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Originally published as JCO Early Release 10.1200/JCO.2005.05.2746 on June 5 2006 © 2006 American Society of Clinical Oncology. Combined-Modality Therapy for Clinical Stage I or II Hodgkin's Lymphoma: Long-Term Results of the European Organisation for Research and Treatment of Cancer H7 Randomized Controlled Trials
From the Departments of Radiotherapy and Hematology, Leiden University Medical Center, Leiden; Departments of Hematology and Radiotherapy, Daniël den Hoed Cancer Center, Rotterdam; Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam; Department of Radiotherapy, Radiotherapeutisch Instituut Limburg, Heerlen; Department of Hematology, University Medical Center Nijmegen, Nijmegen, the Netherlands; Departments of Medical Oncology, Radiotherapy, Pathology, and Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif; Department of Medical Oncology, Centre Henri Becquerel, Rouen; Department of Hematology, Institut Bergonié, Bordeaux; Department of Hematology and the Clinical Research Unit, Centre François Baclesse, Caen, France; Department of Medical Oncology, Centro di Riferimento Oncologico, Aviano, Italy; Department of Oncology, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; and Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenija Address reprint requests to Evert M. Noordijk, MD, Department of Radiotherapy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands; e-mail: e.m.noordijk{at}lumc.nl
PURPOSE: In early-stage Hodgkin's lymphoma (HL), subtotal nodal irradiation (STNI) and combined chemotherapy/radiotherapy produce high disease control rates but also considerable late toxicity. The aim of this study was to reduce this toxicity using a combination of low-intensity chemotherapy and involved-field radiotherapy (IF-RT) without jeopardizing disease control. PATIENTS AND METHODS: Patients with stage I or II HL were stratified into two groups, favorable and unfavorable, based on the following four prognostic factors: age, symptoms, number of involved areas, and mediastinal-thoracic ratio. The experimental therapy consisted of six cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by IF-RT. It was randomly compared, in favorable patients, to STNI and, in unfavorable patients, to six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV hybrid) and IF-RT. RESULTS: Median follow-up time of the 722 patients included was 9 years. In 333 favorable patients, the 10-year event-free survival rates (EFS) were 88% in the EBVP arm and 78% in the STNI arm (P = .0113), with similar 10-year overall survival (OS) rates (92% v 92%, respectively; P = .79). In 389 unfavorable patients, the 10-year EFS rate was 88% in the MOPP/ABV arm compared with 68% in the EBVP arm (P < .001), leading to 10-year OS rates of 87% and 79%, respectively (P = .0175). CONCLUSION: A treatment strategy for early-stage HL based on prognostic factors leads to high OS rates in both favorable and unfavorable patients. In favorable patients, the combination of EBVP and IF-RT can replace STNI as standard treatment. In unfavorable patients, EBVP is significantly less efficient than MOPP/ABV.
In the last 40 years, the treatment of early-stage Hodgkin's lymphoma (HL) has become successful, especially after the introduction of extended-field radiotherapy (EF-RT) and combination chemotherapy.1 Unfortunately, in survivors, high-dose large-field radiotherapy and intensive chemotherapy were followed by severe long-term adverse effects such as sterility, pulmonary and cardiac toxicity, and second cancers.2-11 More recent clinical studies in early-stage HL are exploring treatment strategies that are expected to have less adverse effects but still provide overall survival (OS) rates of 90% or greater.12,13 Since 1964, the Lymphoma Group of the European Organisation for Research and Treatment of Cancer (EORTC) has investigated treatment strategies for stages I and II HL. In the H5 and H6 trials, prognostic factors were used to stratify patients into favorable and unfavorable subgroups, with treatment intensity tailored to the projected clinical outcome.14 In 1988, the H7 trial was designed, aiming at maximal reduction of treatment-related toxicity in early-stage HL.15 Mediastinal bulky mass, as measured by the mediastinal-thoracic (MT) ratio,16 was introduced as a new prognostic factor. On the basis of data from the H2 and H5-F trials14,17 and from the literature,3,18,19 staging laparotomy was abandoned in all patients. Combined-modality treatment was tested for the first time not only in unfavorable patients but also in favorable patients. A newly developed chemotherapy scheme, epirubicin, bleomycin, vinblastine, and prednisone (EBVP), which is a modification of the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) scheme, was used.20-23 The EBVP regimen was expected to have lower cardiac toxicity because of the replacement of doxorubicin with epirubicin,24 less nausea and vomiting because of the replacement of dacarbazine by prednisone, and good tolerance and compliance (with only one injection every 3 weeks and six cycles administered in 4.5 months). This EBVP scheme was combined with reduced radiotherapy. As shown by the Groupe Pierre-et-Marie-Curie trial,25 it seemed possible to replace the classic mantle-field irradiation by a more limited irradiation to previously involved areas only (so-called involved-field radiotherapy [IF-RT]), relying on the chemotherapy for the treatment of microscopic disease in macroscopically uninvolved areas. In this way, the irradiation of normal tissues, such as breast, heart, and lungs, was reduced. The combination of EBVP and IF-RT was central in the study as a common treatment arm in two parallel randomized trials within two prognostic groups. In favorable patients, it was tested against subtotal nodal irradiation (STNI), with the expectation of less toxicity. In unfavorable patients, it was tested against the mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) hybrid scheme,26 combined with radiotherapy, with the aim of equivalent efficacy. The MOPP/ABV hybrid scheme was considered the standard treatment for unfavorable patients when the trial was designed; the superiority of ABVD over MOPP, as proven by the EORTC H6-U study,27 was not yet known.
Patients Patients between 15 and 70 years of age with previously untreated stage I or II supradiaphragmatic HL were eligible. Inclusion was based on the diagnosis made by the local pathologist. All pathology specimens were reviewed by a panel of pathologists (see Appendix), but treatment was not changed on the basis of the review diagnosis. Apart from routine staging work-up (including physical examination, CBC, computed tomography scans of thorax and abdomen, and bone marrow biopsy), the registration of the number of involved areas, the erythrocyte sedimentation rate (ESR) after 1 hour, and the MT ratio16 was mandatory. The five major nodal areas were defined as follows: the whole neck including the supraclavicular area (left and right); the axilla including the infraclavicular area (left and right); and the whole mediastinum including the hilar nodes on both sides (one area). The trial protocol was approved by the Protocol Review Committee of the EORTC and by all local ethics committees. Written informed consent was required before random assignment.
Stratification, Random Assignment, and Treatment
Patients in the H7-U group were randomly assigned to either six cycles of EBVP or six cycles of MOPP/ABV hybrid (mechlorethamine 6 mg/m2 body-surface area intravenously on day 1; vincristine 1.4 mg/m2 body-surface area [maximum dose, 2 mg] intravenously on day 1; procarbazine 100 mg/m2 body-surface area orally on days 1 through 7; prednisone 40 mg/m2 body-surface area orally on days 1 through 14; doxorubicin 35 mg/m2 body-surface area intravenously on day 8; bleomycin 10 mg/m2 body-surface area intramuscularly or intravenously on day 8; and vinblastine 6 mg/m2 body-surface area intravenously on day 8); both regimens were followed by IF-RT (36 to 40 Gy). In all groups, radiation was administered in fractions of 1.5 to 2.0 Gy, five fractions per week, with both fields treated each day.
Response Evaluation
Follow-Up
Statistical Considerations and Stopping Rules
In the H7-F group, the expected 5-year EFS rate was 75% in the standard STNI arm. To demonstrate a difference of 15% (ie, 90% EFS rate in the experimental combined-modality arm), it was necessary to include a total of 266 patients overall (
In the H7-U group, the 5-year EFS rate was anticipated to be 85% in both arms (equivalence trial). Therefore, the overall number of patients to be accrued was 236 ( EFS, OS, and the cumulative probability of second cancer were estimated using the Kaplan-Meier method and compared using the log-rank test. Ninety-five percent CIs of rates were estimated using the Rothman method.28 All analyses were performed on the intent-to-treat basis. Two-sided tests were used in reporting the results. The STATA statistical software was used to analyze data (STATA Corp, College Station, TX). Data were stored using a specific data management program (PIGAS) developed at the Institut Gustave Roussy.29
The EORTC H7 trials were activated in October 1988 and closed to entry in September 1993. Seven hundred twenty-two patients from 47 centers in eight European countries were included (see Appendix). In the H7-F group, 165 patients were randomly assigned to STNI, and 168 patients were assigned to EBVP and IF-RT. In the H7-U group, 195 patients were randomly assigned to MOPP/ABV and IF-RT, and 194 patients were assigned to EBVP and IF-RT. Data were updated on January 1, 2004. The median follow-up time of the whole population was 105 months.
Patient Characteristics
Response, Progression, and Fatal Toxicity During Treatment Table 2 shows that the rates of complete response at the end of treatment were similar in both H7-F arms (94% in the EF-RT arm and 91% in the EBVP and IF-RT arm). There were few disease progressions during treatment in the two groups (1% in the EF-RT arm and 3% in the EBVP and IF-RT arm). In the H7-U arms, the complete response rate after MOPP/ABV was better than after EBVP (86% v 82%, respectively). The progression rate during treatment was low in the MOPP/ABV plus IF-RT arm (4%) and higher in the EBVP plus IF-RT arm (10%). There was one fatal treatment-related toxicity in the H7-F groups, and there were four fatal treatment-related toxicities in the H7-U groups.
Treatment Failure All treatment failures are listed in Table 2. In the H7-F group, there were significantly more treatment failures in the STNI arm, especially in nonirradiated (low abdominal and extranodal) areas. Median time to failure was 14 months in the STNI arm but 31 months in the EBVP arm. In the H7-U group, there were more treatment failures in the EBVP arm, not only in nonirradiated areas but also in irradiated areas. The difference in disease control of nonirradiated areas in favor of MOPP/ABV compared with EBVP is notable.
EFS, OS, and Application of Stopping Rules
In the H7-U group, the EFS rate in the EBVP plus IF-RT arm was 80% after 1 year and 74% after 2 years compared with 95% and 92%, respectively, in the MOPP/ABV arm. This disappointing statistically significant result led us to stop the H7-U trial early in November 1992. The 10-year EFS rate in the EBVP plus IF-RT arm was 68% compared with 88% in the MOPP/ABV arm (P < .001; Fig 3A). The 10-year OS rate also showed a significant difference between the two arms (79% in the EBVP plus IF-RT arm v 87% in the MOPP/ABV arm; P = .0175; Fig 3B).
Deaths and Second Malignancies In the group of 86 patients who died, HL was the most important cause of death (Table 2). Six patients had a revised diagnosis of initial NHL (three in the H7-F group and three in the H7-U group), whereas one patient in the H7-U group had a mediastinal solid tumor. Those seven patients were included in the analyses according to the intent-to-treat principle. They all died from their disease after 0 to 6 years. Of the remaining 79 HL patients, 20 (25%) have died of second malignancy. In total, 33 patients had a second malignancy, of which 20 were fatal. There were nine second cancers in the whole H7-F group (two NHLs and four solid tumors in the STNI arm and two leukemias and one solid tumor in the EBVP arm) and 24 second cancers in the whole H7-U group (one leukemia, six NHLs, and nine solid tumors in the EBVP arm and four cases of myelodysplastic syndrome/leukemia and four solid tumors in the MOPP/ABV arm).
The EORTC Lymphoma Group challenged the premise, which was current in the late 1980s, that EF-RT had to be regarded as standard treatment of early-stage HL. The concept of the H7 randomized trials was to use chemotherapy for remission induction and IF-RT for consolidation, thus minimizing the adverse effects of radiotherapy and improving EFS. We assumed the radiation volume could be reduced from STNI to IF-RT. The German Hodgkin's Study Group proved this assumption to be correct in their HD8 trial.13 An additional measure to diminish toxicity in H7 was to abandon staging laparotomy. Retrospectively, this decision was right because the results of H6-F later showed an inferior EFS in patients with a mantle field after a negative staging laparotomy compared with treatment with STNI alone.27 EBVP combined with IF-RT proved to be effective in favorable patients; the 10-year EFS rate after EBVP and IF-RT was 10% higher than after STNI, whereas the OS rate was 92% in both arms. The schedule was well tolerated. Relapses after EBVP occurred rather late compared with relapses after STNI. Of the five patients who died of second malignancy, one had lung cancer in the radiation field 9 years after initial treatment only; the other four patients (two acute myeloid leukemias, one NHL, and one lung cancer) had extensive salvage treatment for relapse. The EFS rate compares well in both arms with the results of the German Hodgkin's Study Group HD7 trial in favorable patients, which tested the surplus value of two cycles of ABVD preceding STNI.11 In unfavorable patients, MOPP/ABV and IF-RT showed high efficacy, with only a 4% progression rate during treatment and a 10-year OS rate of 87%. The rate of fatal second malignancies (2%) after 10 years seems relatively low. However, the results of EBVP and IF-RT in unfavorable patients were disappointing in several ways; too many progressions during therapy (10%) and too many relapses (21%) were observed that could not all be salvaged, resulting in a significantly lower 10-year OS rate of 79%. The lower control rate in irradiated involved areas suggests that IF-RT alone is not effective enough in these patients with high tumor burden and needs to be combined with effective chemotherapy such as MOPP/ABV. The 11 fatal second malignancies observed in the EBVP arm of the H7-U group never occurred in irradiated areas, and none of the patients were treated for relapse. The four solid tumors (2 to 7 years after treatment) are probably coincidental in this relatively old population (up to 70 years), but the six NHLs and one leukemia are of concern. In the past, radiotherapy was regarded as optimal treatment for early-stage HL. Chemotherapy was avoided, if possible, because it was considered more toxic. In recent years, treatment strategies have changed dramatically. Now, all Hodgkin's patients, even with limited disease, will receive primarily chemotherapy with the following two important aims: first, to control areas of subclinical, nonirradiated disease; and second, to render radiotherapy fields smaller. Using newer chemotherapy schemes without mechlorethamine, procarbazine, and dacarbazine (such as vinblastine, bleomycin, and methotrexate30; etoposide, vinblastine, and doxorubicin31; and EBVP22) and modern antiemetics and growth factors, most acute adverse effects can be avoided or relieved, and the risk of leukemia can be reduced. In high-risk Hodgkin's patients, more effective, although more toxic, regimens (such as ABVD20; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone32 [BEACOPP]; and Stanford V33 [mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone]) are used. Conversely, the previously presumed less toxic radiotherapy proved to be responsible for thyroid, heart, and lung damage2,4 and for induction of second solid tumors such as cancer of lung, upper abdomen, and skin6,7,9,10,34 and especially of the breast.35-38 Although reduction of radiation volumes and of total and fractional dose have had some beneficial influence, overall toxicity of EF-RT alone seems to be worse than the combined toxicity of modern chemotherapy and IF-RT together. At this moment, the best approach for the treatment of favorable HL seems to be the use of the least toxic combined-modality therapy, producing an EFS rate (patient treated and cured without any negative event, or uncomplicated cure) of 90% or more 10 years after diagnosis. In our series, the combination of EBVP and IF-RT approached this limit, but STNI did not. Considering the fact that the mean observation time is almost 10 years, the difference could only become greater in the future because the risk of leukemia in the EBVP group is low but the risk of solid tumors in the STNI group could continue with time. In our opinion, EBVP, which was developed as an alternative for ABVD, merits a serious place in the treatment of limited HL. More recent EORTC trials for favorable patients test the combination of a limited number of chemotherapy cycles and the lowest possible radiotherapy dose to involved areas or even chemotherapy without radiotherapy. Whether chemotherapy alone could be sufficient in patients with early-stage HL is still debatable. Recently, the results of a comparison of ABVD with a strategy that included radiation therapy in patients with limited-stage HL were published.39 After a median follow-up time of 4.2 years, no difference in OS could be detected between patients randomly assigned to receive treatment that included radiotherapy or ABVD alone. Although this study is valuable, STNI would now no longer be used in combined-modality treatment. In unfavorable HL, disease control in involved (especially bulky) areas is crucial. In our study, EBVP was insufficient in this respect, but MOPP/ABV was successful, and it showed few induced malignancies. Successive EORTC trials for unfavorable patients tested the optimal number of cycles of MOPP/ABV and ABVD and explored the potential of BEACOPP in comparison with ABVD. Future developments include response-adapted therapy using positron emission tomography. The new EORTC/Groupe d'Etude des Lymphomes de l'Adulte study (H10) will evaluate whether chemotherapy alone is as effective, but less toxic, as combined-modality treatment in patients with stages I and II favorable or unfavorable HL who are fluorodeoxyglucose-positron emission tomography–scan negative after two cycles of ABVD. Radiation fields will be limited to involved nodes only.
In addition to the authors, the following investigators participated in the study: AZ Middelheim, Antwerp, Belgium: P. Meijnders and R. de Bock; AZ St. Jan, Brugge, Belgium: A. van Hoof; HU Brugmann, Brussels, Belgium: M. Rauis-Morret; Institut Jules Bordet, Brussels, Belgium: D. Bron; Hopital St Pierrre, Brussels, Belgium: P. van Houtte; Centre Hospitalier (CH) de Tivoli, La Louvière, Belgium: J. Michel; UZ Gasthuisberg, Leuven, Belgium: Y. Lievens; CHRU, Annecy, France: C. Martin; Fondation Bergonié, Bordeaux, France: P. Richaud; Centre F. Baclesse, Caen, France: B. Vié; CH Général, Compiegne, France: D. Zylberait; H Edouard Herriot, Lyon, France: D. Assouline; Centre Léon Bérard, Lyon, France: C. Carrie; CH Lyon Sud, Pierre Bénite, France: B. Coiffier; Centre Alexis Vautrin, Nancy, France: T. Conroy; Centre Antoine Lacassagne, Nice, France: A. Thyss and P.-Y. Bondiali; Hotel Dieu, Paris, France: C.-M. Blanc and A. Delmer; H St. Antoine (1), Paris, France: F. Pène; H St. Antoine (2), Paris, France: M. Aoudjhane; H Sud, Rennes, France: C. Chenal and R. Deblay; Centre R. Huguenin, St. Cloud, France: M. Janvier; CMC Foch, Suresnes, France: E. Baumelou; Institut Gustave Roussy, Villejuif, France: M. Hayat  and J.-M. Cosset; Zentralkrankenhaus, Bremen, Germany: C.R. Meier; Centro di Riferimento Oncologico, Aviano, Italy: S. Monfardini; IKA, Amsterdam, the Netherlands: F. Oldenburger and H.P. Muller; NKI, Amsterdam, the Netherlands: J.W. Baars; OLVG, Amsterdam, the Netherlands: K.J. Roozendaal; St. Ignatius Ziekenhuis, Breda, the Netherlands: A.C.J.M. Holdrinet; IKZ, Eindhoven, the Netherlands: J.J. Keuning and M.L.M. Lybeert; MST, Enschedé, the Netherlands: J.H. Meerwaldt; Atrium MC, Heerlen, the Netherlands: M.M. Fickers; IKW, Leiden, the Netherlands: W.B.J. Gerrits; MC and RIF, Leeuwarden, the Netherlands: P. Joosten and W.G.J.M. Smit; IKL, Maastricht, the Netherlands: H.C. Schouten and P. Hupperets; AZ St. Radboud, Nijmegen, the Netherlands: R.W.M. van der Maazen; DDHK, Rotterdam, the Netherlands: M.J.J. Olofsen-van Acht; UZ Dijkzigt, Rotterdam, the Netherlands: M.B. van't Veer and P.J. Lugtenburg; Sophia Ziekenhuis, Zwolle, the Netherlands: M. van Marwijk Kooy; Instituto Portugues de Oncologia, Porto, Portugal: F. Viseu and E.F. Vieira; Institute of Oncology, Ljubljana, Slovenia: R. Tom i ; and Southampton General Hospital, Southampton, United Kingdom: M. Whitehouse.
The following were members of the pathology-review committee: Centre François Baclesse, Caen, France: A.-M. Mandard; Institut Gustave Roussy, Villejuif, France: J. Bosq; Hôtel Dieu, Paris, France: J. Diebold; Netherlands Cancer Institute, Amsterdam, the Netherlands: D. de Jong; St. James University Hospital, Leeds, United Kingdom: K.A. MacLennan; and British National Lymphoma Investigation: M.H. Bennett
The authors indicated no potential conflicts of interest.
The efforts of Nathalie Bonvin and Serge Koscielny in the update of the data are greatly acknowledged.
Preliminary results were presented in Noordijk EM, Carde P, Mandard AM, et al: Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease. Ann Oncol 5:107-112, 1994. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
0.35]) into a favorable (H7-F) or unfavorable (H7-U) group (
= .03; ß = .10, one interim analysis after 3 years of follow-up, log-rank method, two-sided test). In this group, no stopping rules were defined. 
