Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial

Key Points

Question  Does treatment with vocimagene amiretrorepvec (Toca 511) and flucytosine (Toca FC), compared with standard of care (SOC), improve survival among patients with recurrent glioblastoma and anaplastic astrocytoma?

Findings  In this randomized open-label clinical trial of 403 patients assigned to receive Toca 511/FC or SOC, the primary end point of overall survival was not met (11.1 months for the Toca 511/FC group and 12.22 months for the SOC group). Secondary end points did not demonstrate statistically significant differences and rates of adverse events were similar in the 2 groups.

Meaning  Toca 511 and Toca FC treatment did not improve survival for patients with recurrent glioblastoma and anaplastic astrocytoma.

Importance  New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.

Objective  To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC).

Design, Setting, and Participants  A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.

Interventions  Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators’ choice of single therapy: lomustine, temozolomide, or bevacizumab.

Main Outcomes and Measures  The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS.

Results  All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.

Conclusions and Relevance  Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.

Trial Registration  ClinicalTrials.gov Identifier: NCT02414165

High-grade gliomas (HGGs), including grade III anaplastic astrocytoma (AA) and grade IV glioblastoma, are the most aggressive malignant primary brain tumors.¹ Patients with glioblastoma and AA receive maximal safe resection plus radiotherapy with concurrent chemotherapy temozolomide, followed by maintenance temozolomide as standard of care (SOC) treatment. This results in a median overall survival (mOS) ranging from 12.7 months to 3.9 years depending on the tumor grade and the molecular and genetic profile.^2-4 Despite aggressive treatment, nearly all HGGs eventually recur, and there are no effective treatments for this population. For recurrent glioblastoma, the median progression-free survival is as short as 1.8 months⁵ and mOS ranges from 7.1 to 9.8 months.^6-8 Chemotherapies such as lomustine and temozolomide have been approved by the US Food and Drug Administration for treating glioblastoma and AA, but the OS improvement in the recurrent setting is minimal.⁹ New treatments are needed to improve the prognosis of this patient population.

Vocimagene amiretrorepvec (Toca 511) is an investigational γ retroviral replicating vector encoding a transgene for an optimized yeast cytosine deaminase, an enzyme that converts 5-fluorocytosine (5-FC) into 5-fluorouracil in the tumor microenvironment without systemic 5-fluorouracil adverse effects.¹⁰ Preclinical data indicated that Toca 511 and 5-FC treatment kills tumor cells and nearby immunosuppressive cells such as myeloid-derived suppressor cells and tumor-associated macrophages, leading to T-cell priming and durable systemic antitumor immune activity.¹¹ Multiyear durable complete responses have been observed in recurrent HGG patients in a phase 1 resection-injection trial (NCT01470794) with Toca 511/FC.¹² Integrated Toca 511 was commonly detected in tumor and transiently detected in blood. No evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes was observed.¹³

A phase 2/3 randomized clinical trial of Toca 511 and Toca FC vs SOC for treatment of patients with recurrent glioblastoma and AA has been completed. Efficacy, safety, and baseline molecular and immunological results are reported here.

This was a multicenter, randomized, open-label study of Toca 511 and Toca FC vs SOC that was investigator’s choice of single-agent chemotherapy (lomustine or temozolomide) or bevacizumab for patients with first or second recurrence of glioblastoma or AA. Patients were recruited from 67 centers in the US, Canada, Israel, and South Korea, with 58 sites enrolling patients. The trial was conducted from November 30, 2015, to December 20, 2019. This study was approved by the institutional review board and institutional biosafety committee for each site, and all patients provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials. The trial protocol is available in Supplement 1.

Patients aged 18 to 75 years with first or second recurrence of histologically proven glioblastoma or AA were eligible. Additional key inclusion criteria were prior first-line multimodal therapy; tumor size between 1 and 5 cm; adequate laboratory values for surgery; and Karnofsky Performance Status score of at least 70. Key exclusion criteria were multifocal tumor; any active infection requiring systemic antibiotic, antifungal, or antiviral therapy within the previous 4 weeks; or received bevacizumab in the recurrent setting.

Patients were randomized at the time of resection in a 1:1 ratio to either Toca 511 and Toca FC (Toca 511/FC), or SOC group. Stratification was by isocitrate dehydrogenase 1 (IDH1) variant status (variation vs wild type), Karnofsky Performance Status score (70-80 vs 90-100) and geographical region (United States vs Canada vs outside North America). Further methodologic details on randomization and masking are provided in the eMaterials and eMethods in Supplement 2.

Patients in the Toca 511/FC group received 1 dose of approximately 4 mL of Toca 511 (10⁸ TU/mL) injected into the resection cavity wall at the time of resection. Video training was provided for virus delivery as well as optional mentorship from experienced investigators from the similar phase 1 trial (NCT01470794). Approximately 6 weeks after resection, patients began the first cycle with a 7-day course of oral Toca FC dosed at 220 mg/kg/d, and repeated every 6 weeks. Toca FC was taken by patients as long as the drug was tolerated and the investigator believed patients were obtaining benefit. For the SOC group, patients began the first cycle approximately 6 weeks after resection, and the schedule was as follows: lomustine at 110 mg/m² repeated every 6 weeks; temozolomide either at 50 mg/m² once daily continuously or at 150 mg/m² once daily for 5 consecutive days per 28-day cycle that could be increased to 200 mg/m² once daily for 5 consecutive days in the following 28-day cycles; or bevacizumab at 10 mg/kg by intravenous infusion every 2 weeks. The SOC group treatment was continued until confirmed progression or end of treatment.

The primary end point was overall survival (OS), and the secondary end points were safety, durable response rate (DRR), duration of durable response, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS using modified Response Assessment in Neuro-Oncology criteria by independent radiologic review. Two additional secondary end points are not reported herein: patient reported outcome and quality of life and progression-free survival (see the trial protocol in Supplement 1). Further methodologic details on study end points are provided in eMaterials and eMethods in Supplement 2.

Methodologic details of viral safety testing, peripheral blood monitoring, and tumor profiling are provided in eMaterials and eMethods in Supplement 2.

The primary end point was OS, measured from randomization date to death due to any cause; the secondary end points were DRR, durable clinical benefit rate, duration of durable response, OS and DRR by IDH1 variant status, and 12-month OS. The 257 events were needed to detect a hazard ratio (HR) of 0.685 at a 2-sided α of .05 and a power of 85%. The OS end point incorporated group sequential design with the O’Brien-Fleming boundaries as implemented by Lan-DeMets α spending method to avoid inflation of the type I error rate. For the secondary end points, the Holm procedure was planned to adjust for multiplicity. All efficacy analyses included the intent-to-treat population (ITT), and all safety analyses included all randomized patients who underwent resection. Further details on statistical analysis are provided in the eMaterials and eMethods in Supplement 2.

A total of 403 patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) underwent randomization from November 2015 to November 2018 (187 patients in the phase 2 and 216 patients in the phase 3) at 58 institutions in 4 countries, with an enrollment pause from February 2017 to October 2017 between the phase 2 and the phase 3 portion (Figure 1). The last-known follow-up date was May 2019. Patient demographic characteristics and neuro-oncology history were balanced between the two groups (Table 1), and were also balanced between the patients in phase 2 and the patients in phase 3 (eTable 1 in Supplement 2).

For the Toca 511/FC group, 199 patients (99%) received Toca 511 at the time of surgery, and 197 patients (98%) received both Toca 511 and at least one cycle of Toca FC. For the SOC group, 141 patients (70%) received at least one cycle of drug (Figure 1). At data cutoff, the median number of cycles of Toca FC taken by patients on the Toca 511/FC arm was 2 cycles. Maximal survival was achieved in patients who received up to 4 cycles of Toca FC (eFigure 1 in Supplement 2). For the SOC group, the median cycle of metronomic temozolomide was 3, of temozolomide was 3, of lomustine was 2, and of bevacizumab was 4 (eTable 2 in Supplement 2).

At final analysis, 271 deaths were observed, with 141 deaths in the Toca 511/FC group and 130 deaths in the SOC group. The median follow-up for all randomized patients was 22.8 months. A total of 29 patients (9.0% [18 of 201] on the Toca 511/FC arm and 5.4% [11 of 202] on the SOC arm) were continuing treatment at data cutoff. The mOS in the ITT population was 11.1 months for the Toca 511/FC arm and 12.22 months for the SOC arm (HR, 1.06; 95% CI, 0.83-1.35; P = .62) (Figure 2), which did not meet the statistical significance for the study’s primary end point. The preplanned secondary end points also did not demonstrate statistically significant differences in outcomes (eTable 3 in Supplement 2).

In preplanned subgroup analyses, there was no statistically significant effect on mOS in the Toca 511/FC group among patients with IDH1-variant tumors and AA (HR, 0.64; 95% CI:, 0.33-1.24; P = .19; HR, 0.57; 95% CI, 0.28-1.14; P = .11, respectively) (Figures 3; eFigures 2a and 2b in Supplement 2). In the preplanned subgroup analysis of patients at second recurrence (n = 60), improvement in OS was observed, with an mOS of 21.8 months for the Toca 511/FC group (n = 28) and 11.1 months for the SOC group (n = 32) (HR, 0.43; 95% CI, 0.21-0.87; P = .02) (Figure 3; eFigure 2c in Supplement 2) although these numbers would not be statistically significant when adjusted for multiplicity. Demographic characteristics and neuro-oncology history in this subgroup were balanced between the 2 groups (eTable 4 in Supplement 2). In further exploratory post hoc subset analyses in the second recurrence subpopulation, while patient numbers were very small, there was an improvement in survival for patients with IDH1-variant tumors, with mOS not reached for the Toca 511/FC group (n = 8), and 10.9 months for the SOC group (n = 10) (HR, 0.14, 95% CI, 0.03-0.69; P < .001). Also with very small numbers, there was an improvement in survival for patients with AA, with mOS not reached for the Toca 511/FC group (n = 7) and 9.07 months for the SOC group (n = 6) (HRs were not estimated) (eFigure 3 in Supplement 2).

The safety population included 100% (201 of 201) of patients in the Toca 511/FC group and 99% (199 of 202) of patients in the SOC group. No treatment-associated adverse events resulted in deaths in either group, and the most common adverse events for both groups are reported in Table 2.

The presence of Toca 511 DNA and RNA was sampled longitudinally throughout the course of treatment.¹⁴ Quantitative Toca 511 DNA was observed in 4.5% of patients at cycle 1 day 1 and no viral DNA signal was observed at cycle 4-day 1 or beyond in any patients out to 1.5 years (eTable 5 in Supplement 2). Most patients showed quantitative viral RNA signal postsurgery (70.9%) but had cleared signal before cycle 1 day 1 of Toca FC (eTable 5 in Supplement 2). Once a patient’s viral RNA signal dropped below quantitative levels, no additional quantitative signal was detected thereafter. These results are consistent with prior experience under similar trial conditions (NCT01470794).¹⁴

Exploratory baseline molecular and immune profiling were performed to better understand the patient population and balance in this study (eFigures 4-32 in Supplement 2). Analyses of tumor obtained pretreatment during resection indicated that IDH1-variant tumors had a favorable immune cell composition for an immuno-oncology therapy compared with IDH1-wild type tumors (eFigure 26 in Supplement 2), including lower levels of M0 macrophages, higher levels of CD4 memory cells, resting NK cells, and resting dendritic cells than IDH1-wild type tumors. Immune cell composition was similar between the Toca 511/FC and SOC groups, including by ITT population, by subgroups such as histology, number of recurrences, and IDH1 status (eFigure 22 in Supplement 2). Wild-type IDH1 tumors preferentially expressed mRNAs encoding proteins involved in innate immune responses (eFigure 23 in Supplement 2), which could inhibit Toca 511 infection. Variant IDH1 tumors exhibited higher lymphoid compartment cells in baseline peripheral blood mononuclear cells compared with wild-type IDH1 tumors, suggesting that patients with a variant IDH1 tumor have a more robust peripheral immune cell population (eFigure 29 in the Supplement 2).

In a disease with an extremely high unmet need, recent trials such as CheckMate-143 with nivolumab,¹⁵ INTELLANCE 2 with Depatux-M, GLOBE with VB-111 in combination with bevacizumab, have not shown efficacy benefits in recurrent HGG setting.^16,17 Similarly, TOCA 5 did not meet primary objective of improved OS or the secondary end points. Overall, there were no observed significant biases in demographic and specified stratification markers (Table 1), or known molecular prognostic markers (eFigure 4 in Supplement 2) between the groups. Toca 511 and Toca FC were well tolerated with safety comparable to the SOC group, similar to previously reported and as expected in this setting. All patients in the Toca 511/FC group either showed no detectable peripheral virus or had transient signal that was cleared before cycle 4. Baseline peripheral blood immune cell health was also comparable between groups. However, subgroups that appeared to do better on treatment group showed more robust baseline immune cells and reduced immune suppressive cells (eFigures 30 and 31 in Supplement 2). The median numbers of cycle for Toca FC and SOC were low and likely incompatible with the amount given to long-term survivors or to the proposed mechanism of action of Toca 511/FC reported previously^11,12; more cycles might be required to see a therapeutic effect. Suboptimal virus delivery was not practical to assess in this brain cancer setting and whether enough virus was delivered to patients remains unknown.

A preplanned subgroup analysis identified a subgroup with better outcomes. Patients with second recurrence appear to have better outcomes with Toca 511/FC treatment compared with SOC. These differences seem to be independent of other prognostic factors as the tumor molecular profiles between patients at first recurrence or second recurrence are generally similar and lack significant group imbalances between the two groups (eFigures 13, 14, and 28 in Supplement 2). Within the second recurrence population, while patient numbers were small, there was an improvement in survival for patients with IDH1-variant tumors and patients with AA. Patients with IDH1 variants or AA histology have a notably better prognosis than those with IDH1-wildtype and GBM histology as evidenced by longer OS and higher rates of 5-year survival.^18-20 These slower growing, clinically less aggressive (indolent) HGG tumors may have more potential to respond to therapy that may stimulate a local immune response, such as Toca 511 and Toca FC, given the delayed nature of response to immune therapy noted by others in the field.²¹

Although the numbers analyzed were small, a consistent pattern of baseline immune potential was observed in treatment subgroups that demonstrated improvements in survival to Toca 511/FC treatment compared with SOC (eFigures 24, 26-31 in Supplement 2). The uniqueness of the potential mechanisms of action of Toca 511 and Toca FC may contribute to the efficacy advantage observed in these patients. In the phase 1 resection-injection trial (NCT01470794), a durable response rate of 21.7% was observed in patients who met the phase 2/3 trial entry criteria with a median duration of response follow-up of at least 35.7 months as of August 2017.^12,14 In these patients, responses were observed at approximately 6 to 19 months after Toca 511 administration, consistent with an immunologic-based response.

This study has limitations. Study limitations include the small number of cycles of patients receiving treatment, the very small number of patients included in the subgroup analysis, insufficient number of blood and tissue samples collected for biomarker analysis, and variations of Toca 511 distribution in the resection cavity wall.

In this multicenter randomized clinical trial of patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or the secondary efficacy end points. In a small subgroup analysis, a treatment effect was seen in a few patients at second recurrence. The results of this study may help to inform future study designs including population selection and minimum number of Toca FC treatment cycles.

Accepted for Publication: May 27, 2020.

Corresponding Authors: Timothy Cloughesy, MD (primary), Director and Professor, UCLA Neuro-Oncology Program, University of California, Los Angeles, 710 Westwood Plaza, Ste 1-230, Los Angeles, CA 90095 (tcloughesy@mednet.ucla.edu); Michael A. Vogelbaum, MD, PhD, Program Leader of Neuro-Oncology and Chief of Neurosurgery, Professor of Neurosurgery, H. Lee Moffitt Center, 12902 USF Magnolia Dr, Tampa, FL 33612 (michael.vogelbaum@moffitt.org).

Published Online: October 29, 2020. doi:10.1001/jamaoncol.2020.3161

Author Contributions: Dr Kabbinavar had full access to all of the data in the study at the time the initial manuscript was submitted; representative of Denovo Biopharma (Dr Wen Luo) takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cloughesy, Butowski, Landolfi, Chen, Gruber, Ostertag, Kheoh, Kabbinavar.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cloughesy, Butowski, Kim, Chen, Gruber, Rao, Accomando, Ostertag, Montellano.

Critical revision of the manuscript for important intellectual content: Cloughesy, Petrecca, Walbert, Butowski, Salacz, Perry, Damek, Bota, Bettegowda, Zhu, Iwamoto, Placantonakis, Elder, Kaptain, Cachia, Moshel, Brem, Piccioni, Landolfi, Chen, Gruber, Hogan, Ostertag, Montellano, Kheoh, Kabbinavar, Vogelbaum.

Statistical analysis: Gruber, Rao, Hogan, Accomando, Kheoh.

Obtained funding: Gruber.

Administrative, technical, or material support: Petrecca, Walbert, Butowski, Bettegowda, Zhu, Iwamoto, Kim, Elder, Cachia, Moshel, Landolfi, Chen, Gruber, Hogan, Accomando, Ostertag, Montellano, Kabbinavar, Vogelbaum.

Supervision: Cloughesy, Petrecca, Butowski, Bota, Kaptain, Brem, Piccioni, Chen, Gruber, Hogan, Ostertag.

Conflict of Interest Disclosures: Dr Gruber is a member of the board for Tocagen Inc. Drs Rao, Hogan, Accomando, Ostertag, Montellano, Kheoh, and Kabbinavar were Tocagen employees. Dr Cloughesy reported personal fees from Roche, personal fees from Trizel, personal fees from Medscape, personal fees from Bayer, personal fees from Amgen, personal fees from Odonate Therapeutics, personal fees from Pascal Biosciences, personal fees from Del Mar Pharmaceuticals, personal fees from Tocagen, personal fees from Kayopharm, personal fees from GW Pharma, personal fees from Kiyatec, personal fees from AbbVie, personal fees from Boehringer Ingelheim, personal fees from VBL, personal fees from VBI, personal fees from Deciphera, personal fees from Agios, personal fees from QED, personal fees from Merck, personal fees from Genocea, personal fees from Celgene, personal fees from Puma, personal fees from Lilly, and personal fees from BMS outside the submitted work; in addition, Dr Cloughesy had a patent to 62/819322 issued and licensed; and Member of the board for the 501c3 Global Coalition for Adaptive Research and CMO for the entity; Co-founder and board member of Katmai Pharmaceuticals. Dr Petrecca reported other from Tocagen during the conduct of the study. Dr Walbert reported personal fees from Tocagen outside the submitted work. Dr Damek reported grants from Tocagen during the conduct of the study; grants from NovoCure, grants from Kazia Therapeutics, grants from Genentech, grants from Orbus, grants from Roche, and grants from Forma outside the submitted work. Dr Bota reported personal fees from NovoCure and personal fees from Zai Lab outside the submitted work. Dr Bettegowda reported he is a consultant for Depuy-Synthes and Bionaut Pharmaceuticals. The activities associated with those entities are not related to the work presented in this manuscript. Dr Zhu reported grants from Tocagen, Inc and personal fees from Tocagen, Inc during the conduct of the study. Dr Iwamoto reported personal fees from Tocagen during the conduct of the study; personal fees from Merck, personal fees from Guidepoint, grants from BMS, personal fees from NovoCure, personal fees from Alexion, personal fees from AbbVie, and personal fees from Regeneron outside the submitted work. Dr Placantonakis reported personal fees from Tocagen during the conduct of the study; personal fees from Monteris, personal fees from Synaptive, and personal fees from Robeaute outside the submitted work; in addition, Dr Placantonakis had a patent to “Method to treat high grade glioma” pending. Dr Brem reported personal fees from Tocagen during the conduct of the study. Dr Piccioni reported personal fees from Tocagen during the conduct of the study. Dr Chen reported other from Tocagen during the conduct of the study; personal fees from Tocagen outside the submitted work. Dr Gruber reported grants from the US Food and Drug Administration orphan drug grant, other from Apollo Bio, other from Abentis, and other from Denovo Pharma during the conduct of the study; other from Apollo Bio, other from Abentis, and other from Denovo pharma outside the submitted work; in addition, Dr Gruber had a patent to many pending, issued, licensed, and with royalties paid, a patent to many pending, issued, and licensed, and a patent to many pending, issued, and licensed; and Stock and option ownership in Tocagen. Dr Hogan reported other from Tocagen Inc during the conduct of the study. Dr Accomando reported personal fees from Tocagen Inc. during the conduct of the study; personal fees from Tocagen Inc. outside the submitted work. Dr Ostertag reported a patent to US20130130986A1 issued, a patent to US20130323301A1, a patent to US20180021365A1, and a patent to US20140178340A1 . Dr Montellano reported grants from the US Food and Drug Administration Office of Orphan Products Development during the conduct of the study. Dr Kheoh reported other from Tocagen Inc during the conduct of the study. Dr Kabbinavar reported other from Tocagen Inc during the conduct of the study; other from Tocagen outside the submitted work; and Employee of Tocagen Inc. Dr Vogelbaum reported personal fees and other from Tocagen during the conduct of the study; other from Infuseon Theraepeutics and personal fees from Celgene outside the submitted work. No other disclosures were reported.

Funding/Support: The study was sponsored and funded by Tocagen Inc, which developed vocimagene amiretrorepvec (Toca 511) and flucytosine (Toca FC) used in this study, and is now a part of Denovo Biopharma; and it also received a grant awarded by the US Food and Drug Administration Office of Orphan Products Development (FD-R-5732).

Role of the Funder/Sponsor: Tocagen Inc developed the protocol in collaboration with the corresponding authors. Tocagen Inc also was responsible for clinical data collection and management, performed the analyses of the data and was responsible for the preparation, review, and approval of the manuscript and decision to submit the manuscript for publication.

Additional Contributions: We thank Asha Das, MD (a former Tocagen employee) for study design and oversight of study conduct for many years of the TOCA 5 study. We thank the following investigators for enrolling patients in the TOCA 5 study: Nina Martinez (Thomas Jefferson University, Philadelphia, Pennsylvania), Nam Tran (Moffitt Cancer Center, Tampa, Florida), Do-Hyun Nam (Samsung Medical Center, Seoul, South Korea), Chul-Kee Park (Seoul National University Hospital, Seoul, South Korea), David Tran (University of Florida, Gainesville, Florida), Rohan Ramakrishna (Weill Cornell Medical College, New York, New York), Karen Fink (Baylor University Medical Center, Dallas, Texas), Deborah Olin Heros (University of Miami, Miami, Florida), Gelareh Zadeh (Toronto Western Hospital, Toronto, Canada), Garth Nicholas (Ottawa Hospital Regional Cancer Centre, Ottawa, Canada), Vivek Mehta (University of Alberta, Edmonton, Alberta), H. Ian Robins (University of Wisconsin, Madison, Wisconsin), Marshall Piz (CancerCare Manitoba, Winnipeg, Manitoba), Jason Heth (University of Michigan, Ann Arbor), Seem Nagpal (Stanford University, Stanford, California), Michael Pearlman (Colorado Neurological Institute, Engelwood, Colorado), Manmeet Ahulwalia (Cleveland Clinic, Cleveland, Ohio), Nimish Mohile (University of Rochester Medical Center, Rochester, New York), Ryan Merrell (NorthShore University Health System, Evanston, Illinois), David Schiff (University of Virginia Health System, Charlottesville, Virginia), Reid C. Thompson (Vanderbilt University Medical Center, Nashville, Tennessee), Raphael Davis (Stony Brook University Hospital, Stony Brook, New York), David Macdonald (London Regional Cancer Centre, London, Canada), David Baskin (Houston Methodist Hospital, Houston, Texas), Michael Schulder (North Shore University Hospital, Lake Success, New York), Christopher Cifarelli (West Virginia University, Morgantown, West Virginia), Lars Anker (St. Joseph Hospital, Orange, California), John Trusheim (Abbott Northwestern Hospital, Minneapolis, Minnesota), Nicole Shonka (University of Nebraska Medical Center, Omaha, Nebraska), Rachel Grossman (Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel), James W. Leiphart (Inova Neuroscience and Spine Institute, Fairfax, Virginia), Andrew Sloan (University Hospitals Cleveland Medical Center, Cleveland, Ohio), Mariko DeWire (Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio), Jeffrey L. Gross (Associated Neurologists of Southern Connecticut), David Mathieu (Sherbrooke Hospital University Centre, Sherbrooke, Canada, Sin-Soo Jeun (Seoul St. Mary’s hospital, Seoul, South Korea), Jong Hee Chang (Severance Hospital, Seoul, South Korea, Alexander Lossos (Hadassah Medical Center, Jerusalem, Israel).

Data Sharing Statement: See Supplement 3.