|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2009.22.2166 on June 22 2009 © 2009 American Society of Clinical Oncology.
Reply to M.C. ChamberlainJames P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY
Fred Hutchinson Cancer Research Center, Seattle, WA
Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
Arizona Cancer Center, University of Arizona, Tucson, AZ
James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY We thank Dr Chamberlain1 for his comments, as well as for succinctly framing the clinically relevant questions that remain unanswered relative to CNS relapse of systemic aggressive non-Hodgkin's lymphoma. The first question Dr Chamberlain asks is whether there is a consensus that CNS disease is indeed even clinically relevant. To this we would say yes. Dr Chamberlain correctly points out that many patients with CNS relapse have poorly responding or refractory systemic disease. As for the small proportion of patients with isolated CNS relapse, the almost uniform mortality of these patients suggests that more optimal approaches to either prevent or treat CNS recurrences are needed. However, given the small incidence of isolated CNS recurrences, a general prophylaxis strategy to prevent such relapses would unnecessarily expose many patients not destined for CNS relapse to CNS-directed therapy. This is directly germane to Dr Chamberlain's second question as to whether there is a consensus regarding the identification of patients with high-risk features for CNS relapse, as these are the patients one would target in a trial of CNS prophylaxis. In this regard, defining such patients from the literature is confounded by the fact that how CNS relapse is defined and what subgroups of patient had CNS prophylaxis differ from study to study and that the majority of published data, including our own, is from the pre-rituximab era.2–4 However, a consistent finding in most studies, including one recently reported from the German High-Grade Non-Hodgkin's Lymphoma Study Group that evaluated CNS events in patients that received a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone is that patients having one or more extranodal sites have a higher incidence of CNS disease than those with no extranodal site.2–5 The findings of our study demonstrated that CNS relapse is an early event, often occurring either during or shortly after completion of systemic induction therapy, a similar finding having been shown in other studies.2,3 This led us to hypothesize that most patients destined for CNS relapse likely had subclinical CNS disease at diagnosis. We therefore agree with Dr Chamberlain1 that patients at high risk for CNS disease (at a minimum, those having one or more extranodal sites of involvement) should have a CSF evaluation; if they have a positive cytology, they should be treated, rather then prophylaxed, for CNS disease. A more sensitive diagnostic strategy then routine cytology however may be more effective in identifying patients with subclinical disease at diagnosis. In this regard, Hegde et al,6 and most recently Quijano et al,7 have shown the improved sensitivity of flow cytometry in detecting CNS involvement compared with that of routine cytology. The question then becomes whether patients with a negative cytology but a positive flow cytometry would benefit from CNS prophylaxis or CNS treatment, and this needs to be studied in the context of clinical trials. The ambiguity of the practice of CNS prophylaxis is correctly alluded to in Dr Chamberlain's1 last two questions. To date, one would have to agree that there is no definite class I clinical evidence showing that CNS prophylaxis is of benefit, or that prophylaxis even impacts outcome. This then begets the question as to how to best move forward. First, as discussed, given the association of CNS relapse with eventual systemic relapse and the association of CNS relapse with the International Prognostic Index (or components therein), it is logical to conclude that better treatment strategies for patients with high risk of systemic relapse would translate into a lower CNS relapse. Second, carefully designed clinical trials to test the efficacy of CNS prophylaxis are needed. The challenges are many, including identifying the at-risk population, deciding on the prophylaxis to be tested (ie, intrathecal chemotherapy or high-dose methotrexate), and determining how to handle patients having a negative CSF cytology but a positive flow cytometry, as well as determining the number of patients needed for such a study given the small incidence of CNS events. Despite such challenges, a working group of investigators are currently developing such a study. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Chamberlain MC: Natural history of CNS relapse in aggressive non-Hodgkin's lymphoma: What have we learned? J Clin Oncol 27:e26; 2009. 2. Bernstein SH, Unger JM, Leblanc M, et al: Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: A 20-year follow-up analysis of SWOG 8516—The Southwest Oncology Group. J Clin Oncol 27:114–119, 2009. 3. van Besien K, Ha CS, Murphy S, et al: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91:1178–1184, 1998. 4. Hollender A, Kvaloy S, Nome O, et al: Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: A risk model. Ann Oncol 13:1099–1107, 2002. 5. Boehme V, Schmitz N, Zeynalova S, et al: CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: An analysis of patients treated in the RICOVER-60 trial of the German high-grade non-Hodgkin lymphoma study group (DSHNHL). Blood 113:3896–3902, 2009. 6. Hegde U, Filie A, Little RF, et al: High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: The role of flow cytometry versus cytology. Blood 105:496–502, 2005. 7. Quijano S, López A, Manuel Sancho J, et al: Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin's lymphoma: Improved sensitivity of flow cytometry. J Clin Oncol 27:1462–1469, 2009.
Related Article
Related Correspondence
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
