bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-03. A CASE OF PARTIAL HIPPOCAMPAL-AVOIDANCE WHOLE BRAIN RADIOTHERAPY IN A PATIENT WITH METASTATIC INFILTRATION OF THE LEFT HIPPOCAMPUS
Authors: Leskinen Sandra , Shah Harshal , Vojnic Morana , Yaffe Beril , Schneider Shonna , D'Amico Randy , Wernicke A Gabriella
Published: November 2023

In addition to surgical resection and systemic therapy, whole brain radiotherapy (WBRT) is a crucial modality in the treatment of cancers that have metastasized to the brain. It has been shown to improve intracranial disease control and overall survival. However, WBRT also increases the risk of radiation-associated damage to sensitive structures like the hippocampus, often resulting in neurocognitive dysfunction and decline. Hippocampal avoidance WBRT (HAWBRT) has been shown to reduce neurocognitive sequalae without worsening survival outcomes or increasing the risk of metastasis to the spared region compared to conventional WBRT. In cases where both hippocampi cannot be completely spared, the effectiveness of partial hippocampal avoidance on neurocognitive function and tumor control have been poorly described. We present the case of a patient diagnosed with triple negative invasive ductal carcinoma of the breast and disease metastatic to the brain, lung, bones, adrenal glands, and liver. Brain imaging revealed multiple brain metastases, two of which were noted near the left hippocampus. The patient underwent partial HAWBRT with complete avoidance of the right hippocampus and partial avoidance of the left. At 1-year follow-up, there was no evidence of metastasis in or near the partially spared left hippocampus. The patient’s neurocognitive functional status remained consistent with the findings of prospective randomized trials in which total bilateral hippocampal sparing was performed. To our knowledge, no such case has been presented in the literature. Further studies assessing the role of partial hippocampal avoidance in WBRT are needed.
RADT-05. SINGLE VERSUS MULTI-FRACTION STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: RATES OF LOCAL PROGRESSION AND NECROSIS
Authors: Frechette Kelsey , Sara Leier , William Harmsen , Laack Nadia , Mahajan Anita , Yan Elizabeth , Routman David , Kenneth Merrell , Lucido John , Grams Michael , Brooks Jay , Parney Ian , Pollock Bruce , Burns Terry , Sener Ugur , Brown Paul , Breen William
Published: November 2023

PURPOSE

For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases.

METHODS

Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review.

RESULTS

A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p >0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p < 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P < 0.02 for both).

CONCLUSION

While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.
RADT-09. CLINICAL OUTCOMES OF FRACTIONATED STEREOTACTIC RADIOTHERAPY FOR INTACT AND POSTOPERATIVE RADIORESISTANT RENAL CELL CARCINOMA AND MELANOMA BRAIN METASTASES
Authors: Cruz-Chamorro Ruben , Bryant John , Liveringhouse Casey , Nakashima Justyn , Graham Jasmine , Jiang Shirley , Oliver Daniel , Ahmed Kamran , Vogelbaum Michael A , Etame Arnold , Liu James , Beer-Furlan Andre , Tran Nam , Yu Hsiang-Hsuan Michael
Published: November 2023

PURPOSE

Fractionated Stereotactic Radiotherapy (FSRT) may be an optimal strategy for radioresistant renal cell carcinoma (RCC) and melanoma brain metastases (BM). We reviewed our institutional experience of FSRT to intact BM and postoperative cavities for patients with melanoma and RCC.

METHODS

We retrospectively identified consecutive patients with melanoma and renal cell carcinoma with unresected or resected BM treated with FSRT at our institution from 1/2018 to 1/2021. Time to event outcomes were estimated using the Kaplan-Meier method with log-rank tests and multivariable Cox regression analyses.

RESULTS

We identified 44 patients with a total of 64 BM: 31 intact (48.4%) and 33 resected BMs (51.6%). Thirty-six (81.8%) were melanoma and eight (18.2%) were RCC. The majority of intact BM (n = 22/31; 71%) and cavities (n = 21/33; 64%) were treated to 30 Gy (24-30) in 5 fractions and 25 Gy (24-35), respectively. Median PTV volume for intact BM was 5.04 cc (1.2-19.8) and for resected BM was 16.7 cc (4.8-89.1). Median interval from planning MRI to FSRT was 10 days (3-28). Median time from surgery to FSRT was 37 days (9-90). At 18.6 months median follow-up, local and intracranial distant failures were observed in 4 and 20 patients, respectively. Our cohort had a local recurrence-free survival (LRFS) of 83% and overall survival (OS) of 57% at 12 months; no difference between primary FSRT versus surgery followed by FSRT (p = 0.93 and p = 0.52, respectively). On MVA, higher FSRT dose was associated with better local control (p = 0.01). Radiation Necrosis (RN) was observed in eight treatment areas (12.5%). Neither resection status (p = 0.99) nor PTV volume (p = 0.61) were associated with RN.

CONCLUSION

FSRT is associated with low rates of toxicity and clinically significant disease control for both intact and resected melanoma and RCC BM, with higher FSRT dose being correlated with improved control.
RADT-11. THE HEMORRHAGIC RISK OF MELANOMA BRAIN METASTASES AFTER STEREOTACTIC RADIOSURGERY
Authors: Hong Sukwoo , Bouchal Samantha , Bauman Megan , Riviere-Cazaux Cecile , Pumford Andrew , Brown Paul , Yan Elizabeth , Stafford Scott , Markovic Svetomir , Link Michael , Burns Terry , Jusue-Torres Ignacio , Pollock Bruce , Parney Ian
Published: November 2023

OBJECTIVE

This study aimed to analyze the hemorrhagic risk of melanoma brain metastases following SRS.

METHODS

A retrospective analysis was conducted using a prospective institutional database between 1990 and 2021. Lesional hemorrhage was categorized as definite or possible, and hemorrhage severity was graded using CTCAE.

RESULTS

The study identified 291 patients with 1083 lesions. The mean age of patients was 60 ± 15 years, with 61% being male. Median follow-up was 11 months, corresponding to 581 patient-years. Among the patients, 82 (28%) experienced 135 lesional hemorrhages (13%). Of these, 88 lesions in 61 patients were grade 1-2 hemorrhages, 42 lesions in 25 patients were grade 3, and five lesions in five patients progressed from grade 1 to 3. Surgical intervention was required for 17 lesions (2%) in 16 patients (5%). Lesional hemorrhage was associated with radiosurgery performed between 2015 and 2021 (OR, 0.373; 95% CI, 0.231-0.60; p < 0.001), increasing marginal dose (OR, 0.89; 95% CI, 0.82-0.98; p = 0.017), antiplatelet use (OR, 0.192; 95% CI, 0.082-0.45; p < 0.001), and WBRT (OR, 0.51; 95% CI, 0.330-0.77; p = 0.0017). The cumulative lesional hemorrhage risk reached 17–20% at 36 months following radiosurgery, with 95-96% of hemorrhages occurring within the initial year. Median OS was 11 months (95% CI, 9-13 months). Patients who received radiosurgery between 2015 and 2021 exhibited a median OS of 17 months (95% CI, 10-24 months; p < 0.001), while those without hemorrhage had a median OS of 12 months (95% CI, 10-14 months; p = 0.054).

CONCLUSIONS

Definitive hemorrhage risk was 17% for melanoma brain metastases after SRS within the first three years, with 95% of lesional hemorrhages occurring within the initial year. Surgical intervention was necessary in 5% of patients. Hemorrhage risk and overall survival improved after 2015.
RADT-15. INTRACRANIAL OUTCOMES OF DUAL IMMUNE-CHECKPOINT INHIBITION AND SRS COMBINATION IN PATIENTS WITH MELANOMA AND NSCLC BRAIN METASTASES
Authors: Vaios Eugene , Shenker Rachel , Hendrickson Peter , Wan Zihan , Niedzwiecki Donna , Winter Sebastian F , Dietrich Jorg , Salama April , Clarke Jeffrey , Allen Karen , Mullikin Trey , Floyd Scott , Kirkpatrick John , Reitman Zachary
Published: November 2023

INTRODUCTION

The intracranial benefit of offering dual immune checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to melanoma and non-small cell lung cancer (NSCLC) patients receiving SRS for brain metastases is unknown. We hypothesized that D-ICPI improves local control compared to SRS alone.

METHODS

Melanoma and NSCLC patients treated with SRS between 2016-2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence.

RESULTS

288 patients (44% melanoma, 56% NSCLC) with 1,704 brain metastases were included. 53% of patients had symptomatic metastases. Median follow up was 58.8 months. Patients were treated with D-ICPI (28%), S-ICPI (45%), or SRS alone (27%). 12-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95%CI:91.11-96.90%), 91.72% (89.29-93.64%), and 88.22% (84.06-91.41%). Only D-ICPI was significantly associated with reduced LR (p = 0.0032). 173 patients (60%) developed IP. The 12-month cumulative incidence of IP was 41.27% (95%CI:30.27-51.92%), 51.86% (42.78-60.19%), and 57.15% (44.98-67.59%) following D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (p = 0.0408). On multivariate Cox regression, D-ICPI (HR:0.595,95%CI:0.373-0.951,p = 0.0300) and presentation with >10 BMs (2.492,1.68-3.725,p < .0001) remained significantly correlated with IP. Median OS following D-ICPI, S-ICPI, and SRS alone was 26.1 (95%CI:15.5-40.7), 21.5 (16.5-29.6) and 17.5 (11.3-23.8) months. Only D-ICPI trended toward improved OS (p = 0.0772). S-ICPI, fractionation, and timing of immunotherapy were not predictive of clinical outcomes.

CONCLUSIONS

The addition of D-ICPI for melanoma and NSCLC patients undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for symptomatic brain metastasis patients, regardless of fractionation or immunotherapy timing. Toxicity with this combination should be evaluated and balanced against clinical benefits.
RADT-16. A RETROSPECTIVE COMPARISON OF OUTCOMES AFTER WHOLE BRAIN RADIOTHERAPY AND RAPID SIMPLE (RAPPLE) TARGETED THERAPY FOR BRAIN METASTASES IN MATCHED COHORTS OF PATIENTS WITH POOR PROGNOSIS
Authors: Nichol Alan , Parmar Gurjit , Kong Tim , Hamm Jeremy , Liu Mitchell , Lefresne Shilo , Carolan Hannah , Berthelet Eric , Chan Jessica
Published: November 2023

BACKGROUND

For patients whose poor prognosis does not warrant stereotactic radiosurgery, we use the RAPPLE radiotherapy technique to treat multiple brain metastases. RAPPLE uses single-isocenter, coplanar volumetric modulated arc therapy and a non-stereotactic head-shell with IntegraBite™. Brain metastasis are contoured in a single gross tumour volume and expanded by 3 mm to create a planning target volume, covered by 95-110% of 20 Gy in 5 fractions. Our study compares clinical outcomes after RAPPLE and whole brain radiotherapy (WBRT).

METHODS

From January 2017 to December 2021, we identified patients receiving a first course of RAPPLE and matched patients receiving a first course of WBRT. Cox regression was used to analyze overall survival and Fine-Gray analysis was used to analyze intracranial progression. For each cohort, we compared patient-reported fatigue before and 2-6 weeks after radiotherapy.

RESULTS

Each cohort had 137 patients whose median Karnofsky Performance Score was 70. The diagnoses were lung cancer (72%) and other cancers (28%). The median survival was 4.1 months for RAPPLE and 4.2 months for WBRT (log-rank p = 0.8). On multivariable analysis of survival, the radiotherapy technique was not predictive (HR = 0.96, 95%CI: 0.73-1.25, p = 0.7). On multivariable analysis, intracranial progression was more likely after RAPPLE (HR = 1.6, 95%CI: 1.1 – 2.3, p = 0.02). The 18-month risk of intracranial progression was 0.49 for RAPPLE and 0.37 for WBRT (p = 0.04). After RAPPLE, 17% of patients required more focal RT and 4% required salvage WBRT, while after WBRT, 3% required focal RT and 4% required repeat WBRT. After RAPPLE, mean patient-reported fatigue remained stable from baseline to first follow-up (2.18 vs. 2.27, p = 0.9), but after WBRT it worsened (1.95 vs. 2.63, p = 0.002).

CONCLUSIONS

Ninety-six percent of patients treated with RAPPLE avoided WBRT. Patients reported worse fatigue after WBRT.
RADT-19. FACTORS PREDICTIVE OF OUTCOME IN GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR CEREBRAL METASTASES
Authors: Crispi Vassili , Reveendran Dharsshini , Hatfield Paul , Mathew Ryan
Published: November 2023

BACKGROUND

Stereotactic radiosurgery (SRS) in brain metastases is associated with prolonged quality of life, locoregional control, and stabilisation of neurological symptoms. Optimal patient selection is pivotal to achieving improved overall survival (OS). This study aimed to evaluate patient and disease factors associated with optimal outcomes.

METHODS

This retrospective study analysed 3,940 intracranial metastases in 1,113 patients treated with SRS at the Leeds Gamma Knife Centre between 2010 and 2020. Data on primary tumour, Karnofsky performance status (KPS), intracranial disease burden, steroid therapy, and treatment toxicity were recorded. Follow-up MRI imaging was performed at 6 months. OS curves were compared using the Log-Rank test (p < 0.05).

RESULTS

Multivariate analysis revealed primary diagnosis (p < 0.001), KPS (p < 0.001), number of lesions (p = 0.005) and total tumour volume (p = 0.012) as significant predictors of median OS. Breast carried the highest median OS (18 months) compared to gastrointestinal tumours (7 months) and metastases of unknown origin (5 months). Higher functional performance at baseline was associated with greater median OS: from KPS 100 (18 months) to KPS 70 (6 months). Lower intracranial disease burden conferred greater median OS: patients with 1-3 treated lesions survived significantly longer (11 months) than those with 4 or more (9 months)(p = 0.001). Median OS reduced with an increasing total volume of treated metastases: 13 months if <5000mm3, compared to 4 months if >30000mm3. Following SRS, 375(33.7%) patients had new brain metastases with a median time of 6 months. 13.3% of these were local recurrence, and median time to recurrence ranged from 1.5 months in renal primary to 14.3 and 17.7 months in breast and gastrointestinal tumours, respectively. 195(17.5%) patients underwent further SRS with a median time of 7 months.

CONCLUSION

Primary diagnosis, KPS, and intracranial disease burden are significant pre-treatment predictors of OS for SRS in brain metastases.
RADT-28. DISRUPTION OF BIOENERGETICS ENHANCES RADIO-SENSITIVITY OF PATIENT-DERIVED GLIOBLASTOMA TUMORSPHERES
Authors: Yoon HongGyu , Park Junseong , Kim Seo Jin , Shim Jin-kyoung , Lee Eunhee , Choi Ran Joo , Moon Ju Hyung , Kim Eui-Hyun , Kang Seok-Gu
Published: November 2023

INTRODUCTION

Glioblastoma (GBM), the most common primary brain tumor, has been associated with poor prognosis despite various treatment modalities, the surgical resection accompanied by chemotherapy and radiotherapy. Although the importance of radiotherapy is well known, its combination with bioenergetics regulators has not been established in clinical practice. Here, we hypothesized that bioenergetics regulators improve the radio-sensitivity of GBM-tumorspheres (TS).

METHODS

Gene expression profiles of GBM patient-derived TSs were obtained from microarray. In vitro efficacies of the treatment were evaluated using clonogenic assay, 3D invasion assay, neurosphere-formation assay, and apoptosis-analysis. Protein expression was evaluated by western blot, and immunofluorescence was performed for detection of γH2AX foci. In vivo efficacies were confirmed using a mouse orthotopic-xenograft model.

RESULTS

GBM TSs with high-radioresistant or low-radioresistant were selected according to expression levels of radiation response associated genes. In order to select the bioenergetics regulators that significantly increased the radiotherapy effect of GBM-TSs, five bioenergetics regulators were combined which are oxidative-phosphorylation (OxPhos) inhibitor (IM156A), aldehyde-dehydrogenase inhibitor (gossypol) + OxPhos inhibitor (phenformin), fatty acid oxidation inhibitor (etomoxir), pentose-phosphate pathway inhibitor (dehydroepiandrosterone; DHEA) and glycolysis inhibitor (2-deoxy-D-glucose; 2DG). Amongst of these five bioenergetics regulators, DHEA and 2DG significantly augmented the therapeutic efficacies of ionizing radiation (IR) by reducing the survival fraction, stemness, and invasiveness in both high-radioresistant and low-radioresistant GBM TSs. IR combined with bioenergetics regulators (DHEA or 2DG) induced DNA damage response and apoptosis in low-radioresistant GBM TSs. In vivo experiments using a mouse orthotopic-xenograft model confirmed the tendency to prolong survival period and reduced the size in tumor after the combined treatment of 2DG with IR in low-radioresistant GBM TS.

CONCLUSION

These data proposes that the combination of bioenergetics regulators and radiotherapy is more effective than IR monotherapy itself. We expect that this combination regimen can strategically establish as a future treatment practice of GBM.
RADT-32. USING NEUROANATOMICAL SUBSITE TO PREDICT PATTERNS OF GLIOBLASTOMA INFILTRATION: POTENTIAL FOR INDIVIDUALISING RADIATION THERAPY TARGET VOLUME DELINEATION OF THE PARIETAL AND POSTERIOR FRONTAL REGIONS
Authors: Back Michael , Horsley Patrick , Yim Jackie , Drummond James
Published: November 2023

BACKGROUND

Radiation therapy(IMRT) protocols for glioblastoma utilize isotropic margin expansion around neurosurgical cavities/residual contrast enhancing(T1gd) disease. However pathways of infiltration may be associated with white matter tract(WMT) involvement varying between neuroanatomical subsites. Posterior frontoparietal tumours involving posterior cingulate region (PostCing) may have extensive infiltration centrally. This study aims to quantify the PostCing infiltration pathway/relapse sites.

METHODS

Consecutive patients managed for GBMwt with IMRT between 1/2016-6/2022 were classified into 15 neuroanatomical subsites. Tumour segmentation on T1-gadolinium-enhanced(T1gd) and T2-weighted(T2) sequences was performed at diagnosis/relapse. Subsites of Frontal Lobe (Posterior) and Parietal Lobe (Superior/Posterior/Lateral) were identified. On both sequences involvement of adjacent/distant regions (cingulate gyrus, cingulum, splenium, ventricular trigone, parahippocampal-hippocampal gyrus) were identified; as were major WMT: cingulum-parahippocampal formation(CING-PHG), and arcuate fasciculus–inferior longitudinal fasciculus(AF-ILF). Survival was analysed in relation to pattern of infiltration and site of relapse.

RESULTS

Of 348 patients with glioblastoma, fifty-five(16%) involved PostCing region. Pre-IMRT features included near-total resection in 25%; impaired ECOG 2-3 in 47%; and 58% MGMT-methylated. Parietal lobe tumours(67%) were predominantly posterior(42%) with only 7% lateral parietal. WMT involvement was evident in 94% with T1gd(62%), and T2 alone(33%) abnormality. Infiltration to distal sites of cingulum/splenium/PHG was frequent and predictable; correlating to cingulum pathway involvement in 70% of patients. Median RFS and OS was 13.2 months(95%CI: 11.8-14.8) and 16.6 months(95%CI:14.8-18.5) respectively. Distant relapse was evident in 53% of relapses. In the forty-four Stupp60Gy patients, distant relapse occurred later and was associated with improved overall survival(p = 0.02). No difference in RFS(p = 0.82) or OS(p = 0.31) was noted if tract involvement was either T1gd or T2 alone abnormality.

CONCLUSION

For glioblastoma in posterior cingulate region, the infiltration and relapse pathways followed white matter tracts in a predictable distribution with high rate of distant disease at diagnosis and relapse. IMRT potentially may be individualised for neuroanatomical subsite and non-isotropic target volume expansion.
RADT-35. STEREOTACTIC RADIOSURGERY FOR RESIDUAL, RECURRENT, AND METASTATIC HEMANGIOPERICYTOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Yoo Kelly , Park David , Veeravagu Anand , Lee Marco , Marianayagam Neelan , Zamarud Aroosa , Gu Xuejun , Pollom Erqi , Soltys Scott , Chang Steven , Meola Antonio
Published: November 2023

INTRODUCTION

Hemangiopericytomas are infrequent vascular tumors originating from Zimmermann pericytes. The conventional treatment approach involves gross total resection (GTR), followed by adjuvant radiotherapy. Nevertheless, due to their tendency to infiltrate dural sinuses, high degree of vascularity, and anatomic inaccessibility, radical resection may be challenging with substantial risk of recurrence. To address this challenge, stereotactic radiosurgery (SRS) has been proposed as a promising adjuvant therapy. Objectives Our study aims to evaluate the effectiveness and safety of SRS as a potential treatment modality in patients with residual, recurrent, and metastatic hemangiopericytomas.

METHODS

From 1998 to 2023, 27 patients with 101 tumors underwent CyberKnife SRS at Stanford University Medical Center. The median age was 51 years at the time of treatment. The median follow-up period from SRS was 103 months (range: 6-250). All patients underwent upfront surgical resection. The median tumor volume was 1.5 cc. The median single-fraction equivalent dose (SFED) was 19 Gy. The SRS was administered at the 76% of the median isodose line (range: 64-89).

RESULTS

Of the 101 treated tumors, 24 (23.8%) progressed with a median time to recurrence of 30 months. At 10 years, the rates of local tumor control (LTC), overall survival (OS), and progression-free survival (PFS) were 74.3%, 80.8%, and 67%, respectively. In patients with residual lesions, the LTC rates were significantly greater when compared to those with residual or metastatic tumors. There was no significant difference between patients with residual, recurrent, and metastatic hemangiopericytomas in OS and PFS. Notably, no cases of radiation-induced adverse events were detected.

CONCLUSION

Our study provides the largest single-institutional retrospective series with hemangiopericytomas treated with SRS. SRS leads to excellent LTC, PFS, and OS at 10 years with negligible risk for adverse events. Therefore, it is an effective and safe management modality for patients with residual, recurrent, and metastatic hemangiopericytomas.
RADT-36. A SINGLE-CENTRE EXPERIENCE WITH HYPERARC FRACTIONATED STEREOTACTIC RADIOSURGERY [FSRS] FOR BENIGN BRAIN TUMOURS
Authors: Hicks Holly , Samuji Mohd , Barry Laura , Bennett Erica , Toomey Eoin , Kelly Paul
Published: November 2023

BACKGROUND

Treating benign brain tumours with fSRS may have radiobiologic and clinical advantages, such as lower rates of symptomatic oedema and radionecrosis[1]. HyperArc (HA, Varian Medical System) is an isocentric VMAT technique developed for non-coplanar, MLC-based stereotactic radiotherapy with automated optimizations and delivery. Here we report our initial clinical experience of HyperArc fSRS in treating benign brain tumours. MATERIALS AND

METHODS

We retrospectively reviewed 21 cases of benign brain tumours treated at the Bon Secours Radiotherapy Cork between May 2020-May 2023. Clinical and dosimetric parameters are reported.

RESULTS

A total of 21 patients were treated in a total of 105 SRS fractions, all using a 5-fraction regimen (5x5Gy, N = 20). The commonest tumour was meningioma (N = 9), followed by vestibular schwannoma (N = 7) and pituitary adenoma (N = 5). Median patient age was 59 years (range 26-86). Median PTV was 4.65 cc (IQR 1.9-14.6), median number of arcs was 4 (range 3-4), median PTV coverage was 99.6 % (IQR 98.0-99.9). Median prescription isodose was 79%. Median Paddick conformity index and gradient index was 0.86 (IQR 0.83-0.98) and 3.0 (IQR 2.9-3.2) respectively. Median follow-up was 7 months. No patient suffered from toxicity ≥ grade 2 (Common Toxicity Criteria, Version 5). Only 2/21 patients required steroid therapy during fSRS. No patient had a seizure.

CONCLUSION

HyperArc fSRS is a feasible option for benign brain tumours. Initial clinical experience in terms of plan quality and acute toxicity is encouraging. fSRS for benign brain tumours should be prospectively studied. REFERENCES: 1. Lehrer EJ et al IJROBP 2019 Mar1;103(3):610-630
RADT-47. MARGIN REDUCTION WITH THE INTRODUCTION OF INTRA-FRACTIONAL MONITORING USING IDENTIFY SGRT FOR FRAMELESS STEREOTACTIC CRANIAL RADIOSURGERY (SRS)
Authors: Tran Tai , Anderson Lee , Hu Yunfei , Gzelle Cecelia
Published: November 2023

The purpose of this study was to evaluate the potential for margin reduction in clinical treatment settings based on the accuracy of Varian Identify SGRT (Surface-Guided Radiation Therapy). The study considered various factors such as patient setup variations, intrafraction movement, and unique facial features. Identify version 2.3.1 was installed on a Truebeam v2.7 system and commissioned according to AAPM TG3021 test recommendations. Identify generated reports on patient offsets in all six degrees of freedom during motion monitoring. These offsets were retrospectively compared with radiographic images (CBCT and MV planar images) to determine the accuracy of patient positioning achieved using surface guidance. A retrospective analysis of 36 patients was performed for a total of 125 fractions. The characteristics of the patient cohort (age range from 39 – 92 years) consisted of a mixture of 8 benign, 28 malignant lesions, 11 single, 25 standard fully-fractionated treatments and anatomical sites such as parietal, frontal, ventricle, base of skull, pons and acoustic neuromas. RESULTS: show that for this clinical cohort, the variance between Identify and radiographic imaging ranges from -0.02 to 0.08 cm, -0.09 to 0.10 cm, -0.09 to 0.09 cm and -0.81 to 0.74 degrees for the vertical, longitudinal, lateral and rotation respectively. This average variance in the translational axes is 0.0cm ± 0.0014 cm, indicating no directional preference. The 3D vector of the displacement detected achievable by Identify is 1 mm within a 95% confidence interval (CI). Based on the findings, the researchers concluded that a minimum GTV-PTV (Gross Tumor Volume-Planning Target Volume) margin of 1 mm is appropriate for intrafraction monitoring with Identify SGRT on the TrueBeam system for stereotactic cranial treatments. This information can increase the radiation oncologist's confidence in patient positioning during treatment delivery and potentially lead to a decrease in the GTV-PTV margin.
CTIM-02. PHASE 2 TRIAL OF PEMBROLIZUMAB FOR PATIENTS WITH BRAIN METASTASES OF DIVERSE HISTOLOGIES
Authors: Brastianos Priscilla , Kim Albert , Giobbe-Hurder Anita , Lee Eudocia , Lin Nancy , Overmoyer Beth , Wen Patrick , Nayak Lakshmi , Cohen Justine , Dietrich Jorg , Eichler April , Heist Rebecca , Krop Ian , Lawrence Donald , Ligibel Jennifer , Tolaney Sara , Mayer Erica , Winer Eric , Bent Brittany , de Sauvage Magali , Ijad Nazanin , Larson Juliana , Marion Braxton , Nason Sally , Murthy Naina , Summers Elizabeth , Ratcliffe Sherry , Mahar Maura , Shih Helen , Oh Kevin , Cahill Daniel , Gerstner Elizabeth , Sullivan Ryan
Published: November 2023

BACKGROUND

Patients with brain metastases have limited treatment options.The PD-L1/PD-1 pathway is an immune suppressive mechanism in brain metastases.

METHODS

This was a single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases. The target accrual was 58 patients to achieve at least 52 evaluable patients. The primary endpoint was intracranial benefit (complete response, partial response, or stable disease by modified RANO criteria). The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study (type-I error of 10%, power of 89%).

RESULTS

In 57 evaluable patients, median age was 53 (range 28-80). Tumor histologies included breast (n = 35), NSCLC (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), and other (n = 9). For patients with breast cancer, 16 patients had HER-2 positive, 17 had hormone-receptor positive and 11 patients had triple-negative disease. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). Thirty-seven percent of breast cancer patients (90% CI: 24–52%) and 43% of NSCLC patients (90% CI: 13–77%) had intracranial benefit. All four breast cancer subtypes derived efficacy from pembrolizumab. Seven patients, who had either breast cancer, melanoma or sarcoma, had overall survival >2 years. The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema.

CONCLUSIONS

Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases across diverse histologies.
CTIM-07. PHASE IIB RANDOMIZED, BLINDED, CONTROLLED TRIAL EVALUATING NEOADJUVANT PD-1 BLOCKADE COMBINED WITH A2B5+ GLIOMA STEM-LIKE CELL LYSATE-LOADED DCV IN RECURRENT GLIOBLASTOMA (IDH1/2 -)- TRAIL IN PROGRESS
Authors: Yao Yu , Huang Xiaoming , Chen Di , Hu Lang , Zhou Bingyi , Li Chenwei , Chen Lingchao , Zhou Nan , Ji Chunxia , Wang Yuan , Zhou Liangfu
Published: November 2023

Our previous phase II randomized trials have determined that A2B5+ glioma stem-like cell lysate-loaded DC vaccine (GSC-DCV) demonstrates favorable safety and significantly extends the survival of glioblastoma (GBM) (NCT01567202). This study aims to investigate the clinical feasibility and efficacy of the GSC-DCV combined with aPD-1 mAbs neoadjuvant therapy in recurrent GBM (NCT04888611). GBM (IDH1/2 -) patients who had received radiotherapy and TMZ chemotherapy were enrolled in the study after pathologically confirmed recurrence. All patients received aPD-1 mAbs treatment (3mg/kg, up to 200mg) 14±5 days before surgery. Following surgery, eligible patients were randomized in a 1:1 ratio to receive either a combination treatment of aPD-1 mAbs with GSC-DCV or aPD-1 mAbs with placebo. The above-mentioned postoperative therapy was given every three weeks until disease progression or unacceptable toxicity. Besides evaluating treatment response using the iRANO criteria, MRI scans were conducted before each treatment and after surgery (in 72h) to evaluate tumor size/volume to analyze the relationship between tumor burden and prognosis. The primary endpoint of the study was overall survival, while the secondary endpoints included the evaluation of treatment-related adverse events (trAEs) and the measurement of indicators related to the immune response. From October 2021 through May 2023, a total of 22 patients were enrolled and successfully randomized. At the latest follow-up, the two groups were generally balanced with respect to baseline characteristics, encompassing age, gender, KPS, steroid use, MGMTp status, TERTp status, and tumor volume at registration. Notably, differences in survival were observed between the two groups, with respective follow-up periods ranging from 1.3 to 19.9 months and 1.0 to 12.1 months. The incidence of trAEs in all patients was 22.7%, with no grade 3 or higher trAEs observed thus far, and the main adverse event was reactive cutaneous capillary endothelial proliferation (RCCEP).
CTIM-15. T CELL RESPONSE DYNAMICS IN PHASE 3 GLIOBLASTOMA PATIENTS IMMUNIZED WITH AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS TUMOR CELL LYSATE
Authors: Bosch Marnix , Liau Linda , Ashkan Keyoumars
Published: November 2023

BACKGROUND

331 glioblastoma patients were immunized with autologous dendritic cells (DCs) pulsed with autologous tumor cell lysate or placebo in a Phase 3 clinical trial. Immunization with the pulsed DCs was associated with extended overall survival in both newly diagnosed and recurrent disease. Objective: To characterize T cell responses and T cell response dynamics in patients immunized with autologous dendritic cells pulsed with autologous tumor cell lysate.

METHODS

we performed T cell receptor sequencing on peripheral blood mononuclear cells from both newly diagnosed and recurrent glioblastoma patients that were treated with the pulsed DCs. Timepoints from both before and after immunization were compared to understand T cell response dynamics.

RESULTS

Expansion of several hundred new T cell clones as well as more than 700 previously detected T cell clones was detected over time in both newly diagnosed and recurrent GBM patients who were treated with the pulsed DCs. Investigation of the dynamics of the response demonstrated that further expansion was triggered by ongoing immunizations. Correlations between T cell response data and clinical outcomes are ongoing.

CONCLUSION

Immunization with autologous DCs pulsed with autologous tumor cell lysate induces broad spectrum immune responses in patients with glioblastoma.
CTIM-25. EO2401 PEPTIDE IMMUNOTHERAPY + NIVOLUMAB +/- BEVACIZUMAB IN FIRST RECURRENT GLIOBLASTOMA: THE PHASE 1/2 EOGBM1-18/ROSALIE STUDY (NCT04116658)
Authors: Reardon David , Idbaih Ahmed , Vieito Maria , Ghiringhelli François , Stradella Agostina , Tabatabai Ghazaleh , Burger Michael C , Mildenberger Iris , Herrlinger Ulrich , Wen Patrick , Touat Mehdi , Wick Antje , González Macarena , Hervieu Alice , GilMartin Marta , Renovanz Mirjam , Gouttefangeas Cécile , Maia Ana , Bonny Christophe , Paillarse Jean-Michel , Chêne Laurent , Fagerberg Jan , Wick Wolfgang
Published: November 2023

EO2401 expands existing memory T cells recognizing protein sequences from gut bacteria, which cross-react with tumor associated antigens (TAAs). EO2401 contains three CD8 HLA-A2 epitopes with mimicry to glioblastoma-TAAs (IL13Rα2, BIRC5, and FOXM1) and the CD4 epitope UCP2. Patients received EO2401 (300μg/peptide, q2weeks x4, then every 4weeks) with nivolumab (3mg/kg, q2weeks) in cohorts: C1a (n = 21, Ex2→EN; option for symptom directed low-dose bevacizumab [sLDB; 5mg/kg, q2weeks] as anti-edema treatment); C2a/1 (n = 23, EN); C2a/2 (n = 15, EN+sLDB); C2b (n = 6, adjuvant EN+sLDB); C2c (n = 9, neoadjuvant ENx2→surgery→adjuvant EN+sLDB); C3 (n = 26, EN+bevacizumab, q2weeks, 10mg/kg). EO2401/nivolumab+/-bevacizumab safety profile consistent with profile of nivolumab, and when applicable bevacizumab, except the addition of local administration site reactions which occurred in 39% of patients; 96% of events Grade 1/2 and 4% Grade 3. Immune monitoring (peripheral blood, ELISPOT, tetramer assessments) demonstrated expanded mimic specific CD8 T cells with cross-reactivity against the targeted human TAAs. In C2a/1 (83% tested) and in C3 (81% tested), 89% and 95% of tested patients showed expansion. Expansions were early (week 2 after starting EO2401), durable (up to 23 months), and robust (approximately 30% of all peripheral CD8 T cells were mimic specific in 3 clinical responders). In C2c, surgery specimens after two EO2401/nivolumab doses showed increased tumor T cell infiltration versus pre-treatment tumor in 5 of 6 patients. Addition of sLDB to EO2401/nivolumab prolonged treatment duration vs EO2401/nivolumab alone by reducing edema likely worsened by study therapy induced immune cell infiltration. Integration of bevacizumab with EO2401/nivolumab in C3 further increased efficacy in C3. C2a/1vsC2a/2vsC3: median treatment duration 1.4vs3.2vs4.8 months, disease control rate 22%vs40%vs88%, median PFS 1.6vs3.6vs5.5 months; median survival 9.0vs12.6vstoo early (C3 median FU 8.3 mo, survival ongoing up to 2 years). Further follow-up will be presented.
CTIM-28. FIRST-IN-HUMAN TRANSGENE DETECTION 17 MONTHS POST-ADENOVIRAL THERAPY
Authors: Varela Maria , West Molly , Faisal Syed M , Comba Andrea , Castro Maria , Lowenstein Pedro
Published: November 2023

Gene therapy was developed as a promising approach to treat high-grade glioma (HGG). One of the main strategies is suicide gene therapy. This method introduces the expression of an enzyme that converts a non-toxic prodrug to an active toxic compound, thereby causing the death of transduced cells. Specifically, herpes simplex virus thymidine kinase (HSV1-TK) converts the pro-drug valacyclovir into phosphorylated valacyclovir. When cells initiate DNA replication, phosphorylated valacyclovir is incorporated into de novo DNA strands, causing DNA replication to arrest, followed by apoptosis. This approach is lethal only for replicating cells, (i.e., tumor cells), without harming non-dividing brain cells. An infected cell, expressing HSV1-TK, requires two further simultaneous events to induce cell death: (1) to be exposed to valacyclovir and (2) enter into cell division. Without either of these events, the cell will remain alive and will still express HSV1-TK. Previous work from our lab in murine models demonstrated the long-term expression of transgenes β-galactosidase and HSV1-TK up to 12 months after viral therapy administration (Zermansky et al 2001; Barcia et al 2007). We recently completed and published our Phase I clinical trial (NCT01811992), where dual vector viral therapy, Ad-TK/Ad-Flt3L, and valacyclovir was administered to patients suffering from HGG (Umemura et al, 2023). In paraffin embedded tumor samples from recurrent tumors to our surprise we detected HSV1-TK immunoreactivity up to 17 months after initial treatment. HSV1-TK immunoreactive cells were found in five out of eight patients’ samples. We analyzed HSV1-TK expression to further characterize HSV1-TK positive cells using combination immunohistochemistry, allowing us to identify them as tumor cells, neurons, or astrocytes. The presence of HSV-TK positive cells in the recurrent tumors strongly supports the administration of further cycles of pro drug (valacyclovir), following Ad-TK administration.
CTIM-29. FINAL EFFICACY AND CORRELATIVE ANALYSES OF 2-THE-TOP: A PILOT STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Tran David , Chen Dongjiang , Le Son , Ghiaseddin Ashley
Published: November 2023

INTRODUCTION

TTFields induce anti-tumor immunity via the STING and AIM2 inflammasomes. Thus, TTFields-treated GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients.

METHODS

We enrolled 26 ndGBM patients in a pilot study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from pembrolizumab, TTFields starts at cycle 1 of TMZ while pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS versus a case-matched cohort of 56 patients from the EF-14 study. Secondary endpoints include OS, toxicity, and mechanism of response by multiomics of PBMCs and tumors.

RESULTS

The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in controls (HR = 0.377; 95CI: 0.217-0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95CI: 0.301-0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common SAEs were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses confirmed robust T cell activation by TTFields via T1IFN-dependent plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014). Successful clonal replacement of the most expanded T cell clones after pembrolizumab strongly predicted objective responses to the triple combination in a Cox HR fit model (concordance rate = 0.876; P = 0.031).

CONCLUSIONS

The triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated
CTIM-31. CLINICAL IMPACT OF ADDING PEMBROLIZUMAB TO STANDARD OF CARE CHEMORADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Ambady Prakash , Barajas Ramon , Fu Rochelle , Szidonya Laszlo , Huddleston Amy , Popp Lauren , Moussalli Dana , Turchan Maria , Diaz Claire , Edward Neuwelt
Published: November 2023

BACKGROUND

Standard of care (SOC) for newly diagnosed glioblastoma includes radiotherapy plus temozolomide followed by 6 adjuvant cycles monthly temozolomide per the Stupp protocol. We report the secondary objectives of a single arm phase 2 study evaluating the clinical impact of the addition of immune check point inhibitor pembrolizumab to this standard therapy.

METHODS

Patients with histopathology proven glioblastoma (WHO 4) eligible to receive SOC were prospectively enrolled to received pembrolizumab 200 mg iv every 3 weeks for up to 35 doses, progression, development of dose limiting toxicity or withdrawal of consent. Patients also receive ferumoxytol steady state MRI scans at baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or chemoradiotherapy, every 9 weeks thereafter until suspected radiographic progression, and then within 4 weeks from suspected radiographic progression. Primary endpoints of the study were to test the sensitivity and specificity of ferumoxytol steady state imaging for response assessment in this cohort. Secondary objective includes Progression free (PFS) and Overall survival (OS) and toxicity. PFS and OS were analyzed using Kaplan-Meier method.

RESULTS

A total of 52 patients (19 F, 33 M; 43 IHD wt and 9 IDH mu; 25 MGMT gene methylated, 27 unmethylated) were enrolled and included. At a median Follow up of 14.3 months, median PFS was 10.7 m (95% CI:8.1-12.6) and median OS was 14.4 m (95%CI: 12.5-16.9). Two grade 3 or higher toxicities (bullous dermatitis and Steven-Johnson syndrome) were attributed to pembrolizumab.

CONCLUSIONS

Although, the addition of pembrolizumab to SOC was well tolerated in most patients, this study did not see any meaning clinical benefit in PFS or OS with the addition of pembrolizumab in patients with newly diagnosed glioblastoma. Analysis for the primary imaging endpoint is ongoing.
CTIM-32. A PARALLEL COHORT PHASE 2 STUDY OF REGORAFENIB PLUS NIVOLUMAB FOR RECURRENT OR METASTATIC SOLID TUMORS: RESULTS IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM) OR ANAPLASTIC ASTROCYTOMA (AA)
Authors: Simonelli Matteo , Caccese Mario , Larrieu-Ciron Delphine , Franceschi Enrico , Kim Tae Min , Fayette Jerome , Freres Pierre , Robert Marie , Eoli Marica , Luce Sylvie , Portnow Jana , Hirata Yuki , Enya Kengo , Waxman Ian , Jin Lixian , Shah Dipam , Drews Uta , Berre Marie-Aude Le , Lombardi Giuseppe
Published: November 2023

INTRODUCTION

The multikinase inhibitor regorafenib improved overall survival (OS) versus lomustine in relapsed GBM in the randomized phase 2 REGOMA study. The aim of this study was to evaluate the efficacy of regorafenib combined with nivolumab in this setting (NCT04704154).

METHODS

Patients aged ≥ 18 years with recurrent GBM/AA (WHO 2016 classification) after radiotherapy plus temozolomide, and an ECOG performance status (PS) of 0/1, received oral regorafenib 90 mg/day on days 1–21 and intravenous nivolumab 480 mg on day 1 of each 28-day cycle. If tolerated, the regorafenib dose could be escalated to 120 mg/day from cycle 2. Prior regorafenib treatment or immunotherapy was not allowed. The primary endpoint was objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), OS, and safety (MedDRA; CTCAE v5.0).

RESULTS

Of the 36 patients enrolled, 30 were treated and were eligible for analysis. Median age was 60 years, 63% had an ECOG PS of 1, and 90% had GBM (10% AA). All patients discontinued treatment as of the primary analysis (March 9, 2023). One patient had a best-overall partial response (ORR; 3%) and nine (30%) had stable disease. Median number of cycles of regorafenib and nivolumab infusions was three. Median PFS (RANO) was 2.7 months (80% CI 1.8, 7.3) and 6-month PFS was 31.5%. Median OS was 8.0 months (80% CI 4.6, 12.4) and 12-month OS was 33.7%. Thirteen patients (43%) had grade 3/4 treatment-emergent adverse events (TEAEs), which were drug-related in 12 patients (40%). The most common drug-related grade 3/4 TEAEs were AST increase (13%), ALT increase (10%), and hypertension (10%). There were no immune-mediated serious TEAEs or drug-related grade 5 TEAEs.

CONCLUSION

The efficacy results of this study do not support further evaluation of regorafenib combined with nivolumab in GBM/AA. The safety profile was acceptable and manageable.