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Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation?
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
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Clinical commentary
Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? Jacob Y. Shin ⇑, Ja Kyoung Yoon, Aidnag Z. Diaz Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, United States
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Article history: Received 27 January 2017 Accepted 10 July 2017 Available online xxxx Keywords: Gliosarcoma Elderly Adjuvant chemoradiation Survival
a b s t r a c t The objective of our study is to determine the impact of adjuvant chemoradiation on overall survival (OS) for gliosarcoma in septuagenarians and octogenarians. Data were extracted from the National Cancer Data Base (NCDB). Chi-square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 23.0 (Armonk, NY: IBM Corp.) for data analyses. 210 patients with gliosarcoma who underwent resection were identified. 168 (80.0%) patients received adjuvant chemoradiation, and 42 (20.0%) received adjuvant RT alone. Patients were more likely to receive adjuvant chemoradiation if they were male vs. female (85.3% vs. 71.6%, p = 0.016). There was no significant difference in receipt of adjuvant therapy by year of diagnosis, age at diagnosis, race, Charlson/Deyo Score, treatment facility type, tumor size, or extent of surgery. Those who received adjuvant chemoradiation had significantly better one-year OS than those who received adjuvant radiation alone (35.3% vs. 16.2%, p < 0.001). On subset analysis, this significant one-year OS benefit was observed in septuagenarians, those with Charlson/Deyo Score of 0, and in those with tumor size 5 cm. On multivariate analysis, receipt of adjuvant chemoradiation and greater extent of resection were independent prognostic factors for improved OS. Our data suggests that adjuvant chemoradiation is an independent prognostic factor for improved OS in elderly patients with gliosarcoma, and the results of our study can serve as estimated benchmarks for outcome in this growing and important patient population. Its benefit, however, may be limited to septuagenarians and those with lower comorbidity burden. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction In adults, glioblastoma (GBM) is the most common primary malignant brain tumor, and an estimated 12,120 new cases are predicted in the United States for 2016 [1]. The incidence rate in the United States is 3.2 per 100,000 population, and is highest among those aged 75–84 years [1]. The one-year relative survival rate is highest among those 20–44 years of age (67.6%), and lowest among those 75 years (11.0%) [1]. The World Health Organization classifies gliosarcoma as a variant of GBM in that they exhibit both glial and sarcomatous histologic and immunophenotypic elements [2–4], and it accounts for approximately 2–8% of all malignant gliomas [2,5,6]. Patients with the disease are more likely to be male, to have disease primarily located in the temporal lobe, and to have disease metastasis more so than GBM [5–10]. The prognosis for those with GBM is poor, and patients with gliosarcoma may have an even poorer outlook on survival ⇑ Corresponding author at: Department of Radiation Oncology, Rush University Medical Center, 500 S. Paulina St., Chicago, IL 60612, United states. E-mail address: [email protected] (J.Y. Shin).
[6,8,11,12]. The treatment regimen from the landmark Stupp trial, maximal safe tumor resection followed by adjuvant chemoradiation, has become the standard of care for those with GBM [13,14], and that treatment paradigm has been extrapolated for management of gliosarcoma. However, the patient population from the Stupp trial was limited to adult patients 70 years of age. More recently, preliminary results from NCT00482677 have demonstrated a significant survival benefit in those aged 65 years for those receiving hypofractionated radiotherapy with concomitant and adjuvant temozolomide compared to radiotherapy alone [15]. However, there is lack of data regarding the impact of adjuvant chemoradiation in the elderly gliosarcoma population, and, thus, its role remains uncertain. In the United States, the elderly population is expected to grow with increasing life expectancy [16], and thus, optimal care for the elderly has become a very important topic of research [15,17–19]. The objective of this hospital-based study is to determine the impact of adjuvant chemoradiation on overall survival to further understand the relationships between it and outcomes in elderly gliosarcoma patients.
http://dx.doi.org/10.1016/j.jocn.2017.07.002 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
2. Materials and methods 2.1. Patient population Data were extracted from the National Cancer Data Base (NCDB) which included hospital registry data collected from more than 1500 Commission on Cancer (CoC)-accredited facilities representing 70% of newly diagnosed cancer cases annually in the United States [20]. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data used in the study are derived from a deidentified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators. Our study population consists of 210 patients diagnosed with gliosarcoma (ICD-0-3 histology code 9442/3) diagnosed from 2004 to 2013. Patients younger than 70 years, whose primary or adjuvant treatment type were unknown, or who underwent treatment with palliative intent were excluded. Comorbidities as described by the Charlson/Deyo Score were defined by a weighted score derived from the sum of the scores for each of the comorbid conditions listed in the Charlson Comorbidity Score Mapping Table [21,22]. A score of 0 indicated no significant comorbid conditions and higher scores indicated greater comorbidity burden. Because of the small proportion of cases with a Charlson Comorbidity score exceeding 2, the NCDB has truncated the data to 0, 1, and 2 (greater than 1). Adjuvant therapy was defined as treatment following primary resection and was grouped as those either receiving radiotherapy (RT) alone or chemotherapy in addition to radiotherapy (chemoradiation). All patients underwent resection. All patients who received chemotherapy in our analysis received single-agent chemotherapy, presumably temozolomide (TMZ). RT included cases of external beam radiotherapy. Those who received RT had a prescription dose of at least 40 Gy. 2.2. Statistical analysis All data analyses were performed using SPSS 23.0 (Armonk, NY: IBM Corp.). Proportional distribution by adjuvant treatment including differences in demographic, socioeconomic, clinicopathologic, and treatment characteristics were compared using the Chi-square test. Kaplan-Meier estimates were used to analyze overall survival (OS) estimates with the comparison of rates among the groups performed using the two-tailed log-rank test. The OS endpoint was defined as time to death from the date of diagnosis of gliosarcoma. The 2013 subgroup was excluded from one-year OS calculation to allow for a minimum of one year of follow-up for data running through 2013. Cox regression univariate analysis was used to compute hazard ratios (HR) with 95% confidence intervals (CI) to identify independent prognostic factors for OS in multivariate analysis using a forwards selection variable selection process. A two-sided p-value < 0.05 was considered statistically significant. 3. Results 3.1. Patient and treatment characteristics The median age of the study population was 75 years (range: 70–89) (Table 1). 210 septuagenarians and octogenarians were diagnosed with gliosarcoma between 2004 and 2013. 175 (83.3%) were 70–79 years old and 35 (16.7%) were 80–89 years of age. There were 129 (61.4%) males and 81 (38.6%) females. 187 (89.0%) patients were White, 12 (5.7%) Black, 4 (1.9%) Hispanic,
and 3 (1.4%) Asians. 143 (68.1%) had a Charlson/Deyo Score of 0, 51 (24.3%) a score of 1, and 16 (7.6%) a score of 2. 123 (58.6%) patients were treated at a non-academic/research program, and 87 (41.4%) at an academic/research program. 113 (53.8%) had tumor size 5 cm, 57 (27.1%)>5 cm, and 40 (19.0%) unknown size. Of those with known extent of surgery, 49 (58.3%) underwent subtotal resection and 35 (41.7%) gross total resection. 168 (80.0%) patients received adjuvant chemoradiation, and 42 (20.0%) received adjuvant RT alone. Patients were more likely to receive adjuvant chemoradiation if they were male vs. female (85.3% vs. 71.6%, p = 0.016). There was no significant difference in receipt of adjuvant therapy by year of diagnosis, age at diagnosis, race, Charlson/Deyo Score, treatment facility type, tumor size, or extent of surgery. 3.2. Survival outcome The median follow-up for the entire patient cohort was 8.2 months (range: 1.8–65.0). One-year overall survival (OS) for the study population was 31.4% (Table 2). Patients diagnosed at age 70–79 years had significantly better one-year OS than those 80–89 years (34.2% vs. 17.0%, p = 0.030). There was also a significant difference in one-year OS between those undergoing subtotal resection versus total resection (18.8% vs. 29.2%, p = 0.048). Those who received adjuvant chemoradiation had significantly better one-year OS than those who received adjuvant radiation alone (35.3% vs. 16.2%, p < 0.001). On subset analysis, this significant one-year OS benefit was observed in septuagenarians (40.3% vs. 10.0%, p < 0.001) (Fig. 1a) but not in octogenarians (Fig. 1b), those with Charlson/Deyo Score of 0 (34.8% vs. 12.0%, p < 0.001), and in those with tumor size 5 cm (44.5% vs. 17.6%, p < 0.001). 3.3. Multivariate analysis On Cox regression multivariate analysis, adjuvant chemoradiation (Hazard ratio [HR]: 0.525; 95% confidence interval [CI]: 0.356–0.773; p = 0.001) remained an independent prognostic factor for better OS even after adjusting for age at diagnosis (HR: 1.026; 95% CI:0.991–1.063; p = 0.145) which fell out in multivariate analysis, and greater extent of resection (HR: 0.608; 95% CI: 0.409–0.905; p = 0.014) (Table 3). 4. Discussion Our study found adjuvant chemoradiation to be an independent prognostic factor for improved overall survival in elderly patients with gliosarcoma. However, our findings demonstrate that its benefit may be limited to septuagenarians, those with Charlson/Deyo score 0, and tumor size 5 cm. There was no significant difference in receipt of adjuvant chemoradiation by tumor size, extent of resection, or facility type. Maximal, safe tumor resection is the preferred primary treatment for high-grade gliomas, and the impact of extent of resection on outcome in GBM patients has been previously studied with a greater extent of resection demonstrating improved outcomes [23–25]. Indeed, our study on elderly gliosarcoma patients also demonstrated a significant one-year OS benefit for those receiving gross total resection compared to subtotal resection. However, in the pre-operative setting, discussion and evaluation regarding comorbidity and complication risks associated with surgery in this vulnerable population is certainly warranted. In a multiinstitutional retrospective study analyzing 40 GBM patients 80 years of age, 20% of patients suffered post-operative surgical issues and 30% had medical complications [26]. In another retrospective analysis on 319 patients 65 years of age who underwent
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Patient demographic, socioeconomic, clinicopathologic, and treatment characteristics stratified by adjuvant therapy.
Total Year of diagnosis 2004–2008 2009–2013 Age 70–79 years 80–89 years Gender Male Female Race White Black Hispanic Asian Other Unknown Charlson/Deyo Score 0 1 2 Facility Non-Academic/Research Program Academic/Research Program Tumor size 5 cm >5 cm Unknown Extent of surgery Subtotal resection Total resection Unknown a b
Overall
Adjuvant RTa
Adjuvant chemoRTb
210
42
168
103 107
21 (20.4%) 21 (19.6%)
82 (79.6%) 86 (80.4%)
175 35
34 (19.4%) 8 (22.9%)
141 (80.6%) 27 (77.1%)
129 81
19 (14.7%) 23 (28.4%)
110 (85.3%) 58 (71.6%)
187 12 4 3 1 3
37 (19.8%) 4 (33.3%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%)
150 (80.2%) 8 (66.7%) 4 (100.0%) 2 (66.7%) 1 (100.0%) 3 (100.0%)
143 51 16
28 (19.6%) 12 (23.5%) 2 (12.5%)
115 (80.4%) 39 (76.5%) 14 (87.5%)
123 87
26 (21.1%) 16 (18.4%)
97 (78.9%) 71 (81.6%)
113 57 40
19 (16.8%) 10 (17.5%) 13 (32.5%)
94 (83.2%) 47 (82.5%) 27 (67.5%)
49 35 126
9 (18.4%) 8 (22.9%) 25 (19.8%)
40 (81.6%) 27 (77.1%) 101 (80.2%)
Chi-square p-value p = 0.890
p = 0.643
p = 0.016
p = 0.455
p = 0.614
p = 0.624
p = 0.905
p = 0.614
Radiotherapy. Chemoradiation.
Table 2 Kaplan-Meier one-year overall survival stratified by adjuvant therapy.
Total Age at diagnosis 70–79 years 80–89 years Charlson/Deyo Score 0 1 2 Race Non-black Black Facility Non-Academic/Research Program Academic/Research Program Tumor size 5 cm >5 cm Extent of surgery Subtotal resection Total resection a b
Overall
Adjuvant RTa
Adjuvant chemoRTb
Log-rank p-value
31.4% (±3.5)
16.2% (±6.1)
35.3% (±4.0)
34.2% (±3.9) 17.0% (±6.9)
10.0% (±5.5) 42.9% (±18.7)
40.3% (±4.5) 8.9% (±6.0)
30.1% (±4.2) 31.9% (±7.0) 40.0% (±2.6)
12.0% (±6.5) 20.0% (±12.6) 50.0% (±35.4)
34.8% (±4.9) 35.4% (±8.2) 38.5% (±13.5)
32.4% (±3.6) 22.2% (±13.9)
18.2% (±6.7) –
35.9% (±4.1) 40.0% (±21.9)
30.2% (±4.5) 32.9% (±5.4)
21.7% (±8.6) 7.1% (±6.9)
32.7% (±5.2) 38.7% (±6.2)
39.9% (±4.9) 28.9% (±6.8)
17.6% (±9.2) 28.6% (±17.1)
44.5% (±5.5) 28.9% (±7.4)
18.8% (±6.9) 29.2% (±9.3)
14.3% (±13.2) –
29.4% (±11.1) 31.6% (±10.7)
p < 0.001 p = 0.030 p < 0.001 p = 0.533 p = 0.942 p < 0.001 p = 0.158 p = 0.802 p = 0.293 p < 0.001 – p = 0.508 p = 0.075 p < 0.001 p = 0.681 p < 0.001 p = 0.263 p = 0.048 p = 0.023 –
Radiotherapy. Chemoradiation.
resection, 21.9% of patients experienced post-operative complications with 7.7% being neurologic [27]. The role of adjuvant RT in high-grade glioma has been previously examined in prior studies, and the literature suggests that adjuvant therapy following surgery can be considered for appropriate, elderly patients. In the elderly patient population, adjuvant RT
has been associated with an improved median OS when compared with tumor resection alone [26,28–31]. In a study on GBM patients aged 70 years, 85 patients were randomly assigned to receive supportive care or supportive care plus RT, and those receiving RT had significantly improved OS (29.1 vs. 16.9 weeks, p = 0.002) without significantly reducing the quality of life or cognition over
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. a) Kaplan-Meier overall survival among septuagenarians (p < 0.001); b) Kaplan-Meier overall survival among octogenarians (p = 0.533).
Table 3 Cox regression multivariate analysis for overall survival.
a b c
Prognostic factor
Hazard ratio
95% Confidence interval
p-value
Adjuvant treatmenta Age at diagnosisb Extent of resectionc
0.525 1.026 0.608
0.356–0.773 0.991–1.063 0.409–0.905
p = 0.001 p = 0.145 p = 0.014
Adjuvant RT vs. adjuvant chemoRT. Continuous. Subtotal resection vs. Total resection + unknown.
time [28]. In a Surveillance, Epidemiology, and End Results (SEER) analysis on 2836 GBM patients older than 70, those undergoing resection alone had a median OS of 3 months compared to resection followed by adjuvant RT with a median survival of 8 months (p < 0.001) [31]. Multivariate analysis also demonstrated adjuvant RT to be significantly correlated with an improved disease-specific survival (HR: 0.43, p < 0.05). Given the limited patient population numbers with gliosarcoma, no randomized control trials exist investigating adjuvant RT in those specifically with the histology, and prior studies investigating the role of adjuvant RT in these patients have been limited to case series [4–6,8,9,11,12]. In untreated patients with gliosarcoma, the median survival is dismal at only 4 months [7]. In treated gliosarcoma patients, the reported median survival has ranged between 6 and 12 months [4–6,8,9]. Meis et al., showed that the median survival for 26 gliosarcoma patients undergoing adjuvant RT (dose range: 45–81.6 Gy) was 8.3 months, with most receiving chemotherapy [4]. Lutterbach et al., showed that the median survival was 11.5 months in a single-institutional study on 12 gliosarcoma patients diagnosed between 1980 and 1999, with median tumor size 4.5 cm (range: 3–8 cm), and who received adjuvant RT [5]. All patients had local tumor recurrences and died due to neurologic causes within 19.3 months after RT (range: 42.0– 59.2 Gy). Limited data exists on the role of adjuvant chemotherapy for gliosarcoma, particularly regarding its impact with concurrent RT. In a single-institutional study on 46 gliosarcoma patients diagnosed from 2000 to 2010 by Walker et al., 37 patients aged 24– 92 years, received adjuvant TMZ-RT and had a 2-year OS of 20.0% vs. 10.2% not treated with the regimen (p = 0.68) [32]. In contrast, another single-institutional case series on gliosarcoma patients diagnosed between 1996 and 2008, aged 42–90 years, found no significant difference in median survival (10.4 vs. 13.9 months, p = 0.946) or time to disease progression (5 vs. 3 months,
p = 0.13) when comparing those who received adjuvant TMZ-RT to those who did not receive it [11]. For older GBM patients (65– 90 years), preliminary results from NCT00482677 have shown that the addition of concomitant and adjuvant TMZ to hypofractionated RT significantly improves median OS (9.3 vs. 7.6 months, p < 0.001) over RT alone [15]. Importantly, quality-of-life analyses did not demonstrate differences in functional domains of quality-of-life assessments. This study represents a particularly focused investigation on the impact of adjuvant RT with concomitant single-agent chemotherapy on septuagenarians and octogenarians with gliosarcoma. The major strength in our analysis lies in the large patient numbers which allowed for statistical analysis powered for detection of differences in treatment and survival. The NCDB hospital-based cancer dataset is broadly representative of the U.S. population, covering 70% of newly diagnosed cancer cases annually in the United States, thus decreasing selection bias risks that may be associated with smaller analyses [20]. The NCDB is a highly standardized hospital-based cancer registry, undergoing a battery of quality assurance measures and checks while at the same time collecting information on new invasive cancer cases on millions of patients. However, these patients are only reported by Commission-onCancer-accredited facilities, thus possibly introducing hospital selection bias. Our analysis has several limitations intrinsic to any large database retrospective study which may lead to confounding impact of important variables which could not be analyzed in our study including no record on pre- and post-operative imaging, or information on disease progression or recurrence. Also, very few patients in our study had record on MGMT promoter methylation status which has been shown to have a significant effect on GBM patient outcome [33,34]. There is also very minimal information recorded on patient performance status. Only 2.4% of patients had known Karnofsky Performance Status (KPS) among our dataset. It is certainly likely that decisions to proceed with adjuvant therapy are biased by patient performance status which would ultimately affect patient outcome. Elderly patients undergoing aggressive treatments require close attention and monitoring for adverse events to optimize efficacy while at the same time minimizing toxicity [35–38]. It is likely that many elderly patients who do not receive adjuvant therapy do so due to their comorbidities and performance status, and it has been shown that those with KPS > 70 and Charlson Comorbidity Index (CCI) < 3 are more likely to complete treatment [39]. Medicare data show that approximately 40% of patients with cancer have at least one other
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
chronic medical condition, and about 15% have two or more [40]. As such, there are important implications for cancer treatment decisions and, thus, patient outcome [41,42]. Studies have found that those with significant comorbidities are associated with poorer survival in cancer patients compared to those without, and five-year mortality hazard ratios range from 1.1 to 5.8 [43]. Those with comorbidities have not only been associated with poorer outcome, but also poorer quality of life [44]. Cancer patients with significant comorbidities are also more likely to have postoperative complications and mortality is higher in this population [43]. It is possible that these factors could explain the significant OS benefit observed in those receiving adjuvant chemoradiation for those who may not have as many significant comorbidities. In our analysis, we purposely excluded those who did not receive adjuvant therapy as it is likely that these patients had postoperative concerns and/or limitations, likely those with lower KPS, precluding them from proceeding with adjuvant treatment which may overestimate any possible difference in outcome when compared to those receiving adjuvant treatment. Furthermore, removing this subgroup decreases risk for immortal time bias given that these patients may not have lived long enough to complete chemoradiation whereas chemoradiation patients would have survived longer by definition of their treatment course and thereby have more favorable outcome. Notably, all patients in our analysis underwent resection and completed RT to at least a course of 40 Gy. Type and dose of chemotherapy, and adherence to the chemotherapeutic regimen is also not recorded. Of those receiving chemotherapy, however, our investigation limited these patients to include only those receiving single-agent drug, presumably temozolomide. Our study has shown that adjuvant chemoradiation is an independent prognostic factor for improved OS in elderly patients with gliosarcoma, and the results of our study can serve as estimated benchmarks for outcome in this growing and important patient population. Its benefit may be limited to septuagenarians, those with lower comorbidity burden, and those with smaller tumor size. The literature thus far suggests that adjuvant RT with concomitant chemotherapy can be administered without significant toxicity in those with adequate performance status; however, further studies are warranted to evaluate health-related quality of life parameters in this specific patient population. Importantly, careful consideration should be advised when discussing management options between the elderly patient and physician which should include the risks and benefits regarding adjuvant treatment, and quality of life and patient preferences. Future consideration should be given to further elucidate the molecular and clinical features of gliosarcoma for development of a greater number of options for systemic therapies tailored to the patient with the hope for even better prognosis in this aggressive disease. Finally, continued efforts to manage these patients on a multidisciplinary level are essential to optimize their outcomes. Conflicts of interest The authors have no conflicts of interest to disclose. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Ostrom QT, Gittleman H, Fulop J. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-Oncology 2015;17:iv1–iv62.
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx patients with glioblastoma: a propensity-matched analysis. Int J Radiat Oncol Biol Phys 2015;91:109–15. Saito K, Mukasa A, Narita Y, et al. Toxicity and outcome of radiotherapy with concomitant and adjuvant temozolomide in elderly patients with glioblastoma: a retrospective study. Neurol Med Chir (Tokyo) 2014;54: 272–9. Behm T, Horowski A, Schneider S, et al. Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients. Clin Neurol Neurosurg 2013;115:2142–6. Brandes AA, Franceschi E, Tosoni A, et al. Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 2009;115:3512–8. Gerstein J, Franz K, Steinbach JP, et al. Postoperative radiotherapy and concomitant temozolomide for elderly patients with glioblastoma. Radiother Oncol 2010;97:382–6.
[39] Fiorentino A, Balducci M, De Bonis P, et al. Can elderly patients with newly diagnosed glioblastoma be enrolled in radiochemotherapy trials? Am J Clin Oncol 2015;38:23–7. [40] Edwards BK, Noone AM, Mariotto AB, et al. Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 2014;120:1290–314. [41] Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 2000;35:181–200. [42] Satariano WA, Silliman RA. Comorbidity: implications for research and practice in geriatric oncology. Crit Rev Oncol Hematol 2003;48:239–48. [43] Sogaard M, Thomsen RW, Bossen KS, et al. The impact of comorbidity on cancer survival: a review. Clin Epidemiol 2013;5:3–29. [44] Sarfati D, Koczwara B, Jackson C. The impact of comorbidity on cancer and its treatment. CA Cancer J Clin 2016;66:337–50.
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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Clinical commentary
Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? Jacob Y. Shin ⇑, Ja Kyoung Yoon, Aidnag Z. Diaz Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, United States
a r t i c l e
i n f o
Article history: Received 27 January 2017 Accepted 10 July 2017 Available online xxxx Keywords: Gliosarcoma Elderly Adjuvant chemoradiation Survival
a b s t r a c t The objective of our study is to determine the impact of adjuvant chemoradiation on overall survival (OS) for gliosarcoma in septuagenarians and octogenarians. Data were extracted from the National Cancer Data Base (NCDB). Chi-square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 23.0 (Armonk, NY: IBM Corp.) for data analyses. 210 patients with gliosarcoma who underwent resection were identified. 168 (80.0%) patients received adjuvant chemoradiation, and 42 (20.0%) received adjuvant RT alone. Patients were more likely to receive adjuvant chemoradiation if they were male vs. female (85.3% vs. 71.6%, p = 0.016). There was no significant difference in receipt of adjuvant therapy by year of diagnosis, age at diagnosis, race, Charlson/Deyo Score, treatment facility type, tumor size, or extent of surgery. Those who received adjuvant chemoradiation had significantly better one-year OS than those who received adjuvant radiation alone (35.3% vs. 16.2%, p < 0.001). On subset analysis, this significant one-year OS benefit was observed in septuagenarians, those with Charlson/Deyo Score of 0, and in those with tumor size 5 cm. On multivariate analysis, receipt of adjuvant chemoradiation and greater extent of resection were independent prognostic factors for improved OS. Our data suggests that adjuvant chemoradiation is an independent prognostic factor for improved OS in elderly patients with gliosarcoma, and the results of our study can serve as estimated benchmarks for outcome in this growing and important patient population. Its benefit, however, may be limited to septuagenarians and those with lower comorbidity burden. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction In adults, glioblastoma (GBM) is the most common primary malignant brain tumor, and an estimated 12,120 new cases are predicted in the United States for 2016 [1]. The incidence rate in the United States is 3.2 per 100,000 population, and is highest among those aged 75–84 years [1]. The one-year relative survival rate is highest among those 20–44 years of age (67.6%), and lowest among those 75 years (11.0%) [1]. The World Health Organization classifies gliosarcoma as a variant of GBM in that they exhibit both glial and sarcomatous histologic and immunophenotypic elements [2–4], and it accounts for approximately 2–8% of all malignant gliomas [2,5,6]. Patients with the disease are more likely to be male, to have disease primarily located in the temporal lobe, and to have disease metastasis more so than GBM [5–10]. The prognosis for those with GBM is poor, and patients with gliosarcoma may have an even poorer outlook on survival ⇑ Corresponding author at: Department of Radiation Oncology, Rush University Medical Center, 500 S. Paulina St., Chicago, IL 60612, United states. E-mail address: [email protected] (J.Y. Shin).
[6,8,11,12]. The treatment regimen from the landmark Stupp trial, maximal safe tumor resection followed by adjuvant chemoradiation, has become the standard of care for those with GBM [13,14], and that treatment paradigm has been extrapolated for management of gliosarcoma. However, the patient population from the Stupp trial was limited to adult patients 70 years of age. More recently, preliminary results from NCT00482677 have demonstrated a significant survival benefit in those aged 65 years for those receiving hypofractionated radiotherapy with concomitant and adjuvant temozolomide compared to radiotherapy alone [15]. However, there is lack of data regarding the impact of adjuvant chemoradiation in the elderly gliosarcoma population, and, thus, its role remains uncertain. In the United States, the elderly population is expected to grow with increasing life expectancy [16], and thus, optimal care for the elderly has become a very important topic of research [15,17–19]. The objective of this hospital-based study is to determine the impact of adjuvant chemoradiation on overall survival to further understand the relationships between it and outcomes in elderly gliosarcoma patients.
http://dx.doi.org/10.1016/j.jocn.2017.07.002 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
2. Materials and methods 2.1. Patient population Data were extracted from the National Cancer Data Base (NCDB) which included hospital registry data collected from more than 1500 Commission on Cancer (CoC)-accredited facilities representing 70% of newly diagnosed cancer cases annually in the United States [20]. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data used in the study are derived from a deidentified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators. Our study population consists of 210 patients diagnosed with gliosarcoma (ICD-0-3 histology code 9442/3) diagnosed from 2004 to 2013. Patients younger than 70 years, whose primary or adjuvant treatment type were unknown, or who underwent treatment with palliative intent were excluded. Comorbidities as described by the Charlson/Deyo Score were defined by a weighted score derived from the sum of the scores for each of the comorbid conditions listed in the Charlson Comorbidity Score Mapping Table [21,22]. A score of 0 indicated no significant comorbid conditions and higher scores indicated greater comorbidity burden. Because of the small proportion of cases with a Charlson Comorbidity score exceeding 2, the NCDB has truncated the data to 0, 1, and 2 (greater than 1). Adjuvant therapy was defined as treatment following primary resection and was grouped as those either receiving radiotherapy (RT) alone or chemotherapy in addition to radiotherapy (chemoradiation). All patients underwent resection. All patients who received chemotherapy in our analysis received single-agent chemotherapy, presumably temozolomide (TMZ). RT included cases of external beam radiotherapy. Those who received RT had a prescription dose of at least 40 Gy. 2.2. Statistical analysis All data analyses were performed using SPSS 23.0 (Armonk, NY: IBM Corp.). Proportional distribution by adjuvant treatment including differences in demographic, socioeconomic, clinicopathologic, and treatment characteristics were compared using the Chi-square test. Kaplan-Meier estimates were used to analyze overall survival (OS) estimates with the comparison of rates among the groups performed using the two-tailed log-rank test. The OS endpoint was defined as time to death from the date of diagnosis of gliosarcoma. The 2013 subgroup was excluded from one-year OS calculation to allow for a minimum of one year of follow-up for data running through 2013. Cox regression univariate analysis was used to compute hazard ratios (HR) with 95% confidence intervals (CI) to identify independent prognostic factors for OS in multivariate analysis using a forwards selection variable selection process. A two-sided p-value < 0.05 was considered statistically significant. 3. Results 3.1. Patient and treatment characteristics The median age of the study population was 75 years (range: 70–89) (Table 1). 210 septuagenarians and octogenarians were diagnosed with gliosarcoma between 2004 and 2013. 175 (83.3%) were 70–79 years old and 35 (16.7%) were 80–89 years of age. There were 129 (61.4%) males and 81 (38.6%) females. 187 (89.0%) patients were White, 12 (5.7%) Black, 4 (1.9%) Hispanic,
and 3 (1.4%) Asians. 143 (68.1%) had a Charlson/Deyo Score of 0, 51 (24.3%) a score of 1, and 16 (7.6%) a score of 2. 123 (58.6%) patients were treated at a non-academic/research program, and 87 (41.4%) at an academic/research program. 113 (53.8%) had tumor size 5 cm, 57 (27.1%)>5 cm, and 40 (19.0%) unknown size. Of those with known extent of surgery, 49 (58.3%) underwent subtotal resection and 35 (41.7%) gross total resection. 168 (80.0%) patients received adjuvant chemoradiation, and 42 (20.0%) received adjuvant RT alone. Patients were more likely to receive adjuvant chemoradiation if they were male vs. female (85.3% vs. 71.6%, p = 0.016). There was no significant difference in receipt of adjuvant therapy by year of diagnosis, age at diagnosis, race, Charlson/Deyo Score, treatment facility type, tumor size, or extent of surgery. 3.2. Survival outcome The median follow-up for the entire patient cohort was 8.2 months (range: 1.8–65.0). One-year overall survival (OS) for the study population was 31.4% (Table 2). Patients diagnosed at age 70–79 years had significantly better one-year OS than those 80–89 years (34.2% vs. 17.0%, p = 0.030). There was also a significant difference in one-year OS between those undergoing subtotal resection versus total resection (18.8% vs. 29.2%, p = 0.048). Those who received adjuvant chemoradiation had significantly better one-year OS than those who received adjuvant radiation alone (35.3% vs. 16.2%, p < 0.001). On subset analysis, this significant one-year OS benefit was observed in septuagenarians (40.3% vs. 10.0%, p < 0.001) (Fig. 1a) but not in octogenarians (Fig. 1b), those with Charlson/Deyo Score of 0 (34.8% vs. 12.0%, p < 0.001), and in those with tumor size 5 cm (44.5% vs. 17.6%, p < 0.001). 3.3. Multivariate analysis On Cox regression multivariate analysis, adjuvant chemoradiation (Hazard ratio [HR]: 0.525; 95% confidence interval [CI]: 0.356–0.773; p = 0.001) remained an independent prognostic factor for better OS even after adjusting for age at diagnosis (HR: 1.026; 95% CI:0.991–1.063; p = 0.145) which fell out in multivariate analysis, and greater extent of resection (HR: 0.608; 95% CI: 0.409–0.905; p = 0.014) (Table 3). 4. Discussion Our study found adjuvant chemoradiation to be an independent prognostic factor for improved overall survival in elderly patients with gliosarcoma. However, our findings demonstrate that its benefit may be limited to septuagenarians, those with Charlson/Deyo score 0, and tumor size 5 cm. There was no significant difference in receipt of adjuvant chemoradiation by tumor size, extent of resection, or facility type. Maximal, safe tumor resection is the preferred primary treatment for high-grade gliomas, and the impact of extent of resection on outcome in GBM patients has been previously studied with a greater extent of resection demonstrating improved outcomes [23–25]. Indeed, our study on elderly gliosarcoma patients also demonstrated a significant one-year OS benefit for those receiving gross total resection compared to subtotal resection. However, in the pre-operative setting, discussion and evaluation regarding comorbidity and complication risks associated with surgery in this vulnerable population is certainly warranted. In a multiinstitutional retrospective study analyzing 40 GBM patients 80 years of age, 20% of patients suffered post-operative surgical issues and 30% had medical complications [26]. In another retrospective analysis on 319 patients 65 years of age who underwent
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Patient demographic, socioeconomic, clinicopathologic, and treatment characteristics stratified by adjuvant therapy.
Total Year of diagnosis 2004–2008 2009–2013 Age 70–79 years 80–89 years Gender Male Female Race White Black Hispanic Asian Other Unknown Charlson/Deyo Score 0 1 2 Facility Non-Academic/Research Program Academic/Research Program Tumor size 5 cm >5 cm Unknown Extent of surgery Subtotal resection Total resection Unknown a b
Overall
Adjuvant RTa
Adjuvant chemoRTb
210
42
168
103 107
21 (20.4%) 21 (19.6%)
82 (79.6%) 86 (80.4%)
175 35
34 (19.4%) 8 (22.9%)
141 (80.6%) 27 (77.1%)
129 81
19 (14.7%) 23 (28.4%)
110 (85.3%) 58 (71.6%)
187 12 4 3 1 3
37 (19.8%) 4 (33.3%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%)
150 (80.2%) 8 (66.7%) 4 (100.0%) 2 (66.7%) 1 (100.0%) 3 (100.0%)
143 51 16
28 (19.6%) 12 (23.5%) 2 (12.5%)
115 (80.4%) 39 (76.5%) 14 (87.5%)
123 87
26 (21.1%) 16 (18.4%)
97 (78.9%) 71 (81.6%)
113 57 40
19 (16.8%) 10 (17.5%) 13 (32.5%)
94 (83.2%) 47 (82.5%) 27 (67.5%)
49 35 126
9 (18.4%) 8 (22.9%) 25 (19.8%)
40 (81.6%) 27 (77.1%) 101 (80.2%)
Chi-square p-value p = 0.890
p = 0.643
p = 0.016
p = 0.455
p = 0.614
p = 0.624
p = 0.905
p = 0.614
Radiotherapy. Chemoradiation.
Table 2 Kaplan-Meier one-year overall survival stratified by adjuvant therapy.
Total Age at diagnosis 70–79 years 80–89 years Charlson/Deyo Score 0 1 2 Race Non-black Black Facility Non-Academic/Research Program Academic/Research Program Tumor size 5 cm >5 cm Extent of surgery Subtotal resection Total resection a b
Overall
Adjuvant RTa
Adjuvant chemoRTb
Log-rank p-value
31.4% (±3.5)
16.2% (±6.1)
35.3% (±4.0)
34.2% (±3.9) 17.0% (±6.9)
10.0% (±5.5) 42.9% (±18.7)
40.3% (±4.5) 8.9% (±6.0)
30.1% (±4.2) 31.9% (±7.0) 40.0% (±2.6)
12.0% (±6.5) 20.0% (±12.6) 50.0% (±35.4)
34.8% (±4.9) 35.4% (±8.2) 38.5% (±13.5)
32.4% (±3.6) 22.2% (±13.9)
18.2% (±6.7) –
35.9% (±4.1) 40.0% (±21.9)
30.2% (±4.5) 32.9% (±5.4)
21.7% (±8.6) 7.1% (±6.9)
32.7% (±5.2) 38.7% (±6.2)
39.9% (±4.9) 28.9% (±6.8)
17.6% (±9.2) 28.6% (±17.1)
44.5% (±5.5) 28.9% (±7.4)
18.8% (±6.9) 29.2% (±9.3)
14.3% (±13.2) –
29.4% (±11.1) 31.6% (±10.7)
p < 0.001 p = 0.030 p < 0.001 p = 0.533 p = 0.942 p < 0.001 p = 0.158 p = 0.802 p = 0.293 p < 0.001 – p = 0.508 p = 0.075 p < 0.001 p = 0.681 p < 0.001 p = 0.263 p = 0.048 p = 0.023 –
Radiotherapy. Chemoradiation.
resection, 21.9% of patients experienced post-operative complications with 7.7% being neurologic [27]. The role of adjuvant RT in high-grade glioma has been previously examined in prior studies, and the literature suggests that adjuvant therapy following surgery can be considered for appropriate, elderly patients. In the elderly patient population, adjuvant RT
has been associated with an improved median OS when compared with tumor resection alone [26,28–31]. In a study on GBM patients aged 70 years, 85 patients were randomly assigned to receive supportive care or supportive care plus RT, and those receiving RT had significantly improved OS (29.1 vs. 16.9 weeks, p = 0.002) without significantly reducing the quality of life or cognition over
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
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J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. a) Kaplan-Meier overall survival among septuagenarians (p < 0.001); b) Kaplan-Meier overall survival among octogenarians (p = 0.533).
Table 3 Cox regression multivariate analysis for overall survival.
a b c
Prognostic factor
Hazard ratio
95% Confidence interval
p-value
Adjuvant treatmenta Age at diagnosisb Extent of resectionc
0.525 1.026 0.608
0.356–0.773 0.991–1.063 0.409–0.905
p = 0.001 p = 0.145 p = 0.014
Adjuvant RT vs. adjuvant chemoRT. Continuous. Subtotal resection vs. Total resection + unknown.
time [28]. In a Surveillance, Epidemiology, and End Results (SEER) analysis on 2836 GBM patients older than 70, those undergoing resection alone had a median OS of 3 months compared to resection followed by adjuvant RT with a median survival of 8 months (p < 0.001) [31]. Multivariate analysis also demonstrated adjuvant RT to be significantly correlated with an improved disease-specific survival (HR: 0.43, p < 0.05). Given the limited patient population numbers with gliosarcoma, no randomized control trials exist investigating adjuvant RT in those specifically with the histology, and prior studies investigating the role of adjuvant RT in these patients have been limited to case series [4–6,8,9,11,12]. In untreated patients with gliosarcoma, the median survival is dismal at only 4 months [7]. In treated gliosarcoma patients, the reported median survival has ranged between 6 and 12 months [4–6,8,9]. Meis et al., showed that the median survival for 26 gliosarcoma patients undergoing adjuvant RT (dose range: 45–81.6 Gy) was 8.3 months, with most receiving chemotherapy [4]. Lutterbach et al., showed that the median survival was 11.5 months in a single-institutional study on 12 gliosarcoma patients diagnosed between 1980 and 1999, with median tumor size 4.5 cm (range: 3–8 cm), and who received adjuvant RT [5]. All patients had local tumor recurrences and died due to neurologic causes within 19.3 months after RT (range: 42.0– 59.2 Gy). Limited data exists on the role of adjuvant chemotherapy for gliosarcoma, particularly regarding its impact with concurrent RT. In a single-institutional study on 46 gliosarcoma patients diagnosed from 2000 to 2010 by Walker et al., 37 patients aged 24– 92 years, received adjuvant TMZ-RT and had a 2-year OS of 20.0% vs. 10.2% not treated with the regimen (p = 0.68) [32]. In contrast, another single-institutional case series on gliosarcoma patients diagnosed between 1996 and 2008, aged 42–90 years, found no significant difference in median survival (10.4 vs. 13.9 months, p = 0.946) or time to disease progression (5 vs. 3 months,
p = 0.13) when comparing those who received adjuvant TMZ-RT to those who did not receive it [11]. For older GBM patients (65– 90 years), preliminary results from NCT00482677 have shown that the addition of concomitant and adjuvant TMZ to hypofractionated RT significantly improves median OS (9.3 vs. 7.6 months, p < 0.001) over RT alone [15]. Importantly, quality-of-life analyses did not demonstrate differences in functional domains of quality-of-life assessments. This study represents a particularly focused investigation on the impact of adjuvant RT with concomitant single-agent chemotherapy on septuagenarians and octogenarians with gliosarcoma. The major strength in our analysis lies in the large patient numbers which allowed for statistical analysis powered for detection of differences in treatment and survival. The NCDB hospital-based cancer dataset is broadly representative of the U.S. population, covering 70% of newly diagnosed cancer cases annually in the United States, thus decreasing selection bias risks that may be associated with smaller analyses [20]. The NCDB is a highly standardized hospital-based cancer registry, undergoing a battery of quality assurance measures and checks while at the same time collecting information on new invasive cancer cases on millions of patients. However, these patients are only reported by Commission-onCancer-accredited facilities, thus possibly introducing hospital selection bias. Our analysis has several limitations intrinsic to any large database retrospective study which may lead to confounding impact of important variables which could not be analyzed in our study including no record on pre- and post-operative imaging, or information on disease progression or recurrence. Also, very few patients in our study had record on MGMT promoter methylation status which has been shown to have a significant effect on GBM patient outcome [33,34]. There is also very minimal information recorded on patient performance status. Only 2.4% of patients had known Karnofsky Performance Status (KPS) among our dataset. It is certainly likely that decisions to proceed with adjuvant therapy are biased by patient performance status which would ultimately affect patient outcome. Elderly patients undergoing aggressive treatments require close attention and monitoring for adverse events to optimize efficacy while at the same time minimizing toxicity [35–38]. It is likely that many elderly patients who do not receive adjuvant therapy do so due to their comorbidities and performance status, and it has been shown that those with KPS > 70 and Charlson Comorbidity Index (CCI) < 3 are more likely to complete treatment [39]. Medicare data show that approximately 40% of patients with cancer have at least one other
Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002
J.Y. Shin et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
chronic medical condition, and about 15% have two or more [40]. As such, there are important implications for cancer treatment decisions and, thus, patient outcome [41,42]. Studies have found that those with significant comorbidities are associated with poorer survival in cancer patients compared to those without, and five-year mortality hazard ratios range from 1.1 to 5.8 [43]. Those with comorbidities have not only been associated with poorer outcome, but also poorer quality of life [44]. Cancer patients with significant comorbidities are also more likely to have postoperative complications and mortality is higher in this population [43]. It is possible that these factors could explain the significant OS benefit observed in those receiving adjuvant chemoradiation for those who may not have as many significant comorbidities. In our analysis, we purposely excluded those who did not receive adjuvant therapy as it is likely that these patients had postoperative concerns and/or limitations, likely those with lower KPS, precluding them from proceeding with adjuvant treatment which may overestimate any possible difference in outcome when compared to those receiving adjuvant treatment. Furthermore, removing this subgroup decreases risk for immortal time bias given that these patients may not have lived long enough to complete chemoradiation whereas chemoradiation patients would have survived longer by definition of their treatment course and thereby have more favorable outcome. Notably, all patients in our analysis underwent resection and completed RT to at least a course of 40 Gy. Type and dose of chemotherapy, and adherence to the chemotherapeutic regimen is also not recorded. Of those receiving chemotherapy, however, our investigation limited these patients to include only those receiving single-agent drug, presumably temozolomide. Our study has shown that adjuvant chemoradiation is an independent prognostic factor for improved OS in elderly patients with gliosarcoma, and the results of our study can serve as estimated benchmarks for outcome in this growing and important patient population. Its benefit may be limited to septuagenarians, those with lower comorbidity burden, and those with smaller tumor size. The literature thus far suggests that adjuvant RT with concomitant chemotherapy can be administered without significant toxicity in those with adequate performance status; however, further studies are warranted to evaluate health-related quality of life parameters in this specific patient population. Importantly, careful consideration should be advised when discussing management options between the elderly patient and physician which should include the risks and benefits regarding adjuvant treatment, and quality of life and patient preferences. Future consideration should be given to further elucidate the molecular and clinical features of gliosarcoma for development of a greater number of options for systemic therapies tailored to the patient with the hope for even better prognosis in this aggressive disease. Finally, continued efforts to manage these patients on a multidisciplinary level are essential to optimize their outcomes. Conflicts of interest The authors have no conflicts of interest to disclose. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Ostrom QT, Gittleman H, Fulop J. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-Oncology 2015;17:iv1–iv62.
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Please cite this article in press as: Shin JY et al. Gliosarcoma in septuagenarians and octogenarians: What is the impact of adjuvant chemoradiation? J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.07.002