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Originally published as JCO Early Release 10.1200/JCO.2006.07.0482 on July 2 2007 © 2007 American Society of Clinical Oncology. Two Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Plus Extended-Field Radiotherapy Is Superior to Radiotherapy Alone in Early Favorable Hodgkin's Lymphoma: Final Results of the GHSG HD7 Trial
From the First Department of Internal Medicine, Coordination Center for Clinical Trials, and Department of Radiotherapy, University Hospital of Cologne, Cologne; Department of Radiation Oncology, Ludwig-Maximillans Universität München, München; First Department of Internal Medicine, University Hospital of Hamburg; Department of Internal Medicine II, University Hospital Eppendorf, Homburg; Department of Internal Medicine, Kreiskrankenhaus, Gummersbach; Practice for Hematology and Oncology, Diakonie-Hospital, Frankfurt; Department of Hematology, Otto v. Guericke University, Magdeburg; Department of Oncology, University Hospital of Münster, Münster; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; Institute of Pathology, University of Würzburg, Würzburg, Germany; Sezione EMATOLOGIA, Università degli studi "La Sapienza," Roma, Italy; and the Swiss Group for Clinical Cancer Research, Bern, Switzerland Address reprint requests to Andreas Engert, MD, University Hospital of Cologne, Dept I of Internal Medicine, 50924 Cologne, Germany; e-mail: a.engert{at}uni-koeln.de
Purpose To investigate whether combined-modality treatment (CMT) with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by extended-field radiotherapy (EF-RT) is superior to EF-RT alone in patients with early favorable Hodgkin's lymphoma (HL). Patients and Methods Between 1993 and 1998, 650 patients with newly diagnosed, histology-proven HL in clinical stages IA to IIB without risk factors were enrolled onto this multicenter study and randomly assigned to receive 30 Gy EF-RT plus 10 Gy to the involved field (arm A) or two cycles of ABVD followed by the same radiotherapy (arm B).
Results At a median observation time of 87 months, there was no difference between treatment arms in terms of complete response rate (arm A, 95%; arm B, 94%) and overall survival (at 7 years: arm A, 92%; arm B, 94%; P = .43). However, freedom from treatment failure was significantly different, with 7-year rates of 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%; P Conclusion CMT consisting of two cycles of ABVD plus EF-RT is more effective than EF-RT alone.
Hodgkin's lymphoma (HL) has become one of the most curable malignancies in adult oncology, with reported disease-free survival in excess of 80% at 5 years after treatment.1,2 This success is largely due to the introduction of multiagent chemotherapy and improved radiation techniques.3 With a large body of prospectively randomized trials performed by collaborative groups, HL is also one of the most extensively clinically evaluated malignancies. On the basis of clinical staging and risk factors, patients usually are assigned to early favorable (clinical stage [CS] I/II without risk factors), early unfavorable (CS I/II with risk factors), and advanced stages (CS III/IV, some selected IIB). Risk factors discriminating between early favorable and early unfavorable stages include large mediastinal mass, extranodal disease, high erythrocyte sedimentation rate, massive spleen involvement, and three or more areas involved.4 Although radiotherapy had been the mainstay of treatment for patients with early favorable HL, this has been challenged by relapse rates exceeding 30% after radiotherapy only and the risk of secondary malignancies after large-field radiotherapy.5-7 The German Hodgkin Study Group (GHSG) thus conducted the HD7 trial comparing extended-field radiotherapy (EF-RT) alone with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by EF-RT in this group of patients. We report the final analysis of this trial, with a median follow-up of 87 months, proving that combined-modality treatment (CMT) is superior in terms of higher freedom from treatment failure (FFTF) and lower relapse rate when compared with EF-RT alone.
Patients Newly diagnosed patients with histology-proven HL in clinical stages I and II without the clinical risk factors large mediastinal mass (  one third of the maximum thorax diameter), extranodal disease, massive splenic involvement (diffuse infiltrations or > five focal lesions), or high erythrocyte sedimentation rate ( 50 mm/h in asymptomatic or 30 mm/h in symptomatic patients). Patients had to be between age 16 and 75 years, have a Karnofsky performance status more than 70%, and be previously untreated and free of concurrent disease. Patients with impaired heart, lung, liver, or kidney function, previous malignant disease, or HIV-positive status were not eligible. Minimal hematologic requirements included a WBC count more than 3,000/µL and platelet count more than 100,000/µL. Patients were also excluded from the study if they had chronic obstructive lung disease, if they were pregnant or lactating, or if they had HL as part of a composite lymphoma. Biopsy material was examined by the local pathologist and then reviewed centrally by at least one member of a panel of six HL pathology experts. All patients had to provide written informed consent before study entry.
Study Design
Chemotherapy Patients in arm B had two cycles of ABVD applied before radiotherapy. ABVD was administered in standard doses consisting of doxorubicin 25 mg/m2 (days 1 and 14), bleomycin 10 mg/m2 (days 1 and 14), vinblastine 6 mg/m2 (days 1 and 14), and dacarbazine 375 mg/m2 (days 1 and 14). Treatment was postponed until recovery if the WBC was less than 2,500/µL or the platelet count was less than 80,000/µL on the day scheduled for re-treatment. Granulocyte colony-stimulating factor was administered if clinically indicated according to the American Society of Clinical Oncology guidelines until leukocyte recovery.8
Radiotherapy
Evaluation of Response and Follow-Up
Between February 1994 and March 1998, 650 patients were randomly assigned to treatment arms. A total of 23 patients (3.5%) were not qualified for this study and were excluded from additional analysis. Reasons for exclusion were wrong stage/risk factors (n = 11), review pathology diagnosis not HL (n = 8), or severe concomitant disease (n = 4). Therefore, 627 patients were included in this analysis: 311 in arm A and 316 in arm B. The primary end point could be evaluated for all of these patients. Ten patients (six in arm A and four in arm B) did not begin protocol treatment because of the patient's wish (n = 6), protocol violation (n = 2), or change in assessment of treatment required (n = 2). These patients were included in the main analyses. In addition, eight patients in arm A and 22 patients in arm B began but did not complete protocol treatment (11 terminated treatment during chemotherapy, six terminated treatment between modalities, and 13 terminated treatment during radiotherapy). All other patients received the treatment as planned.
Patient Characteristics
Toxicity and Mortality A total of 283 patients in arm B were available for analysis of acute toxicity during ABVD therapy (Table 2). Overall, the most commonly observed toxicities were leukopenia (grade 3, 11%), hair loss ( grade 3, 9.9%), and nausea (grade 3, 4.6%). There were few patients with grade IV toxicity, including leukopenia, nausea, kidney toxicity, and hair loss. A total of 532 patients were included for analysis of acute toxicity during radiotherapy (Table 3). Major toxicities (WHO grade 3) included nausea (4.3%), pharynx (2.1%), and leukopenia (1.7%), with no clinically relevant differences between treatment arms. Thus, two cycles ABVD before radiotherapy did not lead to increased acute toxicity during radiotherapy.
Causes of death during the study and in the follow-up period are listed in Table 4. A total of 51 patients died (8.1%): 28 in arm A and 23 in arm B. There were no significant differences between treatment arms, although mortality due to acute first-line or salvage toxicity was higher in the EF-RT–only arm as compared with the CMT arm (seven v two patients, respectively).
The total number of secondary malignancies was 39 (6.2%). There were three acute myeloid leukemias/myelodysplastic syndromes, 14 non-Hodgkin's lymphomas (NHLs), 21 solid tumors, and one chronic myeloid leukemia. The most often reported solid cancers included small-cell lung (n = 5), skin (n = 4), and breast (n = 3). Eleven of the solid tumors occurred in irradiated areas, three occurred in nonirradiated areas, and for seven tumors it was unknown or unclear (data not shown). There were no significant differences between treatment arms (Table 5). Kaplan-Meier curves for second malignancies also showed similar rates in each arm (Fig 2; P = .52). Between years 2 and 9, the incidence remained fairly constant at approximately 0.8% per year; numbers at risk were too small for reliable estimates (n < 50; SE 3%) beyond year 9. The incidence of second malignancy was higher in older patients (P < .0001) and in those with initial B symptoms (P = .012).
Treatment Outcome and Survival Rates A total of 94.6% (arm A) and 93.9% (arm B) of patients achieved CR (Table 6). The median observation time for all patients was 87 months. Kaplan-Meier plots for FFTF and OS are shown in Figures 3A and 3B. At 7 years, OS was 92% in arm A (95% CI, 88% to 95%) and 94% in arm B (95% CI, 91% to 97%; P = .43). FFTF was 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%). The difference for FFTF was significant (P < .0001). There were markedly more relapses after EF-RT only as compared with CMT (arm A, 21.9%; arm B, 3.2%; Table 6), and slightly more patients with progressive disease (arm A, 2.3%; arm B, 0.6%; P = .084). Of 78 patients who experienced relapse, 76 (97%) received chemotherapy and 11 (14%) had additional radiotherapy. Forty-five percent received bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; 24% received cyclophosphamide, vincristine, procarbazine, and prednisone/ABVD; 19% received ABVD, 6% had some other chemotherapy, and 3% had no salvage treatment; there were no significant differences between treatment arms (data not shown). The survival of these patients after relapse is shown in Figure 4. For the 68 patients experiencing a relapse after EF-RT only (arm A), survival was significantly longer than for those 10 patients experiencing a relapse after CMT (arm B; P = .0033). Similarly, freedom from second failure was significantly better at relapse after EF-RT alone than at relapse after CMT (P = .017).
Whereas initial involvement (all patients) was primarily supradiaphragmatic (a total of 1,324 involved sites, as opposed to 74 involved infradiaphragmatic sites), involvement at relapse in 78 patients was mainly infradiaphragmatic: a total of 69 involved nodal infradiaphragmatic sites were observed (24 mesenteric/para-aortic, 45 iliac/inguinal/femoral), as opposed to 42 involved nodal supradiaphragmatic sites. Thirty-one sites of relapse were extranodal. This pattern was also observed in arm B, in which there were 11 infradiaphragmatic and five supradiaphragmatic involved nodal sites. Relapse was classified as stage I in 16 patients, stage II in 13 patients, stage III in 11 patients, stage IV in 18 patients, unknown in 20 patients, asymptomatic in 36 patients, and symptomatic in 22 patients, with no significant differences between treatment arms. Table 7 describes the FFTF events in each arm analyzed according to the type of event and the time period in which the event occurred. The number of patients failing to reach a CR under protocol therapy was similar in both arms (arm A, 12 patients; arm B, 15 patients). Relapses occurred much more frequently in arm A (n = 68), mostly within years 0 to 1 and 2 to 4, whereas in arm B (n = 10 relapses) no relapses occurred within the first 2 years. Second malignancy deaths (n = 8) occurred in years 2 to 7, although from the incidence curves in Figure 2, it is apparent that more deaths will occur in later years. Deaths from heart (n = 9) and lung (n = 3) disease were distributed over the entire observed time period. Heart-related deaths were not significantly more frequent in arm B (six v three).
Adherence to Radiation Fields The radiotherapy panel reviewed the planning images of 529 patients (84%). Of these reviewed cases, 348 (66%) were assessed as showing at least one type of protocol violation (63% of arm A patients and 68% of arm B patients). Most protocol violations were classified as volume too small (44%), irradiation too protracted in time (24%), or dose too low (12%). Too little irradiation (one or more of the three aforementioned categories) was assessed in 61% of evaluated patients (arm A, 57%; arm B, 65%)—significantly more in arm B than in arm A (P = .035). Only 5% were assessed as showing too much irradiation (ie, volume or dose too large). FFTF did not differ significantly, as assessed using the log-rank test, between patients with and without protocol violations, either for the whole trial or for each arm separately, or between patients with and without too little irradiation, as defined above.
The HD7 study reported here is the largest randomized trial reported to date comparing CMT of two cycles ABVD followed by EF-RT versus EF-RT alone in patients with early favorable HL. A total of 650 patients from 189 centers were enrolled. The following three findings emerge from this study: after CMT, there was superior FFTF (88% v 67%) mainly related to fewer relapses (3% v 22%) as compared with radiotherapy only; there was no difference in response rates and OS between treatment arms; and CMT was not associated with significantly more acute or long-term toxicity, and has emerged as the treatment of choice for this group of patients. For decades, radiotherapy had been the standard of care for patients with early favorable HL. However, relapse rates of up to 30% prompted the evaluation of CMT as induction treatment.1,2 In addition, CMT alleviated the need for aggressive staging procedures including laparotomy.3 A meta-analysis based on individual data of 3,088 patients from 23 randomized trials in which CMT was compared with radiotherapy only supported the role of CMT in early favorable HL.5 In the meta-analysis, the addition of chemotherapy to radiotherapy halved the 10-year risk of failure (15.8 v 32.7%; P < .00001) with a small, nonsignificant improvement in survival (79.4 v 76.5%). Most of the trials included in this analysis were conducted between 1967 and 1988 using mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP-like regimen. The standard of care then changed, with the proof of better efficacy and less toxicity with ABVD when compared with MOPP.9 Randomized controlled trials with ABVD or a similar regimen confirmed that CMT provides better tumor control when compared with the identical RT alone.10-12 Because of its especially good prognosis, the subgroup of favorable early-stage patients with lymphocyte-predominant histology (LPHL) has been treated separately using IF radiotherapy alone in some study groups.11,13,14 A subgroup analysis of the 64 LPHL patients (review histology) in the present data set showed a nonsignificant trend toward better FFTF in the CMT group (7-year FFTF, 96%) compared with the EF-RT–alone group (83%; P = .070). No difference in OS was observed between treatment arms (P = .46). Thus, these results suggest (inconclusively) that CMT improves tumor control even in the favorable LPHL subgroup. Other retrospective investigations have found no difference in outcome between radiation alone and CMT for LPHL.13,15 Apart from the choice of chemotherapy, the question of radiation field size and dose also has been evaluated. It appears that the smaller IF radiation when combined with effective chemotherapy produces similar results as compared with CMT using EF or subtotal lymphoid irradiation (STLI) fields.4,16,17 More recently, the use of CMT has been challenged by the use of chemotherapy alone in patients with early-stage HL.18-20 However, tumor control after chemotherapy alone can be inferior when compared with CMT.21-23 In addition, the European Organisation for Research and Treatment of Cancer (EORTC)/Groupe d'Etude des Lymphomes de l'Adulte had to close the arm with epirubicin, bleomycin, vinblastine, and prednisone (EBVP) only in their H9F trial because of too many recurrences.24 Although they used six cycles of EBVP instead of the more effective ABVD regimen, these data taken together are strong arguments that CMT remains the treatment of choice in early-stage HL until proven otherwise. The significant advances in the treatment of patients with localized HL have created an increasing need to reduce treatment-associated adverse effects as much as possible. In addition to acute toxicity, long-term HL cancer survivors can experience sequelae such as coronary artery disease, heart failure, pulmonary toxicity, gonadal dysfunction, fatigue, and others.25,26 Most concern, however, has been attributed to second malignancies comprising acute leukemias, NHLs, and solid tumors.27-29 Risk factors for the development of second malignancies include radiation dose, field size, and choice of cytostatic drug and total amount administered. In patients with early favorable HL, mortality from causes other than HL increases over time, exceeding the HL-related mortality after 12 to 15 years.6 Thus, treatment results in patients with early favorable HL need to be counterbalanced carefully against late mortality. Importantly, the trial reported here at a median observation time of 87 months showed no difference in number and type of secondary malignancies between CMT (n = 18) and EF-RT alone (n = 21). In total, there were three myeloid leukemias/myelodysplastic syndromes, 14 NHLs, 21 solid tumors, and one chronic myeloid leukemia. With the caveat that more events will occur with longer follow-up, at this time there is no increased risk of secondary malignancies after CMT as compared with EF-RT alone. Similar findings were reported from cancer registries, indicating that the cumulative risk of second malignancies more than 20 years after treatment was higher for those patients receiving EF-RT alone when compared with CMT.30 More recently, a systematic review evaluating secondary malignancies after different treatment modalities in a total of 9,312 patients from 37 trials confirmed that CMT was superior to EF-RT alone in terms of OS (odds ratio [OR], 0.76; P = .0004), progression-free survival (OR, 0.49; P < .0001), and second malignancies (OR, 0.78; P = .03).31,32 The excess in second malignancies was due mainly to solid tumors and seemed to be caused by greater need for salvage therapy after EF-RT alone. One unexpected finding in this trial was that survival in 68 patients who experienced relapse after EF-RT alone was significantly better than for those 10 patients who experienced relapse after CMT (P = .003). Similarly, freedom from second treatment failure was better after EF-RT alone than after CMT (P = .017). We had shown before that the prognosis of patients relapsing after 4 cycles of chemotherapy is similar to those relapsing after 8 cycles of chemotherapy.33 The data presented here suggest that even patients who experienced relapse after two cycles of ABVD followed by EF-RT seem to be more resistant to conventional chemotherapy. Given that OS in HD7 is similar in both treatment arms, one could question whether CMT is the treatment of choice in this group of patients. However, the relapse rate in patients receiving EF-RT only is much higher than in those receiving CMT. In addition, modern CMT strategies use smaller radiation fields, which might contribute to better treatment outcome at relapse. At the time this study was initiated (February 1994), the EORTC had just closed enrollment of their H7F trial comparing six cycles of EBVP followed by IF-RT versus RT only (STLI plus spleen). This strategy produced similar OS and better EFS in the CMT-treated group in a total of 333 patients with early favorable HL. The GHSG HD7 trial presented here used what has since become the chemotherapy of choice (ABVD) but the larger EF-RT. Given that EBVP is inferior to ABVD and EF is not needed in ABVD-based CMT, the H7F trial by the EORTC and HD7 presented here redefined the standard of care for early favorable HL as two cycles of ABVD followed by IF-RT. The EORTC has confirmed the superiority of CMT in their H8F study, in which a total of 272 patients received either radiotherapy only (STLI plus spleen) or three cycles of MOPP/ABV hybrid with IF-RT.12 Interestingly, the 4-year OS was better in the CMT-treated patients (99% v 95%; P = .019). Most GHSG clinical trials for early-stage HL aimed at reducing toxicity: the predecessor study (HD4) had included a total of 376 pathologically staged patients and demonstrated that radiotherapy dose to the noninvolved EF can be reduced from 40 to 30 Gy without loss of efficacy.34 The recently completed HD10/HD11 trials for patients with early HL suggest that reduction of radiation dose in the IF to 20 Gy might be possible after two to four cycles of ABVD, although the final results are still pending.35,36 Importantly, HD10 (with a total of 1,370 randomly assigned patients) also clearly demonstrates that even when combined with IF radiotherapy, two cycles of ABVD are equally effective as four cycles. In addition to possibly defining better biologic or clinical risk factors for patients with early stage HL, the use of positron emission tomography might have an impact on future HL trials not only in the diagnostic work-up,37 but also as an early indicator of response.38 Thus, current plans for the next trial generation in early and advanced HL include the use of positron emission tomography as a prognostic indicator. In summary, the randomized HD7 trial presented here shows that CMT consisting of two cycles of ABVD plus EF-RT is superior in terms of disease control and has similar toxicity compared with EF-RT alone. Thus, CMT is being regarded as standard of care for early favorable HL patients by most groups, with open questions related to the optimal radiation dose and field size.
The author(s) indicated no potential conflicts of interest.
Conception and design: Andreas Engert, Susanne Sehlen, Richard Herrmann, Michael Pfreundschuh, Markus Sieber, Hans Tesch, Dirk Hasenclever, Markus Loeffler, Rolf-Peter Müller, Hans Konrad Müller-Hermelink, Eckhart Dühmke, Volker Diehl Financial support: Richard Herrmann Administrative support: Richard Herrmann, Markus Sieber Provision of study materials or patients: Susanne Sehlen, Claudio Cartoni, Richard Herrmann, Hans Tesch, Astrid Franke, Peter Koch, Maike de Wit, Eckhart Dühmke Collection and assembly of data: Jeremy Franklin, Hans Theodor Eich, Corinne Brillant, Richard Herrmann, Markus Sieber, Maike de Wit, Rolf-Peter Müller, Hans Konrad Müller-Hermelink Data analysis and interpretation: Andreas Engert, Jeremy Franklin, Hans Theodor Eich, Corinne Brillant, Ursula Paulus Manuscript writing: Andreas Engert, Hans T. Eich, Markus Sieber Final approval of manuscript: Andreas Engert, Jeremy Franklin, Hans Theodor Eich, Richard Herrmann, Michael Pfreundschuh, Maike de Wit, Ursula Paulus, Dirk Hasenclever, Markus Loeffler, Rolf-Peter Müller, Volker Diehl
Statistical analysis. The trial was designed to test the hypothesis that combined-modality treatment of two cycles doxorubicin, bleomycin, vinblastine, and dacarbazine followed by extended-field radiotherapy was superior to extended-field radiotherapy alone with respect to the primary end point, freedom from treatment failure. To detect an improvement of 11% to 12% in long-term freedom from treatment failure; with a power of 0.80 at (one sided) significant level .05, a required sample size of at least 400 patients was calculated (Makuch R, Simon R: Cancer Treat Rep 62:1037-1040, 1978). Interim analyses were planned 3, 4, and 5 years after the start of recruitment, and the final analysis was planned after 7.5 years. A truncated sequential probability ratio test as proposed by Whitehead (Whitehead J: The Design and Analysis of Sequential Clinical Trials [ed 2]. Chichester, United Kingdom, Ellis Horwood, 1992) was implemented to monitor the trial and to regulate possible early stopping due to superiority of one arm.
Patients recognized after random assignment as not fulfilling the entry criteria were excluded from the analysis; in all other respects, analysis adhered to the intention-to-treat principle. A sensitivity analysis excluding patients who did not begin protocol therapy was also performed. Analysis of acute toxicities only included patients who had sufficient documentation. Furthermore, the analysis of acute toxicities excluded patients who discontinued therapy before or during the relevant treatment component due to reasons other than toxicity. The
We thank all of the hospitals and practices who contributed to this study; Hiltrud Nisters-Backes, Tina Koch, and Hannlore Ossadnik for the excellent data management; Thomas Schober for managing the database, and Silvia König-Erich for organizing the radiotherapy panel.
Supported by the Deutsche Krebshilfe and the Swiss Group for Clinical Cancer Research. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. published online ahead of print at www.jco.org on July 2, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.0001). This was due mainly to significantly more relapses after EF-RT only (arm A, 22%; arm B, 3%). No patient treated with CMT experienced relapse before year 3. Relapses were treated mainly with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, or with the combination cyclophosphamide, vincristine, procarbazine, and prednisone/ABVD; treatment of relapse was significantly more successful in arm A than in arm B (P = .017). In total, there were 39 second malignancies, with 21 in arm A and 18 in arm B, respectively. The incidence was approximately 0.8% per year during years 2 to 9 and was highest in older patients (P < .0001) and those with "B" symptoms (P = .012). 
2 test was used for arm comparisons of the frequency of WHO grade 3/4 acute toxicities during radiotherapy. Survival data were analyzed using the Kaplan-Meier method (Kaplan EL, Meier P: J Am Stat Assoc 53:457-481, 1958). The log-rank test was used for comparison of survival data between treatment arms. To assess the effectiveness of treatment for relapse, freedom from second failure was defined as the time from relapse until additional progression, additional relapse, additional salvage treatment, or death as a result of any cause, or until last observation if none of these events occurred. Second malignancy incidence was analyzed using the Kaplan-Meier method. 
