Long-Term Results of the R-CHOP Study in the Treatment of Elderly Patients With Diffuse Large B-Cell Lymphoma: A Study by the Groupe d'Etude
http://www.100md.com
《临床肿瘤学》
the Centre Hospitalier Universitaire (CHU) de Brabois, Vandoeuvre les Nancy
Centre Leon Berard, Lyon
Centre Jean Bernard, Le Mans
Institut Paoli Calmette, Marseille
Institut Gustave Roussy, Villejuif
Hpital Bon Secours, Metz
CHU Henri Mondor, Creteil
Centre Becquerel, Rouen
CHU de Lille, Lille
Hospices Civils de Lyon, Pierre-Benite
Hpital Saint-Louis, Paris, France
Universite Catholique de Louvain, Yvoir
Academisch Ziekenhuis Sint-Jan, Bruges, Belgium
ABSTRACT
PURPOSE: To analyze the long-term outcome of patients included in the Lymphome Non Hodgkinien study 98-5 (LNH98-5) comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) in elderly patients with diffuse large B-cell lymphoma.
PATIENTS AND METHODS: LNH98-5 was a randomized study that included 399 previously untreated patients, age 60 to 80 years, with diffuse large B-cell lymphoma. Patients received eight cycles of classical CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 5 days) every 3 weeks. In R-CHOP, rituximab 375 mg/m2 was administered the same day as CHOP. Survivals were analyzed using the intent-to-treat principle.
RESULTS: Median follow-up is 5 years at present. Event-free survival, progression-free survival, disease-free survival, and overall survival remain statistically significant in favor of the combination of R-CHOP (P = .00002, P < .00001, P < .00031, and P < .0073, respectively, in the log-rank test). Patients with low-risk or high-risk lymphoma according to the age-adjusted International Prognostic Index have longer survivals if treated with the combination. No long-term toxicity appeared to be associated with the R-CHOP combination.
CONCLUSION: Using the combination of R-CHOP leads to significant improvement of the outcome of elderly patients with diffuse large B-cell lymphoma, with significant survival benefit maintained during a 5-year follow-up. This combination should become the standard for treating these patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) is the most frequently diagnosed non-Hodgkin's lymphoma (NHL), and more than 50% of these patients are older than 60 years. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen has been considered the gold standard treatment for patients with DLBCL for more than 25 years. Third-generation regimens, despite their promising initial results, did not prove to be better than the standard CHOP regimen.1-3 Dose-intense CHOP-like regimens or high-dose therapy followed by autologous stem-cell transplantation (ASCT) prolong survivals in high-risk patients but these treatments have an increased toxicity in elderly patients.4,5
Rituximab (MabThera
Rituxan Roche, Neuilly-sur-Seine, France), is a chimeric human/murine immunoglobulin G1 monoclonal antibody that binds specifically to the B-cell-surface antigen, CD20. The antibody induces lymphoma cell lysis through different immunologic or direct mechanisms, complement-mediated cytolysis, antibody-dependent cell cytotoxicity, and induction of apoptosis, and acts synergistically with chemotherapy.6-9 In phase II studies, rituximab has demonstrated efficacy in DLBCL alone and in combination with the CHOP regimen (R-CHOP).10,11 In 2002, we published the first analysis of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien study 98-5 (LNH98-5) with a 2-year follow-up showing that the addition of rituximab to CHOP chemotherapy significantly increases the rate of complete response (CR), decreases the rates of treatment failure and relapse, and improves event-free survival (EFS) and overall survival (OS) compared with standard CHOP alone in elderly patients with DLBCL.12 Because the LNH98-5 study was the first study to show a survival benefit of R-CHOP compared with CHOP chemotherapy, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. We report the updated results of the LNH98-5 study with a median follow-up of 5 years.
PATIENTS AND METHODS
Patients
Patients were eligible for enrollment if they were 60 to 80 years old and had previously untreated DLBCL according to the WHO classification.13 Patients were also required to have stage II, III, or IV disease and performance status 0 to 2 according to the Eastern Cooperative Oncology Group scale. Patients were excluded from the trial if they had T-cell lymphoma
a previous history of indolent lymphoma, CNS or meningeal involvement
a history of active cancer during the previous 5 years
any serious active concomitant disease
or if in the opinion of the investigator, their general status did not allow the administration of eight courses of CHOP. Patients were also excluded from the trial if they had a cardiac contraindication to doxorubicin (abnormal contractility on echocardiography), or a neurologic contraindication to vincristine. Finally, patients with positive serology for HIV or a history of unresolved hepatitis B virus infection (defined by the presence of HBs antigen or HBc antibody without HBs antibody) were not included. Patient enrollment was based on the diagnosis of DLBCL at each study center, but a panel comprising at least three hematopathologists conducted a central pathology review to confirm the diagnosis of CD20-positive DLBCL. Characteristics of the 399 patients included in this study are summarized in Table 1. 12
Staging comprised clinical examination, thoracic and abdominal computed tomography scans, blood counts, measurements of lactate dehydrogenase and beta2-microglobulin serum levels, bone marrow biopsy, ECG, echocardiography in patients with a history of cardiac disease or in patients older than 75 years, and CSF examination in patients with bone marrow infiltration or head and neck involvement, or if otherwise clinically indicated.
This study complied fully with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice rules. All patients gave written informed consent to participate.
Random Assignment to Treatment
Patients were centrally randomly assigned to treatment with CHOP or R-CHOP after stratification according to center and age-adjusted International Prognostic Index (aaIPI) scores (scores 0 or 1 v 2 or 3).14
Treatment
Patients treated with CHOP received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 up to a maximum dose of 2 mg on day 1, with prednisone 40 mg/m2/d on days 1 to 5. Patients were treated every 3 weeks for eight cycles. Patients treated with R-CHOP received rituximab 375 mg/m2 on day 1 for each of the eight cycles. Rituximab infusion was interrupted in the event of fever, chills, edema, mucosa congestion, hypotension, or any serious adverse event, and it was resumed later. No complementary radiation therapy was scheduled either on bulky tumors or on persisting masses at the end of treatment.
If a patient developed grade 4 neutropenia or febrile neutropenia after a cycle of CHOP or R-CHOP, all subsequent cycles were administered with granulocyte colony-stimulating factor (G-CSF) support. If new grade 4 neutropenia developed with infection despite of G-CSF support, doses of cyclophosphamide and doxorubicin were decreased by 50% for all following cycles. If grade 4 neutropenia persisted, chemotherapy was discontinued. If a patient developed grade 3 or 4 thrombocytopenia, the doses of cyclophosphamide and doxorubicin were decreased by 50% for all following cycles. If grade 3 or 4 thrombocytopenia persisted, therapy was discontinued. If neutrophils were lower than 1,500/mm3 or platelets lower than 100,000/mm3 before a cycle, the cycle was delayed for up to 2 weeks. If the patient's neutrophil and platelet counts did not increase above these levels after 2 weeks, chemotherapy was discontinued. For patients receiving R-CHOP, rituximab was discontinued if CHOP was discontinued. Subsequent treatments for patients withdrawn from CHOP or R-CHOP therapy were administered at the discretion of the investigator.
Follow-Up
Response to treatment was evaluated after four and eight treatment cycles, or after the planned treatment was discontinued. Thereafter, clinical examination was performed every 3 months for the first 2 years, then every 6 months for the next 3 years, then at the discretion of the investigator. A thoracic and abdominal computed tomography scan was performed after 3 months, then every 6 months during the first 2 years, then annually for 3 more years.
Outcome Measures
The primary efficacy parameter was EFS. Events were defined as disease progression or relapse, institution of a new (unplanned) anticancer treatment, or death as a result of any cause without progression. Secondary efficacy end points included OS, progression-free survival (PFS), disease-free survival (DFS), response rates, and toxicity. The definition of PFS was almost identical to that of EFS with the exception that late deaths not related to lymphoma or its treatment were not counted as treatment failure.15 DFS only includes patients who reached a CR or undocumented CR (CRu) at the end of the treatment. EFS, PFS, and OS were calculated as the time from random assignment to the date of the first reported event. DFS was calculated as the time from response assessment to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. Tumor responses were classified as CR, CRu, partial response, stable disease, or progressive disease according to the proposed International Workshop criteria.15 Survival for patients experiencing disease relapse was defined as duration from first day of the new treatment to time of death or last visit.
Statistical Analysis
Sample size was calculated on the basis of the primary end point or EFS. On the basis of various results obtained in previous studies with CHOP chemotherapy in this patient population, a conservative 3-year EFS rate of 30% was assumed for the CHOP regimen.1 To detect an increase in the 3-year EFS rate from 30% to 45%, it was calculated that 400 patients recruited during 3 years and observed for a minimum of 1 year would be required to provide 80% power at the overall 5% ( = .05, two sided) significance level. One patient was not included in the analyses because she withdrew her informed consent.
EFS, PFS, DFS, and OS were analyzed using the log-rank test and expressed as Kaplan-Meier plots. Analyses of efficacy and safety included all 399 patients randomly assigned between August 1998 and March 2000 and followed the intent-to-treat principle. Statistical analyses were performed with SAS software (SAS Institute, Cary, NC) by the GELA statistical office. All P values are two tailed.
RESULTS
Patient Characteristics and Response to Treatment
Initial characteristics of the 399 enrolled patients are summarized in Table 1. The median age of the patients at time of inclusion was 69 years. Response rates as previously published were 75% and 63% for CR and CRu, 8% and 6% for incomplete responses (partial response and stable disease), 9% and 22% for progressive disease, and 6% and 6% for death during treatment for patients treated with R-CHOP and CHOP, respectively (P = .005).12
EFS
With a median follow-up of 5 years, 248 events have been observed, 106 (52.5% of the patients) in the R-CHOP arm and 142 (72% of the patients) in the CHOP arm (Table 2). Fewer events were observed during treatment in the R-CHOP arm, as reported previously.12 Over time, more patients experienced disease relapse in the CHOP arm than in the R-CHOP arm (34% v 20%
2 test, P < .0001). More patients died in continuous CR in the R-CHOP arm (8%) compared with the CHOP arm (2.5%
2 test, P = .33). However, many of these patients were elderly and most of the deaths were not related to the lymphoma or its treatment but to concomitant diseases already present before the diagnosis of lymphoma or diseases that appeared subsequently, such as solid tumors. No specific pattern of causes of death was observed in these patients: three deaths were related to lymphoma treatment (Table 3), two deaths were related to severe infections, and one death was related to acute myeloid leukemia, all in R-CHOP patients. Five patients died as a result of secondary cancers (three in the CHOP arm and two in the R-CHOP arm). One and nine cardiovascular-related deaths were observed in CHOP and R-CHOP patients, respectively. At the time of analysis, 96 patients (47.5%) in the R-CHOP arm and 55 patients (28%) in the CHOP arm were in continuous CR.
The median EFS was 3.8 years (95% CI, 2.37 to not reached) in R-CHOP patients compared with 1.1 years (95% CI, 0.8 to 1.5) in CHOP patients (P = .00002
Fig 1A). The 5-year EFS was 47% (95% CI, 39.9% to 54.1%) in R-CHOP patients compared with 29% (95% CI, 23.1% to 35.8%) in CHOP patients.
In addition, a stratified analysis according to aaIPI showed the superiority of R-CHOP over CHOP in terms of EFS in low-risk patients (5-year EFS, 63% v 34%
P = .00085) as well as in high-risk patients (41% v 27%
P = .0037
Fig 2A).
PFS
PFS is a more accurate end point to describe disease-related long-term survival because it does not take into account death in continuous CR not related to lymphoma or its treatment.15 In this regard, 14 patients in the R-CHOP arm and five in the CHOP arm that were counted as having had treatment failure events in the analysis of EFS died as a result of diseases that were not related to lymphoma or its treatment (Table 3) and were censored for the PFS analysis. Median PFS was not reached (95% CI, 3.4 to not reached) for R-CHOP patients compared with 1 year (95% CI, 0.8 to 1.5) for CHOP patients (P < .00001
Fig 1B). The 5-year PFS was 54% (95% CI, 46.8% to 61.1%) in R-CHOP patients compared with 30% (95% CI, 24.4% to 37.3%) in CHOP patients. Stratified analysis according to aaIPI showed the superiority of R-CHOP over CHOP in terms of PFS in low-risk patients (5-year PFS, 69% v 34%
P = .00013) as well as in high-risk patients (47% v 29%
P = .00078
Fig 2B).
DFS
DFS analyzes the time to relapse in patients who reached a CR or CRu.15 Patients who died as a result of a non-lymphoma-related reason without disease progression were not counted as having had an event. Median DFS was not reached (95% CI, not reached to not reached) for R-CHOP patients compared with 2.45 years (95% CI, 1.49 to not reached) for CHOP patients (P = .00031). The 5-year DFS was 66% (95% CI, 56.2% to 74.0%) in R-CHOP patients compared with 45% (95% CI, 36.6% to 55.3%) in CHOP patients.
OS
Death as a result of any reason occurred in 107 patients after CHOP treatment compared with 85 patients after R-CHOP treatment, and was mostly related to lymphoma progression. Median OS was not reached (95% CI, not reached to not reached) for R-CHOP patients compared with 3.1 years (95% CI, 2.2 to not reached) for CHOP patients (P = .0073
Fig 1C). The 5-year OS was 58% (95% CI, 50.8% to 64.5%) in R-CHOP patients compared with 45% (95% CI, 39.1% to 53.3%) in CHOP patients. Stratified analysis according to aaIPI showed the significant superiority of R-CHOP over CHOP in terms of OS in low-risk patients (5-year OS, 80% v 62%
P = .023). However, the difference in high-risk patients was only of borderline significance (48% v 39%
P = .062
Fig 2C).
Progression and Salvage Therapy
Of the 399 patients, 202 (50.6%) experienced relapse or progression, including 125 (63%) in the CHOP arm and 77 (38%) in the R-CHOP arm. These patients received different salvage chemotherapy regimens according to each center policy: 14 and three patients were not treated at the time of progression in the CHOP and R-CHOP arms, respectively. Rituximab was not initially available in France and Belgium to treat DLBCL patients who experienced relapse and patients only received standard therapy. Later, rituximab was registered and became available to treat DLBCL: as a result, 22 (20%) of the 109 treated patients in the CHOP arm and nine (12%) of 73 in the R-CHOP arm received rituximab-containing salvage chemotherapy. This explained a difference between the group of patients treated with or without rituximab plus chemotherapy at time of relapse: patients treated without rituximab had a significantly shorter duration of response to CHOP/R-CHOP (P < .01). Otherwise the clinical characteristics and response to initial treatment were comparable in both groups. Salvage chemotherapy regimens were mainly dexamethasone, cisplatin, and cytarabine
etoposide, cytarabine, cisplatin, and methylprednisolone
or ifosfamide, carboplatin, and etoposide regimens. Only one patient received autologous transplantation after salvage therapy.
The 2-year survival rates of re-treated patients were not statistically different for the two initial randomization arms (26% and 31% in R-CHOP and CHOP arms, respectively
P = .83). However, there was a statistically significant difference for survival if patients received a salvage regimen containing rituximab or not: patients treated with a rituximab-containing regimen had a 2-year survival of 58% compared with 24% for those treated without rituximab (log-rank test, P = .00067
data not shown). Figure 3 shows the survival of these patients according to the randomization groups (CHOP and R-CHOP) and to salvage regimens (with or without rituximab). In the CHOP arm, the benefit of the addition of rituximab at time of salvage therapy is statistically significant (log-rank test, P = .002), whereas it is not statistically significant in the R-CHOP arm (log-rank test, P = .23). However, only nine patients received a second regimen with rituximab in the R-CHOP arm. If we only analyzed the 64 patients with duration of response to CHOP/R-CHOP longer than 1 year, patients treated with rituximab have a statistically significantly longer survival than patients treated without rituximab at time of relapse (P = .016
median survival not reached compared with 1 year, respectively). Patients who were refractory to chemotherapy (response to CHOP/R-CHOP less than 1 year) did not show a difference in survival according to salvage treatment.
Toxicity
As previously reported, rituximab did not add toxicity to the CHOP regimen.12 There was a trend to increased occurrence of infections in all R-CHOP patients after the end of treatment (12 in R-CHOP v six in the CHOP group). Deaths without disease progression were more frequent in R-CHOP patients. No specific pattern of causes of death was observed (Table 3).
Nineteen patients have presented a second tumor, 10 in the CHOP group and nine in the R-CHOP group. Two of them might be considered related to treatment: one myelodysplastic syndrome in a CHOP patient and one acute myeloid leukemia in an R-CHOP patient. No pattern was observed for solid tumors, with five lung
three renal
two melanoma and colon
one each ovarian, prostate, head and neck, cutaneous, and breast cancers.
DISCUSSION
In this update, we report the long-term results of the first randomized trial with rituximab in combination with chemotherapy in lymphoma, the results of which were published previously with a median follow-up of 2 years.12 The updated analysis with a median 5-year follow-up confirmed previous results showing a significant prolongation of EFS, PFS, DFS, and OS for patients treated with R-CHOP compared with those treated with CHOP alone. The longer survivals observed in the R-CHOP group is due to lower rates of disease progression during therapy and lower rates of relapse after reaching a CR. Importantly, the EFS, PFS, DFS, and OS curves for R-CHOP and CHOP alone remained separated throughout the follow-up period, indicating that the benefit of combining rituximab with CHOP is durable and translates into an increase in the number of patients who are cured of their lymphoma. After a median follow-up of 5 years, 26% more patients were alive in the R-CHOP arm than in the CHOP arm.
Subgroup analysis showed superior EFS and PFS in patients with both high- and low-risk aaIPI scores. However, we observed a statistically significant superiority of OS only in low-risk aaIPI patients but not in high-risk aaIPI patients, mainly due to a higher mortality rate in high-risk patients from diseases unrelated to lymphoma. As our patients became older, we observed more deaths in CR, particularly in patients treated with R-CHOP, even if there was not a statistically significant difference between the two arms. Most of the CHOP patients died after disease progression, whereas R-CHOP patients did not experience disease relapse. As a logical consequence, patients in the latter group died from other, non-lymphoma-related diseases. We observed that patients with concomitant diseases or those with poor performance status at the time of diagnosis are more prone to die in CR, a fact that is also observed in the general population. We do not believe that this is related to the treatment received by our patients but rather to the fact that our patients followed a typical natural life history.
Since the first publication of our results, several randomized studies testing the addition of rituximab to chemotherapy in different settings have been presented. The Intergroup study (Eastern Cooperative Oncology Group 4494) was more complicated to analyze because of a double randomization, initially between CHOP and R-CHOP, and secondarily for responding patients between no additional treatment and a maintenance treatment with rituximab for 2 years.16 These patients received half of the rituximab dose administered in our study. Patients treated with R-CHOP seemed to do better than those treated with CHOP only, and rituximab maintenance was mainly effective in patients who did not receive rituximab previously. These results might be interpreted as consistent with our findings but a longer follow-up is certainly necessary to draw any final conclusion. Sehn et al17 reported a Canadian population-based retrospective analysis comparing outcomes of 294 DLBCL patients treated with a CHOP-like regimen or R-CHOP-like regimen. Dose and schedule of rituximab administration were similar to the LNH98-5 study. With a median 2-year follow-up, the authors showed that the addition of rituximab to CHOP has resulted in a dramatic improvement in outcome, both in young and elderly patients. Finally, the MabThera International Trial study showed a similar benefit for the combination of rituximab and CHOP-like chemotherapy in young patients with low- and low-intermediate-risk DLBCL.18 Other studies have been conducted in patients with follicular lymphoma or mantle-cell lymphoma and showed the same benefit for the combination of rituximab plus chemotherapy.19,20 These data represent a real breakthrough in the treatment of lymphoma patients and suggest that R-CHOP should become the new standard treatment for patients with DLBCL.
Adverse events were not increased in patients treated with the combination of rituximab plus chemotherapy compared with chemotherapy alone, suggesting that rituximab is well tolerated. Other studies recently published have confirmed this low toxicity. We did not observe any difference between the incidence of secondary hematologic and nonhematologic cancers in the two regimens. Life-threatening or fatal cardiac events were also similar in both arms of the study.
High-dose therapy followed by ASCT is the treatment of choice for patients with relapsed DLBCL who are still responding to salvage therapy.21,22 However, elderly patients are usually not candidates for ASCT because of age and comorbidity, and a regimen that is easily tolerated yet provides a reasonable response rate may be an attractive alternative to more toxic regimens. Rituximab has been shown to be active both as a single agent and in combination with chemotherapy in relapsed or resistant DLBCL.10,23,24 An early phase II study evaluating the combination of rituximab with the etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen in 50 heavily pretreated patients showed a response rate of 64%.25 The EFS and OS at 2 years was 36% and 52%, respectively, with a median EFS and OS of 14 and 29 months, respectively. Our study provides the opportunity to evaluate the rituximab efficacy in patients experiencing relapse who did or did not receive rituximab previously. Although it was not a randomized study, our results support the idea that combined chemotherapy plus rituximab could improve OS when compared with chemotherapy alone in this setting. However, because of the low number of patients re-treated with rituximab, we cannot make a definitive conclusion regarding these patients.
Future studies should focus on decreasing the relapse rate without increasing toxicity in these elderly patients. Rituximab administered as maintenance therapy in patients with CR might decrease the relapse rate by increasing the quality of the response. This modality certainly should be tested in a study designed specifically to answer this question, even if the preliminary results of the Intergroup study seem to invalidate this hypothesis. Although difficult to perform in elderly patients, dose intensification of the CHOP regimen by increasing doses or shortening the administration schedule with G-CSF support could be another way to increase the CR rate and to decrease the relapse rate.5,26,27
Appendix
The following persons and institutions participated in this GELA study: Pathologic review committee—J. Brière, P. Gaulard, J. Bosq, J.F. Emile, B. Fabiani, and T. Petrella
Statistics—E. Lepage and N. Nio
Pharmacist—I. Madelaine
GELA clinical research—M. Fiore, K. Privat, E. Capellani and all CRA who collected the data
study centers (all in France, unless otherwise specified)—Centre Hospitalier Lyon-Sud, Pierre-Benite—B. Coiffier, G. Salles, C. Traulle and C. Thieblemont
Hpital de Hautepierre, Strasbourg—R. Herbrecht
Centre Becquerel, Rouen—H. Tilly
Centre Jean Bernard, Le Mans—P. Solal-Celigny
Institut Paoli Calmette, Marseilles—R. Bouabdallah
Centre Hospitalier Universitaire de Brabois, Nancy—P. Lederlin, P. Feugier
Centre Leon Berard, Lyon—C. Sebban
Institut Gustave Roussy, Villejuif—J.N. Munck, C. Ferme
Centre Hospitalier de Lens, Lens—P. Morel
Hpital Henri Mondor, Creteil—F. Reyes, C. Haioun
Centre Hospitalier de Chambery, Chambery—M. Blanc
Hpital Bon Secours, Metz—B. Christian
Centre Hospitalier Universitaire de Lille, Lille—B. Quesnel
Academisch Ziekenhuis Sint-Jan, Bruges, Belgium—A. Van Hoof
Hpital Saint-Louis, Paris—C. Gisselbrecht, N Mounier, P. Brice
Hpital Purpan, Toulouse—M. Attal
Centre Hospitalier Universitaire Dupuytren, Limoges—D. Bordessoule
Hpital Jean Bernard, Poitiers—V. Delwail
Universite Catholique de Louvain, Yvoir, Belgium—A. Bosly
Centre Hospitalier Universitaire Clemenceau, Caen—M. Macro
Centre Franois Magendie, Pessac—G. Marit
Hpital Pitie Salpetrière, Paris—J. Gabarre
Hpital Andre Mignot, Le Chesnay—S. Castaigne
Centre Hospitalier Universitaire de Nmes, Nmes—E. Jourdan
Centre Hospitalier de la Durance, Avignon—E. Lepeu
Hpital Pasteur, Colmar—B. Audhuy
Centre Antoine Lacassagne, Nice—A. Thyss
Clinique Pasteur, Evreux—N. Albin
Centre Medical Foch, Suresnes—E. Baumelou
Htel Dieu, Paris—A. Delmer
Centre Hospitalier de Brive, Brive—S. Lefort
Centre Hospitalier de Bourg en Bresse, Bourg en Bresse—H. Orfeuvre
Hpital V. Prouvo, Roubaix—I. Plantier
Hpital Bicêtre, Le Kremlin-Bicêtre—G. Tertian
Hpital Necker, Paris—B. Varet
Hpital Beclere, Clamart—F. Boue
Centre Hospitalier Universitaire de Dijon, Dijon—O. Casasnovas and D. Caillot
Universite Catholique de Louvain, Brussels, Belgium—E. Van Den Neste
Institut Curie, Paris—D. Decaudin
Centre Hospitalier Universitaire Saint-Louis-Lariboisière, Paris—H. Dombret, J.P. Fermand, and J.M. Zini
Centre Hospitalier Universitaire de Liège, Liège, Belgium—G. Fillet
Fondation Drevon, Dijon—M. Flesch
Centre Hospitalier R. Dubos, Pontoise—Y. Kerneis
Centre Hospitalier d'Annecy, Annecy—C. Martin
Hpital de Valence, Valence—P.Y. Peaud
Centre Hospitalier de Blois, Blois—P. Rodon
Centre Hospitalier Saint-Vincent, Lille—C. Rose
Htel Dieu, Clermont-Ferrand—P. Travade
Clinique Saint-Jean, Lyon—B. Velay
Hpital de Bayonne, Bayonne—F. Bauduer
Centre Hospitalier de Libourne, Libourne—K. Bouabdallah
Hpital Emile Muller, Mulhouse—J.C. Eisenmann
Hpital Marc Jacquet, Melun—C. Kulekci
Centre Hospitalier Bois de l'Abbaye, Seraing, Belgium—S. Lampertz
Hpital Inter Armees Percy, Clamart—G. Nedellec
Centre Franois Baclesse, Caen—A.M. Peny
Centre Hospitalier Victor Dupouy, Argenteuil—V. Pulik
Hpital de Chalon, Chalon—B. Salles
Centre Hospitalier de Perpignan, Perpignan—X. Vallantin
Centre Hospitalier Robert Ballanger, Aulnay sous Bois—P. Agranat
Centre Hospitalier Universitaire de Nice, Nice—J.P. Cassuto
Centre Hospitalier Hutois, Huy, Belgium—J. Collignon
Centre Hospitalier de la Citadelle, Liège, Belgium—B. de Prijck
Hpital Jolimont, Haine Saint Paul, Belgium—A. Delannoy
Centre Hospitalier Gilles de Corbeil, Corbeil Essonnes—A. Devidas
Hpital La Fontonne, Antibes—J.F. Dor
Hpital Cochin, Paris—F. Dreyfus
Clinique Saint Jean, Brussels, Belgium—C. Dubois
Clinique de Chaumont, Chaumont—G. Dupont
Centre Val d'Aurelle, Montpellier—M. Fabbro
Hpital J. Monod, Le Havre—C. Fruchart
Clinique les Fougères, Dieppe—J.P. Gaillard
Centre Hospitalier Universitaire de Rennes, Rennes—B. Grosbois
Centre Rene Huguenin, Saint-Cloud—M. Janvier
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland—N. Ketterer
Centre Hospitalier du Val de Sambre, Sambreville, Belgium—C. Leroy
Clinique Saint Pierre, Ottignies, Belgium—M. Maerevoet
Hpital des Canaux, Macon—F. Marechal
Hpital Saint Joseph, Gilly, Belgium—P. Mineur
Hpital Saint Joseph, Arlon, Belgium—P. Pierre
Centre Hospitalier Universitaire Nord, Marseille—G. Sebahoun
Centre Hospitalier de Meaux, Meaux—C. Soussain.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: P. Solal-Celigny, Roche
A. Bosly, Roche
C. Gisselbrecht, Baxter, Roche, Schering
B. Coiffier, Genentech, Roche. Honoraria: P. Solal-Celigny, Produits Roche
H. Tilly, Roche
G. Salles, Roche
C. Gisselbrecht, Roche
F. Reyes, Roche
B. Coiffier, Genentech, Roche. Research Funding: A. Bosly, Roche
B. Coiffier, Genentech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Tilly H, Lepage E, Coiffier B, et al: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284-4289, 2003
Cartron G, Watier H, Golay J, et al: From the bench to the bedside: Ways to improve rituximab efficacy. Blood 104:2635-2642, 2004
Cragg MS, Glennie MJ: Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 103:2738-2743, 2004
Eisenbeis CF, Caligiuri MA, Byrd JC: Rituximab: Converging mechanisms of action in non-Hodgkin's lymphoma Clin Cancer Res 9:5810-5812, 2003
Smith MR: Rituximab (monoclonal anti-CD20 antibody): Mechanisms of action and resistance. Oncogene 22:7359-7368, 2003
Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998
Vose JM, Link BK, Grossbard ML, et al: Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 19:389-397, 2001
Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002
Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours: Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France, International Agency for Research on Cancer, 2001
Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253, 1999
Habermann TM, Weller EA, Morrison VA, et al: Phase III trial of rituximab-CHOP (R-CHOP) vs. CHOP with a second randomization to maintenance rituximab (MR) or observation in patients 60 years of age and older with diffuse large B-cell lymphoma (DLBCL). Blood 102:6a, 2003
Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP-rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma (DLBC) in British Columbia (BC). Blood 102:29a, 2003
Pfreundschuh MG, Trümper L, Ma D, et al: Randomized intergroup trial of first line treatment for patients <=60 years with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody rituximab: Early stopping after the first interim analysis. Proc Am Soc Clin Oncol 23:556, 2004 (abstr 6500)
Dreyling MH, Forstpointner R, Repp R, et al: Combined immuno-chemotherapy (R-FCM) results in superior remission and survival rates in recurrent follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). Blood 102:103a, 2003 (suppl 1
abstr 351)
Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005
Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995
Shipp MA, Abeloff MD, Antman KH, et al: International consensus conference on high-dose therapy with hematopoietic stem cell transplantation in aggressive non-Hodgkin's lymphomas: Report of the jury. J Clin Oncol 17:423-429, 1999
Coiffier B: Chemotherapy combined with monoclonal antibodies in the treatment of patients with diffuse large B-cell lymphoma, in DeVita VT, Hellman S, Rosenberg SA (eds): Progress in Oncology 2004. Sudbury, MA, Jones & Bartlett, 2005, pp 220-235
Coiffier B: Effective immunochemotherapy for aggressive non-Hodgkin's lymphoma. Semin Oncol 31:7-11, 2004
Wilson WH, Gutierrez M, O'Connor P, et al: The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R. Semin Oncol 29:41-47, 2002
Coiffier B: Dose intensity or monoclonal antibody in first-line treatment. Hematol J 5:S154-S158, 2004 (suppl 3)
Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 104:634-641, 2004(P. Feugier, A. Van Hoof, )
Centre Leon Berard, Lyon
Centre Jean Bernard, Le Mans
Institut Paoli Calmette, Marseille
Institut Gustave Roussy, Villejuif
Hpital Bon Secours, Metz
CHU Henri Mondor, Creteil
Centre Becquerel, Rouen
CHU de Lille, Lille
Hospices Civils de Lyon, Pierre-Benite
Hpital Saint-Louis, Paris, France
Universite Catholique de Louvain, Yvoir
Academisch Ziekenhuis Sint-Jan, Bruges, Belgium
ABSTRACT
PURPOSE: To analyze the long-term outcome of patients included in the Lymphome Non Hodgkinien study 98-5 (LNH98-5) comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) in elderly patients with diffuse large B-cell lymphoma.
PATIENTS AND METHODS: LNH98-5 was a randomized study that included 399 previously untreated patients, age 60 to 80 years, with diffuse large B-cell lymphoma. Patients received eight cycles of classical CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 5 days) every 3 weeks. In R-CHOP, rituximab 375 mg/m2 was administered the same day as CHOP. Survivals were analyzed using the intent-to-treat principle.
RESULTS: Median follow-up is 5 years at present. Event-free survival, progression-free survival, disease-free survival, and overall survival remain statistically significant in favor of the combination of R-CHOP (P = .00002, P < .00001, P < .00031, and P < .0073, respectively, in the log-rank test). Patients with low-risk or high-risk lymphoma according to the age-adjusted International Prognostic Index have longer survivals if treated with the combination. No long-term toxicity appeared to be associated with the R-CHOP combination.
CONCLUSION: Using the combination of R-CHOP leads to significant improvement of the outcome of elderly patients with diffuse large B-cell lymphoma, with significant survival benefit maintained during a 5-year follow-up. This combination should become the standard for treating these patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) is the most frequently diagnosed non-Hodgkin's lymphoma (NHL), and more than 50% of these patients are older than 60 years. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen has been considered the gold standard treatment for patients with DLBCL for more than 25 years. Third-generation regimens, despite their promising initial results, did not prove to be better than the standard CHOP regimen.1-3 Dose-intense CHOP-like regimens or high-dose therapy followed by autologous stem-cell transplantation (ASCT) prolong survivals in high-risk patients but these treatments have an increased toxicity in elderly patients.4,5
Rituximab (MabThera
Rituxan Roche, Neuilly-sur-Seine, France), is a chimeric human/murine immunoglobulin G1 monoclonal antibody that binds specifically to the B-cell-surface antigen, CD20. The antibody induces lymphoma cell lysis through different immunologic or direct mechanisms, complement-mediated cytolysis, antibody-dependent cell cytotoxicity, and induction of apoptosis, and acts synergistically with chemotherapy.6-9 In phase II studies, rituximab has demonstrated efficacy in DLBCL alone and in combination with the CHOP regimen (R-CHOP).10,11 In 2002, we published the first analysis of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien study 98-5 (LNH98-5) with a 2-year follow-up showing that the addition of rituximab to CHOP chemotherapy significantly increases the rate of complete response (CR), decreases the rates of treatment failure and relapse, and improves event-free survival (EFS) and overall survival (OS) compared with standard CHOP alone in elderly patients with DLBCL.12 Because the LNH98-5 study was the first study to show a survival benefit of R-CHOP compared with CHOP chemotherapy, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. We report the updated results of the LNH98-5 study with a median follow-up of 5 years.
PATIENTS AND METHODS
Patients
Patients were eligible for enrollment if they were 60 to 80 years old and had previously untreated DLBCL according to the WHO classification.13 Patients were also required to have stage II, III, or IV disease and performance status 0 to 2 according to the Eastern Cooperative Oncology Group scale. Patients were excluded from the trial if they had T-cell lymphoma
a previous history of indolent lymphoma, CNS or meningeal involvement
a history of active cancer during the previous 5 years
any serious active concomitant disease
or if in the opinion of the investigator, their general status did not allow the administration of eight courses of CHOP. Patients were also excluded from the trial if they had a cardiac contraindication to doxorubicin (abnormal contractility on echocardiography), or a neurologic contraindication to vincristine. Finally, patients with positive serology for HIV or a history of unresolved hepatitis B virus infection (defined by the presence of HBs antigen or HBc antibody without HBs antibody) were not included. Patient enrollment was based on the diagnosis of DLBCL at each study center, but a panel comprising at least three hematopathologists conducted a central pathology review to confirm the diagnosis of CD20-positive DLBCL. Characteristics of the 399 patients included in this study are summarized in Table 1. 12
Staging comprised clinical examination, thoracic and abdominal computed tomography scans, blood counts, measurements of lactate dehydrogenase and beta2-microglobulin serum levels, bone marrow biopsy, ECG, echocardiography in patients with a history of cardiac disease or in patients older than 75 years, and CSF examination in patients with bone marrow infiltration or head and neck involvement, or if otherwise clinically indicated.
This study complied fully with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice rules. All patients gave written informed consent to participate.
Random Assignment to Treatment
Patients were centrally randomly assigned to treatment with CHOP or R-CHOP after stratification according to center and age-adjusted International Prognostic Index (aaIPI) scores (scores 0 or 1 v 2 or 3).14
Treatment
Patients treated with CHOP received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 up to a maximum dose of 2 mg on day 1, with prednisone 40 mg/m2/d on days 1 to 5. Patients were treated every 3 weeks for eight cycles. Patients treated with R-CHOP received rituximab 375 mg/m2 on day 1 for each of the eight cycles. Rituximab infusion was interrupted in the event of fever, chills, edema, mucosa congestion, hypotension, or any serious adverse event, and it was resumed later. No complementary radiation therapy was scheduled either on bulky tumors or on persisting masses at the end of treatment.
If a patient developed grade 4 neutropenia or febrile neutropenia after a cycle of CHOP or R-CHOP, all subsequent cycles were administered with granulocyte colony-stimulating factor (G-CSF) support. If new grade 4 neutropenia developed with infection despite of G-CSF support, doses of cyclophosphamide and doxorubicin were decreased by 50% for all following cycles. If grade 4 neutropenia persisted, chemotherapy was discontinued. If a patient developed grade 3 or 4 thrombocytopenia, the doses of cyclophosphamide and doxorubicin were decreased by 50% for all following cycles. If grade 3 or 4 thrombocytopenia persisted, therapy was discontinued. If neutrophils were lower than 1,500/mm3 or platelets lower than 100,000/mm3 before a cycle, the cycle was delayed for up to 2 weeks. If the patient's neutrophil and platelet counts did not increase above these levels after 2 weeks, chemotherapy was discontinued. For patients receiving R-CHOP, rituximab was discontinued if CHOP was discontinued. Subsequent treatments for patients withdrawn from CHOP or R-CHOP therapy were administered at the discretion of the investigator.
Follow-Up
Response to treatment was evaluated after four and eight treatment cycles, or after the planned treatment was discontinued. Thereafter, clinical examination was performed every 3 months for the first 2 years, then every 6 months for the next 3 years, then at the discretion of the investigator. A thoracic and abdominal computed tomography scan was performed after 3 months, then every 6 months during the first 2 years, then annually for 3 more years.
Outcome Measures
The primary efficacy parameter was EFS. Events were defined as disease progression or relapse, institution of a new (unplanned) anticancer treatment, or death as a result of any cause without progression. Secondary efficacy end points included OS, progression-free survival (PFS), disease-free survival (DFS), response rates, and toxicity. The definition of PFS was almost identical to that of EFS with the exception that late deaths not related to lymphoma or its treatment were not counted as treatment failure.15 DFS only includes patients who reached a CR or undocumented CR (CRu) at the end of the treatment. EFS, PFS, and OS were calculated as the time from random assignment to the date of the first reported event. DFS was calculated as the time from response assessment to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. Tumor responses were classified as CR, CRu, partial response, stable disease, or progressive disease according to the proposed International Workshop criteria.15 Survival for patients experiencing disease relapse was defined as duration from first day of the new treatment to time of death or last visit.
Statistical Analysis
Sample size was calculated on the basis of the primary end point or EFS. On the basis of various results obtained in previous studies with CHOP chemotherapy in this patient population, a conservative 3-year EFS rate of 30% was assumed for the CHOP regimen.1 To detect an increase in the 3-year EFS rate from 30% to 45%, it was calculated that 400 patients recruited during 3 years and observed for a minimum of 1 year would be required to provide 80% power at the overall 5% ( = .05, two sided) significance level. One patient was not included in the analyses because she withdrew her informed consent.
EFS, PFS, DFS, and OS were analyzed using the log-rank test and expressed as Kaplan-Meier plots. Analyses of efficacy and safety included all 399 patients randomly assigned between August 1998 and March 2000 and followed the intent-to-treat principle. Statistical analyses were performed with SAS software (SAS Institute, Cary, NC) by the GELA statistical office. All P values are two tailed.
RESULTS
Patient Characteristics and Response to Treatment
Initial characteristics of the 399 enrolled patients are summarized in Table 1. The median age of the patients at time of inclusion was 69 years. Response rates as previously published were 75% and 63% for CR and CRu, 8% and 6% for incomplete responses (partial response and stable disease), 9% and 22% for progressive disease, and 6% and 6% for death during treatment for patients treated with R-CHOP and CHOP, respectively (P = .005).12
EFS
With a median follow-up of 5 years, 248 events have been observed, 106 (52.5% of the patients) in the R-CHOP arm and 142 (72% of the patients) in the CHOP arm (Table 2). Fewer events were observed during treatment in the R-CHOP arm, as reported previously.12 Over time, more patients experienced disease relapse in the CHOP arm than in the R-CHOP arm (34% v 20%
2 test, P < .0001). More patients died in continuous CR in the R-CHOP arm (8%) compared with the CHOP arm (2.5%
2 test, P = .33). However, many of these patients were elderly and most of the deaths were not related to the lymphoma or its treatment but to concomitant diseases already present before the diagnosis of lymphoma or diseases that appeared subsequently, such as solid tumors. No specific pattern of causes of death was observed in these patients: three deaths were related to lymphoma treatment (Table 3), two deaths were related to severe infections, and one death was related to acute myeloid leukemia, all in R-CHOP patients. Five patients died as a result of secondary cancers (three in the CHOP arm and two in the R-CHOP arm). One and nine cardiovascular-related deaths were observed in CHOP and R-CHOP patients, respectively. At the time of analysis, 96 patients (47.5%) in the R-CHOP arm and 55 patients (28%) in the CHOP arm were in continuous CR.
The median EFS was 3.8 years (95% CI, 2.37 to not reached) in R-CHOP patients compared with 1.1 years (95% CI, 0.8 to 1.5) in CHOP patients (P = .00002
Fig 1A). The 5-year EFS was 47% (95% CI, 39.9% to 54.1%) in R-CHOP patients compared with 29% (95% CI, 23.1% to 35.8%) in CHOP patients.
In addition, a stratified analysis according to aaIPI showed the superiority of R-CHOP over CHOP in terms of EFS in low-risk patients (5-year EFS, 63% v 34%
P = .00085) as well as in high-risk patients (41% v 27%
P = .0037
Fig 2A).
PFS
PFS is a more accurate end point to describe disease-related long-term survival because it does not take into account death in continuous CR not related to lymphoma or its treatment.15 In this regard, 14 patients in the R-CHOP arm and five in the CHOP arm that were counted as having had treatment failure events in the analysis of EFS died as a result of diseases that were not related to lymphoma or its treatment (Table 3) and were censored for the PFS analysis. Median PFS was not reached (95% CI, 3.4 to not reached) for R-CHOP patients compared with 1 year (95% CI, 0.8 to 1.5) for CHOP patients (P < .00001
Fig 1B). The 5-year PFS was 54% (95% CI, 46.8% to 61.1%) in R-CHOP patients compared with 30% (95% CI, 24.4% to 37.3%) in CHOP patients. Stratified analysis according to aaIPI showed the superiority of R-CHOP over CHOP in terms of PFS in low-risk patients (5-year PFS, 69% v 34%
P = .00013) as well as in high-risk patients (47% v 29%
P = .00078
Fig 2B).
DFS
DFS analyzes the time to relapse in patients who reached a CR or CRu.15 Patients who died as a result of a non-lymphoma-related reason without disease progression were not counted as having had an event. Median DFS was not reached (95% CI, not reached to not reached) for R-CHOP patients compared with 2.45 years (95% CI, 1.49 to not reached) for CHOP patients (P = .00031). The 5-year DFS was 66% (95% CI, 56.2% to 74.0%) in R-CHOP patients compared with 45% (95% CI, 36.6% to 55.3%) in CHOP patients.
OS
Death as a result of any reason occurred in 107 patients after CHOP treatment compared with 85 patients after R-CHOP treatment, and was mostly related to lymphoma progression. Median OS was not reached (95% CI, not reached to not reached) for R-CHOP patients compared with 3.1 years (95% CI, 2.2 to not reached) for CHOP patients (P = .0073
Fig 1C). The 5-year OS was 58% (95% CI, 50.8% to 64.5%) in R-CHOP patients compared with 45% (95% CI, 39.1% to 53.3%) in CHOP patients. Stratified analysis according to aaIPI showed the significant superiority of R-CHOP over CHOP in terms of OS in low-risk patients (5-year OS, 80% v 62%
P = .023). However, the difference in high-risk patients was only of borderline significance (48% v 39%
P = .062
Fig 2C).
Progression and Salvage Therapy
Of the 399 patients, 202 (50.6%) experienced relapse or progression, including 125 (63%) in the CHOP arm and 77 (38%) in the R-CHOP arm. These patients received different salvage chemotherapy regimens according to each center policy: 14 and three patients were not treated at the time of progression in the CHOP and R-CHOP arms, respectively. Rituximab was not initially available in France and Belgium to treat DLBCL patients who experienced relapse and patients only received standard therapy. Later, rituximab was registered and became available to treat DLBCL: as a result, 22 (20%) of the 109 treated patients in the CHOP arm and nine (12%) of 73 in the R-CHOP arm received rituximab-containing salvage chemotherapy. This explained a difference between the group of patients treated with or without rituximab plus chemotherapy at time of relapse: patients treated without rituximab had a significantly shorter duration of response to CHOP/R-CHOP (P < .01). Otherwise the clinical characteristics and response to initial treatment were comparable in both groups. Salvage chemotherapy regimens were mainly dexamethasone, cisplatin, and cytarabine
etoposide, cytarabine, cisplatin, and methylprednisolone
or ifosfamide, carboplatin, and etoposide regimens. Only one patient received autologous transplantation after salvage therapy.
The 2-year survival rates of re-treated patients were not statistically different for the two initial randomization arms (26% and 31% in R-CHOP and CHOP arms, respectively
P = .83). However, there was a statistically significant difference for survival if patients received a salvage regimen containing rituximab or not: patients treated with a rituximab-containing regimen had a 2-year survival of 58% compared with 24% for those treated without rituximab (log-rank test, P = .00067
data not shown). Figure 3 shows the survival of these patients according to the randomization groups (CHOP and R-CHOP) and to salvage regimens (with or without rituximab). In the CHOP arm, the benefit of the addition of rituximab at time of salvage therapy is statistically significant (log-rank test, P = .002), whereas it is not statistically significant in the R-CHOP arm (log-rank test, P = .23). However, only nine patients received a second regimen with rituximab in the R-CHOP arm. If we only analyzed the 64 patients with duration of response to CHOP/R-CHOP longer than 1 year, patients treated with rituximab have a statistically significantly longer survival than patients treated without rituximab at time of relapse (P = .016
median survival not reached compared with 1 year, respectively). Patients who were refractory to chemotherapy (response to CHOP/R-CHOP less than 1 year) did not show a difference in survival according to salvage treatment.
Toxicity
As previously reported, rituximab did not add toxicity to the CHOP regimen.12 There was a trend to increased occurrence of infections in all R-CHOP patients after the end of treatment (12 in R-CHOP v six in the CHOP group). Deaths without disease progression were more frequent in R-CHOP patients. No specific pattern of causes of death was observed (Table 3).
Nineteen patients have presented a second tumor, 10 in the CHOP group and nine in the R-CHOP group. Two of them might be considered related to treatment: one myelodysplastic syndrome in a CHOP patient and one acute myeloid leukemia in an R-CHOP patient. No pattern was observed for solid tumors, with five lung
three renal
two melanoma and colon
one each ovarian, prostate, head and neck, cutaneous, and breast cancers.
DISCUSSION
In this update, we report the long-term results of the first randomized trial with rituximab in combination with chemotherapy in lymphoma, the results of which were published previously with a median follow-up of 2 years.12 The updated analysis with a median 5-year follow-up confirmed previous results showing a significant prolongation of EFS, PFS, DFS, and OS for patients treated with R-CHOP compared with those treated with CHOP alone. The longer survivals observed in the R-CHOP group is due to lower rates of disease progression during therapy and lower rates of relapse after reaching a CR. Importantly, the EFS, PFS, DFS, and OS curves for R-CHOP and CHOP alone remained separated throughout the follow-up period, indicating that the benefit of combining rituximab with CHOP is durable and translates into an increase in the number of patients who are cured of their lymphoma. After a median follow-up of 5 years, 26% more patients were alive in the R-CHOP arm than in the CHOP arm.
Subgroup analysis showed superior EFS and PFS in patients with both high- and low-risk aaIPI scores. However, we observed a statistically significant superiority of OS only in low-risk aaIPI patients but not in high-risk aaIPI patients, mainly due to a higher mortality rate in high-risk patients from diseases unrelated to lymphoma. As our patients became older, we observed more deaths in CR, particularly in patients treated with R-CHOP, even if there was not a statistically significant difference between the two arms. Most of the CHOP patients died after disease progression, whereas R-CHOP patients did not experience disease relapse. As a logical consequence, patients in the latter group died from other, non-lymphoma-related diseases. We observed that patients with concomitant diseases or those with poor performance status at the time of diagnosis are more prone to die in CR, a fact that is also observed in the general population. We do not believe that this is related to the treatment received by our patients but rather to the fact that our patients followed a typical natural life history.
Since the first publication of our results, several randomized studies testing the addition of rituximab to chemotherapy in different settings have been presented. The Intergroup study (Eastern Cooperative Oncology Group 4494) was more complicated to analyze because of a double randomization, initially between CHOP and R-CHOP, and secondarily for responding patients between no additional treatment and a maintenance treatment with rituximab for 2 years.16 These patients received half of the rituximab dose administered in our study. Patients treated with R-CHOP seemed to do better than those treated with CHOP only, and rituximab maintenance was mainly effective in patients who did not receive rituximab previously. These results might be interpreted as consistent with our findings but a longer follow-up is certainly necessary to draw any final conclusion. Sehn et al17 reported a Canadian population-based retrospective analysis comparing outcomes of 294 DLBCL patients treated with a CHOP-like regimen or R-CHOP-like regimen. Dose and schedule of rituximab administration were similar to the LNH98-5 study. With a median 2-year follow-up, the authors showed that the addition of rituximab to CHOP has resulted in a dramatic improvement in outcome, both in young and elderly patients. Finally, the MabThera International Trial study showed a similar benefit for the combination of rituximab and CHOP-like chemotherapy in young patients with low- and low-intermediate-risk DLBCL.18 Other studies have been conducted in patients with follicular lymphoma or mantle-cell lymphoma and showed the same benefit for the combination of rituximab plus chemotherapy.19,20 These data represent a real breakthrough in the treatment of lymphoma patients and suggest that R-CHOP should become the new standard treatment for patients with DLBCL.
Adverse events were not increased in patients treated with the combination of rituximab plus chemotherapy compared with chemotherapy alone, suggesting that rituximab is well tolerated. Other studies recently published have confirmed this low toxicity. We did not observe any difference between the incidence of secondary hematologic and nonhematologic cancers in the two regimens. Life-threatening or fatal cardiac events were also similar in both arms of the study.
High-dose therapy followed by ASCT is the treatment of choice for patients with relapsed DLBCL who are still responding to salvage therapy.21,22 However, elderly patients are usually not candidates for ASCT because of age and comorbidity, and a regimen that is easily tolerated yet provides a reasonable response rate may be an attractive alternative to more toxic regimens. Rituximab has been shown to be active both as a single agent and in combination with chemotherapy in relapsed or resistant DLBCL.10,23,24 An early phase II study evaluating the combination of rituximab with the etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen in 50 heavily pretreated patients showed a response rate of 64%.25 The EFS and OS at 2 years was 36% and 52%, respectively, with a median EFS and OS of 14 and 29 months, respectively. Our study provides the opportunity to evaluate the rituximab efficacy in patients experiencing relapse who did or did not receive rituximab previously. Although it was not a randomized study, our results support the idea that combined chemotherapy plus rituximab could improve OS when compared with chemotherapy alone in this setting. However, because of the low number of patients re-treated with rituximab, we cannot make a definitive conclusion regarding these patients.
Future studies should focus on decreasing the relapse rate without increasing toxicity in these elderly patients. Rituximab administered as maintenance therapy in patients with CR might decrease the relapse rate by increasing the quality of the response. This modality certainly should be tested in a study designed specifically to answer this question, even if the preliminary results of the Intergroup study seem to invalidate this hypothesis. Although difficult to perform in elderly patients, dose intensification of the CHOP regimen by increasing doses or shortening the administration schedule with G-CSF support could be another way to increase the CR rate and to decrease the relapse rate.5,26,27
Appendix
The following persons and institutions participated in this GELA study: Pathologic review committee—J. Brière, P. Gaulard, J. Bosq, J.F. Emile, B. Fabiani, and T. Petrella
Statistics—E. Lepage and N. Nio
Pharmacist—I. Madelaine
GELA clinical research—M. Fiore, K. Privat, E. Capellani and all CRA who collected the data
study centers (all in France, unless otherwise specified)—Centre Hospitalier Lyon-Sud, Pierre-Benite—B. Coiffier, G. Salles, C. Traulle and C. Thieblemont
Hpital de Hautepierre, Strasbourg—R. Herbrecht
Centre Becquerel, Rouen—H. Tilly
Centre Jean Bernard, Le Mans—P. Solal-Celigny
Institut Paoli Calmette, Marseilles—R. Bouabdallah
Centre Hospitalier Universitaire de Brabois, Nancy—P. Lederlin, P. Feugier
Centre Leon Berard, Lyon—C. Sebban
Institut Gustave Roussy, Villejuif—J.N. Munck, C. Ferme
Centre Hospitalier de Lens, Lens—P. Morel
Hpital Henri Mondor, Creteil—F. Reyes, C. Haioun
Centre Hospitalier de Chambery, Chambery—M. Blanc
Hpital Bon Secours, Metz—B. Christian
Centre Hospitalier Universitaire de Lille, Lille—B. Quesnel
Academisch Ziekenhuis Sint-Jan, Bruges, Belgium—A. Van Hoof
Hpital Saint-Louis, Paris—C. Gisselbrecht, N Mounier, P. Brice
Hpital Purpan, Toulouse—M. Attal
Centre Hospitalier Universitaire Dupuytren, Limoges—D. Bordessoule
Hpital Jean Bernard, Poitiers—V. Delwail
Universite Catholique de Louvain, Yvoir, Belgium—A. Bosly
Centre Hospitalier Universitaire Clemenceau, Caen—M. Macro
Centre Franois Magendie, Pessac—G. Marit
Hpital Pitie Salpetrière, Paris—J. Gabarre
Hpital Andre Mignot, Le Chesnay—S. Castaigne
Centre Hospitalier Universitaire de Nmes, Nmes—E. Jourdan
Centre Hospitalier de la Durance, Avignon—E. Lepeu
Hpital Pasteur, Colmar—B. Audhuy
Centre Antoine Lacassagne, Nice—A. Thyss
Clinique Pasteur, Evreux—N. Albin
Centre Medical Foch, Suresnes—E. Baumelou
Htel Dieu, Paris—A. Delmer
Centre Hospitalier de Brive, Brive—S. Lefort
Centre Hospitalier de Bourg en Bresse, Bourg en Bresse—H. Orfeuvre
Hpital V. Prouvo, Roubaix—I. Plantier
Hpital Bicêtre, Le Kremlin-Bicêtre—G. Tertian
Hpital Necker, Paris—B. Varet
Hpital Beclere, Clamart—F. Boue
Centre Hospitalier Universitaire de Dijon, Dijon—O. Casasnovas and D. Caillot
Universite Catholique de Louvain, Brussels, Belgium—E. Van Den Neste
Institut Curie, Paris—D. Decaudin
Centre Hospitalier Universitaire Saint-Louis-Lariboisière, Paris—H. Dombret, J.P. Fermand, and J.M. Zini
Centre Hospitalier Universitaire de Liège, Liège, Belgium—G. Fillet
Fondation Drevon, Dijon—M. Flesch
Centre Hospitalier R. Dubos, Pontoise—Y. Kerneis
Centre Hospitalier d'Annecy, Annecy—C. Martin
Hpital de Valence, Valence—P.Y. Peaud
Centre Hospitalier de Blois, Blois—P. Rodon
Centre Hospitalier Saint-Vincent, Lille—C. Rose
Htel Dieu, Clermont-Ferrand—P. Travade
Clinique Saint-Jean, Lyon—B. Velay
Hpital de Bayonne, Bayonne—F. Bauduer
Centre Hospitalier de Libourne, Libourne—K. Bouabdallah
Hpital Emile Muller, Mulhouse—J.C. Eisenmann
Hpital Marc Jacquet, Melun—C. Kulekci
Centre Hospitalier Bois de l'Abbaye, Seraing, Belgium—S. Lampertz
Hpital Inter Armees Percy, Clamart—G. Nedellec
Centre Franois Baclesse, Caen—A.M. Peny
Centre Hospitalier Victor Dupouy, Argenteuil—V. Pulik
Hpital de Chalon, Chalon—B. Salles
Centre Hospitalier de Perpignan, Perpignan—X. Vallantin
Centre Hospitalier Robert Ballanger, Aulnay sous Bois—P. Agranat
Centre Hospitalier Universitaire de Nice, Nice—J.P. Cassuto
Centre Hospitalier Hutois, Huy, Belgium—J. Collignon
Centre Hospitalier de la Citadelle, Liège, Belgium—B. de Prijck
Hpital Jolimont, Haine Saint Paul, Belgium—A. Delannoy
Centre Hospitalier Gilles de Corbeil, Corbeil Essonnes—A. Devidas
Hpital La Fontonne, Antibes—J.F. Dor
Hpital Cochin, Paris—F. Dreyfus
Clinique Saint Jean, Brussels, Belgium—C. Dubois
Clinique de Chaumont, Chaumont—G. Dupont
Centre Val d'Aurelle, Montpellier—M. Fabbro
Hpital J. Monod, Le Havre—C. Fruchart
Clinique les Fougères, Dieppe—J.P. Gaillard
Centre Hospitalier Universitaire de Rennes, Rennes—B. Grosbois
Centre Rene Huguenin, Saint-Cloud—M. Janvier
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland—N. Ketterer
Centre Hospitalier du Val de Sambre, Sambreville, Belgium—C. Leroy
Clinique Saint Pierre, Ottignies, Belgium—M. Maerevoet
Hpital des Canaux, Macon—F. Marechal
Hpital Saint Joseph, Gilly, Belgium—P. Mineur
Hpital Saint Joseph, Arlon, Belgium—P. Pierre
Centre Hospitalier Universitaire Nord, Marseille—G. Sebahoun
Centre Hospitalier de Meaux, Meaux—C. Soussain.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: P. Solal-Celigny, Roche
A. Bosly, Roche
C. Gisselbrecht, Baxter, Roche, Schering
B. Coiffier, Genentech, Roche. Honoraria: P. Solal-Celigny, Produits Roche
H. Tilly, Roche
G. Salles, Roche
C. Gisselbrecht, Roche
F. Reyes, Roche
B. Coiffier, Genentech, Roche. Research Funding: A. Bosly, Roche
B. Coiffier, Genentech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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