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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3162-3163 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.313
In Reply:Stanford University, Stanford, CA We are pleased that Basaran et al find important implications for the design of future trials in our Eastern Cooperative Oncology Group (ECOG) 1484 report,1 in which we determined that radiotherapy in complete responders reduced the likelihood of failure in involved sites of disease and significantly prolonged 5- and 10-year disease-free survival, the primary end point of the study. No significant difference in overall survival was seen in complete responders in the ECOG 1484 trial. As stated, this was not likely due to late effects of radiation because the proportion of deaths without disease recurrence was slightly greater among the observation patients. We agree with Basaran et al that the observation of a greater number of late relapses after three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy plus radiation compared with eight cycles of CHOP chemotherapy alone in the updated analysis of the Southwest Oncology Group (SWOG) study, together with the paucity of late relapses in either of our study group arms after eight cycles of CHOP chemotherapy, logically leads one to question the optimal duration of treatment in limited-stage diffuse large B-cell lymphoma.2 Also in agreement with Basaran et al, we interpret the excellent outcome in patients achieving partial response in the ECOG 1484 study to be due, in part, to the difficulty in evaluating residual radiographic disease. This fact challenged interpretation of the benefit of consolidative radiotherapy, given to partial responders in our study, similar to the experience in Hodgkin's disease.3 We do not have details on subsequent treatment for patients with progressive disease but, based on the era of the ECOG 1484 study, high-dose therapy was not routine, and rituximab was not available. Since the ECOG 1484 study was conducted, important advances in diagnosis and treatment have been made in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy (plus radiation to bulky sites) boosted failure-free survival at 2 years from 58% to 81% in patients younger than 60 years with an International Prognostic Index of 0 to 1, primarily stage I to II, disease.4 Primary mediastinal (thymic) large B-cell lymphoma, which has a favorable prognosis despite the usual presentation of bulky disease, has been recognized as a unique biologic disease.5,6 Early use of positron emission tomography during induction therapy as a surrogate for treatment efficacy requires more study but preliminary results are highly encouraging.7 As Miller8 points out in the editorial accompanying our results, prolongation of survival is the ultimate definition of efficacy from a patient's perspective but patients are likely to view a five-fold reduction in the local rate of failure and a > 10% decrease in the risk of relapse at 10 years as benefits as well. The results of ECOG 1484 taught us that presence of three or more disease sites was associated with an increased risk of treatment failure and that our imaging techniques were inadequate. Since then, the heterogeneity of diffuse large B-cell lymphoma has become more apparent, and this diversity goes beyond stage, bulk, or International Prognostic Index to biomarkers and their complex interaction with changing treatment.9,10 As we incorporate molecular diagnostics and investigate early response with functional imaging in the context of modern treatments, questions regarding the duration of therapy and the benefits of alternative therapeutics seem more like relevant inquiries than dusty relics. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Horning SJ, Weller E, Kim K, et al: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22:3032-3038, 2004 2. Miller TP, LeBlanc M, Spier C, et al: CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: Update of the Southwest Oncology Group (SWOG) randomized trial. Blood 98:3024A, 2001
3. Aleman BM, Raemaekers JM, Tirelli U, et al: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348:2396-2406, 2003 4. Pfreundschuh M, Truemper 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 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 23:558S, 2004 (suppl; abstr 6500)
5. Savage KJ, Monti S, Kutok JL, et al: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102:3871-3879, 2003
6. Rosenwald A, Wright G, Leroy K, et al: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198:851-862, 2003
7. Spaepen K, Stroobants S, Dupont P, et al: Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin's lymphoma. Ann Oncol 13:1356-1363, 2002
8. Miller TP: The limits of limited stage lymphoma. J Clin Oncol 22:2982-2984, 2004 9. Winter JN, Weller E, Horning S, et al: Rituximab alters the prognostic indicator profile in diffuse aggressive non-Hodgkin's lymphomas. Blood 102:305, 2003 (abstr)
10. Mounier N, Briere J, Gisselbrecht C, et al: Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 101:4279-4284, 2003
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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