bluuebunny/crossref_metadata_2025_split huggingface dataset:
CLRM-18 SCREEN FAILURES IN PHASE III GLIOBLASTOMA CLINICAL TRIALS
Authors: Peters Katherine 
Published: August 2022

Abstract
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

Abstract

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&lt;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&lt;0.001) but was improved compared to patients who developed LMF (HR 10.15, p= p&lt;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

Abstract

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 &lt; 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 &lt; 60 Gy, target coverage &lt; 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

Abstract

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

Abstract
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

Abstract
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&lt;0.01), with shorter ICU (0 vs 1 day, p&lt;0.01) and hospital stays (1 vs. 2 days, p&lt;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&lt;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

Abstract

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

Abstract

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 &gt;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

Abstract

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

Abstract

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.