Early versus late intensification for patients with high-risk Hodgkin lymphoma—3 Cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation

Five-year results of a randomized trial on behalf of the GOELAMS group

Authors

  • Nina Arakelyan MD,

    1. University of Paris-Descartes, Paris, France
    2. Department of Cancer Medicine, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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  • Christian Berthou MD,

    1. Department of Hematology, University Hospital Center, Brest, France
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  • Bernard Desablens MD,

    1. Department of Hematology, Hospital South, University Hospital Center, Amiens, France
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  • Sophie de Guibert MD,

    1. Department of Hematology, University Hospital Center, Rennes, France
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  • Vincent Delwail MD,

    1. Department of Hematologic Oncology and Cellular Therapy, University Hospital Center, Poitiers, France
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  • Marie-Pierre Moles MD,

    1. Department of Hematology, University Hospital Center, Angers, France
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  • Philippe Quittet MD,

    1. Department of Hematology, University Hospital Center, Montpellier, France
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  • Jean-Philippe Jais MD,

    1. University of Paris-Descartes, Paris, France
    2. Laboratory of Biostatistics, University of Paris-Descartes, Paris, France
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  • Pierre Colonna MD,

    1. University of Paris-Descartes, Paris, France
    2. Department of Cancer Medicine, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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  • Jean-Marie Andrieu MD,

    Corresponding author
    1. University of Paris-Descartes, Paris, France
    2. Department of Cancer Medicine, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
    • Cancérologie Médicale, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015 Paris, France
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    • Fax: (011) 33-156092415

  • and the Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang

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    • Authors of the Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) Hodgkin Lymphoma Network also included: Thomas Gastinne (Department of Hematology, University Hospital Center, Nantes, France), Delphine Sénécal (Department of Hematology, University Hospital Center, Tours, France), Jacqueline Dugay (Hospital Center, Le Mans, France), Virginie Lucas (La Source Hospital, Orleans, France), Philippe Casassus (Department of Hematology, Avicenne Hospital, Public Assistance Hospitals of Paris, Bobigny, France), Christiane Ghandour (Seavigne Polyclinic, Rennes, France), Philippe Rodon (Hospital Center, Blois, France), Jean-Pierre Vilque (Cornouailles Hospital Center, Quimper, France), Henry Jardel (Hospital Center, Vannes, France), Bruno Audhuy (Department of Hematology, Hospital Center, Colmar, France), Michèle Schoenwald (La Source Hospital, Orleans, France), Michel Maigre (Hospital Center, Saumur, France), Hervé Maisonneuve (Hospital Center, La Roche-sur-Yon, France), and Michel Flesch (Departmental Hospital Center, Dijon, France).


Abstract

BACKGROUND.

The 5-year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post-treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high-risk factors who were recruited between May 1997 and December 2004.

METHODS.

High-risk CS IIB, III, and IV were defined by the presence of ≥5 involved lymphoid areas, and/or a mediastinal mass ratio ≥0.45, and/or ≥2 extra lymph node sites affected by the disease (for CS IV). In Arm V, 82 patients received 3 courses of combined vindesine (5 mg/m2), doxorubicin (99 mg/m2), carmustine (140 mg/m2), etoposide (600 mg/m2), and methylprednisolone (600 mg/m2) (VABEM) followed by low-dose lymph node irradiation. In Arm A, 76 patients received 4 cycles of ABVD followed by myeloablative combined carmustine (300 mg/m2), etoposide (800 mg/m2), cytarabine (1600 mg/m2), and melphalan (140 mg/m2) and underwent autologous stem cell transplantation.

RESULTS.

After 3 cycles of VABEM, the CR rate was 89% versus 60% after 4 cycles of ABVD. However, after the completion of treatment, the CR rates for Arms V and A were similar (89% and 88%, respectively). The 5-year FFTF rates for Arms V and A also were similar (79% and 75%, respectively) along with the 5-year overall survival rates (87% and 86%, respectively).

CONCLUSIONS.

Early intensification (Arm V) and late intensification (Arm A) were equally effective for treating patients with high-risk/advanced HL. Cancer 2008. © 2008 American Cancer Society.

Since the randomized study published in 1992 by Canellos et al,1 the reference therapy for patients with advanced or high-risk (HR) Hodgkin lymphoma (HL) has remained 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-based combinations. However, almost 15% to 20% of patients failed to respond to these chemotherapy regimens, and 15% to 20% of patients who achieved complete remission developed recurrent disease within 5 years.2, 3

Faced with such unsatisfactory results, in 1996, we designed a phase 2 randomized trial to compare 2 types of more aggressive experimental treatments that were chosen among the most effective salvage therapies for refractory and relapsing HL. Arm V of the trial consisted of a frontline, intensive, nonmyeloablative chemotherapy regimen of vindesine, doxorubicin, carmustine (BCNU), etoposide, and methylprednisolone (VABEM) administered 3 times at 1-month intervals and followed by adjuvant, low-dose lymph node irradiation. This intensive treatment was chosen among several high-dose chemotherapy regimens,4–7 because we already had tested it in a phase 2study.8 The other treatment arm (Arm A) consisted of 4 cycles of ABVD followed by an adjuvant myeloablative chemotherapy regimen of BCNU, etoposide, cytarabine, and melphalan (BEAM) associated with autologous stem cell transplantation (ASCT). This treatment approach already had been tested in patients with refractory or relapsing HL by different groups,9–11 including ours.12 In this article, we report the 5-year results from this multicenter, phase 2, randomized study (the H97-HR trial).

MATERIALS AND METHODS

Patients

From May 1997 to December 2004, all adult patients with HL who were recruited at centers affiliated with the “Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang” were candidate for inclusion in the H97 prospective trials. Initial investigations included physical examination, blood count and differential, sedimentation rate, serum biochemistry profile, chest X-ray, chest and abdomen computed tomography scans, and bone marrow trephine biopsy. Additional examinations to document lesions were used when necessary. All patients were staged according to Ann Arbor criteria.13

In the current study, HR HL was defined as clinical stage (CS) IIB, III, or IV disease with a mediastinal mass ratio ≥45% and/or ≥5 lymphoid areas involved by disease (among the following: Waldeyer ring, right/left cervical lymph nodes, right/left axillary lymph nodes, mediastinal area including hilar lymph nodes, lumboaortic area including coeliomesenteric lymph nodes, right/left pelvic lymph nodes, right/left inguinal and/or femoral lymph nodes, right/left epitrochlear or popliteal lymph nodes, and spleen) and/or ≥2 extranodal sites involved by disease (for CS IV HL). Patients also were classified according to the International Prognostic Index (IPI)14 into 2 groups according to the number of risk factors (0-2 risk factors vs 3-7 risk factors).

To be included in the randomized H97-HR trial (which was approved by the Ethical Committee of Ile de France in December 1996), patients with HR HL had to be ages 18 to 60 years, they had to be seronegative for the human immunodeficiency virus, and they could have no concomitant diseases that prevented them from receiving intensive or myeloablative chemotherapy. Finally, they had to provide their written consent.

Patients were randomized between Arm V (VABEM-radiotherapy) and Arm A (ABVD-BEAM). Randomization tables were prepared by each center and by blocks of 6 patients.

Induction Chemotherapy Regimens

Induction chemotherapy for Arm V consisted of 3 monthly cycles of VABEM (vindesine, 1 mg/m2 on Days 1-5 as a continuous intravenous infusion; doxorubicin [Adriamycin], 33 mg/m2 intravenously on Days 1-3; BCNU, 140 mg/m2 intravenously on Day 3; etoposide, 200 mg/m2 intravenously on Days 3-5; and methylprednisolone, 120 mg/m2 intravenously on Days 1-5). Induction chemotherapy for Arm A consisted of 4 monthly cycles of ABVD (intravenously on Days 1 and 15: doxorubicin, 25 mg/m2; bleomycin, 10 mg/m2; vinblastine, 6 mg/m2; dacarbazine, 375 mg/m2; and methylprednisolone, 120 mg/m2).

Patients in both arms received recombinant human granulocyte–colony-stimulating factor (G-CSF) (lenograstim), 5 μg/kg daily from Day 6 until the neutrophil count reached >1000/μL. From the second cycle, chemotherapy in both arms (always given at full dose) was postponed until neutrophil and platelet counts increased to >1000/μL and >80,000/μL, respectively.

From 2 to 3 weeks after the completion of induction chemotherapy, the remission status of patients in both arms was evaluated. A complete remission was defined as the disappearance of all clinical, radiologic, and histologic (bone marrow) signs of HL. A partial remission was defined as a decrease ≥50% in the size of lymph node lesions accompanied by the complete disappearance of extranodal lesions. Finally, persistent/progressive disease was defined as the persistence of extranodal lesions (whatever the lymph nodes status), and/or a decrease <50% in the size of lymph nodes lesions, or their reapperance/progression.

Adjuvant Treatment of Patients in Complete Remission

Patients in Arm V who achieved complete remission after the completion of 3cycles of VABEM received adjuvant irradiation (20 grays [Gy], 10 Gy per week) that included all initially involved lymph node sites; 16 Gy were added for lymph node masses that initially measured ≥5 cm greatest dimension.

Patients in Arm A who achieved complete remission after 4 cycles of ABVD received the myeloablative BEAM regimen. Cyclophosphamide (4 g/m2 intravenously) was given first followed by subcutaneous injections of G-CSF (10 μg/kg per day) from the third day until the harvesting of peripheral stem cells by cytapheresis. All patients who reached a concentration of CD34-positive stem cells ≥2 × 106 cells/kg received 1 cycle of BEAM (intravenously: BCNU, 300 mg/m2 on Day −7; etoposide, 200 mg/m2 on Days −6 to −3; cytarabine, 400 mg/m2 on Days −6 to −3; and melphalan, 140 mg/m2 on Day −2) followed by ASCT on Day 0. Patients received G-CSF (lenograstim, 5 μg/kg per day) from Day 1 until the neutrophil count reached >500/μL.

Within 30 to 45 days after the administration of the BEAM regimen, patients who had initial lymph node masses that measured ≥5 cm in greatest dimension received involved-field irradiations at a dose of 36 Gy (10 Gy per week).

Consolidation Treatment for Patients in Partial Remission

Patients in both arms who achieved partial remission after the completion of induction treatment received the same treatment as patients who achieved complete remission (invoved-field irradiations after VABEM or the BEAM regimen after ABVD).

Evaluation of Post-Treatment Status and Follow-Up

Four to 6 weeks after the completion of these consolidation treatments, patients' remission status was reevaluated. Complete remission was defined as the disappearance of all clinical, radiologic, and histologic (bone marrow) signs of HL; patients with a residual mediastinal mass, whether it had remained stable or had decreased under irradiation, also were considered to be in complete remission. Persistent/progressive disease after consolidation therapy was defined as the reappearance of lymph node disease and/or the persistence or reappearance of visceral disease. Patients in both arms who had persistent/progressive disease received second-line treatments.

Remission status was checked every 3 months during the first year, then twice each year until the fifth year, and every 18 months thereafter. Disease recurrences were treated by various chemotherapy and radiotherapy regimens whenever possible. All treatment complications were recorded as well as all causes of death.

Statistical Methods

The chi-square test or, when appropriate, the Fisher exact test (2-tailed) was used to compare qualitative data. All survival curves were calculated from the starting date of chemotherapy; observations were censored at the stop date of June 1, 2007. Curves were computed according to Kaplan-Meier method and were compared by using the log-rank test. A P value of .05 (2-sided) was considered the limit of significance for each analysis. No interim analysis was planned during the study.

To calculate freedom from treatment failure (FFTF) rate, the adverse events considered were a lack of complete remission after treatment completion, the occurrence of recurrent disease, and deaths from any cause. To calculate overall survival (OS), the events considered were deaths from any cause.

The primary endpoint of the trial was the 5-year FFTF rate. The secondary endpoint was the 5-year OS rate.

RESULTS

Between May 1997 and December 2004, 162 patients who fulfilled the criteria for HR HL were assigned randomly to 1 of the 2 treatment arms of the H97-HR trial (Table 1). Four patients were dropped from the study after randomization, 1 because he refused the allocated treatment arm, 2 others because of major protocol violations, and 1 because his treatment already had started at the time he was randomized.

Table 1. The Randomized H97-HR Trial for Patients With High-Risk Hodgkin Lymphoma
Treatment Regimens
Arm VArm A
  1. VABEM indicates vindesine, doxorubicin, carmustine, etoposide, and methylprednisolone 6; ABVD, doxorubicin, bleomycin, vincristine, and dacarbazine; D, Day of treatment; BCNU, carmustine; Gy, grays; BEAM, carmustine, etoposide, cytarabine, and melphalan; PMN, polymorphonuclear neutrophils.

Induction chemotherapy
 VABEM (3 monthly cycles)ABVD (4 monthly cycles)
  Vindesine, 1 mg/m2/d continuous infusion (D1–D5) Adriamycin 25 mg/m2/d (D1 and D15)
  Adriamycin, 33 mg/m2/d (D1–D3) Bleomycin 10 mg/m2/d (D1 and D15)
  BCNU 140 mg/m2/d (D3) Vinblastine 6 mg/m2/d (D1 and D15)
  Etoposide 200 mg/m2/d (D3–D5) Dacarbazine 375 mg/m2/d (D1 and D15)
  Methylprednisolone 120 mg/m2/d (D1–D5) Methylprednisolone 120 mg/m2/d (D1 and D15)
Adjuvant/consolidation treatments after complete/partial remission
 Irradiation: 20 Gy on initial involved sites plus 16 Gy on masses initially >5 cmCyclophosphamide 4000 mg/m2/d (D-21) and lenograstim 10 μg/kg/d (D-18 to D-14)
Autologous stem cell harvest (D-14)
BEAM
 BCNU 300 mg/m2/d (D-7)
 Etoposide 200 mg/m2/d (D-6 to D-3)
 Cytarabine 400 mg/m2/d (D-6 to D-3)
 Melphalan 140 mg/m2/d (D-2)
Stem cell transplantation (D0)
Lenograstim 5 μg/kg/d (D1 until PMN >500/μL)
Irradiation: 36 Gy on masses initially >5 cm

Demographic characteristics of the 158 patients who actually participated in the randomized trial are listed in Table 2. Arms V and A were similar in terms of age, sex, histologic subtypes, Ann Arbor stages, and IPI groups. In June 2007, the median follow-up of living patients (64 months; range, 28-123 months) was similar in both arms.

Table 2. Presenting Characteristics of the 158 Patients With High-Risk Hodgkin Lymphoma Treated According to the Randomized H97-HR Trial
CharacteristicAllArm VArm A
No.%No.%No.%
All patients1581008210076100
Sex, women533529352432
Age, y
 Mean34.4 33.5 35.5 
 ≥40442819232533
Histology, nodular sclerosis1308270856079
“B” symptoms1207659726180
Clinical stage IIB21131215912
 With mediastinal mass ratio >0.45151091168
 With ≥5 involved lymphoid areas533423
 With both110011
Clinical stage IIIA161091179
 With mediastinal mass ratio >0.45430045
 With ≥5 involved lymphoid areas1067934
 With both212200
Clinical stage IIIB382418222026
 With mediastinal mass ratio >0.45645611
 With ≥5 involved lymphoid areas25168101722
 With both745623
Clinical stage IV835343524053
 With ≥2 extranodal sites473027332026
 With 1 extranodal site and362316202026
  With mediastinal mass ratio >0.451387968
  With ≥5 involved lymphoid areas20138101216
  With both321123
International prognostic index <3 factors784940493850
  ≥3 Factors674236443141
  Not available1386779

Among the 82 patients in Arm V, 74 patients received 3 cycles of VABEM at the full dose (which left 69 patients in complete remission and 5 patients with persistent/progressive disease). Two patients in good partial remission after 2 cycles of VABEM received a course of BEAM instead of their third VABEM cycle, and 2 patients in complete remission after 1 cycle of VABEM received 2 cycles of ABVD instead of 2 cycles of VABEM. Moreover, 1 patient who developed progressive disease after 2 VABEM cycles was switched to a second-line chemotherapy. Finally, 3 patients died from treatment toxicity (1 after the first VABEM cycle and 2 after the second VABEM cycle). Overall, 73 patients (89%) in Arm V achieved complete remission at the completion of induction chemotherapy, 6 patients had persistent/progressive disease (which led to 5 deaths), and the last 3 patients died from treatment-induced infections.

The median duration of induction chemotherapy (from the day of the first infusion to the day of the last infusion) was 59 days (range, 41-85 days) for the 73 complete responders. The incidence of hematologic side effects is shown in Table 3.

Table 3. Hematologic Toxicities Observed in the Randomized Phase 2 H97-HR Trial for Patients With High-Risk Hodgkin Lymphoma
CharacteristicType of Chemotherapy
ABVDBEAMVABEM
  1. ABVD indicates doxorubicin, bleomycin, vincristine, and dacarbazine; BEAM, carmustine, etoposide, cytarabine, and melphalan; VABEM, vindesine, doxorubicin, carmustine, etoposide, and methylprednisolone; SD, standard deviation.

No. of patients767082
Total no of cycles23770236
 Percentage of cycles with neutrophils <500/μL6.2100100
 Days (mean ± SD) per cycle with neutrophils <500/μL3 ± 18.2 ± 2.23.8 ± 2.5
 Percentage of cycles with neutropenic fever4.178.675.4
 Days (mean ± SD) per cycle with neutropenic fever2 ± 13.9 ± 2.72.5 ± 2.1
 Percentage of cycles with platelets <20,000/μL084.276.2
 Days (mean ± SD) per cycle with platelets <20,000/μL02.8 ± 2.30.9 ± 1.4
 Percentage of cycles with platelet transfusion1.396.477.1
 Percentage of cycles with packed erythrocyte transfusions178.675.8

The 73 patients in Arm V who achieved complete remission after induction chemotherapy received the planned 20-Gy irradiation. Moreover, 62 of those patients received a boost of 16 Gy to lymph nodes that initially measured >5 cm in greatest dimension. The median treatment duration of the 73 complete responders was 168 days (range, 81-295 days).

Among the 73 patients who achieved complete remission, 1 died from acute myelocytic leukemia after 23 months of survival. Nine recurrences developed in patients from Arm V within a median delay of 11 months (range, 8-38 months) after treatment completion; 7 of those recurrences occurred at lymph node sites that initially were affected by disease. Among the 9 patients who developed recurrent disease, 6 patients achieved a second complete remission, and the other 3 patients eventually died from HL.

Among the 76 patients in Arm A, 73 patients received the 4 programmed cycles of ABVD, and the remaining 3 patients received only 1 to 3 cycles, 1 because he suffered from an unexpected neurologic toxicity and the other 2 because their disease progressed. The median duration of induction chemotherapy was 104 days (range, 85-143 days). At the completion of induction chemotherapy, 46 patients (60.5%) were in complete remission, 24 patients were in partial remission, and the remaining 6 patients had persistent/progressive disease (which led to 3 deaths). The 70 responding patients received their planned myeloablative BEAM regimen. It was followed by the reinfusion of CD34-positive peripheral stem cells in 69 patients and by the reinfusion of CD34-positive bone marrow cells (withdrawn by trephine) in the remaining patient. No toxic deaths occurred after BEAM. The incidence of hematologic side effects is shown in Table 3.

At the completion of BEAM chemotherapy, the 46 patients who already were in complete remission before BEAM remained in complete remission, 21 of 24 patients who were in partial remission also achieved complete remission, and the remaining 3 patients had persistent/progressive disease (which led to 2 deaths). Overall, the complete remission rate for Arm A was 88.2%.

Forty-four patients who initially had lymph nodes that measured >5 cm in greatest dimension received adjuvant involved-field irradiations (36 Gy). The median treatment duration of complete responders was 218 days (range, 138-398 days).

Eight recurrences developed in patients from Arm A within a median delay of 8 months (range, 4-32 months) after treatment completion. Seven of those recurrences occurred at lymph node sites that initially were affected by disease. Of those 8 recurrences, 4 (which led to 3 deaths) occurred among the 46 patients who achieved complete remission after 4 cycles of ABVD, and the other 4 recurrences (which also led to 3 deaths) occurred among the 21 patients who achieved complete remission only after the consolidation phase of treatment (BEAM).

An analytic diagram of treatment results from both arms is provided in Figure 1. The complete remission rates for Arm V and Arm A were 89% and 60.5%, respectively (P < .001), at the completion of chemotherapy (3 VABEM cycles and 4 ABVD cycles) and 89% and 88.2%, respectively (P value nonsignificant), at the completion of treatment (3 VABEM cycles plus radiotherapy and 4 ABVD cycles plus BEAM).

Figure 1.

Analytic diagram of treatment results from the randomized H97-HR trial for patients with high-risk Hodgkin lymphoma. ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; BEAM, carmustine, etoposide, cytarabine, and melphalan; ASCT, autologous stem cell transplantation; IF-RT, involved-field radiotherapy; Gy, grays; CR, complete remission; PR, partial remission; PD, persistent/progressive disease; †, died of Hodgkin lymphoma; †AL, died of acute myelocytic leukemia; †FN, died of febrile neutropenia.

The 5-year FFTF rates for Arm V and Arm A were similar (78.9 ± 8.9% and 74.9 ± 9.8%, respectively) (Fig. 2A). The 5-year OS rate for Arm V and Arm A also were similar (86.8 ± 7.8% and 85.9 ± 8.2%, respectively) (Fig. 2B).

Figure 2.

Results from the randomized H97-HR trial for patients with high-risk Hodgkin lymphoma. (A) Overall survival: Arm V, 82 patients, 10 events; Arm A, 76 patients, 10 events. (B) Freedom from treatment failure: Arm V, 82 patients, 17 events; Arm A, 76 patients, 19 events.

DISCUSSION

In this report, we present the 5-year results from a phase 2 randomized trial in 158 patients with CS IIB, III, and IV who were at high risk for failure or recurrence because of their large tumor burden (≥5 lymphoid sites, a mediastinal mass ratio ≥0.45, and/or ≥2 extranodal sites involved by the disease for CS IV). Arm V of the trial consisted of a brief, intensive, frontline chemotherapy regimen (3 monthly cycles of VABEM) followed by involved-field irradiation. Arm A of the trial was consisted of a conventional chemotherapy regimen (4 cycles of ABVD) followed by a late myeloablative chemotherapy regimen (BEAM). We chose these experimental treatments because they were among the most successful for patients with refractory disease or early recurrences.8, 12 Patients in both Arm V and Arm A had the same complete remission rates (89% and 88.2%, respectively) and had similar 5-year FFTF rates (78.9 ± 8.9% and 74.9 ± 9.8%, respectively) and OS rates (86.8 ± 7.8% and 85.9 ± 8.2%, respectively).

Over the last 10 years, both types of experimental treatments have been tested randomly against 6 to 8 cycles of ABVD, which is the reference treatment for patients with advanced HL or HR HL. A multicenter European study that compared a myeloablative chemotherapy regimen (mostly BEAM) after 4 cycles of ABVD (or similar anthracycline-based chemotherapy regimens) with 4 + 4 cycles of ABVD (or similar anthracycline-based chemotherapy regimens) produced the same 5-year FFTF and OS rates.15 Conversely, the Stanford V program, which is a brief (3-month), intensive chemotherapy regimen followed by consolidation radiation therapy16 (a program very similar to Arm V in of our trial), produced FFTF and OS rates that also were similar to the results from 6 to 8 cycles of ABVD.3

Overall, a 3-month intensive chemotherapy regimen followed by involved-field radiation therapy and a late myeloablative chemotherapy regimen preceded by 4 cycles of ABVD produced similar results. Moreover, both types of intensive treatments were not more effective than 6 to 8 cycles of ABVD or ABVD-like regimens.3, 15

A third type of therapeutic approach is based on 6 to 8 courses of combined bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), a chemotherapy regimen that contains 6 cytotoxic agents (instead of 4 for the ABVD combination). The BEACOPP regimen produced better results at increased doses than at standard doses.17 However, because 4 cycles of increased-dose BEACOPP plus 4 cycles standard-dose BEACOPP reportedly produced 3-year results similar to the results produced by 8 cycles of increased-dose BEACOPP,18 it was the less toxic former modality (followed by consolidation radiotherapy) that was compared randomly with the reference chemotherapy (8 cycles of ABVD). The 3-year freedom from progression rate for the BEACOPP arm was higher than that for the ABVD arm (P = .01). However, because of the greater number of toxic deaths in the BEACOPP arm, the 3-year OS rates for both treatments were similar.19 In conclusion, the results from the current randomized H97-HR trial and those from the most recently published studies strongly suggest that 6 to 8 courses of ABVD, a chemotherapy regimen that was designed in 1974,20 remain the reference treatment for patients with advanced and HR HL.21

Ancillary