Publications by authors named "Michael A Vogelbaum"

222 Publications

A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology.

Am Soc Clin Oncol Educ Book 2022 Apr;42:1-8

Department of Neurosurgery, Barrow Neurologic Institute, Phoenix, AZ.

Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.
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http://dx.doi.org/10.1200/EDBK_349175DOI Listing
April 2022

Leveraging the neurosurgical operating room for therapeutic development in NeuroOncology.

Adv Drug Deliv Rev 2022 May 11;186:114337. Epub 2022 May 11.

Department of NeuroOncology, Moffitt Cancer Center, Tampa, FL 33612, United States. Electronic address:

Glioblastoma (GBM) remains a disease with a dismal prognosis. For all the hope and promise immunotherapies and molecular targeted therapies have shown for systemic malignancies, these treatments have failed to show any promise in GBM. In this context, the paradigm of investigation of therapeutics for this disease itself must be examined and modifications considered. The unique challenge of the presence of blood-brain and blood-tumor barriers (BBB/BTB) raises questions about both the true levels of systemic drug delivery to the affected tissues. Window-of-opportunity (WoO) trials in neuro-oncology allow for proof-of-concept at the start of a classic phase I-II-III clinical trial progression. For therapeutics that do not have the ability to cross the BBB/BTB, direct delivery into tumor and/or tumor-infiltrated brain in the setting of a surgical procedure can provide a novel route of therapeutic access. These approaches permit neurosurgeons to play a greater role in therapeutic development for brain tumors.
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http://dx.doi.org/10.1016/j.addr.2022.114337DOI Listing
May 2022

Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline.

J Clin Oncol 2022 May 13:JCO2200333. Epub 2022 May 13.

Moffit Cancer Center, Tampa, FL.

Purpose: American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations.

Methods: "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline" was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations.

Results: The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline.".

Recommendations: Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V to brain tissue to ≤ 10 cm is conditionally recommended.Additional information is available at www.asco.org/neurooncology-guidelines.
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http://dx.doi.org/10.1200/JCO.22.00333DOI Listing
May 2022

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Front Oncol 2022 2;12:854402. Epub 2022 Mar 2.

Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL, United States.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.
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http://dx.doi.org/10.3389/fonc.2022.854402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924127PMC
March 2022

Temozolomide and radiotherapy versus radiotherapy alone in patients with glioblastoma, IDH-wildtype: post-hoc analysis of the EORTC randomized phase 3 CATNON trial.

Clin Cancer Res 2022 Mar 11. Epub 2022 Mar 11.

Erasmus MC, Netherlands.

Purpose: In a post-hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2wt anaplastic astrocytomas with molecular features of glioblastoma (redesignated as glioblastoma, IDH-wildtype in the 2021 WHO classification of CNS tumors).

Experimental Design: From the randomized phase 3 CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.

Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wildtype. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival (HR 1.19, 95%CI 0.82-1.71) or progression-free survival (HR 0.87, 95%CI 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.

Conclusions: In this cohort of patients with glioblastoma, IDH-wildtype temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-4283DOI Listing
March 2022

Surgical and Anatomic Factors Predict Development of Leptomeningeal Disease in Patients with Melanoma Brain Metastases.

Neuro Oncol 2022 Jan 29. Epub 2022 Jan 29.

Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa FL.

Background: Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma.

Methods: A retrospective chart review was performed of 1,162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected.

Results: 827 patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD.

Conclusion: In a single institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.
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http://dx.doi.org/10.1093/neuonc/noac023DOI Listing
January 2022

Balancing maximal resection and functional preservation in surgery for low-grade glioma.

Neuro Oncol 2022 May;24(5):794-795

Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

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http://dx.doi.org/10.1093/neuonc/noac008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9071335PMC
May 2022

Liquid biopsy in gliomas: a RANO review and proposals for clinical applications.

Neuro Oncol 2022 Jan 6. Epub 2022 Jan 6.

Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, USA.

Background: There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring.

Methods: The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, i.e. circulating tumor DNA, circulating tumor cells and extracellular vesicles in blood and CSF.

Results: ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict outcome.

Conclusions: There is need for standardization of biofluid collection, choice of analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
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http://dx.doi.org/10.1093/neuonc/noac004DOI Listing
January 2022

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.

J Clin Oncol 2022 02 21;40(5):492-516. Epub 2021 Dec 21.

University of Virginia Medical Center, Charlottesville, VA.

Purpose: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base.

Recommendations: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.
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http://dx.doi.org/10.1200/JCO.21.02314DOI Listing
February 2022

The presentation of brain metastases in melanoma, non-small cell lung cancer, and breast cancer and potential implications for screening brain MRIs.

Breast Cancer Res Treat 2022 Jan 20;191(1):209-217. Epub 2021 Oct 20.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Purpose: This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin.

Methods: Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method.

Results: A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006).

Conclusion: Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.
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http://dx.doi.org/10.1007/s10549-021-06420-3DOI Listing
January 2022

The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy.

Eur J Cancer 2021 10 20;156:93-108. Epub 2021 Aug 20.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Recent therapeutic advances involving the use of systemic targeted treatments and immunotherapeutic agents in patients with advanced cancers have translated into improved survival rates. Despite the emergence of such promising pharmacological therapies and extended survival, the frequency of metastases in the central nervous system has steadily increased. Effective medical and surgical therapies are available for many patients with brain metastases and need to be incorporated into multi-disciplinary care protocols. The role of neurosurgeons is evolving within these multi-disciplinary care teams. Surgical resection of brain metastases can provide immediate relief from neurological symptoms due to large lesions and provides the histopathological diagnosis in cases of no known primary malignancy. In situations where immunotherapy is part of the oncological treatment plan, surgery may be proposed for expeditious relief of edema to remove the need for steroids. In patients with multiple brain metastases and mixed response to therapeutics or radiosurgery, tumour resampling allows tissue analysis for druggable targets or to distinguish radiation effects from progression. Ventriculo-peritoneal shunting may improve quality of life in patients with hydrocephalus associated with leptomeningeal tumour dissemination and may allow for time to administer more therapy thus prolonging overall survival. Addressing the limited efficacy of many oncological drugs for brain metastases due to insufficient blood-brain barrier penetrance, clinical trial protocols in which surgical specimens are analysed after pre-surgical administration of therapeutics offer pharmacodynamic insights. Comprehensive neurosurgical assessment remains an integral element of multi-disciplinary oncological care of patients with brain metastases and is integral to tumour biology research and therapeutic advancement.
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http://dx.doi.org/10.1016/j.ejca.2021.07.032DOI Listing
October 2021

SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Neuro Oncol 2021 11;23(11):1835-1844

Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Methods: Following the 2017 AAN methodologies, a systematic literature review utilizing PubMed, EMBASE Library, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (class I-IV).

Results: Thirty-seven articles were selected for final analysis. There were limited high-level, class I studies and mostly class II and III studies. The AAN affirmed the value of these guidelines.

Recommendations: In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe antiepileptic drugs (AEDs) to reduce the risk of seizures (level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (level C). Physicians may consider the use of levetiracetam over older AEDs to reduce side effects (level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features when deciding whether or not to prescribe prophylactic AEDs (level U).
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http://dx.doi.org/10.1093/neuonc/noab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563323PMC
November 2021

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

Lancet Oncol 2021 06 14;22(6):813-823. Epub 2021 May 14.

Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, Cedex, France.

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.

Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.

Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.

Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.

Funding: Merck Sharpe & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191233PMC
June 2021

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BMC Cancer 2021 May 15;21(1):552. Epub 2021 May 15.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL, 33612, USA.

Background: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM).

Methods: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist.

Results: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively.

Conclusions: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.
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http://dx.doi.org/10.1186/s12885-021-08302-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126143PMC
May 2021

Evolution of the Neurosurgeon's Role in Clinical Trials for Glioblastoma: A Systematic Overview of the Clinicaltrials.Gov Database.

Neurosurgery 2021 07;89(2):196-203

Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: The therapeutic challenge of glioblastoma (GBM) has catalyzed the development of clinical trials to evaluate novel interventions. With increased understanding of GBM biology and technological advances, the neurosurgeon's role in neuro-oncology has evolved.

Objective: To evaluate the current landscape of procedure-based clinical trials for GBM to characterize this evolution, gain insight into past failures, and accordingly outline implications for future research and practice that may inform future studies.

Methods: The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM. Demographics, specific intervention, trial phase, and main outcome measures were abstracted.

Results: A total of 224 of 2311 GBM trials (9.7%) were identified as procedural, with the majority being based in the United States (155/224, 69.2%), single-center (155/224, 69.2%), and not randomized (176/224, 78.6%). Primary and recurrent GBMs were evenly addressed. The leading interventions were local delivery of therapeutics (50.0%), surgical techniques (33.9%), such as image-guided surgery, and novel device applications (14.3%). Phase I designs predominated (82/224, 36.6%). The top primary outcome was safety/tolerability/feasibility (88/224, 39.3%), followed by survival (46/224, 20.5%). Approximately 17% of studies were terminated, withdrawn, or suspended. Fifty-two linked publications were identified, among which 42 were classified as having a positive result.

Conclusion: Procedural interventions comprised ∼10% of all registered GBM trials. Local delivery of therapeutics, use of surgical imaging techniques and novel device applications, predominantly through phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved reporting of trial designs, outcomes, and results are needed to better inform the field and increase efficiency.
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http://dx.doi.org/10.1093/neuros/nyab169DOI Listing
July 2021

Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.

Neuro Oncol 2021 09;23(9):1547-1559

Pathology Department, Erasmus MC, Rotterdam, the Netherlands.

Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.

Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.

Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.

Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
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http://dx.doi.org/10.1093/neuonc/noab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408862PMC
September 2021

Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma.

Clin Cancer Res 2021 07 16;27(14):3916-3925. Epub 2021 Apr 16.

Medicenna BioPharma, Houston, Texas.

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).

Patients And Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.

Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, < 0.0001; = 0.3) and mRANO ( < 0.0001; = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, = 0.47; central, = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements ( = 0.017), but not central measurements ( = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local ( = 0.66, < 0.0001) and centrally determined reads ( = 0.57, = 0.0007).

Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282697PMC
July 2021

Evidence-based recommendations on categories for extent of resection in diffuse glioma.

Eur J Cancer 2021 05 2;149:23-33. Epub 2021 Apr 2.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories 'biopsy', 'partial resection', 'subtotal resection', 'near total resection', 'complete resection' and 'supramaximal resection'. Definitions rest on reduction of contrast- and non-contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2021.03.002DOI Listing
May 2021

Therapeutic Delivery to Central Nervous System.

Neurosurg Clin N Am 2021 Apr 18;32(2):291-303. Epub 2021 Feb 18.

Department of Neuro-Oncology, Neuro-Oncology Program, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA. Electronic address:

Therapies for glioblastoma face several physiologic hurdles. The blood-brain barrier (BBB) and blood-brain-tumor barrier (BTB) present impediments to therapeutic delivery of drugs to the central nervous system. Strategies to disrupt or bypass the native BBB are necessary to deliver therapeutic agents. Techniques to bypass the BBB/BTB include implantable controlled-release polymer systems, intracavitary drug delivery, direct injection of viral vectors, and infusion via convection-enhanced delivery. Ideal methods and agents to accomplish the goal providing survival benefit are yet to be determined. Further development of methods to break down or bypass the BBB and BTB is necessary for patients with glioblastoma.
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http://dx.doi.org/10.1016/j.nec.2020.12.004DOI Listing
April 2021

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

J Neurooncol 2021 May 19;152(3):591-601. Epub 2021 Mar 19.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Purpose: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT).

Methods: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model.

Results: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001).

Conclusions: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.
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http://dx.doi.org/10.1007/s11060-021-03735-5DOI Listing
May 2021

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Acta Neuropathol 2021 06 19;141(6):945-957. Epub 2021 Mar 19.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 mutations. Patients harbouring IDH1 mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
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http://dx.doi.org/10.1007/s00401-021-02291-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113211PMC
June 2021

Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases.

BMC Cancer 2021 Mar 4;21(1):223. Epub 2021 Mar 4.

Departments of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Background: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation.

Methods: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging.

Results: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis.

Conclusions: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.
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http://dx.doi.org/10.1186/s12885-021-07971-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934378PMC
March 2021

Convection-enhanced drug delivery for glioblastoma: a review.

J Neurooncol 2021 Feb 21;151(3):415-427. Epub 2021 Feb 21.

Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.

Introduction: Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied-combined with the additional costs of performing a trial evaluating CED-has limited the field's ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess.

Materials And Methods: We searched PubMed using the phrase "convection-enhanced delivery and glioblastoma". The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances.

Results: We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM.

Conclusion: While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.
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http://dx.doi.org/10.1007/s11060-020-03408-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034832PMC
February 2021

Neurosurgical involvement in clinical trials for CNS tumors.

J Neurooncol 2021 Feb 21;151(3):367-373. Epub 2021 Feb 21.

Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.

Introduction: Most clinical trials in neurooncology are led by investigators primarily trained in neurology or medical oncology. While neurosurgeons are trained to be problem-solvers and innovators, research training has historically been focused on laboratory-based discovery approaches and formalized training in prospective clinical trials research is not part of routine graduate training.

Methods: We reviewed literature that demonstrates that innovation and problem-solving are integral to the practice of neurosurgery cite multiple examples of advances in technique and technology that may have had an empirical origin but that led to prospective clinical trials resulting in change in practice.

Results: Neurosurgeons have developed and led both traditional (clinical outcome-oriented) and translational prospective clinical trials that have evaluated the best use of currently available therapeutics or tested the ability of novel therapeutics to alter the biology and/or course of disease.

Conclusions: In this review, we focus on a number of the recently developed technologies and therapeutics that were evaluated in clinical trials led or co-led by neurosurgeons. We also highlight some of the barriers that need to be addressed in order to foster neurosurgical participation and leadership in the prospective development of novel therapeutics.
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http://dx.doi.org/10.1007/s11060-020-03438-3DOI Listing
February 2021

A Prospective Validation Study of the First 3D Digital Exoscope for Visualization of 5-ALA-Induced Fluorescence in High-Grade Gliomas.

World Neurosurg 2021 05 6;149:e498-e503. Epub 2021 Feb 6.

Department of Pathology, Moffitt Cancer Center, Tampa, Florida, USA.

Background: We report on the first use of a digital 3-dimensional (3D) exoscope equipped with a 5-aminolevulinic acid (5-ALA) fluorescence visual system.

Methods: We conducted a prospective clinical trial to evaluate the utility and sensitivity/specificity of the Olympus Orbeye 3D digital exoscope when used to visualize 5-ALA-induced fluorescence in patients with high-grade glioma undergoing a clinically indicated craniotomy. At least 2 tissue samples were each obtained from regions of strong, weak. and no fluorescence and evaluated in a blinded manner by a neuropathologist.

Results: Twenty patients were enrolled. Intraoperative fluorescence was observed in 100% of subjects. One hundred twenty-one surgical specimens were collected for histopathological analysis; 40 with strong, 40 weak, and 41 with no visible fluorescence. Histopathology demonstrated 62.8% of samples (n = 76) contained abundant, 20.7% (n = 25) scarce, and 16.5% (n = 20) no tumor cells. Thirty-three of the 40 specimens (82.5%) in the strong fluorescence group correlated with abundant tumor cells and 7 (17.5%) with scarce. Twenty-nine of the 40 specimens (72.5%) in the weak fluorescence group correlated with abundant tumor cells, 7 (17.5%) with scarce, and 4 (10%) with none. Fourteen of the 41 (34.2%) specimens in the no fluorescence group had abundant tumor cells, 11 (26.8%) had scarce, and 16 (39%) had none. The sensitivity was 75% and specificity was 80%. The positive predictive value was 95% and negative predictive value was 39%.

Conclusions: Visualization of 5-ALA-induced tumor fluorescence with use of the Orbeye 3D digital exoscope was feasible and associated with a high positive predictive value.
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http://dx.doi.org/10.1016/j.wneu.2021.01.147DOI Listing
May 2021

Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome.

Clin Cancer Res 2021 04 4;27(7):2038-2049. Epub 2021 Feb 4.

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment-including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment-has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined.

Experimental Design: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM.

Results: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles.

Conclusions: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026586PMC
April 2021

Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging.

Pharmaceutics 2020 Dec 30;13(1). Epub 2020 Dec 30.

OncoSynergy, Inc., Stamford, CT 06902, USA.

Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG).

Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design.

Discussion: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing.

Trial Registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.
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http://dx.doi.org/10.3390/pharmaceutics13010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823464PMC
December 2020

Surgical Management of Glioblastoma: More Than Just Diagnosis and Decompression.

Neurosurg Clin N Am 2021 01 5;32(1):xiii-xiv. Epub 2020 Nov 5.

H. Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612, USA; University of South Florida Morsani School of Medicine Tampa, FL 33612, USA. Electronic address:

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http://dx.doi.org/10.1016/j.nec.2020.09.007DOI Listing
January 2021

Surgical Adjuncts for Glioblastoma.

Neurosurg Clin N Am 2021 Jan 5;32(1):83-91. Epub 2020 Nov 5.

Department of NeuroOncology, Moffitt Cancer Center, Tampa, FL, USA. Electronic address:

Although surgical resection of the solid tumor component of glioblastoma has been shown to provide a survival advantage, it will never be a curative procedure. Yet, systemically applied adjuvants (radiation therapy and chemotherapy) also are not curative and their options are limited by the inability of most agents to cross the blood-brain barrier. Direct delivery of adjuvant therapies during a surgical procedure potentially provides an approach to bypass the blood-brain barrier and effectively treat residual tumor cells. This article summarizes the approaches and therapeutics that have been evaluated to date, and challenges that remain to be overcome.
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http://dx.doi.org/10.1016/j.nec.2020.08.005DOI Listing
January 2021

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.

JAMA Oncol 2020 12;6(12):1939-1946

Cleveland Clinic Foundation, Moffitt Cancer Center, Tampa, Florida.

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.
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http://dx.doi.org/10.1001/jamaoncol.2020.3161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596685PMC
December 2020
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