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Originally published as JCO Early Release 10.1200/JCO.2009.22.0608 on June 22 2009 © 2009 American Society of Clinical Oncology.
Natural History of CNS Relapse in Aggressive Non-Hodgkin's Lymphoma: What Have We Learned?Department of Neurology and Neurological Surgery, University of Washington; Fred Hutchinson Cancer Research Center, Seattle, WA To the Editor: Bernstein et al1 are to be congratulated for their recently reported phase III trial (four-arm randomization) in newly diagnosed patients with aggressive non-Hodgkin's lymphoma (NHL) and assessment of CNS relapse. I would like to make several comments regarding the report and the need for risk stratification regarding CNS-directed therapy in newly diagnosed patients with aggressive NHL. Five key issues appear relevant with respect to CNS prophylaxis in aggressive NHL. First, is there a consensus that CNS disease (mostly lymphomatous meningitis) is clinically relevant? Approximately 55% of all diffuse large B-cell NHL relapse systemically as contrasted with only 2% to 4% relapse in the CNS.1–6 Among patients with CNS relapse, half have poorly responding or refractory systemic disease. Therefore, the number of patients with NHL-isolated CNS is comparatively small. Second, is there a consensus regarding identification of high-risk (for CNS relapse/disease) patients with aggressive NHL? A number of studies have suggested low International Prognostic Index, two or more extranodal sites of disease and site specific disease (ie, testes, breast, parameningeal [sinus, orbit], and bone marrow) defined as large-cell involvement not small cleaved cell define a substantial group of patients at risk for CNS disease.1–6 Notwithstanding this recognition of high-risk features, no study of newly diagnosed aggressive NHL has attempted to stratify patients with respect to CNS risk and CNS-directed therapy. Third, and as mentioned by Bernstein et al,1 high-risk patients are often found at diagnosis (approximately 25%), if evaluated by CSF flow cytometry, to have contamination of the CSF by lymphoma.7 This suggests that a subset of patients with aggressive NHL and without neurological symptoms has occult lymphomatous meningitis at diagnosis. Importantly, CSF flow cytometry appears superior to CSF cytology with appropriate caveats regarding laboratory methodology for demonstrating lymphomatous involvement of the CSF. Notwithstanding this subset of patients with occult lymphomatous meningitis, the majority of patients with CNS relapse have negative CSF evaluation at diagnosis. Nevertheless, the study by Hegde et al7 is compelling for mandatory CSF evaluation in patients defined as at high risk for CNS relapse at time of up-front therapy. Fourth, is there evidence that CNS prophylaxis is of benefit? This query is problematic as for the majority of patients (> 75%), risk of CNS disease is sufficiently low (< 2%) that most randomized trials are not sufficiently powered to determine if CNS-directed therapy is of benefit. Furthermore the inclusion of rituximab into up-front therapy for aggressive NHL as mentioned by Bernstein et al1 may further diminish the risk of CNS disease.6 Lastly, is there evidence that CNS-directed therapy impacts outcome? Stated differently, is there evidence that treatment with CNS-directed therapy, most often intra-CSF chemotherapy or high-dose systemic methotrexate, favorably alters outcome? In patients with established neoplastic meningitis the role of intra-CSF chemotherapy has never been prospectively evaluated and, as such, the use of intra-CSF chemotherapy in part reflects faith-based medicine.7,8 These comments are not meant to diminish the significant effort of Bernstein et al1 in defining the natural history of CNS relapse in aggressive NHL vis-à-vis Southwest Oncology Group trial 8516, but rather ask what have we learned that is new since the initiation of this study and importantly how do we plan to use this information in the design and conduct of new trials for newly diagnosed aggressive NHL? AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. 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. 2. McMillan A: Central nervous system-directed preventative therapy in adults. Br J Haematol 131:13–21, 2005.[CrossRef][Medline] 3. Hollender A, Kvaloy S, Lote K, et al: Prognostic factors in 140 adult patients with non-Hodgkin's lymphoma with systemic CNS involvement: A single center analysis. Eur J Cancer 36:1762–1768, 2000.[CrossRef][Medline] 4. van Besien K, Ha CS, Murphy S, et al: Risk factors, treatment, and outcome of CNS recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91:1178–1184, 1998. 5. Haioun C, Besson, Lepage E, et al: Incidence and risk factors of CNS relapse in histologically aggressive non-Hodgkin's lymphoma uniformly treated and receiving intrathecal CNS prophylaxis: A GELA study of 974 patients. Ann Oncol 11:685–690, 2000. 6. Feugier P, Virion JM, Tilly H, et al: Incidence and risk factors for CNS occurrence in elderly patients with diffuse large B-cell lymphoma: Influence of rituximab. Ann Oncol 15:129–133, 2004. 7. 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 CNS involvement: The role for flow cytometry versus cytology. Blood 105:496–502, 2005. 8. Gleissner B, Chamberlain MC: Lymphomatous meningitis in systemic NHL. J Neurooncol 84:310–321, 2007.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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