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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4322-4324 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.1285
Primary CNS Lymphomas PrognosisUnit of Lymphoid Malignancies and Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy
Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy
Division of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Switzerland Everything should be made as simple as possible, but not simpler. Albert Einstein To the Editor:
We read with great interest the article by Abrey et al1 on a pragmatic and easy to apply prognostic score for primary CNS lymphomas (PCNSL). The proposed score includes two variables, age and performance status (PS), whose prognostic value in PCNSL has been a consolidated knowledge for at least 20 years.2 With these two variables, Abrey et al obtained three prognostic classes: class 1, patients with age In order to evaluate whether the three omitted IELSG variables (LDH serum level, CSF protein concentration, and deep lesions) could add further prognostic information with respect to the three Memorial Sloan-Kettering Cancer Center (MSKCC) classes, we analyzed the prognostic role of both scores on the IELSG database4 and for a series of 41 PCNSL patients enrolled in a recently reported multicenter phase II trial.5 Firstly, the 105 IELSG patients for whom all the five analyzed variables were available were grouped in the three proposed MSKCC classes,1 showing that MSKCC score failed to distinguish class 1 and class 2 prognostic subgroups (Fig 1A). Subsequently, every MSKCC class was divided according to the three IELSG risk groups. This analysis showed that MSKCC classes exhibit an evident, intrinsic prognostic heterogeneity, and that the three omitted IELSG variables allow to further detail the risk of death (Figs 1B to 1D). For instance, 3-year overall survival (OS) for patients with MSKCC class 2 was 91% or 29% (log-rank test, P = .008) if they belonged respectively to low- or intermediate-risk IELSG groups (Fig 1C). Likewise, MSKCC class 3 patients had a 3-year OS of 39% and 0% (P = .02) if they belonged respectively to intermediate- or high-risk IELSG groups (Fig 1D).
When the same analysis was performed on the prospective series of the Methotrexate, Cytarabine, Thiotepa, Idarubicin, Leucovorin, Dexamethasone (MATILDE) trial,5 results were similar. For instance, median OS of MSKCC class 1 patients was 55+ and 26 months (P = .006) if they belonged respectively to low- or intermediate-risk IELSG groups, and median OS of MSKCC class 3 patients were 14 and 5 months (P = .05) if they fit respectively in intermediate and high IELSG risk. Also in this case, groups of patients divided according only to age and PS displayed heterogeneous outcome, requiring the introduction of the other IELSG variables to fine-tune prognosis. It is important to analyze the reasons for which the prognostic role of the IELSG score was not confirmed in the MSKCC database. The major methodologic differences in the identification of both scores regard the analyzed population and the lack of stratification based on treatment in MSKCC analysis. While the IELSG prognostic score was designed and confirmed on a population exclusively composed of patients with newly diagnosed PCNSL,3,5 the study population on which MSKCC score was designed is not well defined. For example, the fact that systemic involvement was excluded only in 269 patients (Abrey et al's Table A21), while survival analysis was performed on 282 patients (Abrey et al's Table 11), suggest that patients with systemic lymphoma (n = 13) were actually included in the analysis. Also patients with unconfirmed diagnosis (n = 14) and primary intraocular lymphoma (PIOL; n = 22) were included in the evaluation of the main variables (ie, age and PS), which was performed on 338 and 285 cases, respectively (Abrey et al's Table A21). While the interpretation biases introduced by patients with systemic lymphoma or unconfirmed diagnosis are obvious, those related to the inclusion of PIOL may regard the good prognosis and excellent PS of these patients (Abrey et al unpublished data), and the impossibility to determine the infiltration of deep regions of the brain since the exclusive involvement of the eyes. Thus, PIOL patients will probably need for different prognostic factors. Multivariate analysis stratified by therapeutic variables confirmed that IELSG score is independent of treatment both in retrospective4 and prospective5 studies, whereas therapeutic variables were not included in MSKCC analysis. This is a relevant caveat considering that studies of new prognostic factors that do not account for treatment are highly confounded and conclusions regarding their clinical utility are difficult to determine.6 Moreover, since therapeutic choice of PCNSL is driven by age and PS,7 the prognostic value of these two variables may result mistakenly emphasized with respect to other factors due to the administration of more effective treatments in younger patients or in patients with better PS. Finally, the score proposed by MSKCC colleagues was established from a retrospective series and was retrospectively applied to previously reported prospective trials. Conversely, the collection of IELSG variables was prospectively planned in a phase II trial,5 and their prognostic value has been confirmed in that trial. In fact, the variables included in the IELSG score can be routinely collected for PCNSL patients if prospectively planned. The score proposed by Abrey et al1 is simple, but simplicity could be to the detriment of accuracy. Present data show that the use of a disease-specific score, which includes LDH serum level, CSF protein level, and involvement of deep regions of the brain other than age and PS will result in a better risk stratification of PCNSL patients enrolled in prospective trials. The IELSG prognostic score, in fact, follows the model of the International Prognostic Index for aggressive lymphomas,8 which includes variables related to aggressiveness, extension and site of disease other than age and PS. We hope that a more diffuse use of the IELSG prognostic score could have a similar impact on clinical practice and prospective trials than those eventually demonstrated for the International Prognostic Index. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS The authors are writing on behalf of the International Extranodal Lymphoma Study Group. REFERENCES
1. Abrey LE, Ben-Porat L, Panageas KS, et al: Primary central nervous system lymphoma: The Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24:5711-5715, 2006 2. Pollack IF, Dade Lunsford L, Flickinger JC, et al: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63:939-947, 1989[CrossRef][Medline] 3. Ferreri AJM, Blay JY, Reni M, et al: Prognostic scoring system for primary CNS lymphomas: The International Extranodal Lymphoma Study Group experience. J Clin Oncol 21:266-272, 2003 4. Ferreri AJM, Reni M, Pasini F, et al: A multicenter study of treatment of primary CNS lymphoma. Neurology 58:1513-1520, 2002[Medline] 5. Ferreri AJM, Dell'Oro S, Foppoli M, et al: MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas. Neurology 66:1435-1438, 2006 6. Hayes DF, Trock B, Harris AL: Assessing the clinical impact of prognostic factors: When is "statistically significant" clinically useful? Breast Cancer Res Treat 52:305-319, 1998[CrossRef][Medline] 7. Corry J, Smith JG, Wirth A, et al: Primary central nervous system lymphoma: Age and performance status are more important than treatment modality. Int J Radiat Oncol Biol Phys 41:615-620, 1998[CrossRef][Medline] 8. Anonymous: A predictive model for aggressive non-Hodgkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993
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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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50; class 2, patients older than 50 with a Karnofsky PS of 
70; and class 3, patients older than 50 plus Karnofsky PS lower than 70. Authors discussed the advantages of their score with respect to the International Extranodal Lymphoma Study Group (IELSG) prognostic score,
