Primary central nervous system lymphoma (PCNSL)

Neuro-Oncology 14(10):1304 1311, 2012. doi:10.1093/neuonc/nos207 Advance Access publication September 5, 2012 NEURO-ONCOLOGY Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan- Kettering Cancer Center Mary R. Welch, Antonio Omuro, and Lisa M. DeAngelis Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York Up to 20% of all primary CNS lymphoma (PCNLS) patients are aged 80 years or older, yet data are limited on how best to treat this rapidly growing population. Despite demographic pressures and the proven efficacy of methotrexate (MTX)-based regimens, automatic deescalation of care based on age is standard practice outside of tertiary care centers. We performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011. Demographic and clinical variables were evaluated as predictors of survival by multivariate analysis. Twenty-three of 24 patients were treated with chemotherapy (92% with high-dose MTX, typically in combination with vincristine and procarbazine). One patient received ocular radiation alone for limited to the eyes. Response to treatment was noted in 62.5% of patients; 9 (37.5%) had refractory. Median overall survival was 7.9 months (95% confidence interval [CI]: 5.8 53), and median progression-free survival was 6.5 months (95% CI: 4.4 29.5). Two-year survival rate was 33%; 3-year survival rate was 17%. Three patients lived more than 4 years postdiagnosis. Most patients tolerated therapy well, and despite low baseline creatinine clearance, no significant renal toxicity was noted. Response status and deep brain involvement were identified as the most important predictors of survival. Multidrug regimens containing high-dose MTX are feasible and efficacious among the oldest patients, particularly those who achieve a complete response by their fifth treatment cycle. Aggressive therapy should be offered to select patients irrespective of advanced age. Keywords: chemotherapy, elderly, primary central nervous system lymphoma, quality of life. Received May 3, 2012; accepted July 23, 2012. Corresponding author: Lisa M. DeAngelis, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (deangell@mskcc.org). Primary central nervous system lymphoma (PCNSL) is a rare variant of non-hodgkin lymphoma confined to the brain, leptomeninges, spinal cord, or eyes. Although it accounts for less than 5% of all primary brain tumors, the age-adjusted incidence of PCNSL has increased substantially over the past 30 years. 1 Nearly half of all cases of PCNSL occur among patients older than 60 years, and 20% of those affected are 80 years or older, yet data are limited on how best to manage the in the elderly. 2 This is due in part to their limited participation in clinical trials, as well as the hesitancy on the part of many clinicians to treat older patients with aggressive therapy. 3 While a few recent studies have attempted to address this gap, data on the oldest patients 80 years or older are lacking. 4,5 Given that this group comprises the fastest-growing segment of the United States population, with a growth rate 3 times that of the total, exploring therapeutic strategies among the very old should be a priority. 6 Older age is a well-established negative prognostic marker, and, compared with their younger counterparts, patients 60 years or older die earlier of their, despite identical therapy with methotrexate (MTX)- based regimens. 7 9 Moreover, those who do survive are more susceptible to neurocognitive sequelae. 10 In an effort to minimize the latter, recent trials have explored the use of MTX-based therapy without wholebrain radiotherapy (WBRT), and while these regimens have been promising, with less cognitive dysfunction and comparable overall survival (OS) times of 14 37 9,11 14 months, responses are less durable. Despite these advances, chemotherapy remains underutilized outside tertiary care centers, particularly among the elderly. According to a population-based Medicare study of 579 patients diagnosed with PCNSL from 1994 to 2002, age was inversely correlated with the chance of treatment with MTX, and up to 82% of patients 80 years or older received either radiotherapy alone or no treatment at all. 3 While it is increasingly clear that such automatic de-escalation of care based on age is not appropriate, caution is warranted. The # The Author(s) 2012. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

elderly are more likely to have compromised renal function, limited bone marrow reserve, and decreased cardiac output physiologic changes that may result in greater toxicity and reduced efficacy from MTX. 15 Identifying clinical predictors that allow clinicians to determine who will benefit from vigorous treatment vs those who will not is important. In this study, we attempt to characterize and evaluate prognostic factors among a cohort of the oldest PCNSL patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC). Study Design Materials and Methods The MSKCC institutional database was used to identify patients with PCNSL who were diagnosed at 80 years or older between 1993 and 2011. Data were collected by chart review, and response was determined by contrast-enhanced MRI or CT. To qualify as a complete response (CR), patients had to have complete disappearance of all contrast-enhancing lesions. To evaluate predictors of OS, we analyzed demographic, clinical, and treatment variables for their impacts on survival time. We examined completion of 5 or more cycles of MTX-based chemotherapy as a measure of a patient receiving reasonably adequate therapy and because this is a time point where we typically perform routine imaging for efficacy. This retrospective study was approved by the MSKCC Institutional Review Board. Statistical Analyses The following baseline demographic variables were studied: patient age, sex, marital status, and year of diagnosis. Clinical variables included Karnofsky performance status (KPS), duration of symptoms prior to treatment, deep brain involvement, presentation with altered mental status, hemiparesis, baseline hemoglobin, and creatinine clearance as calculated by the Cockgroft Gault method. Treatment-related variables included number of MTX cycles and response status. All variables except age were dichotomized in the analysis. A KPS of 70 was used as the cut point, as this defines the capacity for independent self-care. To evaluate time trends over the course of 19 years, patients were dichotomized by diagnosis before and after 2002. Pretreatment anemia was defined as a hemoglobin value less than 10 g/dl, and a creatinine clearance rate of 50 ml/min was selected as a cut point to stratify baseline renal function. 15,16 Patients were also dichotomized based on whether they completed a minimum of 5 cycles of intravenous MTX. OS was measured from the date of diagnosis as defined by the date on which pathological confirmation was obtained until death or last follow-up. Kaplan Meier survival distributions were estimated to assess OS and progression-free survival (PFS). Data were collected through December 31, 2011, which was used as the censoring date for survivors. Univariate Cox proportional hazards models were fit to analyze predictors of survival, and a log-rank test was applied to compare survival curves. A multivariate Cox proportional hazard model was used to analyze predictors of survival that were univariately significant at the a, 0.10 level. Simple logistic regression models were analyzed to identify potential predictors affecting discharge destination. The small sample size precluded multivariate analysis. All statistical analyses were performed using Stata statistical software (Intercooled version 12.0). Patient Characteristics Results Twenty-four patients aged 80 years or older were treated for PCNSL between 1993 and 2011 (Table 1). The median age at diagnosis was 82 (range, 80 90 years), and median KPS was 50 (range, 30 90). There was a predominance of women (67%), and 58% of patients were married. Most patients (71%) were diagnosed after 2002. Fifteen patients (62.5%) presented with cognitive or personality changes, and, in at least 3, diagnosis was delayed because such symptoms were attributed to mild cognitive impairment of aging or frank dementia. Six patients (25%) presented with hemiparesis, 4 (16.6%) with aphasia, and 2 (8.3%) with seizures. Twenty-three had parenchymal brain lesions, and 1 had isolated ocular lymphoma. At diagnosis all patients underwent staging with ophthalmological evaluation, bone marrow biopsy, body imaging, and lumbar puncture. Three (12.5%) had clear evidence of leptomeningeal on analysis of cerebrospinal fluid (CSF); an additional 2 (8.3%) had atypical lymphocytes considered suspicious for lymphoma. Three patients (12.5%) had ocular involvement (1 isolated), and all were confirmed by vitreal biopsy. No patients had systemic or bone marrow involvement. Eight patients (33%) initiated treatment within 1 month of symptom onset; the remainder (67%) had more prolonged symptom duration before seeking medical attention. Once the appropriate diagnosis had been made, however, median time between diagnosis of intracranial and initiation of chemotherapy was 15 days (range, 4 41). Laboratory data required to determine baseline creatinine clearance were available on 20 patients. Of these, 13 (65%) had a clearance rate of 50 ml/min as calculated by Cockcroft Gault; 7 (35%) had values below this, ranging from 28 to 45 ml/min. All patients had normal white cell counts and platelets; 3 (12.5%) initiated treatment with hemoglobin below 10 g/dl. Initial Treatment All but 2 patients (92%) received some form of highdose MTX-based therapy, usually in combination with vincristine and procarbazine (MVP) (Table 2 and NEURO-ONCOLOGY OCTOBER 2012 1305

Table 1. Oldest PCNSL Patient Characteristics Characteristic No. of Patients % of Patients Age at diagnosis, years 80-85 19 79% 85-90 5 21% Sex Women 16 67% Men 8 33% Marital status Married 14 58% Unmarried 10 42% Year of diagnosis Before 2002 7 29% After 2002 17 71% KPS at presentation,70 18 75% 70 6 25% Pre-treatment symptom duration 1 months 16 67%,1 months 8 33% Deep brain involvement Yes 12 50% No 12 50% Ocular involvement Yes 3 13% No 21 87% Positive CSF cytology Yes 3 13% No 19 79% Suspicious 2 8.3% Hemiparesis Yes 6 25% No 18 75% Changes in cognition or personality Yes 15 63% No 9 37% Aphasia Yes 4 17% No 20 83% Seizures Yes 2 8% No 22 92% Creatinine Clearance,50 ml/min 7 29% 50 ml/min 13 54% Missing 4 17% Abbreviations: KPS, Karnofsky performance status; MTX, methotrexate; CSF, cerebrospinal fluid. Appendix). The patient who had isolated ocular lymphoma opted for ocular radiation alone; another wished to avoid inpatient treatment and chose a course of procarbazine, lomustine, and vincristine (PCV) before pursuing supportive care. Among the 22 patients treated with MTX, 17 (77.3%) initiated treatment at a dosage of 3.5 g/m 2. The remaining 5 started at dosages ranging from 1 to 2.5 g/m 2. One patient was treated with 1 g/m 2 in deference to his advanced age (89 years). The oldest patient in the cohort (90 years) started at a dosage of 2 g/m 2 owing to concerns about multiple comorbidities; this was eventually raised to 3 g/m 2 but lowered again to 2.5 g/m 2 when he developed a grade 2 pleural effusion. An 86-year-old also started at 2 g/m 2, but this dosage was later titrated to 3.5 g/m 2. Two additional patients initiated treatment at 2 2.5 g/m 2 owing to low baseline creatinine clearance in the range 28 42 ml/min; they completed MTX at the reduced dosage. Only 2 of the patients who started at 3.5 g/m 2 required dosage reductions. One had his dosage lowered to 1 g/m 2 after a delay in clearance, and no attempts were made to re-escalate. The second patient was given 2.5 g/m 2 for cycles 3 and 5 in response to transient grade 2 elevations in creatinine; all other cycles were at the full dosage. All patients were admitted to the hospital for each cycle of MTX, which was administered every 2 weeks as a 2-hour infusion followed 24 hours later by calcium leucovorin rescue. Vincristine was given at dosages ranging from 1 to 1.4 mg/m 2 on the first day of each cycle, and procarbazine was given on days 1 7 of every other cycle at a dosage of 100 mg/m 2 /day. Patients were discharged from the hospital once their MTX serum level was 100 nmol/l. Two patients were treated with 500 mg/m 2 of rituximab (R) in combination with MTX. Fourteen patients (64% of those treated with MTX) completed at least 5 cycles of MTX, and 5 underwent consolidation therapy with high-dose cytarabine (Ara-C). One patient received Ara-C after only 4 cycles of MTX. Eight patients were either unwilling to continue high-dose MTX or unable to tolerate a full course of treatment due to clinical deterioration or toxicity. No patient with a positive CSF cytology received intrathecal chemotherapy. Vincristine was used in combination with high-dose MTX in all but 2 patients. One received initial treatment at an outside institution whose clinical practice did not include use of this agent. The other patient presented with an ileus, which led treating physicians to withold vincristine out of fear of exacerbating a preexisting autonomic neuropathy. Two patients had their dosages capped at 2 mg daily at the outset of treatment in deference to their age; all other patients received a standard dosage of 1.4 mg/m 2. Only 1 patient underwent a dosage reduction (from 1.4 to 1.2 mg/m 2 ) for a mild peripheral neuropathy. Cranial radiotherapy was used as part of initial treatment in only 1 patient, who received 900 cgy at an outside institution upon discovery of an intracranial mass but prior to pathological diagnosis. Once the diagnosis was established, radiation was stopped and the patient was referred to MSKCC for chemotherapy. No other patient received any treatment prior to MTX. Salvage Treatment Salvage treatment was used in 5 patients. One patient who had clinical and radiographic progression after only 2 cycles of MTX was given a single dose of 1306 NEURO-ONCOLOGY OCTOBER 2012

Table 2. Response summary for the oldest PCNSL patients treated with MTX n CR (% of N) PR (% of N) Refractory (% of N) All treatment 24 14 (58.3) 1 (4.2) 9 (37.5) MTX based a 22 13 (59) 1 (4.5) 8 (36.5) 5 cycles 14 12 b (86) 2 (14),5 cycles 8 1 b (12.5) 1 (12.5) 6 (75) PCV 1 1 (100) Ocular RT 1 1 (100) a 6 patients treated with high-dose MTX also received Ara-C as consolidation; 5 after 5 cycles, 1 after only 4 cycles of MTX. b 1 patient had near-cr with 6 cycles MTX alone but achieved CR after consolidation with Ara-C. c 1 patient had near-cr with 4 cycles MTX alone but achieved CR after consolidation with Ara-C. Abbreviations: CR, complete recovery; PR, partial recovery; MTX, methotrexate; PCV, procarbazine, lomustine, and vincristine; RT, radiotherapy. Ara-C, but she continued to deteriorate clinically and was eventually transferred to a nursing home. Two patients were treated with a combination of R and temozolomide (TMZ): 1 for primary refractory after 5 cycles of MTX and another at recurrence; 1 patient received TMZ alone at recurrence. All 4 of these patients failed to respond to salvage treatment. One patient who developed ocular and intracranial at recurrence achieved a second CR with ocular radiation followed by 7 cycles of R, MTX, and procarbazine. No patient received WBRT for salvage therapy. Outcomes Fifteen patients in this series (62.5%) had a response to initial treatment: 14 CR and 1 partial response (PR) (Table 2). Of the 22 patients treated with MTX-based chemotherapy, 11 (50%) experienced CR with MVP alone. Two patients had near CR following MVP but required consolidation with Ara-C before they achieved CR. One patient with isolated ocular achieved CR with radiation alone. The single patient with PR was lost to follow-up before additional imaging could be obtained. Eight patients treated with MVP (36%) had refractory. The patient treated with PCV had a rapid clinical decline after only 1 cycle and opted to forgo further therapy. Median PFS for the entire cohort was 6.5 months (95% CI: 4.4 29.5). Six patients (25%) were alive at the study s end, 4 without recurrence. Fifteen patients died: 12 from PCNSL, 1 from pulmonary toxicity during MVP treatment, 1 from heart failure after a prolonged period in remission, and 1 from respiratory failure owing to either pneumonia or pulmonary embolism during salvage with R-TMZ. Three patients were lost to follow-up. The median OS for the entire cohort was 7.9 months (95% CI: 5.8 53) (Fig. 1). One-year survival rate from diagnosis was 42%, 2-year survival was 33%, and 3-year survival was 17%. Three patients (12.5%) lived more than 4 years postdiagnosis. Median follow-up for survivors was 15 months. Among patients with CR (n ¼ 14), KPS improved by 20 points, from a median baseline of 60 (40 80) to a median of 80 (60 100). Those who did not achieve CR (n ¼ 10) made no gains in performance status; their median KPS remained 50 (range 30 70). Age, the absence of deep brain involvement, completion of 5 cycles of MTX, and initial CR by MRI or CT were found to be the only significant predictors of OS in the univariate analysis (Table 3). In the multivariate model, only CR status and deep brain involvement achieved statistical significance, with adjusted hazard ratios of 0.2 and 3.3, respectively. Toxicity The majority of patients (n ¼ 14; 58%) tolerated therapy well. During MTX-based treatment, 10 patients experienced a grade III or IV toxicity, primarily bone marrow suppression or infection (Table 4). One patient experienced fatal respiratory failure (grade V dyspnea/hypoxia) from either a pulmonary embolism or pneumonia. Two had exacerbations of baseline congestive heart failure likely related to hydration required for MTX. One patient had a cardiac arrest likely unrelated to treatment; he made a full recovery and died cancer free more than 4 years later of heart failure. While several patients had transient, grade II elevations in creatinine, only 2 dosage reductions of MTX took place for this reason. Time spent hospitalized from date of diagnosis until death or last follow-up was available for 22 patients (Fig. 2 and Appendix). Three received additional care at institutions other than MSKCC, making an accurate Fig. 1. Overall and progression-free survival in oldest PCNSL patients. NEURO-ONCOLOGY OCTOBER 2012 1307

Table 3. Predictors of survival for the oldest PCNSL patients Variable No. (%) of Patients Unadjusted HR (95% CI) P Adjusted HR (95% CI) P Age (continuous variable) 1.2 (1.0 1.4) 0.04 1.1 (0.9 1.3) 0.3 Male gender 8 (33) 0.7 (0.3 2.0) 0.6 Diagnosis after 2002 17 (71) 1.0 (0.3 2.8) 0.92 Pretreatment KPS 70 6 (25) 0.7 (0.2 2.4) 0.6 Symptom duration 1 month 16 (67) 0.5 (0.2 1.4) 0.2 Deep brain involvement 12 (50) 4.1 (1.4 12) 0.01 3.3 (1.0 10.8) 0.05 Hemiparesis 6 (25) 0.6 (0.2 2.0) 0.4 Altered mental status 15 (62.5) 2.4 (0.8 7.4) 0.13 Hemoglobin, 10 3 (12.5) 1.3 (0.4 4.5) 0.7 Creatinine,50 ml/min 7 (30) 1.9 (0.7 5.2) 0.2 Completed 5 cycles of MTX 14 (58.3) 0.3 (0.1 0.8) 0.02 0.6 (0.17 2.1) 0.4 Achieved CR 14 (61) 0.1 (0.04 0.4) 0.00 0.3 (0.07 0.9) 0.04 Significant P values are bolded. Abbreviations: HR, hazard ratio; CI, confidence interval; KPS, Karnofsky performance status; MTX, methotrexate; CR, complete recovery. assessment of complete inpatient time unobtainable. Among those who were treated solely at MSKCC, the median time spent hospitalized was 42.5 days (range, 2 133). Upon completion of initial course of treatment, 17/24 patients (71%) returned home, 1 died of respiratory failure in the intensive care unit after only 1 cycle of MVP, and the remaining 6 were discharged to hospice or a nursing home. Table 4. MVP-related grade III V toxicities in the oldest PCNSL patients, n ¼ 22 patients (%) Grade III Grade IV Grade V Leukopenia 5 (23) 2 (9) Anemia 3 (14) Infection 3 (14) 1 (4.5) Thrombocytopenia 1 (4.5) Thrombosis 1 (4.5) Cardiac 2 (9) Fatigue 1 (4.5) Respiratory failure 1 (4.5) 1 (4.5) Fig. 2. Time spent hospitalized as percent of survival of the oldest PCNSL patients. Discussion The current study demonstrates that treatment with MTX-based regimens is effective and safe among the oldest PCNSL patients and may result in prolonged survival, particularly for those patients who responded after 5 cycles of induction therapy. By study s end, at least 20% of patients had lived more than 30 months from diagnosis, a benchmark typically seen with much younger cohorts. 4,5,17,18 Moreover, as of December 31, 2011, 6 patients (25%) were still alive, with a median follow-up of 15 months. Median OS for the entire cohort was 7.9 months, a value that compares favorably with a median of 7.6 months achieved with WBRT alone for younger patients aged 60 years. 19,20 However, it is substantially less than the 37- to 51-month median survival seen in larger cohorts of all patients treated with a comparable regimen. 11,18,20 Although age dropped out as a significant prognostic factor in our multivariate analysis, this was likely a consequence of the small number of patients. It is noteworthy that only 1 of the 5 patients aged 85 years or older survived more than 1 year, and all 8 patients who survived almost 2 years or longer were aged 80 84 at diagnosis. Despite their advanced age, most of our patients tolerated therapy well. No one developed higher than a grade II nephrotoxicity, and there were only 2 MTX dosage reductions for a transient rise in creatinine. Only 1 patient developed a dose-limiting peripheral neuropathy related to vincristine. In contrast, myelotoxicity was more common in this elderly population, a finding consistent with previous work in geriatric oncology that demonstrated an inverse association between aging and bone marrow reserve. 15,21,22 All patients who initiated treatment at our institution received a combination regimen that included vincristine and procarbazine. The only patient to receive single-agent MTX was treated elsewhere, highlighting important differences in clinical practice and a lack of consensus on the best approach to therapy. While some investigators 1308 NEURO-ONCOLOGY OCTOBER 2012

have questioned the use of multidrug combinations, postulating that they offer limited survival benefit at the cost of added toxicity, studies using single-agent MTX show poor PFS, and a recent randomized phase II trial strongly 23 26 indicates the benefit of combination therapy. A majority of patients (71%) were treated after 2002, yet no one diagnosed prior to this time received WBRT. As the delayed neurocognitive effects of radiation were not fully recognized until the late 1990s, this finding is somewhat unusual and likely reflects MSKCC s more 27 29 vigorous use of MTX. The overall increase in number of octogenarians treated since 2002 also reflects increasing physician comfort with evaluating intracranial masses in the elderly and a growing commitment to their vigorous diagnosis and treatment. Alternative explanations for the upsurge include a change in referral patterns, demographic shifts, and greater awareness of the potential benefits of chemotherapy for PCNSL. There is a growing appreciation for the importance of quality of life in addition to survival, particularly among the elderly. 30 An additional 8 months of life may make chemotherapy worthwhile to many octogenarians, but perhaps less so if much of that time is spent hospitalized. This study is the first to focus exclusively on the oldest PCNSL patients. It is also unique in its reporting of quality-of-life surrogates such as days spent hospitalized and discharge destination. The majority (71%) of patients were able to return home after initial treatment, particularly those who were able to complete all 5 cycles of MTX. While this finding may reflect improved social support among patients who seek and obtain aggressive therapy, it could also be considered predictive of improved clinical outcome. Taken together with our multivariate analysis that identified initial response as a predictor of OS, we might conclude that achieving an objective response after 5 cycles of induction chemotherapy is predictive not only of longer life but also of clinical benefit and improved function. The current study has several limitations. First, there may be significant referral bias among patients treated at MSKCC, as it is less likely that the most debilitated elderly would be sent to a tertiary care center. Second, the retrospective nature of this study means that relevant patient characteristics such as nutritional status, comorbidities, polypharmacy, precise steroid dosing, detailed neurocognitive evaluations, and geriatric assessments were unavailable. Third, the relatively small sample size limited our power to detect potentially important associations between patient characteristics and clinical outcomes of interest. Despite these and other limitations, this is the largest study of patients aged 80 years or older treated for PCNSL. It suggests that many of these patients can tolerate a high-dose MTX-based regimen, and every elderly patient with PCNSL should be evaluated for full-dose chemotherapy. Those who achieve a response by cycle 5 can have substantial benefits in terms of survival and performance status. In contrast, octogenarians who do not respond to induction therapy are unlikely to improve and may be unnecessarily subjected to lengthy hospitalizations and added toxicities with continued treatment. Acknowledgments These data were previously presented as a poster at the 2011 Society of Neuro-Oncology annual meeting. Conflict of interest statement. None reported. References 1. Olson JE, Janney CA, Rao RD, et al. The continuing increase in the incidence of primary central nervous system non-hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer. 2002;95(7):1504 1510. 2. CBTRUS (2010). CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006. Hinsdale, IL: Central Brain Tumor Registry of the United States. www.cbtrus.org. 3. Panageas KS, Elkin EB, Ben-Porat L, Deangelis LM, Abrey LE. Patterns of treatment in older adults with primary central nervous system lymphoma. Cancer. 2007;110(6):1338 1344. 4. Ney DE, Reiner AS, Panageas KS, Brown HS, DeAngelis LM, Abrey LE. Characteristics and outcomes of elderly patients with primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Cancer. 2010;116(19):4605 4612. 5. Zhu JJ, Gerstner ER, Engler DA, et al. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009;11(2):211 215. 6. United States Census Bureau. Age and Sex Composition: 2010. Census Briefs. Hinsdale, IL. May 2011. www.census.gov/prod/cen2010/briefs/ c2010br-03.pdf. 7. Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21(2):266 272. 8. 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. 2006;24(36):5711 5715. 9. Thiel E, Korfel A, Martus P, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010;11(11):1036 1047. 10. Correa DD, DeAngelis LM, Shi W, Thaler H, Glass A, Abrey LE. Cognitive functions in survivors of primary central nervous system lymphoma. Neurology. 2004;62(4):548 555. 11. Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2006;24(28):4570 4574. 12. Freilich RJ, Delattre JY, Monjour A, DeAngelis LM. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology. 1996;46(2):435 439. NEURO-ONCOLOGY OCTOBER 2012 1309

13. Hoang-Xuan K, Taillandier L, Chinot O, et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003;21(14):2726 2731. 14. Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K. Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neurooncol. 2007;85(2):207 211. 15. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457 3465. 16. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA. 1999;281(18):1714 1717. 17. Batchelor T, Carson K, O Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96 07. J Clin Oncol. 2003;21(6):1044 1049. 18. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93 10. J Clin Oncol. 2002;20(24):4643 4648. 19. Nelson DF, Martz KL, Bonner H, et al. Non-Hodgkin s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys. 1992;23(1):9 17. 20. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18(17):3144 3150. 21. Dees EC, O Reilly S, Goodman SN, et al. A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest. 2000;18(6):521 529. 22. Gomez H, Hidalgo M, Casanova L, et al. Risk factors for treatment-related death in elderly patients with aggressive non-hodgkin s lymphoma: results of a multivariate analysis. J Clin Oncol. 1998;16(6):2065 2069. 23. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol. 1998;16(3):859 863. 24. Herrlinger U, Kuker W, Uhl M, et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005;57(6):843 847. 25. O Brien PC, Roos DE, Pratt G, et al. Combined-modality therapy for primary central nervous system lymphoma: long-term data from a phase II multicenter study (Trans-Tasman Radiation Oncology Group). Int J Radiat Oncol Biol Phys. 2006;64(2):408 413. 26. Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus highdose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512 1520. 27. Omuro AM, Ben-Porat LS, Panageas KS, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol. 2005;62(10):1595 1600. 28. Correa DD, Rocco-Donovan M, DeAngelis LM, et al. Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. J Neurooncol. 2009;91(3):315 321. 29. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25(30):4730 4735. 30. Lichtman SM. Guidelines for the treatment of elderly cancer patients. Cancer Control. 2003;10(6):445 453. Appendix Summary of treatment, response, toxicity, and discharge destination among 24 patients with PCNSL diagnosed at age 80 y. Pt. Age Initial Treatment Best Response Grade III/IV Toxicities 1 89 4 cycles MVP, IO M spinal RT Refractory Hospitalization Days/ % OS Discharge OS (mos) Cause of Death 67/35 Home 6.3 PCNSL 2 82 5 cycles MVP CR 65/27 Home 7.9 PCNSL 3 80 6 cycles MVP, IO M CR after Ara-C Incomplete data Home 62.3 LTF 2 4 81 900 cgy of focal RT at OSH, 4 cycles MVP, IO M 2 5 84 1 cycle PCV Refractory CR after Ara-C 110/40 Nursing home 2/2 Nursing home 8.9 PCNSL 3.4 PCNSL 6 82 5 cycles MVP CR Grade III leukopenia 133/8 Home 58.6 PCNSL Grade III anemia 7 80 2 cycles MVP Refractory 43/30 Home 4.8 PCNSL 8 80 7 cycles MVP CR 84/40 Home 6.8 PE v. PNA 9 84 7 cycles MVP CR 52/3 Home 53.0 Heart failure 10 81 3 cycles MVP PR then LTF Grade III anemia Incomplete data Home 25.3 LTF Grade IV neutropenia 11 81 5 cycles M, IO M Refractory Incomplete data Home 4.7 PCNSL Continued 1310 NEURO-ONCOLOGY OCTOBER 2012

Continued Pt. Age Initial Treatment Best Response Grade III/IV Toxicities Hospitalization Days/ %OS 12 83 5 cycles MVP Refractory ; MRI showed partial response, but clinically deteriorated before 13 82 5 cycles MVP Refractory 14 80 5 cycles R-MVP 2 15 82 1 cycle MVP Refractory Discharge OS (mos) Cause of Death Grade III anemia 131/50 Hospice 9.0 PCNSL Grade III neutropenia Grade III lymphopenia Grade III opportunistic infection Grade III hypoxia Grade III congestive heart failure 39/17 Home 7.9 PCNSL CR after MTX 32/2 Home 48.3 Alive Grade IV febrile neutropenia Grade IV thrombocytopenia Grade IV dyspnea 18/100 Died in ICU 0.6 Toxicity 16 80 7 cycles MVP, 2 CR after MTX 36/3 Home 35.0 Alive 17 80 5 cycles MVP, 2 CR after MTX 57/6 Home 31.4 Alive 18 82 Ocular RT only CR 0/0 Home 26.3 Alive 19 90 5 cycles MP CR Grade III neutropenia 71/41 Nursing 5.8 LTF Grade III congestive heart failure home 20 87 2 cycles R-MVP Refractory 21/22 Hospice 3.2 PCNSL 21 80 7 cycles MVP CR 27/4 Home 23.2 Alive 22 86 5 cycles MVP, 2 CR after MTX Grade III leukopenia 27/5 Home 17.2 Alive 23 81 3 cycles MVP, IO M Refractory Grade III device related infection 42/37 Hospice 3.8 PCNSL 24 85 5 cycles R-MVP CR Grade III hypokalemia 59/26 Home 7.6 PCNSL Grade III thrombosis Grade III fatigue Grade III device related infection Abbreviations: M, methotrexate; V, vincristine; P, procarbazine; IO, intra-ommaya; Ara-C, cytarabine; TMZ, temozolomide, R, rituximab; RT, radiation therapy; CR, complete response; PR, partial response; PE, pulmonary embolus; PNA, pneumonia; LTF, lost to follow-up. a Patient s initial MRI demonstrated PR; a follow-up scan noted CR, but this could not be confirmed because patient was LTF. NEURO-ONCOLOGY OCTOBER 2012 1311