1 Department of Hematology, University of Ancona; 2 Department of Hematology, San Martino Hospital, Genova; 3 Department of Hematology, Cervello Hospital, Palermo; 4 Division of Hematology, San Giovanni Hospital, Venezia; 5 Department of Hematology, University of Campinas, Brasil; 6 Department of Medical Oncology-Biostatistics Unit, Genova University and National Cancer Institute, Genova; 7 Division of Oncology, General Hospital, Padova; 8 Division of Hematology, San Maurizio Hospital, Bolzano; 9 Division of Hematology, General Hospital, Noale; 10 Institute of Medicine, University of Ancona; 11 Division of Medicine, General Hospital, Civitanova Marche; 12 Division of Oncology, General Hospital, Sassari; 13 Division of Oncology, San Carlo Borromeo Hospital, Milano; 14 Division of Hematology, San Camillo Hospital, Roma; 15 Institute of Hematology, Parma University, Parma; 16 Department of Medical Oncology, Genova University and National Cancer Institute, Genova, Italy
* Correspondence to: Dr A. Olivieri, Department of Hematology, University of Ancona-Italy, Via Conca n.1 Torrette, 60020 Ancona, Italy. Tel +39-07-15964736; Fax +39-071-2183448; E-mail: a.olivieri{at}ao-umbertoprimo.marche.iy
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Abstract |
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Patients and methods: Among 223 patients aged 1560 years with aggressive, advanced stage NHL, 106 patients were randomized to VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) for 12 weeks (plus HDS/HDT in case of persistent disease) (arm A), and 117 patients to VACOP-B for 8 weeks plus upfront HDS/HDT (arm B).
Results: According to the intention-to-treat analysis, the complete response rate was 75% for arm A and 72.6% for arm B. With a median follow-up of 62 months there was no difference in 7-year probability of survival (60% and 57.8%; P = 0.5), disease-free survival (DFS) (62% and 71%; P = 0.2) and progression-free survival (PFS) (44.9% and 40.9%; P = 0.7) between the two arms. Subgroup analyses confirmed that the best results in terms of survival, DFS and PFS were achieved by patients with large B-cell NHL without bone marrow (BM) involvement, independently of the treatment arm. Results were poorer in other categories of patients and poorest in patients with BM involvement.
Conclusions: Aggressive NHL patients do not benefit from upfront HDS/HDT.
Key words: autologous stem cell transplantation, high-dose sequential therapy, high-grade NHL, VACOP-B
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Introduction |
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The role of HDT in patients with partially responsive disease still remains uncertain [9, 10
].
Retrospective data [1113
] suggest that highintermediate/high-risk NHL in first complete response (CR), as defined by the International Prognostic Index (IPI) [14
], are a suitable target for HDT, but randomized studies could not demonstrate that HDT can improve outcome [15
17
] and an early HDT in high-risk patients resulted to be inferior to chemotherapy [18
].
In a previous randomized study high-dose sequential therapy (HDS) followed by HDT/ASCT achieved a superior event-free survival (EFS) compared with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) in diffuse, large B-cell-type NHL [19].
Our group compared VACOP-B with VACOP-B plus autologous bone marrow transplantation (ABMT) [20] in patients with diffuse, aggressive NHL, as defined by the Working Formulation (WF) [21
]; while the retrospective analysis suggested that high-risk patients could have a significant advantage in terms of disease-free survival (DFS), the outcome in ABMT arm was not significantly better.
This study comparing VACOP-B x12 weeks (plus HDS/HDT in case of failure) versus VACOP-B x8 weeks followed by HDS/HDT was designed to evaluate the usefulness of upfront HDS/HDT versus the flexible strategy HDS when needed.
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Patients and methods |
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Staging procedure
Extent of disease was assessed by physical examination, bilateral BM biopsies, and computed tomography (CT) scan of the chest, abdomen and pelvis. Magnetic resonance imaging and radionuclide scan were performed when necessary. The number and diameter of extranodal sites and tumor masses were determined. All patients underwent restaging at the end of treatment, every 3 months during the first year, every 6 months in the second year and then annually. All necessary tests were performed when clinically required.
Treatment
We randomized 223 patients to receive either: 12-week VACOP-B (arm A, 106 patients); or 8-week VACOP-B followed by HDS with high-dose cyclophosphamide (HD-CY, 7 g/m2) plus granulocyte colony-stimulating factor (G-CSF) and high-dose etoposide (HD-VP, 2 g/m2), plus HDT with BEAM (carmustine, etoposide, cytarabine, melphalan) [23] regimen and ASCT (arm B, 117 patients).
Arm A.
Patients achieving CR or an unconfirmed CR (CRu) [24] underwent follow-up evaluation; for those not achieving CR [partial response (PR), no response (NR) or progressive disease (PD)], rescue treatment with HDS/HDT was planned. Patients in CR after VACOP-B who relapsed were to be treated with DHAP (dexamethasone, cisplatin, cytarabine) regimen for two courses and HDS/HDT.
Arm B.
Patients were to proceed to HDS/HDT after 8-week VACOP-B. Patients relapsing after CR, or showing PD/NR during treatment, received DHAP as salvage treatment.
In both arms patients with bulky disease at diagnosis or residual masses after treatment received involved-field radiotherapy (IFRT) (36004000 cGy in 20 fractions).The trial design is reported in Figure 1.
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Patients were conditioned with BEAM [23] and PBPC were infused 24 h after the melphalan administration.
Supportive care during ASCT has been described elsewhere [20]. Platelet transfusions were given for platelet <10 x 109/l and erythrocyte concentrates were administrated when hemoglobin <8 g/dl; all patients received G-CSF 5 µg/kg/day subcutaneously until neutrophil recovery.
Patient characteristics and assessment of response
Pretreatment characteristics of patients are listed in Table 1. The two groups of patients were matched for the main characteristics. After the pathological review, five patients from arm B were ineligible: one due to serological positivity for hepatitis C and four because of histological error (one Burkitt's lymphoma, two follicular mixed NHL, one Hodgkin's lymphoma); however, they received the planned treatment according to the assigned arm by randomization and were included both in the response analysis and in the survival analysis, according to the intention-to-treat criteria.
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Conventional chemotherapy toxicity and HDS/HDT toxicity were evaluated according to World Health Organization (WHO) criteria.
Statistical methods
Randomization was carried out by telephone from the National Cancer Institute in Genoa, Italy. It was estimated that 223 patients, recruited over 5 years, would ensure a power of 80% (with an alpha error equal to 5%) to detect a 20% difference in 3 years survival rate in favor of the patients assigned to VACOP-B + HDS.
The primary end point was overall survival. Other main objectives were: response rates, DFS, progression-free survival (PFS) and toxicity; the two arms were compared according to the intention-to-treat basis. Patients were considered progression free until one of the following events occurred: recurrence, a second malignancy or death from any cause. DFS only applied to patients who achieved a CR. Duration was calculated from the time of CR assessment to the date of relapse, or last follow-up evaluation that confirmed the patients to be free of lymphoma. Survival was defined as the time from randomization to death, independent of cause, or last follow-up evaluation. Curves were constructed using the method described by Kaplan and Meier [26] and compared using the log-rank test.
The relationship between parameters and outcome was examined by univariate and multivariate analysis according to the Cox hazards regression model. Test statistics for comparison of main objectives were regarded as significant if the two-sided P value was <0.05.
Prognostic factors considered in the stepwise Cox analysis [27] were: sex, performance status (0 versus
1), constitutional symptoms (A versus B), bulky disease (<10 versus
10 cm), number of extranodal sites (0 versus
1), lactate dehydrogenase (LDH) level (normal versus higher than normal), BM involvement at diagnosis (negative versus positive), Ann Arbor stage (II bulky versus III + IV) and spleen (no versus yes). WHO criteria were used for performance status.
Overall survival, PFS and DFS were also retrospectively analyzed according to the IPI score adjusted for age 60 years. Patients were subdivided into four groups (low, lowintermediate, intermediatehigh and high risk) according to the presence of 0, 1, 2 or 3 risk factors (performance status, LDH and Ann Arbor stage).
The 2-test or Fisher's exact test were used to compare groups for toxicity or response rate.
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Results |
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Arm A.
After 12-week VACOP-B ± IFRT, 65 (61.3%) patients achieved CR/CRu (four patients achieved CR after IFRT), 31 (29.3%) patients achieved PR and 10 patients were NR or PD.
Forty-one patients with persistent disease were eligible for HDS/HDT, but 12 (29%) did not receive or complete this therapy owing to progressive disease (10 patients) or cardiac toxicity (two patients). Twenty-nine patients completed HDS/HDT and 15 (51.7%) of them achieved CR (two achieved CR after IFRT).
In conclusion, 80 (75.5%) of 106 patients achieved a CR/CRu, 16 (15%) were PR and 10 (9.5%) progressed.
For the 29 patients undergoing HDS/HDT, median delivery time of HDS/HDT/ASCT was 83 days (range 69124). Patients received a median of 14.8 x 106 CD34+ cells per kilogram of body weight (range 5.332.5) collected with a median of two (range one to five) aphereses. During VACOP-B, the following WHO grade 34 toxicity occurred: granulocytopenia (35%), anemia (8%), infection (2%), mucositis (8%) and peripheral neurotoxicity (5%). Two patients had grade 2 and one patient grade 3 cardiotoxicity. After HD-CY, WHO grade 3 and 4 granulocytopenia was observed in 71% of patients, anemia in 32% and thrombocytopenia in 14%; two patients suffered grade 3 pulmonary infection. Following HD-VP, grade 34 granulocytopenia occurred in 46% of patients and trombocytopenia in 32% of patients. All patients engrafted; median time to granulocyte >0.5 x 109/l was 10 days (range 714). Median time to platelets >20 x 109/l was 10 days (range 918). Infection occurred in 20% of patients and only one patient developed grade 3 infection.
Overall, 38 (36%) patients died: 35 of early or late progression and one (1%) of cardiac failure; two (2%) other patients died of a second neoplasia while in CR after VACOP-B. Currently, 68 out of 106 patients are still alive.
Arm B.
Following 8-week VACOP-B, 79 (68%) patients completed HDS/ASCT.
Seventeen patients (15%) did not receive HDS/ASCT: 10 patients refused while in clinical and instrumental CR after VACOP-B; five were ineligible, one was lost to follow-up and there was one protocol violation.
Median delivery time of HDS/ASCT was 87 days (range 78155). Patients received a median of 15.2 x 106 CD34+ cells per kilogram of body weight (range 3.566.4) collected with a median of two (range one to five) aphereses.
Seven patients did not complete HDS/ASCT procedure because of toxicity: renal toxicity in three; interstitial pneumonia in two; neuropathy in one patient; and perforated stomach ulcer in one patient. Fourteen PD patients did not complete HDS/HDT because of progressive disease and death.
At the end of procedure, 85 (72.6%) patients achieved CR/CRu (four patients achieved CR after IFRT) and 15 (12.8%) patients PR; 17 (14.6%) patients had PD.
During VACOP-B, grade 34 WHO granulocytopenia was observed in 24% of patients: anemia in 3%, mucositis in 2%, infection in 3.6%, renal toxicity in 2% and peripheral neurotoxicity in 2%. After HD-CY, grade 34 granulocytopenia occurred in 82% of patients. Five (6%) patients suffered grade 34 infection. One patient died of interstitial CMV-related pneumonia. Following HD-VP, 38% of patients showed grade 34 granulocytopenia and two patients grade 3 pulmonary infection. One patient died of renal toxicity. All patients engrafted; median time to granulocyte count >0.5 x 109/l was 10 days (range 826); median time to platelets >20 x 109/l was 11 days (range 733). Infection occurred in 30% of patients. One patient developed a grade 3 cardiac toxicity and one grade 3 liver toxicity.
Overall, 45 patients died: five (4%) of treatment-related toxicity; among these one died of interstitial pneumonia after HD-CY, one of kidney failure after HD-VP, three while in CR after HDT/ASCT (acute hepatitis C and B virus and acute encephalitis). Two patients developed a second tumor while in CR after ASCT: one died of acute myeloid leukemia and one was operated on for colon cancer. Currently, 72 of 117 patients are still alive.
According to intention-to-treat basis, the CR rate was similar in the two arms: arm A, 75.5%; arm B, 72.6% (P = 0.06).
Relapse
Arm A.
Twenty-eight (35%) of 80 patients in CR relapsed in a median time of 6 months (range 155). Twelve of them (43%) achieved a second CR: six after DHAP plus HDS/HDT and six after DHAP or different second-line therapy. Ten of them are now alive and well. Among the remaining 16 patients, 14 died of PD, one was lost to follow-up and the last one is alive and well following allogeneic transplantation.
Arm B.
Twenty-two (26%) out of 85 patients in CR relapsed in a median time of 9 months (range 135); six achieved a second CR, three are alive on therapy and 13 died of PD.
Survival
With a median follow-up of 62 months (range 298), the estimated 7-year overall survival of 223 patients was 58.8% [standard error (SE) 3.8%]. On the intention-to-treat basis, no statistically significant difference in 7-year survival was observed between arm A and arm B, with rates of 60% (SE 5.4%) and 57.8% (SE 5.2%), respectively (P = 0.5) (Figure 2). Univariate analysis showed the adverse factors were performance status 1 (P = 0.007), stage IIIIV (P = 0.0025), B symptoms (P = 0.02),
1 extranodal localization (P = 0.02), BM involvement (P = 0.0009) and LDH elevation (P = 0.005). Multivariate analysis showed that BM involvement (P = 0.01) and LDH elevation (P = 0.01) remained significant.
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The overall 7-year PFS probability was 43.6% (SE 4.3%), it was 44.9% (SE 5.1%) for arm A and 40.9% (SE 7.7%) for arm B (P = 0.7), respectively (Figure 2). Univariate analysis selected as negative factors performance status 1 (P = 0.03), stage IIIIV (P = 0.0004),
1 extranodal localization (P = 0.01), BM involvement (P = 0.001) and B symptoms (P = 0.006). In multivariate analysis, stage IIIIV (P = 0.02) and BM involvement (P = 0.015) remained significant.
Subgroup analysis
BM involvement.
According to univariate and multivariate analysis, BM involvement was the most important independent factor predicting a poor outcome. Comparison of patients with or without BM involvement showed a statistically poorer survival (P = 0.0009), DFS (P = 0.02) and PFS (P = 0.001) for patients with BM involvement (Figure 3). There was no difference in overall survival, DFS and PFS regardless of the randomized treatment received in the two patient groups.
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Again no statistical difference was found between the two arms, but these patients showed a statistically better overall survival (P = 0.02), DFS (P = 0.002) and PFS (P = 0.01) over the remaining 103 patients (other histology, T-cell phenotype, BM involvement) (Figure 4).
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Again no statistical difference between the two arms was observed, in terms of overall survival, DFS and PFS, both in low- and high-risk patients (Figure 5).
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Discussion |
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Treatment related-death of 1% in arm A and of 4% in arm B were lower than that reported by us in the same categories of patients with HDT [20] and by others with HDS/HDT [19
] approaches. The incidence of second tumor was similar in the two arms.
Seventeen patients (15%) from arm B patients did not undergo HDS/HDT, in most cases they refused to undergo the transplant procedure after achieving the CR and the majority of these patients are alive and well and should not detract from the statistical analysis as a negative bias. Twelve patients (29%) from arm A and 21 (18%) from arm B, eligible for HDS/HDT, were not able to complete procedure because of PD or treatment-related toxicity.
According to the intention-to-treat analysis, the overall 7-year survival in all patients of patients was 58.8% with a DFS 66.6% and a PFS of 43.6%. These results appeared inferior to those reported by the Milan Group using the HDS/HDT strategy [19] in 1997 and by ourselves using of HDT [20
] in 1998. The Milan group study included only patients with B large-cell NHL (groups G and H/WF) without BM involvement and our study included all categories of aggressive NHL, including patients with BM involvement, and univariate and multivariate analysis showed BM involvement as the most important independent factor predicting a poor outcome.
Patients without BM involvement showed a significantly better outcome and their outcome fit well with our historical data, suggesting that 12 weeks VACOP-B plus HDT is comparable to 8 weeks VACOP-B plus HDS/HDT in similar categories of patients. The subgroup of patients with large B cell NHL, without BM involvement, showed a better outcome, but the best outcome (regardless of the arm of randomization) was observed in patients with large B-cell NHL without BM involvement.
As expected, the IPI subgroup outcome analysis showed a large statistical advantage for low-risk patients, but no advantage was found for one of the two arms either in low- or high-risk patients (Figure 5); high-risk patients showed an outcome comparable to that reported in the past with HDT [1518
].
A recent randomized study suggests the superiority of HDT versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in terms of EFS, but not survival; nevertheless the retrospective analysis showed a statistical advantage both in survival and EFS in highintermediate IPI risk patients [28], like other retrospective data [11
13
, 20
], but again not with the results of the prospective trials [15
18
].
In conclusion, this trial, like other randomized studies, was unable to demonstrate the usefulness of HDS/HDT as front-line treatment for aggressive NHL, without evidence of benefit for given categories of patients with different prognostic score. As different strategies (HDS/HDT in all cases or only when needed) can give similar results in different subsets of patients, we think that in patients under 60 years old, HDS/HDT should be used in case of persistent disease after front-line therapy. The current availability of rituximab for treating patients with CD20+ diffuse large B-cell lymphoma and the superiority of the association CHOPrituximab versus CHOP alone in older patients [29], suggest that it would be of interest to evaluate the opportunity of supplementing the HDS/HDT strategy with rituximab in younger patients; indeed the very promising results claimed also in young patients [30
] suggest the possibility of comparing the two strategies (CHOP-like plus rituximab versus HDS/HDT plus rituximab).
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Acknowledgements |
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Received for publication March 14, 2005. Revision received April 28, 2005. Accepted for publication July 21, 2005.
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References |
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2. Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993; 328: 10021006.
3. Sertoli MR, Santini G, Chisesi T et al. MACOP-B versus proMACE-MOPP in the treatment of advanced diffuse non-Hodgkin's lymphomas: Results of a prospective randomized trial by the Non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1994; 12: 13661374.
4. Cabanillas F, Hagemeister FB, Mc Laughlin P et al. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987; 5: 407410.
5. Velasquez WS, Cabanillas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 1988; 71: 117122.
6. Velasquez WS, Mc Laughlin P, Tucker S et al. ESHAP An effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Oncol 1994; 12: 11691176.
7. Philip T, Armitage JO, Spitzer G et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987; 316: 14931497.[Abstract]
8. Vose JM, Zhang MJ, Rowlings PA et al. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: A report for the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 2001; 19: 406413.
9. Verdonck LF, Van Putten WLJ, Hagenbeek A et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N Engl J Med 1995; 332: 10451051.
10. Martelli M, Vignetti M, Zinzani PL et al. High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabin in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: A prospective randomized Italian Multicenter Study. J Clin Oncol 1996; 14: 534542.
11. Haioun C, Lepage E, Gisselbrecht C et al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: a study of 464 patients. J Clin Oncol 1994; 12: 25432551.
12. Haioun C, Lepage E, Gisselbrecht C et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: Updated results of the prospective study LNH87-2. J Clin Oncol 1997; 15: 11311137.
13. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: Final analysis of the prospective LNH87-2 protocol A Groupe d'Etude des Lymphomes de l'Adult Study. J Clin Oncol 2000; 18: 30253030.
14. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987994.
15. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: Randomized phase III EORTC study. J Natl Cancer Inst 2001; 93: 2230.
16. Kaiser U, Uebelacker I, Abel U et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002; 20: 44134419.
17. Martelli M, Gherlinzoni F, De Renzo A et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: An Italian multicenter randomized trial. J Clin Oncol 2003; 21: 12551262.
18. Gisselbrecht C, Lepage E, Molina T et al. Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 2002; 20: 24722479.
19. Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 12901297.
20. Santini G, Salvano L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: Results of a prospective randomized trial by the Non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16: 27962802.
21. The non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classification of non-Hodgkin's lymphoma: Summary and description of a working formulation for clinical usage. Cancer 1982; 49: 21122135.[ISI][Medline]
22. Carbone PP, Kaplan HS, Musshoff K et al. report of the Committee of Hodgkin's Disease Staging classification. Cancer Res 1971; 31: 18601861.[ISI][Medline]
23. Mills W, Chopra R, McMillan A et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol 1995; 13: 588595.
24. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 1999; 17: 12441253.
25. O'Reilly SE, Hoskins P, Klimo P, Connors JM: MACOP-B and VACOP-B in diffuse large cell lymphomas and MOPP/ABV in Hodgkin's disease. Ann Oncol 1991; 2 (Suppl 1): 1723.[ISI][Medline]
26. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
27. Cox DR. Regression models and life tables. J R Stat Soc 1972; 34: 187220.[ISI]
28. Milpied N, Deconinck E, Gaillard F et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004; 350: 12871295.
29. Coiffier B, Lepage E, Brière J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235242.
30. 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 2001; 19: 389397.
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