bluuebunny/crossref_metadata_2025 huggingface dataset:
BSCI-22 DETERMINING THE EFFECT OF NOVEL SMALL MOLECULE DRUGS AGAINST THE MIGRATION OF BRAIN METASTASIS INITIATING CELLS (BMICS)
Authors: Mobilio Daniel , Kieliszek Agata , Chafe Shawn , Venugopal Chitra , Singh Sheila
Published: August 2022

BACKGROUND

Brain metastases are secondary tumors that predominantly arise from the spread of lung, skin, and breast cancers. The current standard of care for brain metastases is complete surgical resection, with a median survival of four months. Therefore, there is a dire need to discover new therapies that effectively target brain metastases. To do this, we have identified anti-brain metastasis drugs that specifically target brain metastasis initiating cells (BMICs), a cancer stem cell population that is thought to escape standard therapies and has the ability to leave their primary tumor, seed the brain, and form a secondary brain tumor. Since the migration of the BMICs is essential to the development of brain metastases in patients, the main goal of this study was to determine the effect our anti-brain metastasis drugs have against the migration of lung, skin, and breast BMICs.

METHODS

This migration assay utilizes a bi-well silicone structure which effectively establishes a ‘wound’ healing-like migration assay. BMICs are plated in optimized equal concentrations in each silicone bi-well structure to successfully form two cellular mono-layers that are separated by a middle silicone wall. Once cells adhere to the plate the silicone structure is removed and the area between the two cell populations is imaged over time with an in vitro imaging system.

RESULTS

This optimized assay has been used to screen our anti-brain metastasis drugs against the migration of lung, breast, and skin BMICs. Thus far our drugs have been tested against lung and skin BMICs which resulted in a significant decrease in BMIC migration.

SIGNIFICANCE

Since brain metastasis arises from the migration of cancer cells to a secondary organ, it is crucial to discover the effect of anti-brain metastasis drugs on BMIC migration prior to the initiation of preclinical animal trials.
CLRM-08 TARGETING IMMUNE-PAYLOAD TO THE GLIOBLASTOMA TUMOR MICROENVIRONMENT USING A MACROPHAGE-BASED TREATMENT RELYING ON AUTOLOGOUS, GENETICALLY MODIFIED, HEMATOPOIETIC STEM CELL-BASED THERAPY: THE TEM-GBM STUDY (NCT03866109)
Authors: Eoli Marica , Farina Francesca , Gentner Bernhard , Capotondo Alessia , Anghileri Elena , Barcella Matteo , Brambilla Valentina , Bruzzone Maria Grazia , Carrabba Matteo , Cuccarini Valeria , d’Alessandris Giorgio , Meco Francesco Di , Ferla Valeria , Franzin Alberto , Ferroli Paolo , Gagliardi Filippo , Legnani Federico , Mazzoleni Stefania , Mortini Pietro , Naldini Matteo Maria , Olivi Alessandro , Pallini Roberto , Patanè Monica , Paterra Rosina , Pollo Bianca , Saini Massimo , Snider Silvia , Naldini Luigi , Russo Carlo , Finocchiaro Gaetano , Ciceri Fabio
Published: August 2022

We developed an autologous hematopoietic stem cell-based platform designed to deliver IFNa, by a transcriptional and post-transcriptional control mechanism mediated by miRNA target sequences, specifically into the tumor microenvironment (TME) via Tie-2 expressing monocytes (Temferon). As of Feb 2022, 3 escalating doses of Temferon (0.5-2.0x106/kg) were tested across 15 newly diagnosed, unmethylated MGMT GBM patients assigned to 5 cohorts. Follow-up from surgery is 6–28mo (2–25mo after Temferon). To date, no DLTs have been identified. As expected, 1mo after the administration of the highest tested dose, the hematopoietic system of Temferon-treated patients was composed of up to 30% of CD14+ modified cells. Temferon-derived progeny persisted, albeit at lower levels, up to 18mo (longest time of analysis). Despite the substantial proportion of engineered cells, very low concentrations of IFNα were detected in the plasma and in the CSF, indicating tight regulation of transgene expression. SAEs were mostly attributed to conditioning chemotherapy (infections) or disease progression (seizures). 1SUSAR (persistent GGT elevation) occurred. Median OS is 15mo from surgery. Homing of transduced cells to the tumor was demonstrated by the presence of gene-marked cells in the 2nd surgery specimens of 3 out 4 pts belonging to low dose cohorts. Single-cell RNA seq of the TME highlighted a Temferon signature associated with the induction IFNa responsive genes and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from cohort 3, who had PD at D+120 with two distant enhancing lesions, and increased tumor necrosis. 1y following Temferon, with no 2nd-line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter. The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients, and anecdotal evidence for long lasting effects of Temferon in prevention of disease progression.
CLRM-14 INTRATUMORAL EXTRACELLULAR METABOLIC IMPACT OF DFMO AND AMXT 1501 IN LIVE HUMAN GLIOMAS
Authors: Riviere-Cazaux Cecile , Neth Bryan , Rahman Masum , Kizilbash Sani , Burns Terry
Published: August 2022

Gliomas may leverage alternate metabolic pathways in response to metabolism-targeted therapeutic intervention, all of which remain unexplored in the live human glioma, in situ. Defining emergent mechanisms of metabolic resistance in response to therapeutic challenge can help guide rational combinatorial therapies. To date, the metabolic response of gliomas in response to therapeutic intervention has remained poorly understood due to the relative inaccessibility of the live human tumor, in situ. Microdialysis is an underutilized tool that could be leveraged to overcome this longstanding challenge. Data from our ongoing intraoperative microdialysis trial have revealed an upregulation of polyamine metabolism and a novel glioma-associated metabolite, guanidinoacetate (GAA) -- a metabolite co-produced with ornithine, which is required for polyamine synthesis. In a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion (difluoromethylornithine, DFMO) with or without blockade of polyamine uptake (AMXT 1501) to identify candidate extracellular biomarkers of target engagement and cytotoxicity in fifteen post-operative patients who have undergone a standard-of-care planned subtotal resection for high-grade glioma. Intraoperatively, high-molecular-weight catheters will be implanted into the residual tumor and brain adjacent to the resection cavity for post-operative longitudinal monitoring of extracellular metabolites via microdialysis. Polyamines and guanidinoacetate, a candidate biomarker of glioma-upregulated polyamine synthesis, will be monitored throughout therapeutic intervention from post-operative day (POD) 1 to POD5 via longitudinal microdialysis to determine live in situ glioma pharmacodynamic responses to polyamine depletion. Catheters will be removed on post-operative day five prior to discharge. We hypothesize that GAA will reflect local tumor production of polyamine metabolism. Additionally, in situ microdialysis in Phase 0 trials will allow for pharmacodynamic and pharmacokinetic, in addition to metabolic, monitoring, an opportunity which is rarely afforded in most clinical trials due to lack of access to the CNS.
CLRM-15 TRIAL IN PROGRESS: A PHASE 1B/2 STUDY OF GB5121, A NOVEL, HIGHLY SELECTIVE, POTENT, AND CNS-PENETRANT INHIBITOR OF BRUTON’S TYROSINE KINASE (BTKI) FOR RELAPSED/REFRACTORY PRIMARY/SECONDARY CNS LYMPHOMA (R/R PCNSL/SCNSL) AND PRIMARY VITREORETINAL LYMPHOMA (PVRL)
Authors: Soussain Carole , Grommes Christian , Issa Samar , Ward Renee , Peterson Caryn , Cravets Matt , Mathias Anita , Sosa Judith , Kirby Brian , Ding Zhaoqing , Yusuf Isharat , Rose Mark , Steinberg Marcos , Tun Han W
Published: August 2022

BTK plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in primary CNS lymphomas, and hence represents an excellent therapeutic target. Ibrutinib, a first-generation BTKi, was evaluated in phase 1/2 trials for R/R PCNSL, SCNSL, and PVRL, showing limited survival benefit. GB5121 is a novel, orally available, covalent BTKi with superior specificity, CNS penetration, and CNS target occupancy in preclinical testing versus other BTKis including ibrutinib. GB5121 is well-suited for evaluation in CNS lymphoma. This is a phase 1b/2 open-label study of GB5121 in adults with R/R PCNSL, isolated SCNSL or PVRL and will be conducted in three parts: phase 1b dose-escalation, expansion, and phase 2. Eligibility criteria for phase 1b dose-escalation and expansion (N≈30 for each) include age ≥18 years, ECOG≤2, R/R PCNSL, R/R SCNSL with CNS-only relapse, or R/R PVRL. Patients with newly diagnosed PCNSL who cannot tolerate standard high-dose methotrexate-based therapies are also eligible. Patients with prior allogeneic stem cell transplant are excluded. A Bayesian optimal interval design will be employed to perform dose escalation to determine the recommended phase 2 dose (RP2D). In the absence of dose-limiting toxicity (DLT), dose levels will increase sequentially according to a modified Fibonacci approach. Safety, tolerability, PK/PD, DLT, maximum tolerated dose, and preliminary therapeutic activity will be assessed to determine the optimal biological dose informing the RP2D. Phase 1b expansion will further explore therapeutic activity and characterize safety and tolerability of GB5121 at the RP2D. Phase 2 will initiate following RP2D determination. This is a single-arm, open-label study to investigate GB5121 safety and efficacy in patients with R/R PCNSL. Adverse events will be graded per CTCAE v5.0. Clinical response will be determined using International Primary CNS Lymphoma Collaborative Group criteria. Progression-free and overall survival will be evaluated. Enrollment begins May 2022 (NCT05242146).
CLRM-16 PATIENT-FOCUSED DRUG DEVELOPMENT IN NEURO-ONCOLOGY: A PILOT STUDY OF QUALITATIVE PATIENT INTERVIEWS EMBEDDED WITHIN A NEUROFIBROMATOSIS 2 CLINICAL TRIAL
Authors: Merker Vanessa , Von Imhof Liesel , Park Elyse , Babovic-Vuksanovic Dusica , NghiemPhu PhiOanh [Leia] , Yohay Kaleb , Plotkin Scott
Published: August 2022

BACKGROUND

The Food and Drug Administration recently issued guidance on conducting qualitative research to support patient-focused drug development. In prior FDA submissions, qualitative data has been critical to demonstrate the content validity of and meaningfulness of change in quantitative trial endpoints. Qualitative patient interviews embedded within neuro-oncology trials can supplement traditional quantitative measures by providing nuanced information on patients’ treatment priorities, benefit/risk assessments, and quality of life.

METHODS

We interviewed people with neurofibromatosis 2 (NF2) in stage one of the brigatinib arm of a multicenter, phase II, adaptive platform-basket trial for progressive NF2-related tumors (NCT04374305). Transcripts were coded by two analysts using a hybrid inductive/deductive framework; cross-cutting themes were generated using the Framework Method.

RESULTS

16/20 trial enrollees participated in interviews May 2021-March 2022. The radiographic response rate (volume shrinkage ≥20% from baseline) at 6 months for target and non-target tumors was 5% and 22%, respectively. However, most participants rated their change in overall status as minimally (10/16) or much (3/16) improved. Several participants acknowledged their tumor size had not changed significantly but felt tumor stability was an improvement over previously accelerated growth rates; this importantly allowed them to avoid or postpone future surgery. Participants also valued prevention of symptomatic decline, minimal impact of side effects on social roles and activities, the convenience of oral medication, and the sense of hope and agency gained from participating in a trial.

CONCLUSIONS

Virtual, in-depth qualitative interviews were feasible across multiple sites and provided unique information on NF2 patients’ conceptualization of clinical benefit. Qualitative interviews embedded within neuro-oncology trials can reveal 1) whether trial design and choice of outcome measures align with patient priorities; 2) whether and how new treatments improve patients’ quality of life; and 3) what degree of change in quantitative measures such as radiographic progression are clinically meaningful.
CLRM-17 USE OF EXTERNAL CONTROL DATA FOR PLANNING AND ANALYZING GBM TRIALS: READY FOR PRIME TIME?
Authors: Polley Mei-Yin , Schwartz Daniel , Dignam James
Published: August 2022

Randomized controlled trials (RCT) have been the gold standard for evaluating medical treatments for many decades. Randomization reduces systematic biases resulting from treatment or patient selection, whereby the improvement in clinical outcomes may be attributed to the experimental therapy under study. However, RCTs are often criticized for requiring large sample sizes and taking a long time to complete. For newly diagnosed glioblastoma (GBM), the clinical trial landscape has seen little progress since the establishment of the standard of care (SOC) by Stupp. Given the urgent need for better therapies, it has been argued that data collected from patients treated with the SOC from past GBM trials can provide high-quality external control data to supplement concurrent control arm in future trials, thereby increasing drug development efficiency by reducing the number of patients treated with SOC. Herein we consider a new design approach that leverages historical control data in the design and analysis of phase 3 GBM trials. At the first stage, patients are randomized with an equal probability to standard (concurrent control) arm and experimental arm. An interim analysis entails an outcome comparison between the concurrent and external control arms. If comparability is established, the external control data are carried forward to be combined with concurrent control data at the second stage where the randomization ratio is adapted to favor the experimental therapy, thereby reducing the number of patients treated in the concurrent control arm. Using completed phase 3 GBM trials, we elucidate the potential gain in design efficiency and draw caution to scenarios where it may fall short on meeting statistical criteria. We highlight practical challenges in its implementation and conclude that the new method is not ready for definitive phase 3 GBM studies at the current time. This work represents a critical appraisal of this new concept in GBM.
CLRM-18 SCREEN FAILURES IN PHASE III GLIOBLASTOMA CLINICAL TRIALS
Authors: Peters Katherine
Published: August 2022

Glioblastoma (GBM) remains the most common and lethal malignant primary brain tumor in adult patients, with median overall survival ranging from 7 to 22 months. National Comprehensive Cancer Network guidelines encourage participation in clinical trials for both newly diagnosed and recurrent GBM patients. Multiple phase II trials in GBM have yielded promising, positive results, but the translation to phase III results is lacking and has failed to make strides in improving outcomes. These phase III trials universally require many participants, and the expenditure of phase III clinical trials is quite significant, with the median being 21.4 million dollars. With a paucity of ground-breaking phase III clinical trials and the cost expenditure to perform them, understanding screen failures in GBM clinical trials along with an evaluation of causes of screen failures is warranted. Using both ClinicalTrials.gov and PubMed, phase III clinical trials in GBM patients published from 1994 to 2021 were queried. This search, initially in ClinicalTrials.gov, involved using the terms: “glioblastoma” and “GBM” with filters “phase III,” “interventional,” “completed,” “suspended,” and “terminated.” This search was cross-referenced with PubMed for published full articles in English peer-reviewed journals. Fifty-one studies were identified, and 21 out of 51 were appropriate for evaluation of screen failures, with 15 being for newly diagnosed GBM and six being for recurrent GBM. Nine out of 21 (42.9%) did not publish information on screen failures, and in the remaining 12 studies, proportions of screen failures ranged from 0-84.0% for newly diagnosed studies and 9.2-23.2% for recurrent studies, with a combined median percentage of 28.9%. In this analysis, over one-fourth of patients screen failed for GBM clinical trials. Thus, it is prudent to explore the causes of these screen failures, their implications on clinical trial design, and their impact on patient outcomes clinically, financially, and holistically.
CLRM-20 IDENTIFYING RISK FACTORS AND ANALYZING SURVIVAL FOLLOWING PACHYMENINGEAL FAILURE
Authors: Kalyvas Aristotelis , Gutierrez-Valencia Enrique , Weiss Jessica , O’ Halloran Philip J , Mohan Nilesh , Wong Christine , Conrad Tatiana , Millar Barbara-Ann , Laperriere Normand , Bernstein Mark , Zadeh Gelareh , Shultz David , Kongkham Paul
Published: August 2022

OBJECTIVE

Neurosurgery (NS) is an essential modality for large brain metastases (BM). As an adjuvant treatment, stereotactic radiosurgery (SRS) reduces neurocognitive toxicity without affecting post-treatment overall survival (OS) compared to whole brain radiation therapy. Pachymeningeal failure (PMF) beyond the SRS field is a relatively newly described entity, distinct from classical leptomeningeal failure (LMF), and unique to postoperative patients treated with adjuvant SRS. We sought to identify risk factors for PMF in patients treated with NS+SRS.

METHODS

We reviewed a prospective registry (2009 to 2020) and identified all patients treated with NS+SRS. Clinical, radiological, pathological and treatment factors were analyzed. PMF incidence was evaluated using a competing risks model and differences between cohorts were measured using the Fine-Gray method.

RESULTS

144 Patients were identified. Median age was 62 (23-90). PMF occurred in 22.2% (32/144) patients). Univariate analysis indicated female gender (HR 2.65, p=0.013), higher GPA status (HR 2.4, p<0.001), absence of prior radiation therapy (HR N/A, p=0.018), controlled extracranial disease (CED) (HR 3.46, p=0.0038), and contact with the pia/dura (HR 3.30, p=0.0053) as risk factors for PMF. Piecemeal (vs En-bloc) resection also trended towards correlation (HR 2.07, p=0.054). Multivariate Analysis identified contact with pia/dura (HR 3.51, p=0.0053), piecemeal resection (HR 2.38, p=0.027), and CED (HR 3.97, p=0.0016) as significant correlates to PMF. PMF correlated with reduced OS (HR 2.90, p<0.001) but was improved compared to patients who developed LMF (HR 10.15, p= p<0.001).

CONCLUSIONS

PMF is an underrecognized phenomenon that correlates with pre-operative pia/dura contact and piecemeal resection in patients treated with NS+SRS for BM. While less morbid than LMF, it is a critical event that deserves increased vigilance and analysis.
LOCL-02 DOSIMETRIC AND CLINICAL ANALYSIS OF PSEUDO-PROGRESSION VS. RECURRENCE AFTER HYPER-FRACTIONATED RADIOTHERAPY FOR BRAIN METASTASES BASED ON ENHANCED MAGNETIC RESONANCE IMAGING
Authors: Yang Siran , Xiao Jianping , Xu Yingjie , Liu Qingfeng , Zhang Ye , Huang Xiaodong , Chen Xuesong , Wang Kai , Ma Yuchao , Zhao Ruizhi , Wang Shulian , Zhang Hongmei
Published: August 2022

PURPOSE

The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence. The objective of this study is to retrospectively analyze the predictive factors.

METHODS

The study included 123 patients with enlarged brain metastases after hyper-fractionated radiotherapy in our center from 2009 to 2019, and the baseline clinical features, radiotherapy planning parameters, and enhanced magnetic resonance imaging before and after radiation therapy were analyzed. Logistic regression was performed to compare the differences between groups. independent risk factors with P < 0.05 and associated with recurrence was used to establish a predicting nomogram and validated by Bootstrap in internal cohort.

RESULTS

The median volume of lesions was 8.4 cc. The median follow-up time was 68.4 months (interquartile range [IQR], 30.4 – 63.2 months). A total of 76 (61.8%) patients were evaluated as pseudo-progression, 47 patients (38.2%) were evaluated as tumor recurrence. The median time to tumor recurrence and pseudo-progression were 12.9 months (IQR, 8.7 – 19.6 months) and 18.3 months (IQR, 9.4 – 27.8 months) respectively. Variables associated with tumor recurrence included: gross tumor volume ≥ 6 cc, biological effective dose < 60 Gy, target coverage < 96% and no targeted therapy. The area under curve value was 0.730 and mean absolute error in calibration curve was 0.041. Sixty-one patients received salvage therapy, including re-irradiation (n = 32, 26.0%), surgical resection (n = 22, 17.9%) or systemic therapy (n = 22, 17.9%). The survival time in pseudo-progression and tumor recurrence groups were 66.3 months (95% CI, 56.8 – 75.9 months) and 39.6 months (95% CI, 29.2 – 50.0 months, respectively; P = 0.001).

CONCLUSIONS

Clinical and dosimetry features of hyper-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hyper-fractionated radiotherapy for brain metastases. And the individual risk could be estimated by the nomogram effectively.
LOCL-05 CEREBRAL METASTATIC LUNG CARCINOMA: EFFECT OF ALK- AND EGFR-MUTATION STATUS AND SURGICAL MANAGEMENT UPON CLINICAL OUTCOME
Authors: Mannam Sneha Sai , Bray David P , Nwagwu Chibueze D , Goyal Subir , Deibert Christopher P , Pradilla Gustavo , Nduom Edjah K , Olson Jeffrey J , Hoang Kimberly B
Published: August 2022

PURPOSE

There have been many advancements in the surgical and medical treatment of metastatic lung carcinoma. In the post-genomic era, new directed-oncological therapies such as monoclonal antibodies (mAbs) and tyrosine-kinase inhibitors (TKIs) may offer increased survival for lung carcinoma patients with EGFR- and ALK- mutations. No surgical series have investigated the role of these mutations upon patient survival in lung brain metastases (BM).

METHODS

We performed a multi-site, retrospective study of all patients who had BM with primary lung cancer undergoing surgical resection at Emory University Hospital between January 2012 and March 2021. Driver mutational statuses were categorized as EGFR-amplified, ALK-rearranged, or wild-type from biopsied brain tissue. Descriptive, univariate, and multivariate survival analyses were performed.

RESULTS

95 patients (mean age: 65.8 ± 10.6) met the inclusion criteria. 6 (6.3%) had ALK-rearranged mutations and 19 (20.0%) had EGFR-amplified mutations. 9 (9.5%) received second line therapies in the form of TKIs and mAbs. The majority of patients who underwent craniotomies had gross total resection (GTR) (n=72, 79.1%) with 83.5% (95% CI: 71.2-90.8%) and 89.9% (95% CI: 74.9-96.2%) 1-year overall survival (OS) and progression-free survival (PFS), respectively. On univariate analysis, ALK-rearranged (HR: 2.92; 95% CI: 0.57-9.75; p-value = 0.230) and EGFR-amplified (HR: 0.56; 95% CI: 0.15-1.61; p-value = 0.260) mutations were not significantly associated with OS.

CONCLUSION

After assessing ALK- and EGFR- mutations on OS, we found no benefit with mutational status, unlike other cancer types such as Melanoma BRAF mutations. Our low sample size of patients receiving targeted therapies may bias our measures of association to the null hypothesis. However, the OS and PFS in our cohort were better than earlier trials in literature, demonstrating the improvement in systemic lung metastasis therapy. We suspect that as further targeted therapies become available, OS and PFS for lung BM patients will continue to improve.
LOCL-09 SHORT-TERM SEIZURE OUTCOMES IN PATIENTS WITH TREATED WITH LASER INTERSTITIAL THERMAL THERAPY
Authors: Srinivasan Ethan , Edwards Ryan , Lerner Emily , Haskell-Mendoza Aden , Fecci Peter
Published: August 2022

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment modality for intracranial tumor and radiation necrosis (RN). A transient increase in edema following LITT typically resolves within three months post-procedure. We sought to characterize the short-term seizure outcomes during this period for patients undergoing LITT for tumor or RN. A retrospective analysis of 86 consecutive patients treated with LITT from 2015-2019 at a single institution was conducted. Data on baseline demographics, treatment details, and clinical course were collected. Thirty-one (36%) had a seizure within one year following LITT, 19 (22%) of which occurred within the first 90 days post-LITT (71% of all seizures). Forty-three (50%) patients had documented pre-LITT seizures, with 27 (63% of all seizures) of those occurring within 90 days pre-LITT. Between patients with and without post-LITT seizures within the first 90 days, there were no significant differences in gender, age, pre-LITT KPS, pre-LITT volume, pre-LITT resection, pre-LITT stereotactic radiotherapy, pre-LITT chemo- or immuno-therapy, use of AEDs or steroids before or after LITT, location, or pathology at the time of treatment. Patients with seizures in the first 90 days post-treatment were significantly more likely to have received pre-LITT whole brain radiotherapy (WBRT) (32% vs. 9%, p=0.02). Of the 18 patients with pre-LITT seizures within 90 days, 9 (50%) were entirely seizure free in the 90-day post-LITT period. In summary, seizure is a known complication of LITT for intracranial lesions, with the majority occurring in the first 90 days post-procedure. WBRT was significantly associated with 90-day post-LITT seizure, which may represent a diminished neurologic reserve in these patients. These findings may help guide clinicians in determining patients appropriate for LITT and those who may require closer monitoring and longer AED tapers in the short-term period following ablation.
LOCL-10 EVOLUTION OF FUNCTIONAL OUTCOMES AFTER LASER INTERSTITIAL THERMAL THERAPY (LITT) VERSUS RESECTION IN THE TREATMENT OF LESIONS IN OR NEAR THE PRIMARY MOTOR CORTEX
Authors: Srinivasan Ethan , Lerner Emily , Edwards Ryan , Haskell-Mendoza Aden , Jackson Joshua , Huie David , Fecci Peter
Published: August 2022

Laser interstitial thermal therapy (LITT) has become increasingly common, particularly in the treatment of progressive lesions after stereotactic radiosurgery for brain metastases. Previous work has illustrated the sensitivity to its use near critical structures, including the corticospinal white matter tracts. A single-surgeon retrospective study was performed of patients who underwent LITT or open resection for lesions located in or near the primary motor cortex, with functional outcomes graded relative to pre-treatment symptoms at 30, 90, and 180 days. Forty patients met inclusion criteria, with median age 64 years (57-72), and estimated baseline KPS 80 (80-90). Nineteen (47.5%) received LITT and 21 (42.5%) resections with intra-operative motor mapping. LITT patients trended towards smaller maximum diameters (2.1 cm vs 2.8 cm, p<0.01), with shorter ICU (0 vs 1 day, p<0.01) and hospital stays (1 vs. 2 days, p<0.01). At 30 days after treatment, 88.9% of resected patients had stable or improved symptoms compared to 35.3% of the LITT cohort (p<0.01). At 90 days, the difference was 87.5% to 50% (p=0.04), and at 180 days 100% to 85.7% (p=0.3684). When separated by new vs. progressive lesions, steroid responsiveness, and lesion histology, similar though not statistically significant trends were identified. In summary, LITT and resection provided similar functional outcomes in the treatment of lesions in or near the primary motor cortex for patients who survived at least 180 days post-treatment. Patients who received resection tended to have better functional outcomes in the nearer term. These differences are likely due to transient, expected post-LITT edema that subsides with time.
LOCL-12 OUTCOMES OF STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES OF BREAST CANCER IN RELATION TO MOLECULAR SUBTYPES
Authors: Andreasen Lærke Wolf , Persson Gitte , Møller Søren
Published: August 2022

PURPOSE

To determine intracranial outcomes following stereotactic radiosurgery (SRS) for brain metastases of breast cancer in relation to molecular subtypes of HER2 (human epidermal growth factor receptor) overexpression and estrogen receptor (ER) expression.

METHOD

From a retrospective institutional database of SRS using VMAT (volumetric modulated arc therapy) carried out between 2012 and 2019, patients with a primary diagnosis of breast cancer were identified. Outcomes following first course of SRS were analyzed using radiotherapy plans and electronic patient records. Systemic anticancer treatments were not registered. Time to intracranial progression (TTP) was calculated using the Kaplan Meier method as the time between SRS and recurrence, whereas dates of death or last follow up without recurrence were censored. The study was approved by the Danish Patient Safety Authority (nr. 31-1521-125).

RESULTS

The study included 159 patients. 132 patients (83%) underwent a brain MRI examination after SRS and, of these, 101 had recurrence, either local (41%), remote (43%) or both (16%). Tumors were HER2 positive in 50% of cases and 61% were ER positive and 15% were triple negative. The median intracranial TTP was for the whole study group 9.1 months. Median intracranial TTP for patients with the HER2+ / ER+ subtype was 15.4 mos. whereas patients with the triple negative subtype had a significantly shorter median intracranial TTP of 5.1 mos. (p=0.007). Patients with HER2+/ER- and HER2 normal/ER+ had similar median intracranial TTP times of 7.7 mos. and 8.4 mos., respectively (n.s.).

CONCLUSION

This study found high rates of intracranial recurrence following SRS and poor intracranial TTP that was highly dependent on molecular subtypes, reflecting either biological differences or intracranial effect of systemic treatments or both. The study confirms the universally poor prognosis for breast cancer patients with brain metastases and the high frequency of HER2 overexpression in this patient group.
LOCL-15 PERMANENT CARRIER-EMBEDDED CESIUM-131 BRACHYTHERAPY FOR THE SALVAGE TREATMENT OF PREVIOUSLY IRRADIATED, RECURRENT BRAIN METASTASES
Authors: Imber Brandon S , Beal Kathryn , Reiner Anne S , Giantini-Larsen Alexandra , Yang Jonathan T , Aramburu-Nunez David , Cohen Gilad , Brennan Cameron , Tabar Viviane , Young Robert J , Moss Nelson S
Published: August 2022

BACKGROUND

Salvage of recurrent of previously-irradiated brain metastases (rBrM) is a significant clinical challenge. High local failure rates are seen following salvage resection without adjuvant re-irradiation, while reirradiation is associated with high radionecrosis rates. Salvage surgery plus intraoperative Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced integral brain dose versus re-irradiation.

METHODS

A prospective registry of consecutively treated patients with rBrM after prior stereotactic radiosurgery (SRS) was analyzed. Following maximal-safe resection and intraoperative viable-disease confirmation, cavities were implanted with commercially-available, collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies). Prescribed dose was 60Gy at 5mm from the cavity.

RESULTS

Twenty patients underwent 24 operations with Cs131 implantation in 25 cavities. Previous SRS occurred a median of 358d preoperatively (range=56-1334). Median maximum preoperative diameter was 3.0cm (range=1.1-6.3) and enhancing volume was 9.5cm3 (range=0.6-69.7). Gross- or near-total resection was achieved in 60% of lesions. A median of 16 Cs131 seeds (range=6-30), with a median activity of 3.5U/seed were implanted. Maximal preoperative diameter and enhancing volume were weakly associated with the number of implanted seeds (correlation coefficients=0.50, 0.41, respectively). There was one postoperative wound dehiscence in a multiply resected and irradiated patient with hydrocephalus. With median follow-up of 12.5 months, 2 tumors recurred (one in-field, one marginal) resulting in a 1-year progression incidence of 9.8% (95%CI=0.0-23.2). Radiographic seed migration was identified in 7/25 cavities (28%) on surveillance scans ranging from 1.9-11.7 months post-implantation, without clinical sequelae.

CONCLUSIONS

With >1 year of follow-up, intraoperative brachytherapy with commercially-available Cs131 implants was associated with a high rate of local control and a favorable toxicity profile. Modest correlation between preoperative tumor geometry and implanted tiles in the context of high associated cost suggests a need to optimize planning criteria. A randomized trial of salvage resection with or without Cs131 is ongoing (NCT04690348) to assess the incremental benefit of brachytherapy.
LOCL-16 IMPACT OF MGMT PROMOTER METHYLATION STATUS ON TUMOR DYNAMICS DURING WEEKLY ADAPTIVE RADIOTHERAPY FOR GLIOBLASTOMA
Authors: Hudson John M , Stewart James , Zeng K Liang , Chen Hanbo , Ruschin Mark , Soliman Hany , Tseng Chia-Lin , Myrehaug Sten , Husain Zain , Sahgal Arjun , Detsky Jay
Published: August 2022

PURPOSE

Adaptive MRI-guided radiotherapy (RT) on a 1.5T-MR-Linac using reduced clinical target volumes (CTV) of 5mm instead of the 15mm standard for glioblastoma (GBM) is currently being evaluated on the UNITED clinical trial (NCT04726397). We explored the morphological changes that occur during adaptive RT with concurrent temozolomide between tumors with MGMT promotor methylation (MGMT-m) vs. unmethylation (MGMT-um).

METHODS

Thirty patients with IDH-wildtype GBMs were treated with 60Gy in 30 (n=12) or 40Gy in 15 fractions (n=18) (Fx). The CTV included a 5mm expansion on the gross tumor volume (GTV) +/- FLAIR hyperintense areas-at-risk and a 3mm planning target volume. Planning was performed on a pre-treatment reference MRI (FxRef) followed by weekly on-line adaptive re-planning at Fx1, Fx6, etc. acquired on the MR-Linac. Interim fractions were image-guided by pre-beam-on onboard MRI. The GTV/CTVs were quantified by their absolute volumes, volumes relative to the FxRef and the maximum linear distance from the edges of the reference contour to the weekly adapted contours (migration distance, dmig). MGMT promoter methylation status was explored as a fixed effect in a linear mixed statistical model.

RESULTS

Weekly median changes in GTV relative to FxRef in MGMT-um tumors (n=12) were 10.3%, 9.2%, 10.6%, 14.5%, 18.0% and 17.3%, respectively, while for MGMT-m (n=18) were 3.4%, 0.0%, -8.6%, -11.3%, -11.3% and -5.6% (p=0.021). Between FxRef and Fx1, the GTV increased by over 10% in 58% of MGMT-um tumors vs. 33% of MGMT-m tumors. Similar significant trends were observed with the CTVs. MGMT-um tumors had significantly larger dmig compared to tumors with MGMT-m (median 9.6mm vs. 5.8mm, respectively (p=0.018)).

CONCLUSIONS

MGMT-um GBM exhibited significant changes in morphology and migration distance between the time of treatment planning to the first treatment fraction, as well as throughout a course of RT. In this population, our results support a greater frequency of imaging and plan adaptation when applying personalized reduced CTV margins.
MMAP-05 PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES OR LEPTOMENINGEAL METASTASES HARBORING PI3K PATHWAY MUTATIONS: RESULTS FROM THE DOSE-ESCALATION COHORT
Authors: Yang Jonathan , Mann Justin , Pike Luke , Zinovoy Melissa , Young Robert , Offin Michael , Mitchell Ryan , Kazarian Arousiak , Shadat Tamim , Garner James , Simpson Jeremy , Friend John , Gavrilovic Igor , Piotrowski Anna , Wilcox Jessica , Malani Rachna , Diamond Eli
Published: August 2022

INTRODUCTION

Radiation therapy (RT) is an effective treatment for patients with central nervous system metastases, but disease control is poor in patients with tumors that harbor PI3K pathway alterations. We hypothesized that combining RT with paxalisib, a CNS-penetrant small molecule PI3K/mTOR inhibitor, could abrogate this effect via downregulation of prosurvival pathways.

METHODS

This is a single institution, open-label, phase I trial of concurrent paxalisib and RT (NCT04192981) for patients with brain metastases, leptomeningeal metastases, or both with PI3K pathway mutations. Part A comprised a standard 3 + 3 dose escalation of paxalisib at 45mg, 60mg, or 75mg daily for two weeks with concomitant RT. The primary objective was to establish the maximum tolerated dose (MTD) of paxalisib when combined with cranial RT.

RESULTS

Between 3/2020-1/2022, 12 patients were enrolled to Part A, of which 9 were evaluable (3 did not complete protocol therapy). Median followup was 4.5 months (0.9-14.9 months). All patients received paxalisib with whole brain RT (30Gy in 10 fractions)- 10 patients for brain metastases, and 2 for leptomeningeal metastases. The most common histology was breast cancer (4 [33%]), and the most common PI3K pathway alterations were PIK3CA mutation (7 [58%]). No patient experienced dose-limiting toxicity (DLT) at 45mg paxalisib daily with concurrent RT, and 2 experienced DLT at 60mg paxalisib: 1 with grade 3 nausea and vomiting and 1 with grade 4 enterocolitis and neutropenia. When combined with cranial RT, the paxalisib MTD was established at 45mg/day. We also observed robust response with all evaluable patients experiencing partial or complete response per RANO-BM within 3 months of protocol therapy.

CONCLUSION

A MTD of 45mg/day has been established for paxalisib with concurrent cranial RT in patients with solid tumor brain metastases and leptomeningeal metastases harboring PI3K pathway mutations. Additional patients are being recruited to an expansion cohort at this dose (Part B) to confirm safety and preliminary evidence of activity.
MMAP-08 CHEMO-REIRRADIATION (NORMOFRACTIONATED VS. HYPOFRACTIONATED) WITH OR WITHOUT BEVACIZUMAB IN RECURRENT ADULT DIFFUSE HIGH-GRADE GLIOMA (COBRA): PHASE III RANDOMIZED CONTROLLED TRIAL WITH A 2 X 2 FACTORIAL DESIGN
Authors: Baviskar Yamini , Dasgupta Archya , Chatterjee Abhishek , Kanan Sadhana , Epari Sridhar , Sahu Arpita , Puranik Ameya , Patil Vijay , Moiyadi Aliasgar , Gupta Tejpal
Published: August 2022

BACKGROUND

Adult diffuse high-grade gliomas (HGG) predominantly recur locally despite adequate treatment. At recurrence, salvage chemo-reirradiation (CTRT) provides durable local control with significant risk of symptomatic radionecrosis (RN). Reirradiation (reRT) is delivered using either conventional fractionation (CFRT) or hypofractionation based on institutional preferences. Studies have shown that the addition of bevacizumab, a monoclonal antibody inhibiting vascular endothelial growth factor to reRT reduces the risk of RN and potentially improves survival, providing strong scientific rationale for the combination.

OBJECTIVE

Primary endpoint would be a composite endpoint of 1-year event-free survival (EFS) comprising recurrence, symptomatic RN or death as an event. Secondary endpoints include progression-free survival, cumulative incidence of symptomatic RN, and overall survival. Quality-of-life assessment and health-economics would be tertiary endpoints.

METHODS

Target population includes adults with local recurrence (radiology and/or histology) of biopsy-proven diffuse HGG >2-years from primary RT. This is an open-label, phase III randomised control trial using a 2 x 2 factorial design comparing the addition of bevacizumab to chemo-reirradiation (test arm) versus chemo-reirradiation alone (control arm) using a superiority hypothesis. Patients in test arm will receive 6 months of bevacizumab (5mg/kg) 2 weekly, along with standard 6 cycles of temozolomide, starting 1 month following reRT completion. All patients will be further randomized to CFRT (50.4-55.8Gy/28-31/5.5-6 weeks) as control arm versus moderately HFRT (35Gy/10 fractions/2 weeks) as test arm in 1:1 ratio using a non-inferiority hypothesis. The desired sample size is 257 (two-sided alpha 0.05, power 80%, and 10% attrition rate) with a superiority hypothesis of 1-year EFS 45% (bevacizumab with CTRT) vs 30% (CTRT), and non-inferiority hypothesis of 25% (HFRT) vs 37% (CFRT),with delta of 12%.

DISCUSSION

The study will answer critical questions regarding the role of bevacizumab in recurrent HGG along with reRT, along with the differences in outcomes using normofractionated or hypofractionated RT.
NEIM-01 INCIDENCE AND DIAGNOSTIC TECHNIQUES FOR LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASIS
Authors: Henry Katie , Overholt Brandon , Sinson Grant , Pinheiro Fernando Santos , Bovi Joseph
Published: August 2022

BACKGROUND

Leptomeningeal disease (LMD) is malignant infiltration of the pia mater and cerebrospinal fluid (CSF) space. LMD carries a poor prognosis with median survival of a few months. Annually, 110,000 patients in the United States are diagnosed with LMD. The incidence is rising because of improvements in control of primary cancers and recognizing that LMD is a late sequelae of some malignancies. Definitive diagnosis of LMD is made by CSF cytology and/or spine MRI, although neither tool shows robust sensitivity. The diagnostic challenges for LMD have led to a lack of uniformity in the diagnostic approach.

METHODS

A systematic chart review of brain metastasis patients was conducted at Froedtert Hospital between 2019-2021. Information on primary cancer, LMD suspicion, work up, confirmation, treatment, and survival were collected and analyzed.

RESULTS

Among 151 patients with brain metastasis, 86 were suspected and 29 were confirmed to have LMD. Of the confirmed patients, the most common primary cancers were lung (n=8, 27.6%) and breast (n=8, 27.6%). Most patients (n=24, 82.8%) underwent both LP and MRI. LMD was confirmed by positive cytology in a minority of cases (n=9, 31%), with most patients being confirmed by positive MRI or clinical findings alone (n=20, 69%). All LPs had over 10 mL of CSF sent to analysis. A median of 2 LPs were required before a positive cytology confirmed the diagnosis. Due to small sample size, no statistical analysis was made to correlate positive LP with primary cancer sites.

CONCLUSION

Less than one third of cancer patients with confirmed LMD have positive cytology, despite the majority (>80%) of them undergoing LP. The dissonance between diagnostic strategies and confirmatory results is expected considering the low sensitivity of LPs; however, it highlights the need for more precise diagnostic tools, and development of a data-based strategy for LMD confirmation.
NEIM-02 DEVELOPMENT OF A DEEP LEARNING MODEL FOR DISCRIMINATING TRUE PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Moassefi Mana , Faghani Shahriar , Conte Gian Marco , Rouzrokh Pouria , Kowalchuk Roman O , Trifiletti Daniel , Erickson BradleyJ
Published: August 2022

INTRODUCTION

Glioblastomas (GBMs) are highly aggressive tumors. Despite multimodal treatment, its median overall survival ranges between 16 and 20 months. The standard treatment regimen consists of surgical resection followed by concurrent chemoradiotherapy and adjuvant temozolomide. Despite temozolomide’s effectiveness, it may cause the clinical challenge of treatment-related progression also known as pseudoprogression(PsP). Usually, PSP resolves or stabilizes without further treatment, whereas a true progression (TP) requires more aggressive management. Identifying PSP from TP will affect the patient’s treatment plan. Conventional magnetic resonance imaging (MRI) reading techniques cannot distinguish these entities. This study investigated the feasibility of using deep learning to distinguish PsP from TP.

METHOD

We included GBM patients who met our inclusion criteria. We evaluated all cases to see if they had a new enhancing lesion within the original radiation field or an increase in the size of an existing lesion. The challenging MRIs were collected. Clinical notes regarding tumor and recurrence location, clinical history, and medication were collected. We labeled the ones who stayed stable or improved in the imaging and clinical situation as PSP and those with further imaging and clinical deterioration as TP. We coregistered Contrast-enhanced-T1 MRIs with T2-weighted images for each patient. We performed five-fold cross-validation to generalize the performance. We trained A 3-D Densenet121 model to establish the prediction. We selected the best models with the highest accuracy.

RESULT

After reviewing 1000 patients, we included 124 patients whose imaging showed suspicious progression and their medicational histories were completely retrievable; 63 PsP, and 61 TP. We developed a deep learning model based on the whole dataset. The 5-fold cross-validation revealed that the mean area under the curve (AUC) was 0.81.

CONCLUSION

We report the development of a deep learning model that diagnoses PsP from TP in patients who received temozolomide. Further refinement and external validation are required prior to widespread adoption in clinical practice.
SPCR-01 RAPIDPLAN HIPPOCAMPAL SPARING WHOLE BRAIN MODEL VERSION 2 - HOW FAR CAN WE REDUCE THE DOSE?
Authors: Liu Hefei , Clark Ryan , Magliari Anthony , Foster Robert , Reynoso Francisco , Schmidt Matthew , Gondi Vinai , Abraham Christopher , Curry Heather , Kupelian Patrick , Khuntia Deepak , Beriwal Sushil
Published: August 2022

BACKGROUND

Whole-brain radiotherapy (WBRT) has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration. Recent clinical trials have shown that limiting radiation dose to the hippocampus is associated with decreased cognitive toxicity. In this study, we updated an existing Knowledge Based Planning (KBP) model to further reduce dose to the hippocampus and improve other dosimetric plan quality characteristics.

METHODS

42 clinical cases were contoured according to NRG-CC001 guidelines. A new dosimetric scorecard was created as an objective measure for plan quality. The new Hippocampal Sparing Whole Brain Version 2 (HSWBv2) model adopted a complex recursive training process and was validated with five additional cases. HSWBv2 treatment plans were generated on the Varian HalcyonTM and TrueBeamTM systems and compared against plans generated from the existing (HSWBv1) model released in 2016.

RESULTS

On the HalcyonTM platform, 42 cases were re-planned. Hippocampal D100% from HSWBv2 and HSWBv1 models had an average dose of 5.75 Gy and 6.46 Gy, respectively (p<0.001). HSWBv2 model also achieved a hippocampal Dmean of 7.49 Gy, versus 8.10 Gy in HSWBv1 model (p<0.001). Hippocampal D0.03CC from HSWBv2 model was 9.86 Gy, in contrast to 10.57 Gy in HSWBv1 (p<0.001). For PTV_3000, D98% and D2% from HSWBv2 model were 28.27 Gy and 31.81 Gy, respectively, compared to 28.08 Gy (p=0.020) and 32.66 Gy from HSWBv1 (p<0.001). Among several other dosimetric quality improvements, there was a significant reduction in PTV_3000 V105% from 35.35% (HSWBv1) to 6.44% (HSWBv2) (p<0.001). On five additional validation cases, dosimetric improvements were also observed on TrueBeamTM.

CONCLUSION

In comparison to published data in addition to the HSWBv1 model, the HSWBv2 model achieved higher quality HA-WBRT treatment plans through further reductions in hippocampal dose while improving target coverage and dose conformity/homogeneity. HSWBv2 model is shared publicly.