The first-line treatment of patients with Hodgkin s lymphoma

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1 ORIGINAL ARTICLE Combined Modality Treatment of Hodgkin s Lymphoma Beate Klimm, MD, and Andreas Engert, MD, PHD Abstract: Substantial clinical progress over the last decades has improved the first-line treatment and prognosis of patients with Hodgkin s lymphoma (HL). This success is mainly based on the introduction of combined modality treatment strategies including chemotherapy in all risk groups and important progress in radiation techniques. The knowledge emerging from numerous clinical trials as well as better staging and imaging techniques helped to develop more effective therapies. According to our current knowledge, a stage and risk factor-based allocation into early favorable, early unfavorable, and advanced stages remains a suitable instrument to tailor risk-adapted therapy. In most of the study groups, patients with early stage HL receive 2 to 4 cycles of chemotherapy followed by radiotherapy to the involved field. The treatment for advanced stages usually consists of 6 to 8 cycles, more intensive regimen, and radiotherapy for residual masses. Here, we review results from current clinical trials and discuss new therapeutic approaches in the combined modality treatment of HL. Key Words: Hodgkin s lymphoma, clinical study, clinical trial, combined modality treatment, chemotherapy, radiotherapy, PET, response adapted therapy, review (Cancer J 2009;15: ) The first-line treatment of patients with Hodgkin s lymphoma (HL) is tailored according to stage and risk profile at diagnosis. Patients with clinical stages I and II without any risk factor are allocated to the early-stage favorable group, those with risk factors to the early-stage unfavorable group. Patients with stages III and IV disease are assigned to the advanced-stage risk group. The stage is determined according to the Cotswolds staging classification. 1 Besides stage and B symptoms, which include fever, night sweats, and weight loss, most groups have implemented relevant prognostic factors such as larger tumor mass, including bulky disease 10 cm or a large mediastinal tumor 1/3 of thoracic diameter. However, there are small differences in the definition of risk factors used and the classification of certain subgroups of HL patients among the different study groups in the Europe and the United States. In the United States, usually patients are either allocated to early or advanced stages. The definitions of treatment groups according to the different study groups in the Europe and the United States are presented in Table 1. All chemotherapy abbreviations mentioned in this article are explained in Table 2. From the Department I of Internal Medicine and the German Hodgkin s Study Group (GHSG), University Hospital Cologne, Germany. This research is supported in part by the German Cancer Aid (Deutsche Krebshilfe) and the Competence Network Malignant Lymphomas (Kompetenznetz Maligne Lymphome), sponsored by the German Federal Ministry of Science and Education (Bundesministerium für Bildung and Forschung). Reprints: Prof. Dr. Andreas Engert, MD, PhD, Chairman of the German Hodgkin Study Group, Professor for Internal Medicine. Hematology & Oncology, Department I of Internal Medicine I, University Hospital of Cologne. Kerpener Str. 62: D Köln. Germany. a.engert@uni-koeln.de Copyright 2009 by Lippincott Williams & Wilkins ISSN: /09/ TREATMENT OF EARLY-FAVORABLE HL Radiotherapy In the treatment of early stages, extended-field (EF) radiotherapy had been considered standard treatment modality for many years. With this technique, radiation was delivered to all initially involved and adjacent lymph node regions, leading to large irradiation fields compared with the involved-field (IF) radiotherapy, which is restricted to the initially involved lymph node regions only. Together with the successful introduction of MOPP 2 and ABVD 3 chemotherapy for advanced stages in the 1980s, the paradigmatic shift from radiation alone to additional chemotherapy in early stages was accelerated by the realization of long-term toxicity and mortality related to large radiation fields and radiotherapy doses. Longer follow-up of patients who underwent EF-radiotherapy revealed severe late effects as competing causes of death, such as heart failure, pulmonary dysfunction, and secondary malignancies. Furthermore, although complete remission was generally achieved, there was a higher risk of relapsing from the first-line treatment when EF-radiotherapy alone was administered. 4 Two different strategies were explored to prevent these relapses: either applying even more intensive radiotherapy or adding chemotherapy for early-favorable stages to control occult lesions. 5 The latter strategy produced better outcomes and at the same time enabled reduction of radiotherapy to the IF for this risk group. Thus, radiotherapy alone is almost obsolete, with 1 exception: patients with the first diagnosis of nodular lymphocyte predominant subtype of HL (LPHL) in clinical stage IA without risk factors are usually not included in ongoing trials for classic HL. On the basis of this very favorable prognosis, treatment with 30 Gy IF-radiotherapy alone is an option for patients with stage IA of this subtype. Although being less toxic, this strategy seems to produce similar responses for LPHL IA patients compared with combined modality treatment. 6 Experimental approaches for these patients focus on the humanized monoclonal anti-cd20 antibody rituximab, which has given impressive results in relapsed LPHL. 7 Compared with IA patients with LPHL, advanced LPHL stages at initial diagnosis have less favorable outcomes and are thus treated according to protocols used for classic HL. 8 Chemoradiotherapy and Chemotherapy Most centers and groups in the Europe and the United States have now accepted combined modality treatment consisting of 2 to 4 cycles of ABVD followed by 30 Gy IF-radiotherapy as the standard of care for early-favorable stage disease. Several randomized studies confirmed the superiority of combined modality treatment over radiotherapy alone. Other trials were conducted to investigate and reduce radiation fields and dose and, likewise, to decrease chemotherapy drug combinations and duration of treatment. The Southwest Oncology Group demonstrated that patients treated with combined modality therapy consisting of 3 cycles of doxorubicin and vinblastine followed by subtotal lymphoid irradiation (STLI) had a markedly superior outcome in terms of freedom from treatment failure The Cancer Journal Volume 15, Number 2, March/April

2 Klimm and Engert The Cancer Journal Volume 15, Number 2, March/April 2009 TABLE 1. Definition of Treatment Groups of the EORTC/GELA, GHSG, and NCIC/ECOG Treatment Group EORTC/GELA GHSG NCIC/ECOG Early-stage favorable CS I II without risk factors (supradiaphragmatic) CS I II without risk factors Standard risk group: favorable CS I II (without risk factors) Early-stage unfavorable CS I II with 1 risk factors (supradiaphragmatic) CS I, CSIIA 1 risk factors; CS IIB with C/D but without A/B Standard risk group: unfavorable CS I II (at least one risk factor) Advanced stage CS III IV CS IIB with A/B; CS III IV High risk group: CS I or II with bulky disease; intraabdominal disease; CS III, IV Risk factors (RF) A. Large mediastinal mass A. Large mediastinal mass A. 40 yr B. Age 50 yr B. Extranodal disease B. Not NLPHL or NS histology C. Elevated ESR* C. Elevated ESR* C. ESR 50 mm/h D. 4 involved regions D. 3 involved areas D. 4 involved nodal regions * 50 mm/h without or 30 mm/h with B symptoms. GJSG, German Hodgkin Lymphoma Study group; EORTC, European Organization for Research and Treatment of Cancer; GELA indicates Groupe d Etude des Lymphomes de l Adulte; ECOG, Eastern Cooperative Oncology Group; NCIC, National Cancer Institute of Canada; ESR, erythrocyte sedimentation rate. TABLE 2. Regimen MOPP COPP ABVD ABV AVD AV EBVP VAPEC-B ChIVPP/EVA MOPPEBVCAD Chemotherapy Regimens Used in HL and Their Drug Combinations Stanford V BEACOPP (baseline, escalated or 14) Drug Combinations Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine Adriamycin (doxorubicin), Bleomycin, Vinblastine Adriamycin (doxorubicin), Vinblastine, Dacarbazine Adriamycin (doxorubicin), Vinblastine Epirubicin, Bleomycin, Vinblastine, Prednisone Vincristine, Adriamycin (doxorubicin), Prednisolone, Etoposide, Cyclophosphamide, Bleomycin Chlorambucil, Vinblastine, Procarbazine, Prednisolone, Etoposide, Vincristine, Adriamycin (doxorubicin) Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone, Epidoxorubicin, Bleomycin, Vinblastine, CCNU (Lomustine), Alkeran, Vindesine Mechlorethamine, Adriamycin (doxorubicin), Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone Bleomycin, Etoposide, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Procarbazine, Prednisone (FFTF: 94% vs. 81% at 3 years) than those receiving STLI alone. 9 Another study from Milan revealed that STLI can be effectively replaced by IF-radiotherapy after short duration ABVD chemotherapy, while maintaining a very similar progression-free (97%) and overall survival (OS, 93%) at 5 years. 10 The European Organization for Research and Treatment of Cancer (EORTC) and the Groupe d Etude des Lymphomes de l Adulte demonstrated that combined modality with either 6 courses of EBVP (H7F trial) or 3 courses of MOPP/ABV (H8F trial) followed by IF-radiotherapy yielded a significantly better event-free survival (EFS) than achieved by subtotal nodal irradiation alone. 11,12 The aim of their H9F trial was to evaluate a possible dose reduction of radiotherapy (36 Gy or 20 Gy or no radiotherapy) after administering 6 cycles of EBVP. However, the arm without radiotherapy was closed prematurely because of a higher relapse rate than expected. 13 Although EBVP was used instead of ABVD in this setting, the use of chemotherapy alone in early-favorable stages should currently still be regarded as experimental. Another randomized trial for nonbulky, asymptomatic stage I-III HL failed to demonstrate superiority of ABVD radiotherapy over ABVD alone; however, the total number of patients was small and all patients received 6 cycles of ABVD, even those in clinical stages I and II without risk factors. 14 A combined modality approach was also established in the HD7 trial of the German Hodgkin s Study Group (GHSG). In this trial, 2 cycles of ABVD plus EF-radiotherapy were shown to be superior to EF-radiotherapy 144 alone in terms of FFTF (88% vs. 67% at 7 years). The OS was equal in both arms because of effective salvage treatment. 15 Further improvement of treatment with respect to the excellent long-term survival rates seems difficult. Thus, strategies to reduce drug dose and toxicity while maintaining efficacy are being pursued. In the subsequent HD10 trial of the GHSG, a possible reduction in chemotherapy from 4 to 2 cycles of ABVD or IF-RT from 30 to 20 Gy was evaluated. In the interim analyses, no significant differences in FFTF and OS were detected between 4 cycles of ABVD and 2 cycles of ABVD or between patients receiving different doses of radiotherapy (30 Gy vs. 20 Gy), but final result have to be awaited. 16 The aim of the current GHSG HD13 trial is to omit the presumably less-effective drugs, bleomycin or dacarbazine, from the ABVD backbone. Patients were thus randomized between 2 cycles of ABVD, ABV, AVD, or AV followed by 30 Gy IF-radiotherapy. However, the arms without dacarbazine (ABV and AV) had to be closed prematurely for safety reason because of more events in these arms. The next trial of the GHSG (HD16) and the current trial of the EORTC (H10F) incorporate positron emission tomography (PET) as a tool, which will hopefully help to evaluate early response to treatment and further reduce chemotherapy or avoid radiation for a part of patients with very good prognosis. A selection of recent and ongoing studies in patients with earlyfavorable HL is given in Table Lippincott Williams & Wilkins

3 The Cancer Journal Volume 15, Number 2, March/April 2009 Treatment of HL TABLE 3. Selected Trials for Early-Stage Favorable Hodgkin s Lymphoma Trial Therapy Regimen No. Pts. Outcome References SWOG no A. 3 (Dox. Vinbl.) STLI (36 40 Gy) % (FFTF); 98% (OS) 9 B. STLI (36 40 Gy) % (FFTF); 96% (OS); (3 yr) Milan A. 4 ABVD STLI 65 97% (FFP); 93% (OS) 10 B. 4 ABVD IF-RT 68 97% (FFP); 93% (OS); (5 yr) EORTC/GELA H7F A. 6 EBVP IF-RT (36 Gy) % (EFS); 92% (OS) 11 B. STNI % (EFS); 92% (OS); (10 yr) EORTC/GELA H8F A. 3 MOPP/ABV IF-RT (36 Gy) % (EFS, 5 yr); 97% (OS, 10 yr) 12 B. STNI % (EFS, 5 yr); 92% (OS, 10 yr) EORTC/GELA H9F A. 6 EBVP IF-RT (36 Gy) % (EFS); 98% (OS) 13 B. 6 EBVP IF-RT (20 Gy) % (EFS); 100% (OS) C. 6 EBVP (no RT) % (EFS); 98% (OS); (4 yr) closed because of high relapse rate GHSG HD7 A. EF-RT 30 Gy (40 Gy IF) % (FFTF); 92% (OS) 15 B. 2 ABVD EF-RT 30 Gy (40 Gy IF) % (FFTF); 94% (OS); (7 yr) GHSG HD10 A. 4 ABVD IF-RT (30Gy) 847 Interim anal yr is (2 yr) 16 B. 4 ABVD IF-RT (20Gy) All pts C. 2 ABVD IF-RT (30Gy) 96.6% (FFTF) D. 2 ABVD IF-RT (20Gy) 98.5% (OS) GHSG HD13 A. 2 ABVD IF-RT (30Gy) Ongoing trial B. 2 ABV IF-RT (30Gy) B. and D. closed prematurely for safety C. 2 AVD IF-RT (30Gy) D.2AV IF-RT (30Gy) reason (many events) SWOG indicates Southwest Oncology Group: EORTC, European Organization for Research and Treatment of Cancer; GELA, Groupe d Etude des Lymphomes de l Adulte; GHSG, German Hodgkin s Lymphoma Study Group: EF/IF-RT, extended/involved-field radiotherapy; STLI, subtotal lymphoid irradiation; STNI, subtotal nodal irradiation; FFTF, Freedom of treatment failure; FFP, freedom from progression; EFS, event-free survival; OS, overall survival. TREATMENT OF EARLY-UNFAVORABLE HL From Extended to Involved Field Radiotherapy Patients with early-unfavorable HL generally qualify for combined modality treatment. However, the ideal chemotherapy and radiation combinations are not yet clearly defined, and there is an ongoing desire to optimize treatment in this risk group. This is further being attempted by reducing radiation doses and field sizes in a similar manner to that for early-favorable stages. Several trials seem to indicate that the reduction of field size does not compromise the efficacy of treatment. Bonadonna et al 10 compared STLI with IF-radiotherapy after 4 cycles of ABVD in patients with early-favorable and unfavorable stages and reported a similar treatment outcome in both arms. In their H8U trial, the EORTC randomized patients between 6 cycles of MOPP/ABV 36 Gy IF-radiotherapy, 4 cycles of MOPP/ ABV 36 Gy IF-RT, or 4 cycles MOPP/ABV STLI. There was no difference between arms in terms of response rates, failure-free survival, or OS. 12 The GHSG HD8 trial randomized patients receiving 2 alternating cycles of COPP/ABVD to either extended (arm A) or involved field radiation (arm B). Final results at 5 years did not indicate differences between the 2 arms in terms of FFTF (86% and 84%) and OS (91% and 92%); however, more toxicity was reported in the patients who were treated with EF-radiotherapy. 17 A National Cancer Institute of Canada/Eastern Cooperative Oncology Group trial favored combined modality treatment over ABVD alone in unfavorable nonbulky stage IA/IIA HL. 18 Furthermore, a recent retrospective analysis supports the use of approximately 30 Gy IF-radiotherapy after a good response to ABVD, 19 a strategy that has been adopted in the ongoing GHSG and EORTC trials. Optimization of Chemotherapy In early-unfavorable stages, efforts were made to improve the efficacy of chemotherapy by altering drugs and schedules as well as the number of cycles. In the past, alternation or hybridization of a MOPP-like regimen with ABVD did not produce better outcomes when compared with ABVD alone. Furthermore, studies in advanced-stage HL indicated that ABVD alone is equally effective and less myelotoxic compared with alternating MOPP/ABVD, and both are superior to MOPP alone. 20 Thus, a combined modality treatment consisting of 4 courses of ABVD followed by 30 Gy IF-radiotherapy is considered standard treatment for patients with early-unfavorable HL. Despite the excellent initial remission rates obtained with ABVD and radiotherapy, approximately 15% of patients in earlyunfavorable stages relapse within 5 years and about another 5% suffer from primary progressive disease. These outcome rates are rather similar to those in patients in advanced stages when treated with more intensive regimens. Thus, study groups are currently evaluating different regimens for the early-unfavorable group that were previously pioneered for the treatment of advanced stages. In their ongoing intergroup trial no. 2496, the Eastern Cooperative Oncology Group and Southwest Oncology Group are assessing whether the Stanford V regimen (12 weeks) is superior to 6 cycles of ABVD. In another approach, 4 cycles of ABVD were compared with 4 cycles of BEACOPPbaseline by the EORTC-Groupe d Etude des Lymphomes de 2009 Lippincott Williams & Wilkins 145

4 Klimm and Engert The Cancer Journal Volume 15, Number 2, March/April 2009 TABLE 4. Selected Trials for Early-Stage Unfavorable Hodgkin s Lymphoma Trial Therapy Regimen No. Pts. Outcome References EORTC/GELA H8U A. 6 MOPP/ABV IF RT (36 Gy) % (EFS, 5 yr); 88% (OS, 10 yr) 12 B. 4 MOPP/ABV IF RT (36 Gy) % (EFS, 5 yr); 85% (OS, 10 yr) C. 4 MOPP/ABV STNI % (EFS, 5 yr); 84% (OS,10 yr) GHSG HD8 A. 2 COPP ABVD EF RT (30 Gy) % (FFTF); 91% (OS) 17 Bulk (10Gy) B. 2 COPP ABVD IF RT (30 Gy) % (FFTF); 92% (OS); (5 yr) Bulk (10Gy) SWOG/ECOG no A. 6 ABVD IF RT (36 Gy) to bulk ( 5 cm) B. 12 wk Ongoing trial Stanford V IF RT (36 Gy) to bulk ( 5 cm) EORTC/GELA H9U A. 6 ABVD IF RT % (EFS); 95% (OS) 21 B. 4 ABVD IF RT % (EFS); 94% (OS) C. 4 BEACOPP bas. IF RT % (EFS); 93% (OS); (4 yr) GHSG HD11 A. 4 ABVD IF RT (30Gy) 1293 Interim analysis (3 yr) 22 B. 4 ABVD IF RT (20Gy) All pts C. 4 BEACOPP bas. IF RT (30Gy) 87% (FFTF) D. 4 BEACOPP bas. IF RT (20Gy) 96% (OS) GHSG HD14 A. 4 ABVD IF RT (30Gy) Ongoing trial B. 2 BEACOPP esc. 2 ABVD IF RT (30Gy) SWOG indicates Southwest Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GELA, Groupe d Etude des Lymphomes de l Adulte; GHSG, German Hodgkin s Lymphoma Study Group; ECOG, Eastern Cooperative Oncology Group; EF/IF-RT, extended/involved-field radiotherapy; STNL, subtotal nodal irradiation; FFTF, Freedom of treatment failure; EFS, event-free survival; OS, overall survival. l Adulte (H9U trial) and by the GHSG (HD11 trial). In addition, 2 EORTC trials analyzed whether 4 cycles of combined modality treatment are equally effective as 6 cycles (EORTC: H8U and H9U trial). In the H9U study, patients were randomly assigned to 6 cycles of ABVD or 4 cycles of ABVD or 4 cycles of BEACOPP-baseline, followed by 30 Gy IF-Radiotherapy in all arms. After a median follow-up of 4 years, no significant difference was observed between the 3 different treatment arms with respect to EFS or OS. 21 Interim results of the GHSG HD11 trial demonstrated very similar rates of FFTF and OS. At 3 years, there was no difference with respect to outcome, either between the ABVD and BEACOPP-baseline arms or between 30 Gy and 20 Gy IF-radiotherapy. Although it should be taken into account that these are relatively early data, currently there is no evidence for changing treatment from 4 to 6 cycles of ABVD or for recommending 4 cycles of BEACOPP-baseline in this group of patients. 22 However, the low FFTF in this risk group led the GHSG to a further intensification of treatment. In the ongoing HD14 trial for early-unfavorable stages, the BEACOPP escalated regimen was introduced, which had shown high efficacy in the treatment of advanced HL. 23 Patients were randomized to receive either 4 cycles of ABVD or 2 cycles of BEACOPP escalated plus 2 cycles of ABVD, both followed by 30 Gy IF-radiotherapy. The latter approach looks very promising at 3 years. In their current EORTC trial H10U, the EORTC incorporates PET and applies a risk-adapted schedule. Concerning radiotherapy, a new involvednode method leading to even smaller fields is being tested. 24 A selection of recent and ongoing studies in patients with earlyunfavorable HL is given in Table 4. TREATMENT OF ADVANCED-STAGE HL Advent of ABVD Chemotherapy Before the introduction of combination chemotherapy, more than 95% of patients with advanced HL succumbed to their disease 146 within 5 years. Thus, remission rates in excess of 50% achieved with MOPP were a major breakthrough in oncology. MOPP was successfully used for many years for advanced-stage disease, resulting in long-term remission of nearly 50%. 2,25 The regimen was then replaced by ABVD, after a series of large multicenter trials had proven the superiority of ABVD and alternating MOPP/ABVD over MOPP alone. 26,27 Hybrid regimens such as MOPP/ABV were only equally effective when compared with alternating MOPP/ABVD and even rapidly alternating multidrug regimens such as COPP/ ABV/IMEP did not result in better outcome. 28,29 However, more acute toxicity and a higher incidence of leukemia was reported after MOPP/ABV hybrid when compared with ABVD. 25 Therefore, ABVD was regarded the standard regimen against which all new combinations had to be tested. Nevertheless, a long-term follow-up report of 123 patients that had been treated with ABVD for advanced HL revealed a failure free survival of only 47% and an OS of 59% after 14.1 years. 30 New Chemotherapy Options Several groups tried to improve the ABVD results by developing new regimens with additional drugs and by increasing dose intensity and dose density with the support of colony-stimulating factors and modern antibiotics. These new approaches include multidrug regimens such as Stanford V, MOPPEBVCAD, VAPEC-B, ChlVPP/EVA, and BEACOPP variants Stanford V was developed as a short-duration, reducedtoxicity program and applied weekly over 12 weeks. Consolidating radiotherapy to sites of initial disease was employed. With an estimated 5-year freedom from progression of 89% and OS of 96%, this regimen produced very promising responses. However, the data were generated at a single center. 31 A prospectively randomized multicenter comparison of Stanford V with MOPPEBVCAD and ABVD showed that this regimen was inferior in terms of response rate (76% vs. 89% and 94%) and PFS (73% vs. 85% and 94%) in a 2009 Lippincott Williams & Wilkins

5 The Cancer Journal Volume 15, Number 2, March/April 2009 Treatment of HL TABLE 5. Selected Trials for Advanced Hodgkin s Lymphoma Trial Therapy Regimen No. Pts. Outcome Ref. Intergroup Italy A. ABVD (6 cycles) 98 83% (FFS); 86% (FFP); 90% (OS) 32 B. Stanford V (12 wk) 89 67% (FFS); 76% (FFP); 83% (OS) C. MEC hybrid (six courses) ( RT initial 88 85% (FFS); 93% (FFP); 90% (OS) (5 yr) bulk/residual mass) Intergroup GB and Italy A. ChlVPP/EVA hybrid (6 cycles) % (FFP); 78% (EFS); 89% (OS) 33 B. VAPEC-B (11 wk) ( RT initial bulk/ residual mass) % (FFP); 58% (EFS); 79% (OS) (5 yr) GHSG HD9 A. COPP/ABVD (4 cycles) % (FFTF); 75% (OS) 34 B. BEACOPP baseline (8 cycles) % (FFTF); 80% (OS) C. BEACOPP escalated (8 cycles) % (FFTF); 86% (OS) (10 yr) GHSG HD12 A. 8 BEA esc th interim analysis (4 yr) 35 B. 8 BEA esc. 345 All patients C. 4 BEA esc. 4 BEA baseline % (8Besc) vs. 86% (4 4) (FFTF) D. 4 BEA esc. 4 BEA baseline (A. C.: % (8Besc) vs. 91% (4 4) (OS) RT bulk/residual mass) GHSG HD15 A. 8 BEA esc. Trial closed, results awaited 37 B. 6 BEA esc. Negative predictive value for PET: 94% (12 mo) C. 8 BEA-14 ( RT to PET residual mass 2.5 cm) Intergroup no ABVD 4 BEA esc. 4 BEA baseline Ongoing trial EORTC,... SWOG indicates Southwest Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GELA, Groupe d Etude des Lymphomes de l Adulte; GHSG, German Hodgkin s Lymphoma Study Group; ECOG, Eastern Cooperative Oncology Group; EF/IF-RT, extended/involved-field radiotherapy; STNI, subtotal nodal irradiation; FFS, failure-free survival; FFP, freedom from progression; FFTF, freedom from treatment failure; EFS, event-free survival; OS, overall survival. multicenter setting. ABVD was still the best choice when it was combined with optional, limited irradiation. 32 These conflicting results might be partially explained by the use of less radiotherapy in the randomized setting and the better treatment quality of singlecenter reports. The Manchester group developed VAPEC-B, an abbreviated 11-week chemotherapy program and conducted a randomized comparison with the hybrid ChlVPP/EVA. After 5 years, EFS and OS were significantly better with ChlVPP/EVA than with VAPEC-B (EFS: 78 vs. 58%; OS: 89 vs. 79%). 33 The GHSG HD9 trial compared COPP/ABVD, BEACOPP baseline, and BEACOPP escalated. Results from 1195 randomized patients showed a clear superiority of escalated BEACOPP over BEACOPP-baseline and COPP/ABVD at 5 years. 23 The follow-up data at 10 years confirmed these results: with a median follow-up of 112 months, the FFTF and OS rates were 64% and 75% in the COPP/ABVD group, 70% and 80% in the BEACOPP baseline group, and 82% and 86% in the BEACOPP-escalated group. 34 The subsequent GHSG HD12 trial aimed at deescalating chemotherapy and radiotherapy by comparing 4 courses of BEACOPP-escalated with 4 courses of escalated and 4 courses of baseline BEACOPP, with or without consolidating radiation to initial bulky and residual disease. In an interim analysis of HD12 at 4 years, there was no significant difference in the FFTF and OS between the different arms so far, but final results are awaited. 35 In the following HD15 trial, patients were randomized between 8 courses of BEACOPP-escalated, 6 courses of BEACOPP-escalated, or 8 courses of BEACOPP-14, which is a time-intensified variant of BEACOPP-baseline. 36 Additional radiotherapy was only applied to residual lesions 2.5 cm positive by PET. The chemotherapy question is not yet solved; however, PET demonstrated a high negative predictive value for progression or early relapse for patients with residual disease after the first-line chemotherapy in advanced-stage HL. 37 The question whether escalated BEACOPP is superior to ABVD alone in a randomized setting is currently being evaluated in an intergroup trial initiated by the EORTC (no ). Here, 8 cycles of ABVD are being compared with 4 cycles of BEACOPP-escalated followed by 4 cycles of BEACOPP-baseline. Further intensification of the first-line therapy in high-risk patients by employing high-dose chemotherapy and autologous stem cell transplantation after 4 instead of 8 cycles of ABVD did not improve outcome compared with conventional treatment. 38 A selection of recent and ongoing studies in patients with advanced-stage HL is given in Table 5. Role of Consolidating Radiotherapy and PET The role of consolidating radiotherapy after effective chemotherapy in the treatment of patients with advanced HL is still subject to clinical research. A meta-analysis comparin 1 g combined modality approaches and chemotherapy alone reported equal tumor control and even better OS in patients treated with chemotherapy alone. 39 Therefore, randomized trials currently evaluate the impact of radiotherapy after effective chemotherapy for advanced HL. A study conducted by the EORTC indicated that consolidating IF-RT did not result in better outcome in patients who had already achieved a complete remission after 6 to 8 cycles of MOPP/ABV, although radiotherapy may be beneficial to patients with partial remissions. 40 Longer follow-up of the GHSG HD12 trial and the HD15 trial may help to define the role of radiotherapy for residual disease. In the HD15 trial, PET scan was used as a tool to analyze tumor activity in residual masses after chemotherapy. Radiotherapy was only applied to PET-positive residual lesions 2.5 cm. The approach led to a substantial lower number of patients receiving radiotherapy than in 2009 Lippincott Williams & Wilkins 147

6 Klimm and Engert The Cancer Journal Volume 15, Number 2, March/April 2009 previous GHSG studies. The method showed a high negative predictive value; thus, consolidation radiotherapy might be omitted in PET-negative patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. 37 In addition, there are data from smaller trials with ABVD suggesting that early PET scan during chemotherapy may discriminate between responders and nonresponders and thus have a potential role for use in response-adapted strategies. 41,42 This approach is currently being investigated in larger randomized GHSG and EORTC studies for advanced-stage HL. Elderly HL Patients Although there is substantial variety in the health status among elderly patients with HL, the age at diagnosis remains an unfavorable risk factor, particularly in patients with advanced stages. In most groups, patients are considered elderly if they are older than 60 years. Factors such as more aggressive disease, more frequent diagnosis of advanced stage, comorbidity, poor tolerance of treatment, failure to maintain dose intensity, shorter survival after relapse, and death because of other causes contribute to the poorer outcome of elderly patients. A retrospective analysis of GHSG trials showed that elderly patients have a poorer risk profile, more treatment-associated toxicity, a lower dose-intensity and higher mortality as major factors for poorer outcome. 43 Generally, elderly patients without major comorbidities who are sufficiently fit to tolerate standard therapy have a treatment outcome comparable with that of younger patients. Whenever possible, elderly patients should be treated with a doxorubicin-containing regimen; however, the BEA- COPP regimen is too toxic for patients over 60 years. 44 Furthermore, large radiotherapy fields should be avoided. 45 Whether the results of new approaches such as ChlVPP-ABV, ODBEP, PVAG, BACOPP, or VEPEMB would be superior compared with ABVD or equal and less toxic is currently a matter of speculation because of the lack of randomized studies. SUMMARY Currently, combined modality treatment strategies including 2 to 4 cycles of ABVD chemotherapy followed by 30 Gy IFradiotherapy is the standard treatment for patients with early stages of HL at diagnosis. Patients in the early-favorable risk group achieve an FFTF of more than 90% and an OS of about 95% at 5 years. Patients in the early unfavorable group have an FFTF of about 84% and an OS of 91%. 12,15,17 In many centers 6 to 8 cycles of ABVD plus consolidating radiotherapy to residual disease is still considered the gold standard for patients with advanced-stage HL. The GHSG recommends BEACOPP escalated for patients under the age of 60 because of significant better outcome rates. With ABVD, Stanford V, and MOPPEBVCAD the 5-year failure-free survival rates were 78%, 54%, and 81%. Corresponding 5-year OS rates were 90%, 82%, and 89%. 32 With BEACOPP escalated FFTF and an OS rates of 87% and 91% were observed at 5 years. 23 With regard to these excellent results, modern treatment strategies aim at further optimizing chemotherapy by simultaneously reducing therapy-induced acute and long-term toxicities. Potential future strategies may use response-adapted therapy approaches guided by early-pet scan and may successfully implement new drugs and experimental strategies in the first-line treatment. 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