Earlyrecognition of renal cell carcinoma (RCC) is critical to optimizing patient outcomes. Unfortunately, the presence of RCC is often asymptomatic initially.1An estimated 30% of patients are synchronously diagnosed with stage IV RCC, with common sites of metastasis including the lung, brain, and bone.2RCC metastasizes to the brain in 4%–17% of cases.1–3The treatment of advanced RCC has improved with the development of targeted inhibitors of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin, including sunitinib and everolimus, respectively.4,5More recently, programmed death cell death protein 1 (PD-1; i.e., nivolumab) and programmed death ligand 1 (PD-L1; i.e., atezolizumab) immune checkpoint inhibitor (ICI) therapies and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor (i.e., ipilimumab) have been shown to be effective in the treatment of advanced RCC.6–8
In a phase 3 randomized clinical trial, nivolumab demonstrated improved overall survival (OS) compared with everolimus and had fewer grade 3 and 4 adverse events, suggesting the possible superiority of ICI in the treatment of advanced RCC.6However, consistent with prior prospective studies, patients with untreated or symptomatic intracranial disease were excluded.6,7Until recently, the decision to treat patients with RCC brain metastases (BMs) with ICI was based on extrapolation of prospective data regarding the treatment of melanoma and non–small cell lung cancer (NSCLC) BM9–12and the treatment of extracranial RCC metastasis.6,7
A phase 2 multicenter trial (NIVOREN) evaluated the efficacy of nivolumab in the treatment of RCC BM that had failed VEGF-directed therapies.13The intracranial objective response ratio (ORR) (12%) was discordant with the extracranial ORR (21%), which is inconsistent with observations from similar melanoma and NSCLC BM trials.9–13However, no comparison with targeted therapies was made. Therefore, the role of ICI in the treatment of RCC BM remains unknown.
The primary aim of the study was to address the efficacy of ICI in the treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course.
开云体育世界杯赔率
Patients
A retrospective review of 425 patients receiving systemic therapy for RCC at The Ohio State University Wexner Medical Center from 2011 to 2018 was conducted. Patients with a history of multiple primary cancers and those with incomplete records of their treatment were excluded from analysis. BMs were diagnosed by MRI in 113 patients during the study period.
Clinical Assessment
Patient demographics, systemic and intracranial disease progression, systemic therapeutic regimen, and local BM management data were collected. RCC diagnosis was determined by histopathological analysis at the time of primary disease resection or biopsy of the metastatic site. Disease progression was defined as tumor growth or new metastatic foci on radiographic surveillance imaging. Surveillance imaging varied based on the extent of disease and ranged from 1 month to annually. Intracranial disease was assessed by location relative to the tentorium and maximum diameter (in cm) of the dominant or solitary BM at time of initial diagnosis. The OS from RCC diagnosis (OSRCC) and OS from BM diagnosis (OSBM) were recorded. Performance status was determined according to the Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) scores and with recursive partitioning analysis (RPA).14A good performance status was a KPS score ≥ 70 and/or ECOG score 0 or 1.
Treatment
Systemic therapy regimens were evaluated for each patient (Fig. 1). Information regarding the agents used, the timing of initiation and discontinuation, and progression of intra- and extracranial disease in relation to systemic treatment was recorded. Patients were further subcategorized based on whether targeted therapy or ICI was initiated prior to potential intracranial involvement to determine the probability of BM development. Not all patients would go on to develop BMs. Given the retrospective nature of the presented study, the initiation of or change to the systemic therapy regimen was at the discretion of the treating oncologist. Patients treated with ICI may have been treated previously with targeted agents, whereas those in the targeted therapy group had not previously received ICI. Additional details regarding the implementation of local intracranial interventions, such as stereotactic radiosurgery (SRS) and/or neurosurgical intervention, were evaluated among the patients with BMs for their effect on OS.
Treatment group breakdown of the patient cohort.
Statistical Analysis
Statistical analysis was conducted using IBM SPSS version 25 (IBM Corp.). Shapiro-Wilk tests were used to determine normality of distribution for continuous variables. Patient characteristics were analyzed with descriptive statistics, and normally distributed continuous variables were compared by two-tailed independent-sample t-tests and for nonnormally distributed continuous variables, comparison was made by a Mann-Whitney U-test. Pearson’s two-tailed chi-square test was used to compare categorical variables across treatment groups. OSRCC, OSBM, and local intracranial progression-free survival (PFS) were compared using Kaplan-Meier curves and log-rank tests. Cox proportional hazards models were used to determine significance of covariate effect on survival among patients with BMs. Statistical significance was considered at p < 0.05.
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the IRB of The Ohio State University. Consent was not required to conduct the reported IRB-approved research. No identifiable patient characteristics are published.
Results
Patient Characteristics
该研究包括425例诊断为碾压混凝土and treated with targeted therapies and/or ICI. The mean age at RCC diagnosis was 58.7 ± 10.5 years (± SD), and 70.4% of patients were male. Extracranial metastases were diagnosed in 97.2% of patients, and the initial site of metastasis most frequently involved the lungs (30.4%), bones (14.4%), brain (4.2%), or multiple sites (30.1%). A total of 113 patients (9.5%) developed intracranial metastases. Patients with intracranial disease had a mean of 2.3 ± 2.8 BMs at the time of diagnosis, and the maximum diameter of the solitary or dominant lesion was 1.7 ± 1.5 cm. Furthermore, 11.5% of patients presented with synchronous primary and intracranial diagnosis. The majority (83.2%) of intracranial disease was supratentorial (Table 1).
Characteristics of 113 RCC patients with BMs
| Characteristic | Value |
|---|---|
| Mean age RCC Dx, yrs (SD) | 57.8 (9.1) |
| Mean age BM Dx, yrs (SD) | 59.8 (8.8) |
| Male sex, % | 72.6 |
| Site of initial metastasis, % | |
| Brain | 15.9 |
| Lung | 31.0 |
| Bone | 13.3 |
| Multiple | 32.7 |
| Other | 7.1 |
| Mean no. of BMs (SD) | 2.3 (2.8) |
| Synchronous diagnosis of BM, % | 11.5 |
| Location of BM, n (%) | |
| Supratentorial | 94 (83.2) |
| Infratentorial | 7 (6.2) |
| Both | 12 (10.6) |
| Mean BM diameter, cm (SD) | 1.7 (1.5) |
| Mean no. of extracranial metastases at BM Dx (SD) | 1.94 (1.7) |
| Tx characteristics, n (%) | |
| Resection of BM | 37 (32.7) |
| Radiation to BM | 85 (75.2) |
| Systemic therapy initiated after BM | 58 (51.3) |
| Checkpoint inhibitors | 33 (29.2) |
| Nivolumab | 27 (23.9) |
| Nivolumab & ipilimumab | 6 (5.3) |
| Molecular TT | 80 (70.8) |
Dx = diagnosis; TT = targeted therapy; Tx = treatment.
There was no significant difference in patient demographics, including sex, age at primary cancer, and number of BMs among the two treatment groups. Patients with good performance status, considered as a KPS score ≥ 70 (78.8% vs 73.8%, p = 0.82) and ECOG score 0 or 1 (75.8% vs 71.3%, p = 0.85), were evenly distributed across the ICI and molecular targeted therapy cohorts, respectively. Comparison of intracranial disease characteristics between ICI and targeted therapy groups, including the number of BMs at diagnosis (1.55 ± 0.9 vs 2.61 ± 3.3, p = 0.13), supratentorial location of the disease (84.8% vs 82.5%, p = 0.65), and maximum tumor diameter (2.14 ± 1.95 vs 1.49 ± 1.23 cm, p = 0.05), did not differ significantly. The rate of hemorrhage and spine metastasis development were similar between groups. There was a significantly higher rate of leptomeningeal disease (LMD) in patients receiving ICI (Table 2).
Comparison of the 113 RCC patients with BMs by treatment group
| Characteristic | ICI | TT | p Value |
|---|---|---|---|
| No. of patients | 33 | 80 | |
| Male sex | 24 (72.7) | 58 (72.5) | 0.98* |
| Mean age at RCC Dx, yrs | 56.6 (8.7) | 58.3 (9.2) | 0.38† |
| Mean age at BM Dx, yrs | 59.4 (8.6) | 60.0 (8.9) | 0.75† |
| KPS score ≥70 | 26 (78.8) | 59 (73.8) | 0.82* |
| ECOG score 0 or 1 | 25 (75.8) | 57 (71.2) | 0.85* |
| RPA I | 6 (18.2) | 14 (17.5) | 0.90* |
| RPA II | 20 (60.6) | 45 (56.2) | 0.85* |
| RPA III | 6 (18.2) | 17 (21.2) | 0.82* |
| Mean no. of BMs at BM Dx | 1.55 (0.9) | 2.61 (3.3) | 0.13‡ |
| Location of BM | 0.65* | ||
| Supratentorial | 28 (84.8) | 66 (82.5) | |
| Infratentorial | 1 (3.0) | 6 (7.5) | |
| Both | 4 (12.1) | 8 (10.0) | |
| Mean BM diameter, cm | 2.14 (1.95) | 1.49 (1.23) | 0.05‡ |
| LMD | 7 (21.2) | 4 (5.0) | 0.002* |
| Hemorrhagic BM | 18 (54.5) | 45 (56.2) | 0.87* |
| Spine metastases | 15 (45.5) | 27 (33.8) | 0.24* |
| Brain op | 14 (42.4) | 23 (28.8) | 0.16* |
| Brain radiotherapy | 29 (87.9) | 56 (70.0) | 0.045* |
| Brain op & radiotherapy | 11 (33.3) | 16 (20) | 0.15* |
Values are presented as the number of patients (%) or mean (SD) unless stated otherwise. Boldface type indicates statistical significance.
Chi-square test.
T-test.
Mann-Whitney U-test.
Treatment Characteristics
Treatment with systemic therapy was divided among patients who received targeted therapies only (n = 300, 70.6%) and those receiving some regimen containing ICI (n = 125, 29.4%). All patients receiving ICI were treated with nivolumab; only 12 received combination nivolumab and ipilimumab therapy and none received ipilimumab alone. Among patients with BMs (n = 113), 33 patients (29.2%) received ICI; in 8 of these patients, therapy was initiated prior to BM diagnosis. Eighty (70.8%) of the 113 patients with BMs were treated with targeted therapies; of these patients, treatment was initiated prior to BM diagnosis in 47 patients. Furthermore, 90 patients (79.6%) underwent additional intracranial intervention with resection, SRS, or a combination of both. The number of patients who underwent surgical intervention alone (42.4% vs 28.8%, p = 0.16) or a combination of surgical intervention and radiotherapy (33.3% vs 20.0%, p = 0.15) was similar within the ICI and molecular targeted therapy groups. However, patients in the ICI therapy group were more likely to receive SRS alone compared with the targeted therapy group (87.9% vs 70.0%, p = 0.045) (Table 2). Five patients were noted to have undergone resection without SRS due to patient preference, lack of follow-up, or death prior to treatment. At the conclusion of data collection, only 5 patients had died of neurological disease, regardless of treatment group.
OS Benefit From ICI Therapy
The OSRCCamong all 425 patients treated with systemic agents was 56.2 months (95% CI 46.0–66.4 months). Among the 113 patients who developed BMs, the median OSRCCwas 32.1 months (95% CI 24.2–39.9 months), with 1-, 2-, and 5-year survival rates of 78.6%, 61.4%, and 36.1%, respectively, without regard to treatment regimen. Patients with BMs receiving ICI therapy (n = 33, 29.2%) had a median OSRCCof 77.2 months (95% CI 49.2–105.2 months), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The OSRCCfor patients treated with targeted therapies only was 25.2 months (95% CI 19.9–30.4 months), with 1-, 2- and 5-year survival rates of 72.2%, 52.8%, and 25.3%, respectively (n = 80, 70.8%). The OSRCCwas significantly prolonged for patients receiving ICI compared with those receiving molecular targeted therapy alone (p < 0.001) (Fig. 2 left).
Survival analysis.Left:Kaplan-Meier curve showing the OSRCCto the time of death compared by treatment group via the log-rank test.Right:Kaplan-Meier curve showing the OSBMto time of death compared by treatment group via the log-rank test. Patients lost to follow-up were censored from analysis and are represented by thetick markson the curves.
The OSBMfor the 113 patients diagnosed with BMs was 12.3 months (95% CI 8.7–15.9 months). Among patients receiving ICI (n = 33), the OSBMwas 21.7 months (95% CI 11.6–31.8 months), with 1-, 2-, and 5-year survival rates of 69.7%, 48.0%, and 27.2%, respectively. Those treated with targeted therapies (n = 80) had an OSBMof 8.9 months (95% CI 4.7–13.1 months), with 1-, 2-, and 5-year survival rates of 42.5%, 24.4%, and 10.4%, respectively. Use of ICI therapy during their disease course was associated with a significant increase in OSBMcompared with targeted therapies alone (p = 0.001) (Fig. 2 right).
Among the patients with BMs treated with ICI (n = 33), a select few were treated with combined nivolumab and ipilimumab therapy (n = 6, 18.2%), while the remaining patients received monotherapy nivolumab (n = 27, 81.8%). Treatment with combined ICI therapy trended toward increased OSBMcompared with monotherapy ICI, although the difference was not statistically significant (49.4 vs 19.0 months, p = 0.31).
The OSBMwas also evaluated after stratifying the treatment groups by initiation of treatment before or after BM diagnosis. Among patients treated with targeted therapies, the OSBMwas 18.6 months when treatment was initiated after BM diagnosis compared with 6.3 months when initiated before (p < 0.001). Patients treated receiving ICI demonstrated an OSBMof 26.2 months when initiated after BM diagnosis compared with 5.4 months when initiated before (p = 0.016) (Fig. 3).
Survival analysis of patients treated before versus after BM diagnosis.Left:Kaplan-Meier curve showing the OSBMto time of death among patients treated with targeted therapies alone compared by initiation of therapy before or after BM diagnosis via a log-rank test.Right:Kaplan-Meier curve showing the OSBMto time of death among patients treated with ICI compared by initiation of therapy before or after BM diagnosis via the log-rank test. Patients lost to follow-up were censored from analysis and are represented by thetick markson the curves.
Covariables that may have impacted OSBMin patients with BMs were evaluated by multivariate Cox regression analysis. Age at RCC and BM diagnoses, number of BMs at the time of diagnosis, supratentorial location of disease, and good performance status scores (KPS score ≥ 70 and ECOG score 0 or 1) did not significantly impact OSBM. BM resection did not significantly impact OSBM(HR 0.98, 95% CI 0.57–1.68; p = 0.94), whereas SRS was associated with improved OSBM(HR 0.41, 95% CI 0.25–0.66; p < 0.001). These results are summarized inTable 3.
Cox regression analysis of OSBM for 113 patients with BMs
| HR | 95% CI for HR | p Value | ||
|---|---|---|---|---|
| Lower | Upper | |||
| Tx w/ ICI | 0.54 | 0.32 | 0.91 | 0.02 |
| Age at RCC Dx | 0.98 | 0.90 | 1.06 | 0.58 |
| Age at BM Dx | 1.02 | 0.93 | 1.11 | 0.66 |
| Op | 0.98 | 0.57 | 1.68 | 0.94 |
| SRS | 0.41 | 0.25 | 0.66 | <0.001 |
| KPS score ≥70 | 1.86 | 0.59 | 5.85 | 0.29 |
| ECOG score 0 or 1 | 0.35 | 0.12 | 1.06 | 0.06 |
| Diameter | 0.89 | 0.78 | 1.01 | 0.07 |
| No. of BMs at BM Dx | 0.98 | 0.90 | 1.08 | 0.72 |
| Supratentorial | 1.25 | 0.80 | 1.95 | 0.32 |
Boldface type indicates statistical significance.
Risk of BM Development With Early ICI
系统性治疗开始前的潜力intracranial involvement in 367 (86.4%) of the 425 patients. Eight percent of the 100 patients treated with ICI would go on to develop BMs compared with 17.6% of the 267 patients who received targeted therapies alone. The OR among patients receiving ICI (OR 0.41, 95% CI 0.18–0.89; p = 0.021) suggests a lower probability of intracranial involvement compared with those receiving targeted therapies alone (Fig. 4).
BM发展的风险比。BM dev的风险elopment among patients treated prior to intracranial involvement was compared by treatment group and is displayed as a hazard function curve. Patients who were lost to follow-up or did not develop BMs were censored from analysis and are represented by thetick markson the curve.
Discussion
Newly developed targeted and ICI therapies have provided substantial increases in OS and ORR for patients with stage IV cancer, including RCC.4–8In head-to-head, phase 3 randomized clinical trials, ICI therapies have demonstrated better OS and ORR compared with targeted therapies and diminished adverse events.6–8However, patients with BMs were excluded from these trials, and the utility of ICI in these patients remains unclear.6–8The present study is the first to evaluate for potential survival benefit in patients with RCC BMs treated with ICI compared with targeted therapies.
ICI in the Treatment of RCC BM
Currently, the clinical decision to use ICI in the treatment of RCC BMs is extrapolated from prospective clinical trials evaluating advanced RCC without BMs, as well as trials evaluating melanoma and NSCLC BMs,6–11in which combination nivolumab and ipilimumab have been shown to be more efficacious than nivolumab monotherapy.7,9,15
The NIVOREN phase 2 multicenter trial was the first published prospective trial to evaluate nivolumab in the treatment of RCC BM.13Seventy-three patients with RCC BMs were evaluated. Among patients treated with nivolumab alone (n = 39), the intracranial ORR (12%) was approximately half that of the extracranial ORR (21%).13Local PFS was noted to be improved among patients previously receiving SRS compared with patients treated with nivolumab alone (4.8 vs 2.7 months; HR 2.036, 95% CI 1.081–3.833; p = 0.0277).13The intracranial ORR was unexpectedly low, and therefore the authors concluded that intracranial activity of nivolumab monotherapy does not provide adequate control by itself.13
Newer ICI strategies for advanced RCC employ a combination of nivolumab with concurrent ipilimumab, which has been shown to further improve OS in patients without BMs compared with nivolumab monotherapy and molecular targeted agents.6,7Preliminary data from an active phase 3b/4 clinical trial (identifier no. NCT02982954,ClinicalTrials.gov) demonstrated that combination nivolumab and ipilimumab therapy, followed by maintenance nivolumab, in previously untreated, asymptomatic RCC BM patients (n = 28) led to an intracranial ORR of 28.6% and median PFS of 9.0 months.16The extracranial ORR was not reported, but other work indicated a 42% extracranial ORR with combined nivolumab and ipilimumab in advanced RCC without BM.7Consistent with prior data for patients treated with nivolumab monotherapy, results from these trials suggest that RCC BMs may not respond to ICI as well as melanoma and NSCLC BMs.7,9–12,16,17
In the present study, a significant increase in OS among BM patients treated with ICI was observed compared with those treated with molecular targeted agents. In fact, OSBMapproached the survival benefit of ICI described in prior work regarding stage IV RCC without BMs.6–8The 1-year OSBMof 69.7% among patients treated with ICI was similar to the 1-year OS of 67% of those treated with nivolumab only in the NIVOREN trial.13Additionally, a 2.6-fold increase in OSBMwas noted in patients treated with combined nivolumab and ipilimumab compared with nivolumab monotherapy in this study. The lack of statistical significance (p = 0.31) was likely secondary to the small and disproportionately sized subgroups analyzed. Further studies are needed to understand the clinical benefits of combined ICI regimens compared with monotherapy, as suggested by preliminary data from the NCT02982954 trial and correlation of the results from non-RCC BM studies.9,13,16
两治疗组进一步分层nd compared by initiation of treatment before or after BM diagnosis. Interestingly, while ICI decreased the rate of BM development when treated prior to potential development, when survival from BM diagnosis is compared, the patients in whom BMs developed, despite early treatment with ICI, did worse than those in whom ICI was initiated after BM development. This is likely because of the severity of disease at the time of progression through ICI. A similar pattern was noted in the targeted therapy group, suggesting that late development of BMs is an indicator of poor prognosis at initiation of systemic therapy.
While lack of significant, radiographically observable intracranial response in the above trials is disappointing, the presented study suggests an ongoing role for ICI in patients with BMs from RCC. When treated with ICI, these patients have improved OS compared with those treated with molecular targeted agents. The survival benefit from ICI seems to be optimal when patients are treated with concurrent nivolumab and ipilimumab, which is consistent with data from clinical trials in advanced RCC without BMs and non-RCC BMs.7,9,10,15Increased survival in our cohort was independent of patient demographics, performance status, and intracranial disease burden, with the exception of an association with improved OS when receiving SRS. While out of the scope of the current study, previous melanoma and NSCLC BM research has suggested further enhanced ORR and OS when a combination of SRS and ICI are used.
ICI in the Prevention of BM
Prevention of BM in patients with metastatic RCC is important for improving quality of life and OS. A 2011 retrospective review of 154 RCC patients treated with tyrosine kinase inhibitors reported a 5-year actuarial rate of BM of 17%, which is consistent with the findings among patients treated with targeted therapies in the present study.18Of note, this study occurred prior to FDA approval of ICI for advanced RCC and therefore a comparison against ICI was not made.18,19
不像之前的调查,目前的研究公司luded patients treated since FDA approval of nivolumab and ipilimumab in the treatment of advanced RCC. Our study seems to be the first to evaluate the role of early ICI treatment in the prevention of RCC BM development. The findings suggest that the use of ICI prior to the development of BM may decrease the probability of RCC BM development. The likelihood of BM development with ICI in RCC patients without intracranial involvement was found to be less than half of that for patients treated with molecular targeted agents only. It is possible that treatment with ICI could lead to reduced intracranial disease via a reduction in circulating tumor cells with the potential to seed the brain. In addition, ICI could promote the immune-mediated destruction of preexisting micrometastases within the brain parenchyma.20,21Based on this observation, it seems that maximal benefit from ICI treatment may be achieved when initiated early in the RCC disease course, rather than at the time of intracranial involvement or progression of intracranial disease. Interestingly, despite lower rates of BMs, the rate of LMD was higher among patients receiving ICI in our cohort. It is likely that longer OS as a result of ICI treatment increases the risk of eventual LMD. Among the patients with LMD, ICI treatment significantly increased OR compared with targeted therapies (94.3 vs 32.5 months, p = 0.002). While the current study suggests that ICI improves both OSRCCand OSBMamong patients with BMs, survival remains shorter compared with those who do not develop BMs. Thus, the use of therapeutic agents for the prevention of BM development is an important treatment goal.
Limitations
Conclusions should be made with caution given limitations inherent to the retrospective nature and relatively small sample size of the present study. The time frame of the study was selected to coincide with the increasing use of targeted therapies and ICI. However, availability and knowledge regarding these agents have evolved rapidly during this period, which likely influenced varying treatment protocols preferred by an oncologist. ICI was approved for advanced RCC by the FDA in 2011; therefore, access to ICI early in the disease course may not have been possible in all cases.
Additional local BM treatment with resection, SRS, or both could not be controlled among our cohort. Candidates for aggressive procedures, such as surgery, are often considered to be in better health. There was a similar distribution of patients who underwent resection between the groups (p = 0.16), but there was a slightly higher utilization of radiotherapy in the ICI group (p = 0.045). Increasing use of radiotherapy with ICI is likely because of changes in hospital protocols due to the ever-increasing data in support of combination SRS and ICI therapies.22–26
Conclusions
ICI has drastically improved survival in advanced RCC; however, its role in the treatment of RCC BMs is not well understood. The current study suggests that ICI has an important role in both the prevention of BM development and improving survival metrics despite previous studies observing poor intracranial response rates. While initiation of ICI has been suggested to take precedence over aggressive local management in melanoma and NSCLC BMs, such a conclusion cannot yet be made for RCC BMs. Further study of the relationship of ICI in the setting of surgical and radiosurgical intervention is critical to improving outcomes in patients with RCC BMs.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
概念和设计:老人、Damante打猎oon, Olencki. Acquisition of data: Elder, Damante, Gibbs, Pezzutti, Olencki. Analysis and interpretation of data: Elder, Damante, Huntoon, Pezzutti, Olencki. Drafting the article: Elder, Damante, Huntoon, Gibbs. Critically revising the article: Elder, Damante, Huntoon, Gibbs, Olencki. Reviewed submitted version of manuscript: Elder, Damante, Huntoon, Gibbs. Approved the final version of the manuscript on behalf of all authors: Elder. Statistical analysis: Elder, Damante. Administrative/technical/material support: Elder. Study supervision: Elder, Huntoon.
Supplemental Information
Previous Presentations
Portions of this work were presented as a poster at the 24th Annual Meeting and Education Day of the Society for Neuro-Oncology, Phoenix, Arizona, November 20–24, 2019.
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