German Hodgkin's Lymphoma Study Group Trials: Lessons from the Past and Current Strategies

Comprehensive Review German Hodgkin’s Lymphoma Study Group Trials: Lessons from the Past and Current Strategies Andreas Draube, Karolin Behringer, Volker Diehl

Abstract Over the past decades, Hodgkin’s lymphoma has become one of the most curable tumors in adults. This is mainly because of large clinical trials using risk-adapted, highly effective therapy modalities. For a long time, radiation therapy was the standard for treating patients with Hodgkin’s lymphoma. Within the past 20 years, management has undergone a paradigm shift from the use of chemotherapy as an adjunct to radiation therapy in advanced-stage disease to combined therapy modalities with chemotherapy and involved-field irradiation in early stages and time- and dose-intensified effective drug regimens in advanced stages. Modern therapeutic strategies aim at reducing therapyassociated acute and late toxicities, while maintaining the highest tumor control. Founded in 1978, the German Hodgkin’s Lymphoma Study Group has initiated numerous clinical trials contributing to the high cure rate in all stages of this lymphoma entity. This article gives an overview of the German Hodgkin’s Lymphoma Study Group trials and a review of the current treatment strategies.

Clinical Lymphoma & Myeloma, Vol. 6, No. 6, 458-468, 2006 Key words: Chemotherapy, Cotswald’s staging classification, Prognostic Factors, Combination Therapy

The adoption of combination chemotherapy to the treatment of early-stage Hodgkin’s lymphoma (HL) in the late 1970s and the development of more aggressive chemotherapy regimens for advanced stages in the 1980s and 1990s led to the high cure rates achieved in HL today (Figure 1). Approximately 80% of patients in all anatomic stages and of all histologic subtypes can be cured with modern treatment management.1 Patients with early favorable or early unfavorable (intermediate) disease receive 2 or 4 cycles of chemotherapy, respectively, followed by involved-field radiation therapy (RT; IFRT; 20-30 Gy). Patients with advanced-stage disease receive 6-8 cycles of more aggressive chemotherapy. The role of RT for patients with advanced-stage HL with complete remission after combination chemotherapy is still in debate.2 The introduction of effective high-dose salvage chemotherapy for relapsed disease, a better definition of prognostic factors, and the realization of the important issue of treatment-associated late toxicity have further improved a riskadapted management of the disease.3 At the moment, the main challenge is the development of strategies that decrease late toxicity and mortality, while retaining the efficacy of currently used drug combinations. Department of Internal Medicine I, University of Cologne, Germany Submitted: Feb 25, 2005; Revised: Mar 15, 2006; Accepted: Mar 30, 2006 Address for correspondence: Volker Diehl, MD, German Hodgkin’s Lymphoma Study Group, University of Cologne, Joseph-Stelzmann-Str 9, 50924, Cologne, Germany Fax: 49-221-478-86654; e-mail: [email protected]

Figure 1 Treatment of Advanced-Stage Hodgkin’s Lymphoma During the Past Decades 100

Overall Survival (%)

Introduction

80

60

40 Escalated BEACOPP (1993-2004) Baseline BEACOPP (1993-1998) COPP plus ABVD (1988-1993) Only Alkylating Agents (1965) No Treatment (1940)

20

0

2

4

6

8

The German Hodgkin’s Lymphoma Study Group (GHSG) has become one of the world’s largest study groups in malignant lymphoma. At the moment, 502 centers from 9 European countries are participating in ongoing trials. This article describes results from previous study generations (Tables 1-3)4-13 and the designs of the ongoing fifth study generation (Table 4). In a chronologic overview, they are discussed in the context of results found by other international study groups.

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458 • Clinical Lymphoma & Myeloma May 2006

10

Years

Table 1 Former German Hodgkin’s Lymphoma Study Group Trials: Early Stage Favorable4-6 Study

Study Design

Time Period

Number of Patients

Result

HD44

EFRT 40 Gy (arm A) EFRT 30 Gy plus IFRT 10 Gy (arm B)

1988-1994

376

RFS: A = B OS: A = B

HD75

EFRT 40 Gy (arm A) ABVD × 2 plus EFRT 40 Gy (arm B)

1994-1998

617

FFTF: B > A OS: A = B

HD106

ABVD × 4 plus IFRT 30 Gy (arm A) ABVD × 4 plus IFRT 20 Gy (arm B) ABVD × 2 plus IFRT 30 Gy (arm C) ABVD × 2 plus IFRT 20 Gy (arm D)

1998-2002

1131 (847 Eligible in 2nd interim analysis in August 2003)

No significant difference so far

Stage I/II without risk factors. Abbreviation: RFS = relapse-free survival

Prognostic Factors and Treatment Groups An important issue in the treatment of HL is the stratification of patients to risk-adapted tailored therapies. An enormous endeavor has been made to introduce clinically relevant, reproducible, and internationally accepted prognostic factors. For patients with advanced-stage disease, the International Prognostic Score has been developed under the leadership of the GHSG to identify patients for further treatment intensification or reduction.14 The 7 adverse prognostic factors listed in Table 5 were significant in the final Cox regression model (relative risk, 1.26-1.49; P < 0.001 to 0.011).15 Stratification of patients according to International Prognostic Score is used in many cooperative study groups worldwide. For early stages, anatomic stage; number of involved lymph node areas; increased erythrocyte sedimentation rate; and systemic symptoms like fever, night sweat, and weight loss are still the major determinants for a risk-adapted therapy. Recently, bulky disease (> 10 cm in diameter or a mediastinal mass [* 1/3 of the thoracic diameter]) has emerged as a third widely accepted prognostic factor. In 1989, the Cotswold’s staging method was introduced as a modification of the Ann Arbor classification (Table 6).15 It includes information about prognostic factors such as mediastinal mass, other bulky nodal disease, and extent of subdiaphragmatic disease. According to the traditional separation in early and advanced stages, most centers within the United States treat patients at stage

I-IIA (early stages) with combined modality strategies. Subtotal nodal or extended-field irradiation is rarely used now because of the impact of late toxicities like secondary solid tumors. Advanced stages (III/IV and usually stage IB and IIB, bulky disease > 10 cm in diameter) are assigned for an extensive chemotherapy protocol. In Europe, the European Organisation for Research and Treatment of Cancer (EORTC) and the GHSG introduced a subdivision of patients with stage I/II disease in early-stage favorable and early-stage unfavorable (intermediate) disease depending on the presence or absence of defined risk factors as listed in Table 7. The division into these 3 prognostic groups allowed more precise tailoring of a risk-adapted therapy and remained the stratification instrument for the current GHSG trials.

Former and Current Treatment Strategies of the German Hodgkin’s Lymphoma Study Group Early-Stage Favorable Hodgkin’s Lymphoma Table 1 shows an overview of the closed GHSG trials.4-6 In 1988, the GHSG initiated the HD4 trial, randomizing patients with early-stage favorable HL to receive 40 Gy extended-field RT (EFRT) or 30 Gy EFRT with an additional 10 Gy to involved fields.4 Complete remission rates in both treatment arms were 98%. After a median follow-up of 86 months, there was no

Table 2 Former German Hodgkin’s Lymphoma Study Group Trials: Early Stage Unfavorable (Intermediate)7-10 Study Design

Time Period

Number of Patients

Result

HD17

COPP/ABVD × 2 plus EFRT 40 Gy (arm A) COPP/ABVD × 2 plus EFRT 20 Gy plus 20 Gy to initial bulk (arm B)

1978-1988

180

FFTF: A = B OS: A = B

HD58

COPP/ABVD × 2 plus EFRT 30 Gy plus 10 Gy to initial bulk (arm A) COPP/ABV/IMEP × 2 plus EFRT 30 Gy plus 10 Gy to initial bulk (arm B)

1988-1993

973

FFTF: A = B OS: A = B

HD89

COPP/ABVD × 2 plus EFRT 30 Gy plus 10 Gy to initial bulk (arm A) COPP/ABVD × 2 plus IFRT 30 Gy plus 10 Gy to initial bulk (arm B)

1993-1998

1064

FFTF: A = B OS: A = B

ABVD × 4 plus IFRT 30 Gy (arm A) ABVD × 4 plus IFRT 20 Gy (arm B) Baseline BEACOPP × 4 plus 30 Gy IFRT (arm C) Baseline BEACOPP × 4 plus 20 Gy IFRT (arm D)

1998-2002

1363 (1047 Eligible at 4th interim analysis in August 2003)

No significant difference so far

Study

HD1110

HD1: stage I, II, IIIA with risk factors; HD5: stage I, II with risk factors, stage IIIA; HD8: stage I, IIA with any risk factor, stage IIB with risk factor C or D, stage IIIA without any risk factor; HD11: stage I, IIA with any risk factor, stage IIB with risk factor C or D. Risk factor definition according to Table 7.

Clinical Lymphoma & Myeloma May 2006 • 459

German Hodgkin’s Lymphoma Study Group Trials Table 3 Former German Hodgkin’s Lymphoma Study Group Trials: Advanced Stages7,11-13 Study Design

Time Period

Number of Patients

Result

HD37

COPP/ABVD × 3 plus IFRT 20 Gy (arm A) COPP/ABVD × 3 plus COPP/ABVD × 1 (arm B)

1984-1988

288

FFTF: A = B OS: A = B

HD611

COPP/ABVD × 4 (arm A) COPP/ABV/IMEP × 4 (arm B) Followed by IFRT to bulk/residual mass

1988-1993

588

FFTF: A = B OS: A = B

HD912

COPP/ABVD × 4 (arm A) Baseline BEACOPP × 8 (arm B) Escalated BEACOPP × 8 (arm C) Followed by IFRT to bulk/residual mass

1993-1998

1195

FFTF: C > B > A OS: C > A

HD1213

Escalated BEACOPP × 8 plus 30 Gy to bulk/residual mass (arm A) Escalated BEACOPP × 8 (arm B) Escalated BEACOPP × 4 plus baseline BEACOPP × 4 plus 30 Gy to bulk/residual mass (arm C) Escalated BEACOPP × 4 plus baseline BEACOPP × 4 (arm D)

1998-2002

1597 (1396 Eligible in the 4th interim analysis in July 2004)

No significant difference so far

Study

HD3: stage IIIB, IV; HD6: stage IIIB, IV; HD9: stage IIB with risk factor A or B, stage IIIA with any risk factor, stage IIIB, IV; HD12: stage IIB with risk factor A or B, stage III, IV. Risk factor definition according to Table 7.

Table 4 Current German Hodgkin’s Lymphoma Study Group Trials Stage Risk Factor

IA, IB, IIA

IIB

IIIA

IIIB, IV

HD13*

None • 3 Involved Regions

HD14

Increased ESR†

HD15

Large Mediastinal Mass Extranodal Disease *Exception: lymphocyte-predominant Hodgkin’s lymphoma (stage IA without risk factors). †ESR • 50 without B symptoms or • 30 with B symptoms. Abbreviation: ESR = erythrocyte sedimentation rate

Table 5 Risk Factors for Advanced-Stage Hodgkin’s Lymphoma15 International Prognostic Score Factors Serum albumin level < 4 g/dL Hemoglobin level < 10.5 g/dL Male sex Age • 45 years Stage IV disease (according to the Ann Arbor classification) Leukocytosis (• 15,000/mm3) Lymphocytopenia (< 600/mm3 or < 8% of white cell count or both)

significant difference between relapse-free (78% vs. 83%) and overall survival (OS) rates (91% vs. 96%). Most of the patients experiencing relapses reached a continuous second remission after salvage therapy. To reduce the relapse rate, the succeeding GHSG HD7 trial investigated the combination of 2 cycles of ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) chemotherapy in combination with EFRT in comparison with EFRT alone.5 With a median observation time of 5 years at the final analysis in November 2003, OS rates in both arms were similar (94%). However, the

460 • Clinical Lymphoma & Myeloma May 2006

freedom from treatment failure (FFTF) rate was superior for the combined treatment group (91%) compared with the RT-alone group (75%). Other study groups that compared EFRT alone with a combined therapy, mainly using IFRT, came to similar results.16-18 Thus, today, EFRT alone is abandoned by most centers in favor of a combined therapy using short-duration chemotherapy and IFRT. The GHSG HD10 trial was a 2-by-2 multifactorial designed study comparing 2 or 4 cycles ABVD followed by 20 Gy or 30 Gy IFRT.6 The interim analysis after 24 months resulted in pooled OS and FFTF rates of 99% and 97%, respectively, without significant differences between the arms so far. A further improvement of OS seems unlikely with regard to the already obtained excellent long-term results. Thus, ongoing and recently completed studies attempt to reduce the long-term treatment-associated complications, while maintaining high cure rates. Open questions concern the optimal number of chemotherapy cycles, the optimal chemotherapy regimen, and the optimal radiation volume and dose. Because the GHSG HD7 and HD10 trials resulted in very good outcomes for the combination of RT with 2 cycles of chemotherapy, the current GHSG HD13 trial has been designed for a further reduction of toxicity; the 4-arm tailored study compares the ABVD regimen with ABV (doxorubicin/bleomycin/vinblastine), AVD (doxorubicin/vinblastine/dacarbazine), and AV (doxorubicin/ vinblastine). Accordingly, the necessity of bleomycin and dacarbazine will be assessed. After 2 cycles of chemotherapy, all patients receive 30 Gy IFRT (Figure 2; Table 4). Patients with nodular lymphocyte– predominant HL in stage IA without risk factors are excepted and will be treated with IFRT (30 Gy) alone. Early-Stage Unfavorable (Intermediate) Hodgkin’s Lymphoma For the treatment of patients with early-stage unfavorable (intermediate stage) HL, combined-modality treatment including chemotherapy followed by IFRT is the generally accepted standard. Ongoing studies aim at optimizing effectiveness at an acceptable degree of toxicity. For a long time, 4-6 cycles of MOPP (mechlorethamine/vincristine/procarbazine/

Andreas Draube et al Table 6 Cotswold’s Staging Classification15 Stage

Description

Stage I

Involvement of a single lymph node region or lymphoid structure (eg, spleen, thymus, Waldeyer’s ring) or involvement of a single extralymphatic site.

Stage II

Involvement of • 2 lymph node regions on the same side of the diaphragm (hilar nodes, when involved on both sides, constitute stage II disease); localized contiguous involvement of only 1 extranodal organ or site and lymph node region(s) on the same side of the diaphragm (IIE). The number of anatomic regions involved should be indicated by a subscript (eg, II3).

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which might also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only 1 extranodal organ site (IIIE) or both (IIISE).

III1

With or without involvement of splenic, hilar, celiac, or portal nodes.

III2

With involvement of para-aortic, iliac, and mesenteric nodes.

Stage IV

Diffuse or disseminated involvement of • 1 extranodal organs or tissues, with or without associated lymph node involvement.

Designations Applicable to Any Disease Stage A

No symptoms.

B

Fever (temperature > 38°C), drenching night sweats, unexplained loss of > 10% of body weight within the previous 6 months.

X

Bulky disease (a widening of the mediastinum by more than one third or the presence of a nodal mass with a maximal dimension > 10 cm).

E

Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.

prednisone) or ABVD and additional EFRT were considered the gold standard. In many European countries, COPP (cyclophosphamide/vincristine/procarbazine/prednisone) has been used instead of MOPP. The history of the GHSG trials is summarized in Table 2.7-10 In a preceding study, responding patients were randomized to receive 40 Gy EFRT or 20 Gy EFRT plus 20 Gy to initial bulk (GHSG HD1 trial) each after 2 cycles of alternating COPP/ABVD.7 After a median follow-up of 11 years, there was no significant difference in outcome for the different RT doses (OS, 79%; FFTF, 67%). The following study (GHSG HD5 trial) confirmed that EFRT dose can safely be reduced to at least 30 Gy (with an additional 10 Gy on bulky sites) when administered after 2 cycles of alternating COPP/ ABVD.8 The HD5 trial further demonstrated that 2 cycles of the rapid-alternation regimen COPP/ABV/IMEP (ifosfamide/ methotrexate/etoposide; OS, 88%; FFTF, 79%) are not superior to 2 cycles of conventional alternating COPP/ABVD (OS, 88%; FFTF, 80%). The question of whether radiation fields could be reduced only to the involved sites after adequate chemotherapy was answered by the Milano group19 and the GHSG with the

HD8 trial.9 The latter compared RT of 30 Gy extended field plus 10 Gy to bulk tumor (> 5 cm) with 30 Gy IFRT plus 10 Gy to bulk tumor after 2 alternating cycles of COPP/ABVD. Between 1993 and 1998, a total of 1204 patients were enrolled onto this study. One thousand sixty-four patients were eligible for evaluation. After a median follow-up of 54 months, there was no significant difference between both treatment arms in terms of FFTF (extended field, 85.5% vs. involved field, 84.2%) and OS (extended field, 90.8% vs. involved field, 92.4%). There were also no significant differences in terms of complete remissions, progressive disease, relapses, deaths, and secondary neoplasia. However, acute side effects like leukopenia, thrombocytopenia, nausea, and gastrointestinal toxicities were more frequent in the EFRT treatment arm. Thus, 4 cycles of effective chemotherapy, eg, ABVD, followed by IFRT defines the current standard. However, with this strategy, approximately 5% of patients will still have progressive disease, and another 15% will relapse within the next 5 years. To improve these results, the recently closed GHSG HD11 trial compared the efficacy of 4 cycles of ABVD with 4 cycles of the dose-equivalent

Table 7 Definition of Treatment Groups According to the EORTC and GHSG Characteristic Risk Factors Early Stage Favorable Early Stage Unfavorable (Intermediate) Advanced Stage

EORTC

GHSG

Large mediastinal mass Age • 50 years Increased ESR* • 4 Involved regions

A: Large mediastinal mass B: Extranodal disease C: Increased ESR* D: • 3 Involved regions

Clinical stage I/II without risk factors (supradiaphragmatic)

Clinical stage I/II without risk factors

Clinical stage I/II with • 1 risk factor

Clinical stage I, IIA with • 1 risk factors Stage IIB with risk factors C and D but without A and B

Clinical stage III/IV

Clinical stage IIB with risk factors A and B Clinical stage III/IV

*ESR • 50 without B symptoms or • 30 with B symptoms. Abbreviation: ESR = erythrocyte sedimentation rate

Clinical Lymphoma & Myeloma May 2006 • 461

German Hodgkin’s Lymphoma Study Group Trials Figure 2 German Hodgkin’s Lymphoma Study Group HD13 Trial for Early-Stage Favorable Disease Stage I/II Without Risk Factors A-D

Figure 3 German Hodgkin’s Lymphoma Study Group HD14 Trial for Early-Stage Unfavorable Disease Stage I, IIA with Risk Factors A-D; Stage IIB with Risk Factors C and D

ABVD ABVD

ABV ABV

AVD AVD

AV AV

30 Gy IFRT

30 Gy IFRT

30 Gy IFRT

30 Gy IFRT

Risk factor definitions as described in Table 7.

but time-intensified baseline BEACOPP (bleomycin/etoposide/ doxorubicin/cyclophosphamide/vincristine/procarbazine/ prednisone) regimen.10 Both regimens were followed by an IFRT of 30 Gy or 20 Gy. The fourth interim analysis in August 2003 included 1047 eligible patients. After a median followup of 24 months, the FFTF rate for all patients was 90%, and the OS rate was 97%. So far, neither a difference between the ABVD and the baseline BEACOPP regimen nor between 20 Gy and 30 Gy of IFRT have been detected. Accordingly, the ongoing GHSG HD14 trial (initiated in January 2003) randomly assigned patients to receive 4 cycles of ABVD or 2 cycles of intensified BEACOPP plus 2 cycles of ABVD followed by 30 Gy IFRT (Figure 3; Table 4). Of note, other study groups investigated whether the use of chemotherapy alone might be sufficient in patients with limitedstage HL.20 The largest randomized trial was conducted by the National Cancer Institute of Canada Clinical Trials Group in collaboration with the Eastern Cooperative Oncology Group. Patients were allocated to receive 4-6 cycles of ABVD alone or a standard therapy that included EFRT. With a median follow-up of 4.2 years and an evaluation of 399 patients, 5-year freedom from disease progression was superior in patients receiving EFRT (93% vs. 87%). However, no difference in OS was detected (94% vs. 96%). Mainly, this was because of an enhanced rate of fatal late treatment-related toxicities. This was also true for patients stratified into an unfavorable cohort.21 A direct comparison of these findings to the recent GHSG trials is limited by the fact that EFRT was used. Nevertheless, the further follow-up of these results is of great importance, and a debate about the role of RT for patients with limited-stage disease has been aroused. Advanced-Stage Hodgkin’s Lymphoma The Pioneer Combination Regimens. Until the development of effective combination chemotherapy a few decades ago, advancedstage HL was a fatal disease. At the National Cancer Institute, De Vita and colleagues achieved a 50% cure rate with the MOPP regimen.22,23 MOPP-like regimens replacing mechlorethamine with chlorambucil or cyclophosphamide resulted in similar efficacy. In 1975, Bonadonna et al introduced the ABVD regimen, initially developed for patients whose disease had recurred after MOPP.24 The comparison of MOPP and ABVD using 3 cycles of each regimen followed by EFRT and 3 additional cycles of the

462 • Clinical Lymphoma & Myeloma May 2006

ABVD ABVD ABVD ABVD 30 Gy IFRT

Escalated BEACOPP Escalated BEACOPP ABVD ABVD 30 Gy IFRT

Risk factor definitions as described in Table 7.

same chemotherapy demonstrated a superiority for ABVD. The freedom from tumor mortality rate for MOPP was 67% and 86% for ABVD.25 However, because both regimens are highly active and have no overlapping toxicities, it was obvious to test MOPP and ABVD in various combinations to attempt to increase cure rates further. A pivotal trial compared MOPP, ABVD, and MOPP/ABVD without additional RT.26 The long-term followup of this study over 15 years resulted in a failure-free survival rate of approximately 45%-47% and an OS of approximately 60%-62% for ABVD and MOPP/ABVD. With regard to failurefree survival, ABVD was similar to MOPP/ABVD and both were superior to MOPP alone. Patients with ABVD had a lower risk for leukemia and loss of fertility.27 Subsequently, other large multicenter trials tested the efficacy of hybrid regimens. The MOPP/ABV hybrid was as effective as alternating MOPP/ABVD28 but more effective than sequential MOPP and ABVD.29 The GHSH HD6 trial compared alternating COPP/ABV/IMEP with COPP/ABVD and also found no superiority for the rapidly alternating hybrid regimen compared with the standard alternating COPP/ABVD regimen (OS, 73% vs. 73%; FFTF, 54% vs. 56%; Table 3).11 In addition to the previously mentioned Cancer and Leukemia Group B long-term results,27 the important question as to whether the inclusion of MOPP in the conventional setting and scheduling adds therapeutic benefit or merely enhances toxicity was finally answered by Duggan et al.30 Freedom from treatment failure and OS at 5 years were similar for ABVD and MOPP/ABV. Clinically significant acute pulmonary and hematologic toxicities were more common with MOPP/ABV, and this regimen was also associated with a higher incidence of myelodysplastic syndromes and secondary leukemias. On the other hand, after 6-8 cycles of ABVD, an enhanced rate of cardiotoxicity occurred, which was enhanced more after additional RT. Nevertheless, by then, ABVD was the accepted standard chemotherapy used for the treatment of advanced-stage HL against which all new drug combinations had to be tested. New Chemotherapy Regimens. The acceptable short- and long-term toxicity after ABVD was favorable in this regimen.

Andreas Draube et al Figure 4 Results from the German Hodgkin’s Lymphoma Study Group HD9 Trial A

100

Freedom from Treatment Failure (%)

Escalated BEACOPP

80 Baseline BEACOPP COPP/ABVD

60

40

20

0

Escalated BEACOPP vs. COPP/ABVD; P < 0.001 Escalated BEACOPP vs. Baseline BEACOPP; P < 0.001 COPP/ABVD vs. Baseline BEACOPP; P = 0.04

20

40

60

80

100

120

Months

B

100 Escalated BEACOPP Baseline BEACOPP

Overall Survival (%)

However, the high failure rate of 37% at 5 years and an 18% death rate, of which 50% were caused by progressive Hodgkin’s disease (Intergroup trial),30 and the 15-year follow-up results by the Cancer and Leukemia Group B trial27 with a failurefree survival rate of about 47% were still unsatisfactory. Thus, new regimens were addressing the following factors: new drugs or drug combinations and dosage, including dose density and schedule.27,30-31 Most trials initiated in the early 1990s introduced etoposide as a novel chemotherapeutic agent and used higher doses than in ABVD. Stanford V (mechlorethamine/doxorubicin/vinblastine/ vincristine/bleomycin/etoposide/prednisone/granulocyte colony-stimulating factor [G-CSF]) was designed as a shortduration regimen that was given weekly for a total of 12 weeks followed by RT to initial bulky sites and macroscopic splenic disease.32 The 5-year freedom from progression rate in the phase II single-center trial of 142 patients was 89%, and the OS was 96% at 5.4 years. There was little midterm toxicity, and fertility could be preserved in men and women. A more recently presented follow-up at 6.9 years mainly confirmed these results.33 The current E2496 Intergroup trial is comparing Stanford V with ABVD. The results of this trial are expected with high interest, especially because the HD 9601 trial of the Italian Intergroup unexpectedly found Stanford V to be inferior in terms of response and failure-free survival in comparison with ABVD and MEC (mechlorethamine/ lomustine/vindesine/melphalane/prednisone/epidoxorubicin/ vincristine/procarbazine/vinblastine/bleomycin).34,35 The Manchester group developed an abbreviated 11-week chemotherapy regimen, VAPEC-B (vincristine/doxorubicin/ prednisone/etoposide/cyclophosphamide/bleomycin). In a randomized trial, it was compared with the hybrid ChlVPP/ EVA (chlorambucil/vinblastine/procarbazine/prednisolone/ etoposide/vincristine/doxorubicin) followed by RT applied to previous bulky or residual disease.36 After a median follow-up of 4.9 years, freedom from progression (82% vs. 62%), eventfree survival (78% vs. 58%), and OS rates (89% vs. 79%) were significantly better for ChlVPP/EVA than for VAPEC-B. Thus, the study had to be stopped after 26 months. In 1992, the GHSG designed the BEACOPP regimen based on the same drugs as in COPP/ABVD but excluding vinblastine and dacarbazine and adding etoposide. Further increase of efficacy was attempted by increasing dose density and dose intensity. Baseline BEACOPP consisted of doses equivalent to COPP/ABVD but was recycled at day 22 rather than day 29. In addition, for escalated BEACOPP (bleomycin/etoposide/ doxorubicin/cyclophosphamide/vincristine/procarbazine/ prednisone), intensified doses of cyclophosphamide, etoposide, and doxorubicin were introduced with the help of the hematopoietic growth factor G-CSF. After encouraging pilot and dose-finding studies, the GHSG HD9 trial was initiated (Table 3).12,37,38 The 3-arm study compared COPP/ABVD, baseline BEACOPP, and escalated BEACOPP in patients with advanced-stage HL. Consolidative RT was applied to sites of initial bulk (30 Gy) or residual disease (40 Gy) after 8 cycles of chemotherapy. At the final analysis in 2001, 1195

80 COPP/ABVD

60

40

20

0

Escalated BEACOPP vs. COPP/ABVD; P = 0.002 Escalated BEACOPP vs. Baseline BEACOPP; P = 0.06 COPP/ABVD vs. Baseline BEACOPP; P = 0.16

20

40

60

80

100

120

Months (A) Kaplan-Meier analysis of the probability of FFTF and (B) overall survival for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP. P values were calculated using the log-rank test for all 3 pairwise differences between treatment groups.

patients were eligible for evaluation. Freedom from treatment failure at 5 years was significantly higher in both BEACOPP arms compared with COPP/ABVD, and there was a further FFTF superiority for escalated BEACOPP compared with baseline BEACOPP (87% for escalated BEACOPP, 76% for baseline BEACOPP, and 69% for COPP/ABVD). Also, a major difference could be observed for the rate of primary progressive disease, which was significantly lower for escalated BEACOPP (2%) in comparison with baseline BEACOPP (8%) and COPP/ABVD (10%). Overall survival rates for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP were 83%, 88%, and 91%, respectively. The difference in survival between COPP/ABVD and escalated BEACOPP was highly significant (P = 0.002; Figure 4). Because of the inferior results for COPP/ ABVD, this treatment arm had to be closed at the first interim analysis in 1996.12 Based on these results, the GHSG defined 8 cycles of escalated BEACOPP as their new standard regimen for the treatment of advanced-stage HL. As expected, escalated

Clinical Lymphoma & Myeloma May 2006 • 463

German Hodgkin’s Lymphoma Study Group Trials Figure 5 German Hodgkin’s Lymphoma Study Group HD15 Trial for Advanced-Stage Disease Stage IIB with Risk Factors A and B; III and VI

Escalated BEACOPP x 8 EPO or placebo

Escalated BEACOPP x 6 EPO or placebo

BEACOPP-14 x 8 EPO or placebo

Restaging PR • 2.5 cm

CR, PR < 2.5 cm

PET Results Negative

Positive 30 Gy (to Residual Tumor)

Follow-up Risk factor definitions as described in Table 7. BEACOPP-14: dosage is the same as in baseline BEACOPP but the regimen is given in 14-day intervals with G-CSF support. Patients in all treatment arms are randomized to receive erythropoietin (EPO) or placebo. Only patients with PET-positive residual disease are assigned to receive consolidative RT.

BEACOPP was associated with greater acute hematologic toxicity. Thus, a higher number of red blood cell and platelet transfusions had to be given. Also, cases of secondary acute myeloid leukemia and myelodysplastic syndrome, possibly related to etoposide, were higher (for escalated BEACOPP, baseline BEACOPP, and COPP/ABVD, 9, 4, and 1 cases, respectively). However, the total rate of secondary malignancies was highest in the COPP/ABVD treatment arm, with 4.3% compared with 3.4% in the escalated BEACOPP arm. The death rates at 5 years, including all acute and late causes of death, were 18.8% for COPP/ABVD, 13% for baseline BEACOPP, and 8.6% for escalated BEACOPP. Thus, with regard to OS as the ultimate denominator for the benefit of a treatment strategy, 10 more patients of 100 died in the COPP/AVBD arm. In addition to the current GHSG HD15 trial described herein, the ongoing EORTC 20012 trial is of high interest. In this worldwide study under participation of the National Cancer Institute of Canada, the British National Lymphoma Investigation, and other international collaborative groups, 8 cycles of ABVD will be compared with 4 cycles of escalated BEACOPP plus 4 cycles of baseline BEACOPP. Role of Radiation Therapy in the Treatment of Advanced-Stage Hodgkin’s Lymphoma. Several phase III trials had been designed to analyze the necessity of additional RT after intensive chemotherapy, also considering RT-induced late toxicities. The GHSG HD3 trial already addressed the role of low-dose (20 Gy) IFRT versus 1 cycle of COPP/ABVD chemotherapy in patients with complete remission after initial chemotherapy with COPP/ABVD (Table 3).7 The most recent update analysis was conducted in April 2003 and still found no significant difference in FFTF (48%) or OS (63%) rates between both treatment arms. A metaanalysis published in 1998 gave further concerns about the benefit of consolidative RT.39 In the GHSG

464 • Clinical Lymphoma & Myeloma May 2006

HD12 trial, patients were randomly assigned to receive 8 cycles of escalated BEACOPP or 4 cycles of escalated BEACOPP plus 4 cycles baseline BEACOPP, followed by RT (30 Gy) to initial bulk and residual tumor or no further treatment (Table 3).13 The fourth interim analysis in July 2004 included 1396 eligible patients. After a median observation time of 30 months, the FFTF rate was 88%, and the OS rate was 94% for the total cohort. The rate of acute myeloid leukemia and myelodysplastic syndrome (11 of 1396 patients) at this early point of analysis was lower than in the HD9 trial.13 Nine percent of patients in the “no further RT” arm were assigned by a review panel to receive 30 Gy RT because of minor response or residual disease > 1.5 cm. So far, there has been no difference between the treatment arms. In the recently published EORTC #20884 trial, patients who exhibited a complete remission after 6-8 cycles of MOPP/ABV were randomly assigned to receive IFRT or no further treatment.40 The IFRT did not improve relapse-free survival or OS rates. However, patients who exhibited a partial response and were treated with additional RT had an overall 5-year survival rate of approximately 85%-90%, which was comparable with patients exhibiting complete response after chemotherapy alone. Thus, today, consolidative RT should only be given to patients exhibiting a partial response after 6-8 cycles of an anthracycline-containing regimen or a minor response with residual nodal lesions. Facing the current results of the GHSG HD12 trial, it seems that after a highly active regimen like escalated BEACOPP, only a minority (< 20%) of patients need consolidative RT for residual lesions. Positron emission tomography (PET) imaging might help to discriminate between scarred and vital tumor tissue in residual lesions, and this is under investigation in current trials. Current GHSG HD15 Trial. In this 3-arm trial, the GHSG tests a de-escalation of the BEACOPP regimen: 8 cycles of escalated BEACOPP versus 6 cycles of escalated BEACOPP versus 8 cycles of BEACOPP-14, a baseline-dosage regimen applied in a 14-day schedule that demonstrated excellent results in a pilot study. Furthermore, the trial addresses the pivotal question of whether PET is the suitable diagnostic tool to use in deciding whether to spare consolidative RT after reaching a complete remission after effective chemotherapy (Figure 5, Table 4). The BEACOPP-14 regimen is given in a 14-day schedule, applied with the help of G-CSF. The final analysis of a multicenter pilot study with 32 participating centers was performed in August 2002. Patients received 8 cycles of BEACOPP-14, and in 77%, it was possible to apply the schedule within 16 days. Consolidative RT was administered to 70% of patients. With a median follow-up of 34 months, the estimated FFTF rate was 90%, and the OS rate was 97%. The hematologic toxicity was moderate, ranging between that seen in the escalated and baseline BEACOPP regimens.41 Because emerging data point out the superiority of PET scanning in diagnostic accuracy of assessing the presence of residual disease in comparison with computed tomography imaging alone, this technique is implemented into the HD15 trial.42-44 Consolidative RT (30

Andreas Draube et al Gy) is given only to PET-positive residual disease (* 2.5 cm). Secondary endpoints of the trial are to investigate the influence of erythropoietin on the quality of life, the need for red blood cell transfusions, and the FFTF by a placebo-controlled medication. In addition, the study is accompanied by genomic profiling and pharmacogenomic investigations. Identification of genomic profiles at risk for an enhanced therapy-related toxicity, eg, life-threatening hematologic toxicity or, in contrast, at risk for an abrogated drug-induced tumor response might further help to individualize therapy concepts in the future. Refractory or Relapsed Hodgkin’s Lymphoma Because of the enormous outcome improvement for patients with HL, need for secondary treatment remains for < 20% of all patients. Conventional chemotherapy is the treatment of choice for patients who experience relapse after initial RT for early-stage disease. The survival of these patients is at least equal to that of patients with advanced-stage disease initially treated with chemotherapy.45,46 For patients with relapsed disease after initial chemotherapy treatment, options depend on several factors, such as initial treatment regimen, time since first-line treatment, stage of disease at relapse, localization (“outfield” or “infield” relapse), and patient age. Possible salvage treatment strategies include: salvage RT (in the case of strictly localized relapse), salvage chemotherapy, highdose chemotherapy with autologous stem cell transplantation, or even allogeneic stem cell transplantation.47-51 The length of remission after first-line chemotherapy is an important prognostic factor in regard to success of subsequent salvage therapy.52 Patients with primary progressive disease (patients who never reached a complete remission) treated with conventional chemotherapy have the worst outcome. In contrast, the projected 20-year OS rates for patients with early relapse (relapse after complete remission within 12 months after the end of therapy) and late relapse (after complete remission > 12 months after the end of therapy) treated with conventionaldose salvage regimens are 11% and 22%, respectively.53 From the GHSG database, in addition to “time to relapse,” clinical stage and anemia at relapse were found as relevant prognostic factors, which can be used to form a prognostic score for patients at relapse.46 High-dose chemotherapy with autologous stem cell support has been shown to produce 30%-65% long-term diseasefree survival in selected patients with refractory and relapsed disease.47,54-57 Two randomized trials supported the evidence for the superiority of high-dose chemotherapy. In the British National Lymphoma Investigation trial, patients with relapsed or refractory HL were treated with conventional-dose miniBEAM (carmustine/cytarabine/etoposide/melphalan) or highdose BEAM with autologous stem cell transplantation. The actuarial 3-year event-free survival was significantly higher in the high-dose treatment arm with 53% vs. 10%.58 The largest randomized multicenter trial was conducted by the GHSG/ European Bone Marrow Transplantation (EBMT) group.59 Patients with relapsed disease were randomized to receive 4 cycles of DexaBEAM (dexamethasone/BEAM) or 2 cycles of

Figure 6 German Hodgkin’s Lymphoma Study Group HDR-2 Trial for Relapsed Hodgkin’s Lymphoma R E G I S T R A T I O N

D H A P

D H A P PBSC

D H A P

D H A P

R A N D O M I Z E

B E A M

C T X

M T X

V P 16

B E A M

After 2 cycles of DHAP, patients are randomized to receive 3 cycles of sequential high-dose chemotherapy before final high-dose BEAM with autologous peripheral stem cell transplantation or to receive high-dose BEAM directly. Peripheral blood stem cells are collected after first (and/or second) cycle of DHAP. Abbreviations: CTX = high-dose cyclophosphamide; MTX = high-dose methotrexate plus vincristine; PBSC = peripheral blood stem cells; VP16 = high-dose etoposide

DexaBEAM followed by high-dose BEAM with autologous stem cell transplantation. The FFTF rates for the high-dose treatment arm and the conventional salvage treatment arm were 55% and 34%, respectively. Overall survival rates were not significantly different. With regard to the question of which patients benefit from high-dose chemotherapy, this study had another important finding: The FFTF improvement could be achieved for patients with early and late relapse. The recently reported 7-year update confirmed the results in favor of the high-dose chemotherapy. The finding of no significant difference with regard to OS might be partly because of the fact that one third of the patients receiving conventional-dose salvage therapy finally received a transplantation at further relapse.60 Today, high-dose chemotherapy with autologous stem cell transplantation is widely used as standard salvage therapy for eligible patients with primary progressive disease or relapse after full-course multiagent chemotherapy at least as effective as ABVD with or without RT. An exception is patients with relapse only in primary involved but unirradiated lymph node sites. In 1997, the GHSG initiated a multicenter phase II trial with sequential high-dose chemotherapy and final high-dose BEAM with autologous stem cell transplantation for relapsed or primary progressive HL.61 After 2 cycles of DHAP (dexamethasone/ high-dose cytarabine/cisplatin), patients exhibiting partial or complete remission received sequential high-dose chemotherapy with cyclophosphamide, methotrexate plus vincristine, and etoposide before final high-dose BEAM. With a follow-up of 30 months, the freedom from second failure and the OS rate for patients with primary progressive disease were 41% and 48%; for patients with early relapse, 62% and 81%; and for patients with late relapse, 65% and 81%, respectively.62 Based on these results, the current HDR-2 trial run by the GHSG, the EORTC, and the EBMT randomly compares the efficacy of standard high-dose BEAM with sequential high-dose chemotherapy after initial standard chemotherapy with 2 cycles of DHAP for patients with early or late relapse (Figure 6). Allogeneic transplantation remains an experimental modality. The existence of a graft-versus-Hodgkin’s effect is

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German Hodgkin’s Lymphoma Study Group Trials still questionable, and an analysis from the EBMT reports unacceptable transplantation-related mortality rates.63,64 Transplantation-related mortality seems to be lower after reduced-intensity conditioning regimens before transplantation. However, graft-versus-host disease and high relapse rates remain major problems.65 Patients designated for allogeneic transplantation should be enrolled in studies, eg, in Europe, such as the HD-R Allo trial run by the EBMT. Immunotherapy approaches in Hodgkin’s disease have been tested for several years. Early clinical trials evaluating antibodies with immunotoxin compounds were somehow disappointing.66 However, newer clinical studies using radioimmunoconjugates gave some promising results as shown for Yittrium 90– labeled antiferritin antibodies and Iodine 131–labeled murine anti-CD30 antibodies.67,68 Because hematologic toxicity is a limiting side effect, results of ongoing trials combining radioimmunoconjugate therapy with autologous stem cell transplantation are awaited with interest. More progress was achieved by the development of a humanized (SGN-30) and a fully human (MDX-060) anti-CD30 antibody. Studies done so far demonstrate an excellent tolerability and an antitumor activity in some patients.69,70 The further evaluation in regard to response rates is pending.

Conclusion Over the past decades, HL has become a highly curable disease. The GHSG trials have considerably contributed to the current knowledge and, at least in Europe, to the clinical treatment practice. The integration of patients into defined prognostic groups with a subsequent and consequent, riskadapted, tailored therapy plays a pivotal role in the curative success rate in this disease. So far, the discrimination in early-stage favorable, early-stage unfavorable, and advancedstage disease according to anatomic stage, B symptoms, and the described further prognostic factors, is the best tailored and clinically applicable stratification system. However, the continuing debate between the US clinicians and the European colleagues as to whether we need an intermediate stage remains. Ongoing subgroup analyses in early stages of HL should try to further discriminate the subgroups, especially considering the group of patients with early-stage unfavorable HL, for even better custom-tailored therapy. For early-stage favorable and unfavorable disease, the combined-modality treatment consisting of chemotherapy and IFRT represents the current gold standard. Because further treatment improvement for early-stage favorable HL might not be possible, the major aim is to reduce acute and long-term toxic side effects. Therefore, in the current GHSG trial, the ABVD regimen is compared with modalities without bleomycin and dacarbazine. In contrast, for the treatment of early-stage unfavorable HL, the escalated BEACOPP regimen in combination with ABVD has been introduced in order to increase treatment outcome. For patients with advanced-stage disease, the escalated BEACOPP regimen has improved FFTF and OS compared with the former standard COPP/ABVD. Thus, today, for the GHSG, escalated BEACOPP represents the standard treatment

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for patients with advanced-stage HL. The current GHSG trial addresses the question of whether 6 cycles of escalated BEACOPP or 8 cycles of the BEACOPP-14 variant with less dose intensity but higher dose density maintains the efficacy of 8 cycles of escalated BEACOPP while reducing toxicity. Because only a minority of patients benefit from consolidative RT, in the HD15 trial, local irradiation is reserved for patients with PET-positive residual disease. Pharmacogenomic research accompanies the ongoing study generation and might help in further therapy individualization in the future. Patients with progressive or relapsing disease after conventional multiagent chemotherapy regimens should be considered for eligibility for high-dose chemotherapy with autologous stem cell transplantation, which has proven to be the best curative option. The current randomized HDR-2 trial investigates whether sequential high-dose chemotherapy further improves the outcome observed after standard high-dose BEAM for patients with early or late relapse. As previously described, to some extent, new developments in targeted therapy approaches are promising. Results from these studies are at an early stage. However, combining targeted therapy with standard chemotherapy/RT in the future as successfully done in other tumor entities seems to be more conceivable than some years ago.

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