Neuro-Oncology Practice

Neuro-Oncology Practice Neuro-Oncology Practice 3(2), 71 76, 2016 doi:10.1093/nop/npv043 Advance Access date 16 October 2015 Anaplastic astrocytoma and non-1p/19q co-deleted anaplastic oligoastrocytoma: long-term survival, employment, and performance status of survivors Elena I. Pentsova, Anne S. Reiner, Katherine S. Panageas, and Lisa M. DeAngelis Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY (E.I.P., L.M.D.); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY (A.S.R., K.S.P.) Corresponding Author: Elena I. Pentsova, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065 (pentsove@mskcc.org). Background. Despite optimal treatment for patients with anaplastic gliomas, median survival is 2 to 5 years, but some young adults survive longer. We sought to evaluate the functional and employment status of long-term survivors (5 years or more) diagnosed with anaplastic astrocytoma or non-1p/19q co-deleted anaplastic oligoastrocytoma. Methods. We retrospectively identified patients with a diagnosis of anaplastic glioma at Memorial Sloan Kettering Cancer Center from 1999 to 2005. We reviewed demographics, pathology, 1p/19q status, survival, and treatment. Overall survival was estimated by the Kaplan-Meier method. Results. There were 195 patients; 167 with anaplastic astrocytoma and 28 with anaplastic oligoastrocytoma. All patients were observed either to death or last follow-up. Sixty-four patients (33%) were identified as long-term survivors; 58% of these were men. The median age of the long-term survivors was 39 years and the median Karnofsky Performance Score was 100 at diagnosis. Thirteen patients underwent stereotactic biopsy, 7 had a gross total resection, and 44 a subtotal resection. Fifty-four patients completed radiation therapy as initial treatment; 54 received chemotherapy. Five years following diagnosis, median KPS was 90 and 55% of longterm survivors were employed and remained fully functional. Conclusions. One-third of patients with non-co-deleted anaplastic glioma were long-term survivors, and more than one-half of longterm survivors resumed their prior level of employment and activity. However, a significant proportion could not return to normal function. These findings have serious implications for the social and financial status of these predominantly young adult survivors. Keywords: Anaplastic astrocytoma, anaplastic oligoastrocytoma, employment. Anaplastic glioma (AG) has an annual incidence of approximately 5 per 100 000 people and accounts for only 6.8% of all primary brain tumors. 1 These aggressive gliomas often affect young adults in the prime of life causing significant disability as well as death. Despite optimal therapy, long-term survival of 5 or more years is inversely related to age and has been reported in 48% of patients age 20 to 44 years, 29% of those age 45 to 54 years, and 9% of those age 55 to 64 years. 2,3 The standard treatment for AG remains controversial, but typically includes radiotherapy and chemotherapy, 4,5 similar to treatment for glioblastoma. 6 8 Long-term survivors of malignant glioma, particularly glioblastoma, usually have significant cognitive impairment and neurological deficits attributed to the disease and treatment. 9,10 The functional and employment status of the adult AG survivor is unknown, but is more important given the greater potential for long-term survival. We sought to identify long-term survivors of an AG to assess the late consequences, performance status, and employment status of these survivors. Patients and Methods We retrospectively identified patients 18 years or older who were diagnosed with AG at Memorial Sloan Kettering Cancer Center (MSKCC) between January 1, 1999 and November 31, 2005. This study was approved by the MSKCC Institutional Review Board. All patients were identified through the institutional and Department of Neurology databases available at our institution. We included patients with histologically confirmed anaplastic astrocytoma (AA) and those with anaplastic oligoastrocytomas (AOA) who had 1p/19q intact, 1p intact and 19p not tested, and AOA with unknown 1p/19q status. Patients with AOA known to be 1p/19q co-deleted and anaplastic oligodendrogliomas Received 12 May 2015, Advance Access publication 16 October 2015 # The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 71

were excluded. Patients with pre-existing low-grade gliomas were included only if anaplastic transformation was confirmed by histological diagnosis; the date of pathologic demonstration of anaplasia was considered the date of AG diagnosis. Pathology for all cases was reviewed at MSKCC. Initial treatment of eligible patients included surgery, radiation therapy with or without chemotherapy, or chemotherapy alone. Follow-up extended through August 31, 2012. Statistics Overall survival was calculated from date of AG diagnosis until date of death or last follow-up. Survival was estimated by the Kaplan-Meier method and comparisons between groups were made using the log-rank test. To investigate the association between variables of interest and employment status at 5 years, logistic regression models were used in which being employed at 5 years was the outcome, with adjustment for baseline employment status. Variables of interest were separately modeled and included sex, age at diagnosis, histology, Karnofsky Performance Score (KPS), and tumor location. Analyses were done in SAS version 9.2 (Cary, NC). Study Design For the purpose of this study, long-term survivors were defined as those with AG who lived more than 5 years from the time of tissue diagnosis. As per inclusion criteria, all patients were evaluated in our institution and had follow-up either by clinic visits or through a medical-record review for 5 years or more. We sought to assess their performance and employment status 5 years+6 months from diagnosis. Employment data were collected from chart reviews and by interviewing the patients primary neurooncologists. Data on cognitive status were collected from patient s/caregiver s reports at the visit, from neurologic examinations, and from Mini-Mental State Examinations if performed; we also used any available neurocognitive evaluations although these were rare. If a patient had hemiparesis that significantly affected his or her mobility, was wheelchair bound and unable to perform activities of daily living, was significantly aphasic, had a prominent visual deficit, or had severe gait abnormalities, then the patient was considered to have a severe neurologic deficit. Patients with poor memory, poor judgment, and requiring significant assistance to write checks or shop, or patients with frequent, uncontrolled seizures on multiple antiepileptic medications reporting difficulty with memory and concentration were considered to have severe cognitive impairment. If a patient was a full-time homemaker when AG was diagnosed and returned to that activity, it was considered equivalent to returning to full-time employment. If a patient was retired at the time of AG diagnosis and developed neurologic or cognitive impairment, it was considered equivalent to being unemployed. For a patient who was unable to return to work after diagnosis or went on disability, his or her employment status changed to disability. Results Patient Characteristics A total of 207 patients with an AG were seen at MSKCC in this time interval. Twelve patients were seen as a second opinion only and were excluded from our analysis. The remaining 195 patients were observed either to their death or last follow-up (Table 1). One hundred eleven patients (57%) were men. Median age at diagnosis was 42 years (range, 19-79 years); 167 patients (86%) were diagnosed with AA, and 28 (14%) with AOA, 14 of whom had an unknown 1p/19q status. Pre-existing low-grade glioma was present in 28 patients (14%). The frontal lobe was invaded by tumor in 91 patients (47%). At diagnosis the median KPS was 90 (range, 30-100). Subtotal resection was performed in 124 patients (64%), gross total resection in 10 (5%), and biopsy only in 61 (31%). One hundred sixty-three patients (84%) received radiation therapy and 151 (77%) received chemotherapy as initial treatment. Higher KPS (P,.0001), younger age at diagnosis (P ¼.0005) and extent of surgical resection (P,.0001) were prognostic factors in predicting longer survival. Median overall survival of the entire cohort was 2.5 years (95% CI, 2.0-3.5) from AG diagnosis and median follow-up for survivors was 7.8 years (Fig. 1). At the last follow-up, 153 patients were dead and 42 were alive. Long-term Survivors Sixty-four patients (33%) were long-term survivors. Median age at diagnosis was 39 years (range, 22-72 years); 5% of patients were 65 years or older. Thirty-seven (58%) patients were men. Fifty-two (81%) were diagnosed with an AA, and 12 (19%) had AOA; 4 of the AOAs had intact 1p/19q, 1 had intact 1p, and 1p/19q was not tested in 7. Pre-existing low-grade glioma was seen in 9 patients (14%). At diagnosis, median KPS was 100. After adjusting for employment at baseline, those with higher KPS (P ¼.04) at diagnosis and women (P ¼.01) were more likely to be employed at 5 years. The variables of age at diagnosis, histology (AOA vs AA), or tumor location (frontal vs other) were not associated with statistically significant differences in employment status among long-term survivors. Median survival of the long-term survivors was 9.7 years (95% CI, 7.5-no upper limit) from diagnosis. Thirty-seven patients (58%) had tumor progression; in 23 patients tumor recurred within 5 years. At last follow-up 34 (53%) patients were alive. Initial Treatment for Long-term Survivors Forty-four patients (69%) underwent subtotal resection, 7 (11%) had gross total resection, and 13 (20%) had biopsy only. Fifty-four patients (84%) received radiation therapy, 7 did not, and no information was available for 3. Fifty-four patients (84%) received chemotherapy: 31 temozolomide; 9 carmustine; 6 procarbazine, lomustine and vincristine; 5 carmustine and temozolomide in a clinical trial; 1 temozolomide and carboplatin; 1 lomustine and temozolomide; and 1 poly-iclc; 5 did not receive chemotherapy and 5 had no information. Employment Status and Functional Assessment for Long-term Survivors At diagnosis, 53 long-term survivors (83%) were employed full time; 37 were professionals, 10 were white-collar employees, and 6 were blue-collar employees. Eight patients (13%) were unemployed; 3 retired before their brain tumor diagnosis and the remaining 5 had frequent seizures, aphasia, or hemiparesis that prevented them from doing their jobs (Table 2). No information 72 Neuro-Oncology Practice

Table 1. Patient characteristics All 5 y OS a 95% CI a Log-rank P Value b LTS c (n ¼ 195) (%) (%) (n ¼ 64) Sex Male 111 (57%) 35 26.1 44.1.53 37 (58%) Female 84 (43%) 36 25.7 46.8 27 (42%) Age Median 42 y.0005 39 y Range 19 79 y 22 72 Histology AA 167 (86%) 46 27.3 64.6.31 52 (81%) AOA 28 (14%) 34 26.4 41.1 12 (19%) Location Frontal lobe 91 (47%) 36 25.9 46.0 30 (47%) Temporal lobe 38 (19%) 28 14.0 43.0 10 (16%) Parietal lobe 23 (12%) 33 13.1 52.5.95 7 (11%).2 lobes 33 (17%) 42 24.5 58.6 13 (20%) Brainstem/occipital 10 (6%) 47 14.2 79.2 4 (6%) Extent of resection Biopsy 61 (31%) 21 11.0 31.6 13 (20%) Subtotal resection 124 (64%) 38 29.1 46.5,.0001 44 (69%) Total resection 10 (5%) d d 7 (11%) Initial KPS 80 100 141 (72%) 46 37.5 54.2 61 (95%) 70 41 (21%) 8 0 16.7,.0001 3 (5%) Unknown 13 (7%) Radiation therapy for AG e Yes 163 (84%) 54 (84%) No 10 (5%) 7 (11%) Unknown 22 (11%) 3 (5%) Chemotherapy for AG e Temozolomide 93 (48%) 31 (48%) Other chemotherapy 58 (29%) 23 (36%) No 17 (9%) 5 (8%) Unknown 27 (14%) 5 (8%) Abbreviations: LTS, long-term survivor ( 5 years); AA, anaplastic astrocytoma; AOA, anaplastic oligoastrocytoma; KPS, Karnofsky Performance Score; AG, anaplastic glioma; OS, overall survival; CI, confidence interval. a This is the Kaplan-Meier estimate and corresponding 95% CI for the percentage of patients from the entire cohort (n ¼ 195) who survived 5 or more years in the specified category. b P value is for the comparison of the survival curves of the specified categories. c This column presents the 64 patients who survived 5 or more years and their distribution across the specified categories. d No events before 5 years. e Dates of receipt for radiation therapy and chemotherapy were not available, therefore no time-dependent results could be provided for these 2 variables. on employment status was available for 3 patients. Fifty-six patients (88%) had a normal neurologic exam, 6 (9%) had mild neurologic or cognitive impairment, and 2 (3%) had severe neurologic deficit. Fifty-six patients had information on employment status at both time points and 57 had information on their functional status (Table 3). Only 34 patients (61% of previously employed patients) remained employed full or part-time at 5 or more years from diagnosis; 2 of these patients reported some degree of cognitive problems and 5 had mild neurological impairment. Seven employed patients at the 5-year mark had disease progression but were able to maintain their employment. Only 5 out of 9 patients with pre-existing low-grade glioma were able to maintain their employment. The remainder of the 15 previously employed patients were not able to maintain their employment. One (2%) previously unemployed patient was able to find a job and remained employed 5 years from diagnosis. Six (11%) remained unemployed (Table 3). Among patients with known functional status at baseline and 5 years later, 29 patients (51%) had either maintained or improved to normal function 5 years later. Overall functional impairment, either neurologic or cognitive, was observed in 28 long-term survivors at the 5-year mark (Table 3). Neuro-Oncology Practice 73

Discussion This cohort of AG patients had a fairly typical median overall survival of only 2.5 years. However, more than 30% of patients were long-term survivors. Using the classification scheme defined by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis, class I patients (age, 50 years old, normal mental status) have an estimated median survival of almost 5 years, 11 13 and most of our long-term survivors fit this profile. Our findings are similar to results of RTOG/ECOG (Eastern Cooperative Oncology Fig. 1. Kaplan Meyer estimates of overall survival (OS) for 195 patients with anaplastic gliomas (AG). Table 2. Employment status and functional assessment at baseline and 5 years in long-term survivors Group) studies reporting long-term survival rates of up to 35% for patients with AA who are treated with radiation therapy only. 14 Interestingly, the RTOG data showed that only 29% of patients treated with radiation therapy plus chemotherapy survived 5 years or more. The natural history of anaplastic oligodendrogliomas and co-deleted AGs is more protracted, with a longer time to disease progression than AG with intact 1p/19q. 15 Co-deleted AG responds better to treatment, and some patients receive less vigorous therapy at diagnosis. 16,17 Thus, we eliminated these patients in an effort to identify a cohort of patients with a similar natural history of disease and typical treatment pattern, which could have affected patients functional status at 5 years. The inclusion of the four AOA long-term survivors whose deletion status was not tested did not affect our findings so we retained them in our analyses. One of the goals of this study was to identify how survivors were affected by the diagnosis and treatment of AG, whether they remained active members of society, and whether they were able to maintain or return to work. The majority of studies on employment status describe problems in cancer survivors of breast or mixed cancer populations who had lost their jobs or quit working within 6 years of diagnosis. 18 Unemployment and early retirement become even more obvious issues for patients with brain tumors who already have localized brain damage and receive treatments directed to the brain lesion. Patients with primary brain tumors may experience greater levels of work limitations than survivors of other types of cancers or healthy adults. 19 Current literature on neurocognitive assessment in glioma patients suggests that patients with brain tumors may Variable Level Long-term Survivors Long-term Survivors with Known Status N % c N % c Employment Status at Baseline Yes 53 83 53 87 No 8 13 8 13 N/A 3 5 Employment Status at 5 y Yes 35 55 35 63 No 21 33 21 38 N/A 8 13 Functional Assessment at Baseline Normal 56 88 56 88 Mild deficit a 6 9 6 9 Severe deficit b 2 3 2 3 Functional Assessment at 5 y Normal 29 45 29 51 Mild deficit a 11 18 11 19 Severe deficit b 17 27 17 30 N/A 7 11 a Defined as: Mild neuro deficit and/or mild cognitive decline. b Defined as: Severe neurologic deficit and/or severe cognitive decline. If a patient had hemiparesis that significantly affected his or her mobility, was wheelchair bound and unable to perform activities of daily living, was significantly aphasic, had a prominent visual deficit, or had severe gait abnormalities, then the patient was considered to have a severe neurologic deficit. Patients with poor memory, poor judgment, and requiring significant assistance to write checks or shop, or patients with frequent, uncontrolled seizures on multiple antiepileptic medications reporting difficulty with memory and concentration were considered to have severe cognitive impairment. c Percentages may not add to 100 due to rounding. 74 Neuro-Oncology Practice

Table 3. Change in employment status and functional assessment from baseline to 5 years in long-term survivors Employment Status at Baseline a Employment Status N b ¼ 56 % e at 5 y a A. Employment at Baseline and 5 Y Yes Yes 34 61 Yes No 15 27 No Yes 1 2 No No 6 11 Functional Assessment at Baseline c Functional N d ¼ 57 % e Assessment at 5 y c B. Functional Assessment at Baseline and 5 Y Normal Normal 27 47 Normal Mild 10 18 Normal Severe 12 21 Mild Normal 2 4 Mild Mild 1 2 Mild Severe 3 5 Severe Severe 2 4 a Yes is defined as yes or homemaker. No is defined as no or disabled or retired. b Only included patients with known information at both time points. c Where mild is mild neurologic deficit and/or mild cognitive decline. Severe is severe neurologic deficit and/or severe cognitive decline. d Only included patients with known information at both time points. e Percentages may not add to 100 due to rounding. experience a decrease in nonverbal recall and some aspects of executive function related to duration of disease and treatment with radiation and chemotherapy, which could affect their employment status. 20,21 The majority of our long-term survivors had an excellent overall performance status with a median KPS of 100 at diagnosis. However, for this cohort of young adults, only 55% of previously employed patients were employed 5 years or more from diagnosis. Of those employed at diagnosis with known employment status at baseline and 5 years, 34 (61%) retained their employment across a broad range of employment activities, including those who returned to professional activities. We were unable to assess whether patients in all types of industries were able to perform at the same level 5 years later, or received special accommodations or flexible working hours from their employer. Interestingly, 7 patients employed at the 5-year mark, or their caregivers, reported some degree of cognitive problems, especially with short-term memory and neurologic impairment. This raises an important concern as to whether the patients returned to work with limitations or at reduced level. Fifteen (27%) previously employed patients suffered from further disease progression and prominent neurologic deterioration and were not employed 5 years from diagnosis, almost certainly because they were unable to work. Forty-four percent of longterm survivors with known functional status at baseline and at 5 years had functional and neurologic decline, making any employment impossible. Previous studies have focused on quality-of-life and neurocognitive status in cancer survivors. 22 The majority of such studies have been limited by either a small number of patients, short follow-up of 12 months, or patients who predominantly had diagnoses of glioblastoma. 21,23 High quality-of-life scores at diagnosis are associated with improved survival. Progressive memory loss and cognitive decline in long-term survivors with high-grade gliomas have been attributed to chemoradiotherapy. 9,24 However, no prior study has examined the long-term employability of survivors. Patients have also described being overwhelmed with the diagnosis and have experienced depression, fatigue, and emotional distress, with depression being the single-most-important independent predictor of quality of life. 25 27 Evaluations of cognitive domains, quality of life, and neuropsychiatric symptoms are necessary to identify treatable causes of disability in long-term survivors, but the effect of these variables on employment and whether treatment can improve employability are unknown. However, this is a critical issue for these predominantly young adults who often have significant familial financial responsibilities. This study had several limitations, particularly its retrospective nature. KPS and job description at diagnosis were reported in the majority of patients, but these were missing in a significant number of patients 5 years later. For patients who returned to employment, we could not assess whether or not they returned to work in a comparable position. Whether chemotherapy or radiotherapy contributed to work-related problems 5 years from diagnosis was unclear because there were too few patients in each category. We attempted to assess employment status for all survivors; however, data points were missing. No quality-of-life or neuropsychological assessment was done prospectively. Despite those barriers, we found that 55% of long-term survivors were employed 5 years or more from diagnosis. The quality of that employment and the reasons why 45% remained unemployed are pressing issues. The ongoing prospective phase III CAT- NON study for patients with AG has been capturing data on quality of life and cognitive function using Mini-Mental State assessment tools. Developing evaluation tools to understand work-related problems in brain tumor patients is necessary. Unfortunately, the CAT- NON study will not be collecting employment status prospectively. Ideally, a work limitation questionnaire would be completed at diagnosis and prospectively on follow-up examinations to understand those factors associated with a greater likelihood employability. 28,29 A neurocognitive evaluation at diagnosis, at 6 months, at 12 months, and annually thereafter would facilitate development of cognitive and occupational rehabilitation programs for long-term survivors of a brain tumor, similar to those for patients with traumatic brain injury and breast cancer survivors. 30 Our findings expose a critical issue regarding functional capacity for young adults with AG or AOA. While many such patients can have productive lives after diagnosis and treatment, a significant proportion remains functionally compromised and unemployable.thishasseriousimplicationsforsurvivorshipofthis predominantly young adult population and warrants our attention with prospective study. Funding None declared. Acknowledgments We thank Judith Lampron for her editorial assistance. Neuro-Oncology Practice 75

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