First-Line Treatment and Outcome of Elderly Patients with Primary Central Nervous System Lymphoma (PCNSL) – A Systematic Review and Individual Patient Data Meta-Analysis
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AbstractAbstract 3655BackgroundPrimary central nervous system lymphoma (PCNSL) is an aggressive lymphoma with devastating prognosis. High-dose methotrexate (HD-MTX) in combination with HD-cytarabine builds the backbone of current treatments. Elderly patients constitute 45% of cases, exhibit poor outcome and frequent iatrogenic toxicity. However, research efforts to optimize therapy in this subgroup have been neglected. On this background, we conducted a systematic review (SR) and individual patient data meta-analysis (IPDMA) to provide comprehensive evidence-based management strategy for elderly patients with PCNSL.Patients and MethodsSR: We searched MEDLINE and EMBASE without language restriction. Eligibility criteria were prospective/retrospective observational studies or randomized trials (RCT) (all N>=10) that exclusively focused on first-line therapy/outcomes in immunocompetent PCNSL patients ≥60 years. Eligible studies were evaluated for methodological quality and reporting of the following baseline characteristics: Age, performance status (PS), involvement of deep brain structures (IDB), serum LDH at baseline, cerebro-spinal fluid (CSF) protein concentration elevation, neurotoxicity (as reported), specific co-morbidity indices, and functional status. For the IPDMA, investigators of eligible studies were asked to provide individual patient data. Minimal eligibility criteria: Age at baseline, details about first-line therapy, and follow-up information. If no data were available, studies were included in the SR, but not in the IPDMA. To maximize statistical power and generalizability, published/unpublished data from other international collaborators were included. Impact of different first-line treatments on overall survival (OS) was investigated using time dependent mixed effects multivariable Cox regression models (age and PS as fixed effects, study/database as random effect).ResultsSR: We identified 13 eligible studies including 583 patients in total, median age 68–76, published from 1996–2011. Design of studies: prospective (3 multicenter [1 RCT]; 2 single center), retrospective (4 multicenter and single-center, respectively). Accrual of the RCT was recently finished, but publication is pending. From published studies, information about age and therapy was given throughout, for clinical performance in 77%, for LDH and CSF protein in 15%, and IDB in 38%. Functional status was reported in only one study. From the identified 13 studies, 261 individual patient data were available for our IPDMA and pooled with 408 patients from other databases; altogether 669 patients diagnosed from 1977–2011. Preliminary results IPDMA: 50% were male, median age 68 (60–70 [N=431], 70–80 [N=211], >80 [N=22]); median KPS was 60% (10–100%). Therapy regimens widely varied. Overall response to first-line treatment was 65% (45% CR, 19% PR). After a median follow-up of 23 months (1–171), 44% were still alive, with a 3-year OS of 32% [95%CI, 29–37%]. Grouping by time of diagnosis revealed improvement for patients diagnosed after 1997 (N=462) (P<0.001). In multivariate analysis, MTX-based poly-chemotherapy (CT) (N=474) was associated with improved OS (Hazard ratio [HR] 0.69, 95% CI 0.52–0.91) compared to non-MTX regimens (N=195); this was consistent among patients who received consolidating WBRT (HR 0.33, 95% CI 0.01–0.66) and those who did not (HR 0.46, 95% CI 0.23–0.89). In patients who received any MTX-based poly-CT, addition of CHOP-like components (N=90) was not associated with improved OS (HR 0.98, 95% 0.65–1.48). Although any WBRT showed an overall trend for superior OS, it was associated with a 4-fold risk increase for neurotoxicity (Odds Ratio 4.21, 95% CI 2.23–8.21). Further results of treatment patterns and explorative comparisons will be presented at the meeting.ConclusionThis international meta-analysis revealed widely varying treatment approaches and demonstrates that prognosis for elderly PCNSL patients is still poor. However, improvement over the last decades was observed. MTX-based poly-CT was associated with better outcome compared to non-MTX containing approaches. The addition of CHOP-like regimens to HD-MTX did not improve outcome. WBRT was associated with better outcome, but also clearly increased risk of neurotoxicity. Prospective trials designed ad hoc for elderly PCNSL patients are promptly needed.Disclosures:No relevant conflicts of interest to declare.
