy in three patients , mantle and MVPP in four patients ) , and have been excluded from the study . Complete remission was achieved in 48 of 53 patients regardless of substage or therapy . Seven have relapsed , one after MVPP and six after TNI . The predicted freedom-from-relapse after MVPP was 96 % compared with 60 % after TNI , both at 10 years ( p less than 0.01 ) . The relapse pattern was the same for both substages in the group receiving TNI . Although overall survival of patients receiving TNI was identical to that of those receiving MVPP , TNI must be considered inappropriate therapy for stage IIIA Hodgkin 's disease if permanent freedom-from-recurrence is the goal Abstract One hundred and two patients with previously untreated Hodgkin 's disease , stages IB through IIIB , were r and omized within their pathological stage to receive total-lymphoid radiation , eithe This paper reports the five-year follow-up ( range , 1 - 8 years ) of 56 patients with pathologic stage IIIA Hodgkin 's disease r and omized for chemotherapy alone or chemotherapy followed by radiotherapy to previous areas of disease ( 26 treated with mustine , vinblastine , procarbazine , and prednisolone [ MVPP ] alone , 30 with MVPP and radiotherapy )  . Of the 56 patients 53 ( 95 % ) achieved a complete remission with chemotherapy and of these only five ( 9 % ) have relapsed ; three died of Hodgkin 's disease . There was no improvement in relapse-free survival associated with the uses of radiotherapy following chemotherapy but in view of the small numbers of relapses and the excellent results following chemotherapy alone , a significant improvement could not be expected . The use of MVPP alone can be recommended as an alternative therapy for patients with stage IIIA Hodgkin 's disease . This avoids both the physical and psychologic morbidity associated with the high relapse rate following extensive primary radiotherapy and the necessity of combined modality treatment for about half these patients . The question of whether radiotherapy should be given to areas of previous bulk following chemotherapy has not yet been answered in this trial which is continuing The Acute Leukemia Group B has studied the effect of combining chemotherapy and intensive radiotherapy in patients with stage III Hodgkin 's disease .  Toxicity was most severe in patients given chemotherapy first and in patients 50 years or older . The combination therapy could be given with relative ease after splenectomy . At three years , the median survival time of all patients has not been reached , but already a pronounced effect of age upon survival has been found . The median survival is 18 months for patients 50 years or older , 32 months for those patients between 30 and 49 years old , and after 48 months no median is in sight for the youngest age group BACKGROUND Failure to reach complete remission ( CR ) with chemotherapy in advanced stages of Hodgkin 's disease is considered a poor prognostic factor for progression-free and overall survival . The role of radiotherapy after chemotherapy-induced remission is controversial . PATIENTS AND METHODS In 1989 , the EORTC/GPMC started a r and omized phase III trial on involved-field RT ( IF-RT ) after MOPP/ABV hybrid-induced remission in patients with stage III/IV Hodgkin 's disease . In this ongoing trial , patients in CR after chemotherapy  are r and omized between IF-RT and no further treatment . Patients in partial remission ( PR ) all receive IF-RT .  Patients , age 15 - 70 years , with previously untreated stage III/IV Hodgkin 's disease are eligible . The r and omized treatment arms are still blinded . The interim analysis of May 1996 focuses on the outcome of patients in chemotherapy-induced PR . RESULTS A total of 405 of 493 registered patients were evaluable for response to chemotherapy . Fifty-nine percent of patients attained a CR , 37 % a PR , and only 4 % failed to respond . The IF-RT was actually given to 90 % of the PR patients . After a median follow-up of 43 months , the five year progression-free and overall survival for patients in PR was 75 % and 87 % , respectively . CONCLUSION IF-RT after MOPP/ABV-induced partial remission in stage III/IV Hodgkin 's disease produces excellent failure-free and overall survival . Early intensification of treatment of this group of patients is not indicated 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 Four hundred sixty patients enrolled in a r and omized trial of involved field ( IF ) and extended field ( EF ) radiotherapy for Hodgkin 's disease Stages I and II in the years 1967 to 1973 have been followed to a maximum of 13 years . Minimum time at risk is 6 years , and median follow‐up is 8 years . Actuarial survivals are 85 % IF and 87 % EF at 5 years . The overall st and ardized risk ratio comparing IF with EF is 1.3 , implying a 30 % excess mortality in IF , a nonsignificant difference . For males the risk ratio is 1.7 and significant , whereas for females it is 0.6 , a nonsignificant reduction in risk with IF therapy . Extension‐free survival was significantly better in the EF group than in the IF within 2 years after treatment , and that benefit persists to the current follow‐up , with extension‐free survivals of 42 % IF and 64 % EF at 5 years . The risk ratio is 1.7 . Favorable survival is significantly correlated with initial characteristics of female sex , age younger than 40 years , and histologic type nodular sclerosis or lymphocyte predominance . Histologic type is the most powerful predictor in the total series , but its prognostic value is not seen in patients staged with laparotomy . Six cases of leukemia have been reported in this series , among whom less than one case would be expected at general population rates . All leukemias have occurred in 167 patients who required  chemotherapy  for extension of Hodgkin 's disease after initial radiotherapy , implying an increased risk following chemotherapy of more than 200‐fold The study population included 136 patients with stage IA , IB , IIA , IIB , or IIIA1 Hodgkin 's disease . The median follow-up is 7.5 years . Among the 30 patients with peripheral IA disease , all patients achieved a complete response ( CR ) with radiation therapy , and no patient has relapsed . Patients of other stages were r and omized to receive radiation therapy or mechlorethamine , vincristine , procarbazine , and prednisone ( MOPP ) . Among the 51 patients r and omized to receive  radiation therapy  , 49 ( 96 % ) achieved complete remission , 17 ( 35 % ) have relapsed , and 10 ( 20 % ) have died . Fifty-two of the 54 ( 96 % ) assessable patients r and omized to receive MOPP obtained CRs , seven ( 13 % ) have relapsed , and four ( 7 % ) have died . The projected 10-year disease-free survival of patients r and omized to receive radiation therapy is 60 % ; for those r and omized to receive MOPP , it is 86 % ( P2 = .009 in favor of MOPP ) . The projected 10-year overall survival for patients r and omized to radiation therapy is 76 % , and for MOPP-treated patients it is 92 % ( P2 = .051 in favor of MOPP ) . When the r and omized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis , the disease-free ( 67 % for radiation v 82 % for MOPP ) and overall survival ( 85 % for radiation v 90 % for MOPP ) were not significantly different between the two arms . Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups : stage IIIA1 or massive mediastinal disease , no B symptoms , initial erythrocyte sedimentation rate greater than 20 mm , four or more sites of disease , and younger than age 40 years . Preliminary analysis of this ongoing study shows that  MOPP chemotherapy  is at least as effective as radiation therapy  in the treatment of the specific groups of early-stage Hodgkin 's disease patients r and omized . The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed PURPOSE A r and omized trial design ed to compare mechlorethamine , vincristine , procarbazine , and prednisone (MOPP)/doxorubicin , bleomycin , vinblastine , and daccarbazine ( ABVD ) ( regimen A ) with ABVD plus low-dose regional ( extended-field ) radiation therapy ( EF RT ) ( regimen B ) for the treatment of children and adolescents with stages III and IV Hodgkin 's disease was conducted by the Children 's Cancer Group ( CCG-521 ) from 1986 until 1990 . PATIENTS AND METHODS One hundred eleven eligible patients were r and omized , 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin 's disease . RESULTS Overall survival ( S ) is 87 % at 4 years and event-free survival ( EFS ) is 82 % . Patients r and omized to ABVD plus EF RT have a 4-year EFS of 87 % compared with 77 % for patients r and omized to MOPP/ABVD ( P = .09 , two-sided ) . Patients r and omized to ABVD plus EF RT have a 4-year S of 90 % compared with 84 % for patients r and omized to MOPP/ABVD ( P = .45 , two-sided ) . Significant prognostic factors in multivariate analysis for EFS are stage of disease , erythrocyte sedimentation rate ( ESR ) at diagnosis , liver size at diagnosis , and , among stage III patients , the size of the mediastinal mass at diagnosis . The acute toxicities of treatment are largely hematopoietic in nature , whereas acute pulmonary and cardiac toxicities are modest and not limiting . CONCLUSION The results of this study show that , in advanced-stage Hodgkin 's disease in children , equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen ; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing . It is clear , however , that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin 's disease in pediatric patients A progress report is presented of a r and omized clinical trial being conducted at Stanford University to test the value of combination chemotherapy following total lymphoid irradiation for patients with Hodgkin 's disease . One hundred and thirteen previously untreated patients , with intermediate stages of disease , IB to IIIB , have been entered into the trial . The tolerance of patients to the prolonged aggressive treatment program is considered acceptable . With maximum follow‐up , approaching 4 years since onset of treatment , significant improvement in disease‐free survival has been observed , and overall survival is excellent . The factors which should make for a cautious interpretation of these early results are review ed The H5 study of supradiaphragmatic Hodgkin 's disease in clinical stages I-II consisted of two controlled trials adapted to patients considered to have either favorable or unfavorable characteristics , based on prognostic factors identified in two former studies by the European Organization for Research and Treatment of Cancer . Of 494 patients , 257 who were classified as having unfavorable prognosis qualified for the more intensive treatment and consequently were spared a staging laparotomy . They were r and omized either to total nodal irradiation ( TNI ) ( 132 patients ) or to treatment with mechlorethamine , vincristine , procarbazine , and prednisone ( MOPP ) alternated with mantle irradiation ( MOPP X 3-mantle irradiation-MOPP X 3 ; 3 M ) ( 125 patients ) . In complete responders ( 96 % ) , the 6-year relapse-free survival was 77 % in the TNI arm and 91 % in the 3 M arm ( P = .02 ) . Relapses in the initially involved and irradiated mantle area were less frequent in patients started on MOPP . The 6-year actuarial total survival ( TS ) ( TNI , 82 % , and 3 M , 89 % ; P = .05 ) appeared to favor the 3 M arm , but this difference disappeared when patients dying from causes unrelated to cancer were excluded from analysis . In men less than or equal to 40 years old , there was no difference in relapse-free survival , freedom from disease progression , or TS between the groups receiving TNI and 3 M . Thus , TNI is a short and appealing treatment , especially because it preserves fertility . The same observation was true in women less than or equal to 40 years old . In addition , even irradiation less than TNI , which is meant to spare the ovaries , provided a TS similar to that for 3 M Eighty-seven patients with newly diagnosed Hodgkin 's disease , pathologic stages IA , IIA , IIB and IIIA , were assigned at r and om to receive either extended field radiotherapy alone or that therapy followed by six cycles of MOPP ( nitrogen mustard , Oncovin , procarbazine , prednisone ) chemotherapy .  Patients were entered into the study from January 1970 to January 1974 . Patients were followed for a median of 69 + months from the end of all treatments . Patients whose disease was less than stage IIIA had a 31 per cent relapse rate with radiotherapy alone compared to a 6 per cent relapse rate with combined modality treatment ( P = 0.04 ) . No deaths from Hodgkin 's disease have occurred in patients who received combined modality therapy , whereas 24 per cent of the patients who received radiotherapy alone have died with active disease . However , three patients with stage IIIA disease who were treated with both modalities have died from other causes ( myocardial infa rct ion , adenocarcinoma of lung , acute leukemia ) .  Combined modality therapy of patients with early Hodgkin 's disease may be superior to radiotherapy alone , especially for certain subgroups of patients discussed in detail PURPOSE The management of early-stage Hodgkin 's disease in the United States is controversial . To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkin 's disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients , a phase III intergroup trial was performed . PATIENTS AND METHODS Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkin 's disease were r and omized without staging laparotomy to treatment with either subtotal lymphoid irradiation ( STLI ) or combined-modality therapy ( CMT ) consisting of three cycles of doxorubicin and vinblastine followed by STLI . RESULTS The study was closed at the second , planned , interim analysis because of a markedly superior failure-free survival ( FFS ) rate for patients on the CMT arm ( 94 % ) compared with the STLI arm ( 81 % ) . With a median follow-up of 3.3 years , 10 patients have experienced relapse or died on the chemoradiotherapy arm , compared with 34 on the radiotherapy arm ( P < .001 ) . Few deaths have occurred on either arm ( three deaths on CMT and seven deaths on STLI ) . Treatment was well tolerated , with only one death on each arm attributed to treatment . CONCLUSION These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone . Extended follow-up is necessary to assess freedom from second relapse , overall survival , late toxicities , patterns of treatment failure , and quality of life To determine if the use of adjuvant radiotherapy to sites of initial bulky disease and adequate modern chemotherapy in patients with advanced stages ( IIIB and IV ) Hodgkin 's disease could improve duration of remission and overall survival .  Patients previously untreated with pathologically documented advanced stages Hodgkin 's disease were r and omly assigned to received chemotherapy alone with EBVD regimen ( epirubicin , bleomycin , vinblastine and dacarbazine ) :  56 patients or combined therapy : The same chemotherapy regimen following by adjuvant radiotherapy ( 35 Gy ) to sites of initial bulky disease ( tumor mass > 7 cm diamenter ) : 54 patients .  Five year overall survival rates were 88 % ( 48 patients ) and 60 % ( 34 patients ) from combined therapy compared to chemotherapy alone respectively ( p < 01 ) ( 95 % confidence interval ( CI ) : for the difference 18 % to 39 % ) . Five-year failure free survival were 83 % and 50 % respectively ( p < 01 ) ( 95 % CI for difference : 22 % to 35 % ) . Toxicity was moderate and well tolerate . No death-related treatment were observed . After a median follow-up of 66 months , no second solid neoplasmas or acute leukemia has been observed . The use of adjuvant radiotherapy to sites of initial bulky disease following the use of modern chemotherapy in patients with advanced stages Hodgkin 's disease improve outcome with increase in failure free survival and overall survival , with moderate toxicity . More r and omized clinical trials are warranted to define this therapeutic approach
BACKGROUND Second malignancies ( SM ) are a major late effect of treatment for Hodgkin 's disease ( HD ) .
Reliable comparisons of SM risk between alternative treatment strategies are lacking .
OBJECTIVES Radiotherapy ( RT ) , chemotherapy ( CT ) and combined chemo-radiotherapy ( CRT ) for newly-diagnosed Hodgkin 's disease are compared with respect to SM risk , overall ( OS ) and progression-free ( PFS ) survival .
Further , involved-field (IF-)RT is compared to extended-field (EF-)RT .