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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2246-2252
CLINICALOBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Groupe d'études des Lymphomes de l'Adulte,
Hôpital Saint-Louis, Paris, France; Department of Hematology,
Centre Léon Bérard, Lyon, France; Department of Hematology,
Hôpital Henri Mondor, Créteil, France; Department of
Medicine, Hôpitaux de Brabois, Vandoeuvre, France; Department of
Hematology, Hôpital de la Salpétrière, Paris, France;
Department of Hematology, Cliniques Universitaires St Luc, Brussels,
Belgium; Department of Hematology, Hôpital du Bocage, Dijon,
France; Department of Hematology, Hôpital Universitaire
Dupuytren, Limoges, France; Hematology Institute, Hôpital
Saint-Louis, Paris, France; Department of Hematology, Centre
Hospitalier Lyon-Sud, Pierre Bénite, France; Department of
Pathology, Hôpital Edouard-Herriot, Lyon, France; and Department
of Biostatistics and Medical Information Systems, Hôpital Henri
Mondor, Créteil, France.
The treatment of advanced Hodgkin's disease (HD) with chemotherapy
(CTx) alone or combined modality treatments has been controversial. In
1989, we designed a randomized study to compare 2 cycles of CTx to
(sub)total nodal irradiation (RTx) as consolidation treatments for
patients with stage IIIB/IV HD in complete remission (CR) or good
partial response after 6 cycles of CTx. A total of 559 patients were
randomized to receive 6 cycles of MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine) hybrid (n = 266) or ABVPP (n = 267).
After induction treatment, 418 patients could be evaluated for the
consolidation phase. With a median follow-up of 48 months, the 5-year
disease-free survival estimates were 80% for 8 cycles of MOPP/ABV,
82% for 6 cycles of MOPP/ABV plus RTx, 68% for 8 cycles of ABVPP, and 75% for 6 cycles of ABVPP plus RTx (P = .01).
The 5-year disease-free survival estimates did not differ between CTx
and RTx, 74% and 79%, respectively (P = .07). After
MOPP/ABV, the 5-year overall survival estimates did not differ between
CTx and RTx, 85% and 88%, respectively (P = .2). After
ABVPP, the 5-year survival estimates were 94% for CTx and 78% for RTx
(P = .002). These results showed that RTx was not superior
to CTx consolidation after doxorubicin-induced CR for patients with
advanced HD. Because of the uncertainty of obtaining a prolonged second
remission for patients relapsing after CTx and RTx and the possible
long-term effects of RTx, we prefer 8 cycles of CTx as standard
treatment when a CR has been achieved after 6 cycles.
(Blood. 2000;95:2246-2252)
The optimal therapeutic strategy for patients with
advanced Hodgkin's disease (HD) remains undefined. Major advances
have been achieved with the use of chemotherapy (CTx)
combined or not with radiation therapy. However, despite complete
remission (CR) rates ranging from 80% to 97%, up to 40% of CR
patients will subsequently relapse.1-5 In an attempt to
minimize the risk of relapse after CR following induction
CTx, adjuvant radiotherapy (RTx) was evaluated in uncontrolled or
retrospective studies6,7 and randomized clinical
trials.5,8-13 In the late 1980s, the role of RTx
remained controversial, and its advantage in terms of
survival was not demonstrated.8 Ten years later, the
potential benefit of combined treatment over CTx alone has not
yet been definitively demonstrated. Trials that compared
additional RTx versus no further treatment failed to demonstrate a
benefit in terms of survival5; 2 studies showed an
advantage of combined treatment only for disease control, with
significant reduction of nodal infield relapses9 or
prolonged failure-free survival.10 Trials that compared
additional RTx versus additional CTx did not show any advantage of RTx
in terms of survival.8,11-13 More recently, a meta-analysis
of trials with parallel RTx/CTx design showed that the use of RTx was
associated with significantly poorer overall survival.14
That study brought to light the importance of taking into consideration
the risk for disease-unrelated fatal events.
The objectives of the study were to compare 2 doxorubicin-containing
regimens and to compare RTx versus CTx as consolidation treatments for
patients who had achieved a CR or a partial response (PR) of at least
75% after 6 cycles of chemotherapy. When this trial was initiated,
response to initial CTx was known to be a prognostic factor, and
investigators of the Groupe d'études des Lymphomes de
l'Adulte opted for a strategy including early salvage therapy for poor responders. As a consequence, this trial included salvage therapy for patients who did not achieve a response of at least
75% after induction CTx or who relapsed after CR. This paper reports
an interim analysis of the results of the first-line therapy.
Study design
Patient eligibility
Diagnostic studies
Treatment The patients were randomly assigned to 1 of 2 CTx regimens: MOPP/ABV hybrid or ABVPP. MOPP/ABV hybrid CTx was given according to the University of British Columbia regimen.4 In an attempt to reduce alkylating agents, the ABVPP regimen was previously developed11 and consisted of doxorubicin, 30 mg/m2 intravenously (IV), on day 1; bleomycin, 5 mg/m2 IV, on days 1 and 8; vinblastine, 5 mg/m2 IV, on days 1 and 8; procarbazine, 100 mg/m2, on days 1-14; and prednisone, 40 mg/m2, on days 1-14. Cycles were repeated every 28 days if the absolute neutrophil count was more than 1.6 × 109/L and the platelet count was more than 125 × 109/L. The ratio of actual/planned full-dose CTx for 3 drugs (nitrogen mustard, procarbazine, and doxorubicin) was calculated. The average percentage was used to describe the amount of consolidation CTx given. A reduction of doses was defined as an actual/planned ratio of less than 0.85.Evaluation of response and follow-up Patients were clinically evaluated after 4 and 6 cycles of CTx and at completion of treatment. Routine staging procedures included hematologic and blood biochemistry studies, ESR measurement, chest radiograph, and plain film of the abdomen when a lymphangiogram had been performed initially. CT scans that were abnormal at diagnosis were repeated after 4 cycles of CTx, after 6 cycles in the case of a PR, and at the completion of treatment. When a previous bone marrow biopsy had been abnormal, the bone marrow was reassessed after 4 cycles. Most patients with bulky mediastinal disease at diagnosis and PR of less than 75% after initial CTx had a gallium scan or lymph node biopsy, if necessary. Patients were reevaluated every 3 months during years 1 and 2, every 4 months during year 3, every 6 months during years 4 and 5, and then yearly.Statistical analyses All analyses were performed on an intention-to-treat basis. The stopping date was set at June 1, 1998. Patient characteristics, response rates, and toxicities were compared with 2
tests. Survival duration was calculated from the time of the first
randomization (induction treatment) to the stopping date, date of
death, or date of last follow-up evaluation when the stopping date had
not yet been reached. Disease-free survival was calculated as the
interval between the date of achieving CR and the stopping date,
relapse, death, or date of last follow-up evaluation when the stopping
date had not yet been reached. Event-free survival was measured as the
interval between the date of the first randomization and the stopping
date, progression, death, or date of last follow-up evaluation when the
stopping date had not yet been reached. The event-free survival
analysis included patients with stable disease, patients who progressed
under treatment, partial responders (all patients who had received
salvage therapy), all complete responders who subsequently relapsed,
and deaths from all causes. Disease-free survival, event-free survival,
and overall survival were estimated using the Kaplan-Meier
method16 and were compared according to treatment group by
log-rank tests17 at the P=.05 significance level.
All statistical analyses were carried out with use of SAS 6.12 software
(SAS Institute, Cary, NC). Relative risks were estimated using the Cox regression model.18 All regression models
were restricted to the patients with complete datasets.
Patient characteristics Between July 1, 1989, and December 1, 1996, 559 patients were enrolled for the study; 278 patients were assigned to receive MOPP/ABV and 281 to the ABVPP induction regimen. Twenty-four were considered ineligible for analysis: 11 who were not properly enrolled (8 with clinical stage IIA, IIB, or IIIA disease; 2 aged 14 and 68 years; and 1 with an abnormal left ventricular ejection fraction and a contraindication to receive doxorubicin) and 13 whose histologic diagnoses were changed after reevaluation. Two patients could not be evaluated because of missing information on treatment; these patients were excluded from the final analysis. Thus, the study population consisted of 533 patients, including 266 in the MOPP/ABV group and 267 in the ABVPP group. The median age of the 352 (66%) men and 181 (34%) women was 32 years. The histologic classification distribution was as follows: 79% nodular sclerosis, 10% mixed cellularity, 2% lymphocyte depletion, and 9% unclassifiable due to unsatisfactory quality of material available for reevaluation. A total of 214 (40%) patients entering this study were classified as having HD stage IIIB (including 9 with stage IIIEB), 62 (12%) as having stage IVA, and 257 (48%) with stage IVB. The clinical characteristics of the patients at presentation and according to treatment arm are listed in Table 1. These characteristics did not differ between the 4 treatment arms. According to the international prognostic score for advanced HD, the distribution of patients in each risk group was as follows: 90% for patients with a score of 2 or above, 61% for patients with a score of 3 or above, and 34% for patients with a score of 4 or above. The mediastinum was involved in 78% of the patients (n = 416), and the MT ratio was at least 0.33 in 15% (n = 82). Among the patients, 48% had pulmonary hilar involvement, 26% had lung involvement, and 16% had liver involvement.
Induction treatment After 6 cycles of induction CTx, 267 patients (50%) achieved CR, 193 patients (36%) achieved PR of at least 75%, 23 patients (4%) achieved PR of 50% to less than 75%, 36 patients (7%) failed to respond or progress, and 14 (3%) died during or after these 6 cycles. Response rates did not differ between the 2 induction regimens of CTx: among patients treated with MOPP/ABV, CR or PR of at least 75% was obtained in 51% and 34%, respectively; among patients treated with ABVPP, CR or PR of at least 75% was obtained in 49% and 39%, respectively.Consolidation treatment A total of 115 patients were not randomized to receive the consolidation treatment for the following reasons: early death (n = 11); PR to induction CTx, which required salvage therapy (n = 59); treatment-related toxicity (n = 13); underlying diseases (n = 3); patient refusal (discontinuation of treatment after induction, n = 3; randomization refusal in RTx arm, n = 4); and protocol violation (n = 22). With few exceptions, these latter 22 patients received consolidation treatment with CTx or RTx. A total of 418 patients were randomized: 208 to consolidation CTx and 210 to RTx. However, 400 of these 418 patients (96%) received the consolidation treatment according to randomization. Among the 208 patients randomized to CTx, 205 actually received CTx; 3 patients refused the treatment; 29% of the patients (50 of 175 assessable patients) received consolidation CTx with a reduction of doses. Among these patients, 5 died: 3 of progressive disease and 2 of treatment-related causes. Among the 210 patients randomized to RTx, 195 patients received this therapy and 15 did not for the following reasons: patient refusal (n = 6), protocol violation (n = 3), and progressive disease immediately after randomization (n = 6). A total of 183 patients (87%) received RTx to the planned volumes (mantle field, paraaortic, and spleen areas, n = 96; mantle field, inverted Y, and spleen areas, n = 87). The planned volumes of RTx were partially delivered in 12 patients (mantle, n = 8; sub-diaphragmatic, n = 4) for the following reasons: protocol violation of RTx (n = 5), progressive disease during RTx (n = 4), premature termination at the patient's request (n = 2), and toxic death (n = 1). The planned radiation doses were not completed in 31 patients (15%) who experienced hematologic toxicity. Finally, 152 patients (72%) received radiation according to the assigned volumes and doses, and 58 patients (28%) did not. Among these 58 patients, 18 died: 13 of progressive disease, 2 of treatment-related causes, 2 of second cancers, and 1 of intercurrent disease. After consolidation treatment, 394 of 418 randomized patients (94%) achieved CR, 2 patients achieved PR, 19 patients suffered early disease progression, and 3 patients died during consolidation RTx. The CR rate by treatment arms (induction CTx plus consolidation treatment) is shown in Table 2.
Disease-free survival Among the 394 patients who achieved CR, 75% were predicted to be alive without disease after 5 years (95% confidence interval [CI], 70%-80%). The 5-year disease-free survival estimates for patients treated with MOPP/ABV or ABVPP were 81% (95% CI, 75%-87%) and 71% (95% CI, 65%-77%), respectively (P = .009). The 5-year disease-free survival estimates for the 4 treatment arms are shown in Table 2, and disease-free survival curves are shown in Figure 2; the 4 treatment arms differed significantly (P = .01). The 5-year disease-free survival estimates of patients treated with consolidation CTx or RTx were 74% (95% CI, 68%-80%) and 79% (95% CI, 73%-85%), respectively; no difference was observed between the 2 consolidation arms when randomized patients were stratified according to the induction regimen (P = .07) (Figure 3). The predicted 5-year disease-free survival estimate was 75% (95% CI, 71%-79%) for the 102 patients with bulky disease who achieved CR and 76% (95% CI, 68%-84%) for the 292 patients without bulky disease who achieved CR (P = .7). No difference was observed between the 2 consolidation arms when randomized patients with bulky disease were stratified as a function of the regimen (P = .5). According to univariate analysis, 2 factors adversely affected disease-free survival: hemoglobin less than 10.5 g/L (P = .01) and inguinal involvement (P = .05).
Event-free survival The overall event-free survival probability for the entire population was 62% at 5 years (95% CI, 58%-66%). The 5-year event-free survival estimate for patients treated with MOPP/ABV or ABVPP was 66% (95% CI, 60%-72%) and 56% (95% CI, 50%-62%), respectively (P = .1). Predicted event-free survival did not differ significantly between the 4 treatment arms (Table 2; P = .07).Overall survival The median follow-up of patients who survived was 48 months (range, 8-109 months), with 79% of them predicted to be alive at 5 years (95% CI, 75%-84%). The 5-year survival estimate of patients treated with MOPP/ABV or ABVPP was 79% (95% CI, 73%-85%) and 80% (95% CI, 74%-86%), respectively (P = .4). The 5-year survival estimates for the 4 treatment arms are shown in Table 2, and overall survival curves are shown in Figure 4. The 4 treatment arms differed significantly (P = .01). After patients were analyzed according to induction treatment arms, no significant difference was observed for survival after 8 cycles of MOPP/ABV or 6 cycles of MOPP/ABV plus RTx, with a 5-year survival probabilities of 85% (95% CI, 77%-93%) and 88% (95% CI, 80%-96%), respectively (P = .2). In contrast, survival differed significantly after 8 cycles of ABVPP or 6 cycles of ABVPP plus RTx, with predicted 5-year survival estimates of 94% (95% CI, 88%-100%) and 78% (95% CI, 68%-88%), respectively (P = .002). The estimated 5-year survival was 80% (95% CI, 72%-88%) for the 137 patients with bulky disease and 80% (95% CI, 76%-84%) for the 396 patients without bulky disease (P = .9). Ninety patients died (49 in the MOPP/ABV group and 41 in the ABVPP group). The major causes of death were HD progression (47%) and treatment-related complications (23%) during initial treatment or salvage therapy. The causes of death are given in detail in Table 3. Intercurrent causes of death were as follows: infection, 3; respiratory insufficiency, 1; suicide, 1; urologic fistula, 1; unknown, 6.
Toxicity The short-term adverse events of induction and consolidation treatments are summarized in Table 4. During RTx, thrombocytopenia (less than 50 × 109/L) was seen in 22% of the patients, resulting in a temporary postponement (2-8 weeks) of treatment for 23% of the patients and discontinuation for 16% of patients who did not receive the planned treatment. Fourteen patients suffered grade 5 (fatal) toxicities (ABVPP group, n = 6; MOPP/ABV group, n = 8). Eleven patients died during induction CTx (ABVPP group, n = 3; MOPP/ABV group, n = 8), and 3 patients died during RTx after ABVPP. Among the 14 treatment-related deaths, 10 resulted from infection and 12 occurred in patients at least 45 years old.
This randomized study does not demonstrate any advantage of RTx over CTx as consolidation treatment at the time of CTx-induced CR or good PR in patients with stage IIIB/IV HD. After MOPP/ABV regimen, similar disease-free survival and overall survival rates were observed in both CTx and RTx consolidation arms. After the ABVPP regimen, no statistically significant difference could be detected, in terms of disease-free survival, between the consolidation treatments; however, an interaction between induction and consolidation treatments was significant for overall survival. The comparison between 2 doxorubicin-containing regimens showed that ABVPP was inferior to MOPP/ABV in terms of disease-free survival, but no differences were found in terms of event-free survival and overall survival.
The authors thank the following clinicians and pathologists who actively participated in this study: C. Allard, M. André, R. Angonin, D. Assouline, B. Audhuy, G. Auzanneau, J.C. Barats, Y. Bastion, P. Bensimon, F. Berger, P. Bey, P. Biron, M. Blanc, M. Bontemps, D. Bordessoule, A. Bosly, K. Bouabdallah, S. Boucheron, T. Bouillet, O. Boulat, P. Brice, J. Brière, J.C. Brouet, D. Caillot, C. Carrie, R.O. Casasnovas, S. Castaigne, G. Catanzano, D. Cazals-Hatem, F. Charlotte, A.M. Chesneau, B. Christian, J.P. Clauvel, B. Coiffier, P. Colin, F. Cosnard, M.F. D'Agay, J. d'Anjou, E. Deconinck, A. Delannoy, M. Delos, H. Demeaux, A. de Mascarel, T. De Revel, A. Devidas, J. Diebold, M. Diviné, C. Doyen, M. Dray, G. Dupont, B. Dupriez, E. Dupuy, C. Duval, B. Duvert, M. Echard, J.C. Eisenmann, J.M. Emberger, P. Fargeot, J.P. Fermand, A. Ferrant, D. Fière, M. Flesch, M. Floiras, J. Frija, N. Froment, J. Gabarre, P. Gaulard, H. Gautier, J.P. Gérard, C. Gisselbrecht, H. Guy, D. Guyotat, C. Haioun, Hamels, C. Hennequin, M. Janvier, J. Jaubert, R. Jeandel, Y. Kerneis, J.P. Knop, F. Kohser, C. Lavignac, P. Lederlin, R. Lefur, E. Legouffe, R. Leloup, M. Lenoble, P. Maingon, G. Marit, J.P. Marolleau, C. Martin, C. Maylin, V. Meignin, C. Merignargues, J.L. Michaut, J.M. Micléa, P. Mineur, M. Monconduit, P. Morel, F. Morvan, G. Nédellec, H. Noel, E. Oksenhendler, P.Y. Peaud, T. Petrella, C. Platini, J.P. Pollet, M. Raphael, M. Raymond-Gelle, O. Reman, P. Renaudier, M. Resbeut, F. Reyes, B. Richard, M. Rochet, B. Roullet, J.F. Rossi, C. Rozec, A. Rozenbaum, B. Salles, G. Salles, H. Schill, M. Simon, P. Solal-Céligny, E. Solary, A. Stamattoullas, P. Thirion, A. Thyss, J.D. Tigaud, H. Tilly, J. Troncy, L. Vandenbossche, B. Velay, M. Vincent, L. Voillat, and J.M. Zini. We are indebted to Catherine Balmale for assistance with data management, Nicolas Mounier for helpful comments on the statistical analyses, and Janet Jacobson for editing the English article.
Submitted June 24, 1999; accepted December 7, 1999.
Reprints: Christophe Fermé, Groupe d'études des Lymphomes de l'Adulte, Centre Hayem, Hôpital Saint-Louis, 1 avenue C. Vellefaux, 75475 Paris Cedex 10, France.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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M. Sieber, H. Bredenfeld, A. Josting, T. Reineke, U. Rueffer, T. Koch, R. Naumann, F. Boissevain, P. Koch, P. Worst, et al. 14-Day Variant of the Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone Regimen in Advanced-Stage Hodgkin's Lymphoma: Results of a Pilot Study of the German Hodgkin's Lymphoma Study Group J. Clin. Oncol., May 1, 2003; 21(9): 1734 - 1739. [Abstract] [Full Text] [PDF]
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G. P. Canellos New Treatments for Advanced Hodgkin's Disease: An Uphill Fight Beginning Close to the Top J. Clin. Oncol., February 1, 2002; 20(3): 607 - 609. [Full Text] [PDF]
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C. Ferme, N. Mounier, M. Divine, P. Brice, A. Stamatoullas, O. Reman, L. Voillat, J. Jaubert, P. Lederlin, P. Colin, et al. Intensive Salvage Therapy With High-Dose Chemotherapy for Patients With Advanced Hodgkin's Disease in Relapse or Failure After Initial Chemotherapy: Results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial J. Clin. Oncol., January 15, 2002; 20(2): 467 - 475. [Abstract] [Full Text] [PDF]
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S. Camilleri-Broet, J. Audouin, C. Ferme, J. Briere, K. Pulford, P. Gaulard, M. Divine, E. Macintyre, G. Delsol, and F. Berger ALK is not expressed in Hodgkin disease Blood, March 15, 2001; 97(6): 1901 - 1902. [Full Text] [PDF]
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D. C. Linch, R. G. Gosden, T. Tulandi, S.-L. Tan, and S. L. Hancock Hodgkin's Lymphoma: Choice of Therapy and Late Complications Hematology, January 1, 2000; 2000(1): 205 - 221. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
MOPP/ABV (mechlorethamine, vincristine, procarbazine,
prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine) hybrid
or ABVPP
risk of 0.05 and 
risk of 0.10) for patients
achieving CR or PR of at least 75% after induction CTx. Secondary
objectives included assessment of responses, overall survival,
toxicities of the 2 induction regimens, and results of salvage therapy
with high-dose CTx for patients not achieving CR or PR of at least 75%
after induction CTx.
