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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 916-917 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9358
In ReplyFred Hutchinson Cancer Research Center, and the University of Washington, Seattle, WA
Southwest Oncology Group, and the James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY We have read with interest Dr Nabhan’s letter concerning our article published in the September 1, 2006, issue of the Journal of Clinical Oncology.1 In this article, we documented long-term results of a multicenter trial that enrolled 90 eligible patients who were treated with this chemoradioimmunotherapy regimen a median of 5.1 years earlier, and we documented an overall 5-year survival (OS) rate of 87% and a progression-free survival (PFS) rate of 67%. The 5-year estimates of OS and PFS were each 23% better (absolute difference) than the corresponding figures for patients treated on previous Southwest Oncology protocols with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone and represented the best outcomes obtained in this disease in any Southwest Oncology Group (SWOG) trial. In his letter, Dr Nabhan protests the choice of CHOP for the S9911 study and for the successor randomized phase III Intergroup trial (Protocol S0016) that randomly assigns patients with stage III-IV follicular lymphoma (FL) to either a rituximab plus CHOP (R-CHOP) regimen or a CHOP followed by tositumomab/iodine I-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA) regimen. We acknowledge Dr Nabhan’s contention that there is no uniform consensus regarding the optimal front-line therapy for advanced-stage follicular lymphoma and that various experts in the field advocate different approaches including single-agent rituximab, rituximab plus cyclophosphamide, vincristine, and prednisione (R-CVP), rituximab plus fludarabine, mitoxantrone, and dexamethasone (R-FND) or R-CHOP. Despite this debate, we believe the choice of CHOP was reasonable and that the answer to Dr Nabhan’s question, "It’s follicular... .so, why CHOP?" was clearly enunciated in the original article describing this research trial.1 For a full exposition of this controversial decision, we refer Dr Nabhan to our original publications on the trial1,2; however, we will briefly summarize the reasons the CHOP regimen was selected.
First, the SWOG Lymphoma Committee believed that the use of a moderately aggressive regimen such as CHOP was most likely to produce a state of minimal tumor burden, which was considered the ideal setting for immunotherapy. Second, other adjuvant immunotherapies (eg, interferon alfa) have been shown to produce an advantage in terms of progression-free or overall survival only in studies using aggressive doxorubicin-containing chemotherapy regimens such as CHOP and not when combined with regimens such as chlorambucil or CVP.3 Finally, a pilot trial by Czuczman et al4,5 combining CHOP chemotherapy with concurrent rituximab demonstrated a promising 95% overall response rate and a median progression-free survival of more than 7 years in newly diagnosed patients with advanced follicular lymphoma. These impressive results prompted many practicing community oncologists to embrace R-CHOP as their preferred regimen for FL before the initiation of the SWOG studies. Indeed, contrary to Dr Nabhan’s assertion that American community oncologists are reluctant to employ CHOP in newly diagnosed FL, a recent large "patterns of care" study presented by Friedberg et al at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006,6 documented that CHOP-containing regimens are selected more commonly by US hematologists and oncologists for initial therapy of FL than any other regimen, with Dr Nabhan expresses concern that CHOP is excessively toxic for FL patients. Though we do not contend that all FL patients should receive CHOP, we note that there was not a single treatment-related death on the S9911 study, and that only 1% of patients experienced significant congestive heart failure. Nevertheless, we agree that patients who are elderly, have congestive heart failure, have very low tumor burdens, and are asymptomatic might be more appropriately treated with less intense regimens. We emphasize, however, the striking efficacy of CHOP combined with anti-CD20 antibodies and suggest that investigative attempts using potent regimens such as those on S9911 and S0016 are justified in clinical trials aiming to improve the natural history of FL, which is generally considered to be an incurable disease. Finally, we would like to dispel the erroneous assertion that the S0016 randomized trial is accruing poorly. In fact, this study has now been endorsed by all three major US oncology groups, including the Southwest Oncology Group, Cancer and Leukemia Group B, and the Eastern Cooperative Oncology Group, as well as the Clinical Trials Support Unit of the National Institutes of Health. More than 400 patients have already been registered on this Intergroup effort, with a planned enrollment of 500 patients. Indeed, the current accrual rate of 11 to 15 patients per month is in excess of the accrual rate of nine to 10 patients per month that was anticipated when the study opened. At this rate, we anticipate completing accrual and closing the trial in 2007. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Richard I. Fisher, Genentech, GlaxoSmithKline, Millennium Stock: N/A Honoraria: Oliver W. Press, Genentech; Richard I. Fisher, Genentech, GlaxoSmithKline, Millennium Research Funds: N/A Testimony: N/A Other: N/A REFERENCES
1. Press OW, Unger JM, Braziel RM, et al: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24:4143-4149, 2006 2. Press OW, Unger JM, Braziel RM, et al: A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 102:1606-1612, 2003 3. Rohatiner AZ, Gregory W, Peterson B, et al: A meta-analysis of randomized studies evaluating the role of interferon alpha as treatment for follicular lymphoma. Proc Am Soc Clin Oncol 21:264a, 2002 (abstr 1053) 4. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999 5. Czuczman MS, Weaver R, Alkuzweny B, et al: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: Nine-year follow-up. J Clin Oncol 22:4711-4716, 2004 6. Friedberg JW, Huang J, Dillon H, et al: Initial therapeutic strategy in follicular lymphoma (FL): An analysis from the National LymphoCare Study (NLCS). J Clin Oncol 24:428S, 2006 (suppl; abstr 7527)
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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47% of 959 patients treated with CHOP, 21% oncologists selecting rituximab alone, 15% choosing R-CVP, and 
