Evolution of Radiation Therapy Within the German Hodgkin Study Group Trials

Authors: Hans Theodor Eich MD, PhD a , a , Jan Kriz MD a and Rolf-Peter Müller MD, PhD a
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  • a From the Department of Radiation Oncology, University of Münster, Germany, and Department of Radiation Oncology, University of Cologne, Germany.

Since its beginning, more than 16,000 patients have been enrolled in the multicentric randomized trials of the German Hodgkin Study Group (GHSG) for adult patients. Within 6 study generations, the treatment of Hodgkin lymphoma has been developed stepwise by using the results of the completed protocols. Now the sixth generation is active. According to the role of radiotherapy, the study group successfully evaluated different dose–effect relationships and could also prove the efficacy of involved-field radiotherapy in early stages in combination with effective chemotherapy. Currently, a radiation dose of 20 Gy to the involved field after a mildly aggressive chemotherapy (2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD]) should be the standard for early-favorable stages according to the GHSG classification. In early-unfavorable or intermediate-risk stages, involved-field radiation therapy with 30 Gy is sufficient; the optimal chemotherapy has to be fixed. For the advanced stages, the question of radiotherapy is still unclear. Preliminary results of the GHSG and others show that additive radiotherapy after intensive chemotherapy might be useful for elective subgroups of patients. The extensive radiotherapy quality assurance program, performed by the GHSG and its radiotherapy reference center, has proven to be successful and necessary to ensure that, with reduced radiation doses and reduced radiation volumes, precise radiotherapy, as defined by the protocol, will be performed by the participating radiotherapy departments.

Radiotherapy (RT) is a key modality in the treatment of Hodgkin lymphoma (HL), and clinical trials are increasing the understanding of its role in the management of this disease. The German Hodgkin Study Group (GHSG), based at the University of Cologne, is the largest international study group on HL.1 Pivotal studies that have influenced international standards of care include the combined modality approach of a short course of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and involved-field RT (IF-RT) in the early stages of HL,2,3 and the development of the BEACOPP chemotherapy regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in advanced stages.4

The development of RT within the consecutive study generations is remarkable. Over the years, field design and radiation techniques changed dramatically from extended field RT to IF-RT (Table 1). In view of high cure rates, the major goal today is to minimize radiation fields and dose to reduce consecutive treatment-related side effects. In the ongoing study generation (HD17), a new target volume definition—the “involved node (IN)” concept—is being compared with standard IF-RT.

Table 1

Five Generations of Randomized Clinical Trials in the Treatment of Primary Early-Favorable, Intermediate (Early-Unfavorable), and Advanced-Stage Hodgkin Lymphoma

Table 1

These achievements were supported by the RT reference center of the GHSG within the Department of Radiation Oncology at the University of Cologne, which performed quality assurance (QA) programs of the group's clinical studies. The HD4 study showed the importance of this. Major protocol violations with particular reference to the design of the radiation fields were associated with a statistically significant reduction in freedom from treatment failure (FFTF).5

The possibility of more accurate staging through using new imaging techniques, such as CT, MRI, and PET, in recent years has resulted in advances such as the definition of early-favorable, early-unfavorable, and advanced stages, and more specific, risk-adapted treatment strategies.

Early-Favorable HL

Extension of disease is still the most important risk factor. As reported by the Stanford group6 in the 1980s, RT alone resulted in complete remission rates of 100% and recurrent-free survival of 80% in pathologic stages (PS) IA, IIA, and IIB without mediastinal bulky disease. Polychemotherapy was able to treat most of the recurrences successfully. However, other well-recommended study groups could not confirm these excellent results.710

Because secondary cancers were reported in up to 10% of patients after high-dose extended field (EF)-RT, the GHSG created the HD4 study, which tested in a randomized setting a dose reduction of 10 Gy in the EF (EF-RT 40 Gy vs. EF-RT 30 Gy/IF-RT 40 Gy) for patients with PS IA, IB, IIA, IIB with no risk factors (large mediastinal mass, extranodal extension, massive spleen involvement, ≥ 3 lymph node areas, high erythrocyte sedimentation rate [ESR]). Staging laparotomy was obligatory in this protocol. The goal of this study was to reduce treatment-related side effects (especially secondary treatment–induced solid tumors) without compromising results. Results in 376 evaluable patients showed no statistically significant differences in recurrence-free and overall survivals between the treatment arms,5 but the overall recurrence rate approached 20%. Because of a very sufficient salvage therapy, recurrence-free survival after 7 years increased to 80% and the overall survival was 93%.

A careful analysis of the recurrences could show that most of these recurrences occurred outside the radiation fields and could be rated as a diagnostic miss of the initial staging.

In the HD4 protocol of the GHSG, a wide-spread QA program was initiated for the first time. An RT treatment plan was created for every randomized patient by the RT reference center based on the documented extent of disease on standardized case report forms. After completion of RT, the simulation and verification films of every patient were sent to the RT reference center and analyzed by an expert panel. Results of this analysis showed that major deviations from the RT prescription resulted in a reduced FFTF and proved to be a statistical univariate prognostic factor.1,5

The primary goal of the initial treatment of early-stage HL without risk factors should be the lowest possible recurrence rate, and therefore considerations of further protocols resulted in combining radiotherapy with not-too-toxic chemotherapy for control of subclinical microscopic Hodgkin involvement.

The HD7 protocol randomized patients into 2 treatment arms. Arm A consisted of RT alone (30 Gy EF/40 Gy IF), whereas arm B consisted of the combined modality approach: 2 cycles of ABVD followed by RT (30 Gy EF/40 Gy IF) for early-favorable stages (PS IA, IIA, IIB without risk factors) as in HD4. The spleen was irradiated with 36 Gy in both treatment arms because staging laparotomy was not obligatory. ABVD chemotherapy was chosen because of the well-known toxicity profile (no extensive cardiac or pulmonary side effects) and the relatively low infertility rate. At a median observation time of 87 months, no difference was seen 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, FFTF was significantly different, with 7-year rates of 67% in arm A and 88% in arm B. This was mainly because of significantly more relapses after EF-RT only (arm A, 22%; arm B, 3%). No patient treated with combined modality treatment experienced relapse before year 3.11

These results compare favorably with a metaanalysis about multimodal combined treatment of RT and chemotherapy versus RT alone in early-stage HL,12 and also with results from the groups from Stanford (with vinblastine, bleomycin, and methotrexate [VBM]), Manchester (with vinblastine, doxorubicin, prednisolone, etoposide, cyclophosphamide, and bleomycin [VAPEC-B]), and the EORTC (with epirubicin, bleomycin, vinblastine, and prednisone [EBVP]), which reported a better outcome for early-stage or favorable disease after radiochemotherapy.1315

In reference to the role of radiation in the treatment of HL, the HD10 trial represents a very decisive step, because irradiation was performed as IF-RT in all treatment arms. Radiation dose–effect relationships for HL are only reported as retrospective analyses, never as prospective randomized trials, and mostly for radiation therapy only. No substantial data exist for the combined modality treatment of radiotherapy and chemotherapy. Therefore, the HD10 trial was initiated to answer 2 questions for early-favorable HL: which radiation dose is necessary after effective chemotherapy and how much chemotherapy is needed to control subclinical disease. Therefore, patients with PS IA, IIA and IIB without risk factors were randomized in a 4-arm study between an IF-RT dose of 30 versus 20 Gy, and between 2 versus 4 cycles of ABVD.3

To ensure that RT was performed as exactly as possible according to the RT prescriptions in the protocol, an extensive QA program was initiated that consisted of prospective RT planning by the RT reference center in Cologne based on clinical and laboratory data and all pretreatment diagnostic imaging.16

Because involvement of the mediastinum is a special problem in the treatment of HL,17 the GHSG developed a special guideline for RT of the mediastinum to minimize cardiac toxicity after chemotherapy with adriamycin and RT. The upper mediastinum was irradiated selectively in cases of suprabifurcal involvement only. In case of involvement of the lower mediastinum only or involvement of the upper and lower mediastinum, the whole mediastinum was irradiated.18

Final analysis of the HD10 trial showed no significant difference between the chemotherapy regimens with respect to FFTF (P = .39) and overall survival (P = .61). After 5 years, the FFTF was 93% with the 4-cycle ABVD regimen and 91.1% with the 2-cycle ABVD regimen. Regarding the RT doses, no significant difference was seen in FFTF (P = 1.00) or overall survival (P = .61). The FFTF at 5 years was 93.4% in the 30-Gy group and 92.9% in the 20-Gy group. Thus, 2 cycles of ABVD followed by 20 Gy of IF-RT is regarded as the new standard of care in the treatment of early-favorable HL.3

The goal of the following study (HD13) was to further decrease of early and late toxicities. In a 4-arm randomized fashion, 4 different chemotherapy regimens were tested, consisting of 2 cycles of ABVD (arm A), ABV (arm B), AVD (arm C), or AV (arm D), keeping the IF-RT on the level of 30 Gy in all treatment arms. An interim analysis showed more relapses in the treatment arms without dacarbazine (arm B and D), and therefore these were closed earlier.19

The ongoing HD16 trial (Figure 1) is using fluorodeoxyglucose (FDG)-PET for treatment guidance after 2 cycles ABVD chemotherapy. In the standard treatment arm, all patients receive 20 Gy of IF-RT regardless of the PET result. In the experimental arm, FDG-PET–positive patients are irradiated with 20 Gy of IF-RT. Patients with a negative FDG-PET undergo no further treatment. Unless no final results are available, the use of PET for treatment guidance is not advised outside of clinical trials.

Early-Unfavorable HL

Combined modality therapy consisting of chemotherapy and radiotherapy is the standard treatment approach to the early-unfavorable or intermediate stages of HL, according to the definition of the GHSG (PS I, IIA, and IIB with risk factors such as large mediastinal mass, extranodal involvement, high ESR, ≥ 3 lymph nodes).

In a 2-arm randomized setting, the HD8 trial tested the question of EF-RT versus IF-RT (plus 10 Gy to bulky areas in each treatment arm) after 2 cycles of cyclophosphamide, vincristine, procarbazine, prednisone (COPP) and ABVD. The final analysis of 1136 patients showed no statistical significant difference between the arms in complete remissions after treatment (98% vs. 97%), FFTF (86% in both arms), or overall survival (91% vs. 94%). Patients who received IF-RT reported a significantly lower acute toxicity compared with those treated with EF-RT.4,20

Figure 1
Figure 1

HD16 trial for patients with early-favorable stage Hodgkin lymphoma.

Abbreviations: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; CS, clinical stage; ESR, erythrocyte sedimentation rate; IF, involved-field; RF, risk factors.

*Large mediastinal mass, extranodal disease, high ESR, or 3 or more areas

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 9; 10.6004/jnccn.2011.0088

Because prognosis and treatment results of patients in early-unfavorable stages of HL were comparable to those in advanced stages, the goal of future studies is to intensify chemotherapy and fix the dose of radiation to the IF.

In a randomized 4-arm study, the HD11 trial tested the ABVD regimen versus an intensified chemotherapy, consisting of treatment with the BEACOPP regimen, followed by IF-RT of 30 or 20 Gy.21 This study randomly assigned 1395 patients to either arm A (4 cycles of ABVD + 30 Gy IF-RT), arm B (4 cycles of ABVD + 20 Gy IF-RT), arm C (4 cycles BEACOPP baseline + 30 Gy IF-RT), or arm D (4 cycles of BEACOPP baseline + 20 Gy IF-RT).

The FFTF at 5 years was 85%, overall survival was 94.5%, and progression-free survival was 86%. BEACOPP baseline was more effective than ABVD when followed by 20 Gy of IF-RT (5-year FFTF difference, 5.7%). No difference was seen between BEACOPP baseline and ABVD when followed by 30 Gy of IF-RT (5-year FFTF difference, 1.6%). Similar results were observed for the RT question: after 4 cycles of BEACOPP baseline, outcomes with 20 Gy were not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8%–4.2%]), whereas after 4 cycles of ABVD, a relevant inferiority of 20 Gy cannot be excluded (5-year FFTF difference, -4.7%; 95% CI, -10.3–0.8). A reduction of RT dose from 30 to 20 Gy IF-RT seems justified only in combination with BEACOPP baseline, but not with a less effective chemotherapy, such as 4 cycles of ABVD.21

In a 2-arm randomized study, the following HD14 trial for patients with early-unfavorable stages compared 2 different intensified chemotherapy regimens (4 cycles of ABVD vs. 2 cycles of BEACOPP escalated/2 cycles of ABVD) by keeping the IF-RT dose of 30 Gy in both treatment arms.22 The third preplanned interim analysis of this trial showed a significantly better progression-free survival for the more intensive “2 + 2” arm at 3 years (“2 + 2”: 97%; ABVD: 91%; P < .0017). Upfront intensification with only 2 cycles of escalated BEACOPP improves outcome in this group of patients; however, one can argue about the clinical relevance of a 6% absolute improvement in progression-free survival in the presence of the putative increased toxicity (e.g., gonadal damage and secondary malignancies).

The ongoing HD17 trial (Figure 2) also introduces FDG-PET after completion of chemotherapy, which consists of 2 cycles of BEACOPP escalated followed by 2 cycles of ABVD to stratify between PET-positive and PET-negative patients. Patients with a negative PET scan are randomized between 30 Gy IF-RT versus no further treatment. Patients with a positive PET scan are randomized between 30 Gy IF-RT versus 30 Gy IN-RT. The IN-RT concept for patients with early-stage HL was recently introduced by the EORTC/GELA Lymphoma Group within the Intergroup study H10. In this study, radiation fields are designed to irradiate the initially involved lymph nodes exclusively and to encompass their initial volume as a consolidation after ABVD chemotherapy. The rationale for this approach is based on the observation that after chemotherapy alone, most relapses of HL occur in previously involved nodes. Because this concept has never been tested in a randomized trial, the GHSG is comparing it with standard IF-RT in the HD17 trial.23

Figure 2
Figure 2

HD17 trial for patients with early-unfavorable stage Hodgkin lymphoma.

Abbreviations: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone; CS, clinical stage; esc, escalated; ESR, erythrocyte sedimentation rate; IF, involved-field; IN, involved node; RF, risk factors; RT, radiotherapy.

*High ESR, or 3 or more areas

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 9; 10.6004/jnccn.2011.0088

Advanced-Stage HL

The basis of successful treatment of patients in the advanced stages of HL is intensive polychemotherapy. Since the introduction of MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone) by de Vita in the sixties,24 prognosis for long-term survival has become markedly better but could not overcome a certain level until BEACOPP and its modifications had been developed by the GHSG. The role of consolidative RT in advanced HL depends on the efficacy of the prior chemotherapy. A randomized EORTC study showed that consolidation with IF-RT did not improve outcomes in patients experiencing complete remission after 6 to 8 courses of alternating MOPP and ABV, but potentially improved the outcomes of those experiencing partial remission.25

The HD9 trial tested the newly developed BEACOPP regimen against the GHSG standard COPP/ABVD chemotherapy regimen. Patients with advanced stages (clinical stage [CS] IIB, IIIA with risk factors; PS IIIA + splenic involvement; CS/PS IIIB; and CS/PS IV) were randomized into 3 treatment arms: 4 cycles of COPP/ABVD, 8 cycles of BEACOPP escalated, or 8 cycles of BEACOPP baseline. Consolidative RT (30 Gy) was applied in patients with initial bulky disease (≥ 5.0 cm) or residual disease (≥ 1.5 cm). Results of 1195 randomized patients showed a clear superiority of BEACOPP escalated over BEACOPP baseline and COPP/ABVD at 5 years and also at 10 years.4,26 At 10 years, the FFTF and overall survival rates were 64% and 75% for COPP/ABVD, 70% and 80% for BEACOPP baseline, and 82% and 86% for BEACOPP escalated, respectively.26 However, toxicity of BEACOPP escalated remains a concern. The subsequent HD12 trial therefore had the goal of deescalating chemotherapy by comparing 4 courses of BEACOPP escalated with 4 courses of BEACOPP baseline (“4 + 4”). The role of RT was tested by a second randomization to either consolidative RT to initial bulky and residual disease or no RT. At 5 years, the overall survival, FFTF, and progression-free survival rates were 91%, 85.5%, and 86.2%, respectively. Statistically, more patients with progressive disease were documented with the “4 + 4” arm. Concerning the RT question, the study was biased because of a central review.27 Almost 10% of patients were irradiated who had originally been randomized to the observation arm. Thus far, unpublished data from the HD12 trial indicate a benefit of RT to residual disease in terms of progression-free survival. Thus, outside of clinical trials, the GHSG still considers 8 cycles BEACOPP escalated followed by RT to residual disease as standard treatment for patients with advanced-stage HL.

Figure 3
Figure 3

HD18 trial for patients with advanced-stage Hodgkin lymphoma.

Abbreviations: BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone; esc, escalated; RT, radiotherapy; R, rituximab.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 9; 10.6004/jnccn.2011.0088

In the GHSG HD15 trial, 311 of 817 patients (38%) showed residual disease (≥ 2.5 cm), as determined by CT after the completion of chemotherapy with BEACOPP. At that time, 79% (n = 245) of these patients had a negative PET scan. These patients did not receive any additional RT. However, PET-positive patients were irradiated in the region of residual tumor. The progression-free survival was 96% for PET-negative patients and 86% for PET-positive patients. Compared with the limited literature, the prognosis of PET-positive patients is still good because of the consolidative RT.28 The negative predictive value for PET after chemotherapy was defined as 94%.

The ongoing HD18 trial (Figure 3) evaluates early PET-determined response. All patients receive a PET scan after 2 cycles of BEACOPP escalated. Patients who are PET-positive receive 6 further cycles of BEACOPP escalated. PET-negative patients are randomized to either the standard regimen of 6 additional cycles of BEACOPP or only 2 additional cycles. RT is applied in the region of PET-positive residual disease (≥ 2.5 cm) after completion of chemotherapy, similar to the procedure in HD15.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

References

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    Eich HT, Gosmann A, Engert A. A contribution to solve the problem of the need for consolidative radiotherapy after intensive chemotherapy in advanced stages of Hodgkin’s Lymphoma-analysis of a quality control program initiated by the radiotherapy reference center of the German Hodgkin Study Group. Int J Radiat Oncol Biopl Phys 2007;69:11871192.

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Correspondence: Hans Theodor Eich, MD, PhD, Department of Radiation Oncology, University of Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany. E-mail: hans.eich@uk-koeln.de
  • View in gallery

    HD16 trial for patients with early-favorable stage Hodgkin lymphoma.

    Abbreviations: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; CS, clinical stage; ESR, erythrocyte sedimentation rate; IF, involved-field; RF, risk factors.

    *Large mediastinal mass, extranodal disease, high ESR, or 3 or more areas

  • View in gallery

    HD17 trial for patients with early-unfavorable stage Hodgkin lymphoma.

    Abbreviations: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone; CS, clinical stage; esc, escalated; ESR, erythrocyte sedimentation rate; IF, involved-field; IN, involved node; RF, risk factors; RT, radiotherapy.

    *High ESR, or 3 or more areas

  • View in gallery

    HD18 trial for patients with advanced-stage Hodgkin lymphoma.

    Abbreviations: BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone; esc, escalated; RT, radiotherapy; R, rituximab.

  • 1

    Diehl V, Josting A, eds. 25 Years German Hodgkin Study Group. Germany: Medizin & Wissen; 2004.

  • 2

    Engert A, Schiller P, Josting A. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early stage unfavourable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin Lymphoma Study Group. J Clin Oncol 2003;21:36013608.

    • Search Google Scholar
    • Export Citation
  • 3

    Engert A, Pluetschow A, Eich HT. Reduced treatment intensity in patients with early stage Hodgkin’s Lymphoma. N Engl J Med 2010;363:640652.

    • Search Google Scholar
    • Export Citation
  • 4

    Diehl V, Franklin J, Pfreundschuh M. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:23862395.

    • Search Google Scholar
    • Export Citation
  • 5

    Duehmke E, Franklin J, Pfreundschuh M. Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin’s disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 2001;19:29052914.

    • Search Google Scholar
    • Export Citation
  • 6

    Rosenberg SA, Kaplan HS. The evolution and summary results of the Stanford randomised clinical trials of the management of Hodgkin’s disease: 1962–1984. Int J Radiat Oncol Biol Phys 1985;11:522.

    • Search Google Scholar
    • Export Citation
  • 7

    Mauch P, Tarbell N, Weinstein H. Stage IA and IIA supradiaphragmatic Hodgkin’s disease: prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation. J Clin Oncol 1988;6:15761583.

    • Search Google Scholar
    • Export Citation
  • 8

    Noordijk EM, Carde P, Dupouy N. 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. J Clin Oncol 2006;24:31283135.

    • Search Google Scholar
    • Export Citation
  • 9

    Shore T, Nelson N, Weinerman B. A metaanalysis of stages II Hodgkin’ disease. Cancer 1990;65:11551160.

  • 10

    Wasserman TH, Trenker DA, Fineberg B, Kucik N. Cure of early stage Hodgkin’s disease with subtotal nodal irradiation. Cancer 1991;68:12081215.

    • Search Google Scholar
    • Export Citation
  • 11

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