An Update on H3K27M-altered Diffuse Midline Glioma: Diagnostic and Therapeutic Challenges in Clinical Practice.

H3K27-altered diffuse midline glioma (DMG H3K27-altered) is a relatively newly-designated WHO entity which primarily affects the midline structures of the central nervous system (CNS), including the brainstem (predominantly pontine region), thalamus, midbrain, or spinal cord, and primarily affects children and young adults. Despite the proximity of these tumors to eloquent areas in the CNS, novel stereotactic approaches have facilitated the ability to obtain tissue diagnoses without significant morbidity, providing molecular diagnostic information in more than half of patients. Conventionally fractionated radiation therapy to a total dose of 54-60 Gy in 27-30 fractions and 24 Gy in 12 fractions play a crucial role in the definitive treatment of these tumors in the primary and salvage settings, respectively. Hypofractionated regimens may allow for accelerated treatment courses in selected patients without jeopardizing disease control or survival. The decision to add concurrent or adjuvant systemic therapy mainly relies on the physicians' experience without solid evidence in the literature in favor of any particular regimen. Recently, novel agents, such as ONC201 have demonstrated promising oncologic outcomes in progressive/recurrent tumors and are currently under investigation in ongoing randomized trials. Given the scarcity of data and well-established guidelines due to the rare nature of the disease, we provide a contemporary overview on the molecular underpinnings of this disease entity, describe the role of radiotherapy and systemic therapy, and present practice management principles based on the published literature.

Proton Therapy: Current Status and Controversies.

Expert commentary on the evolving role of proton therapy, discussing the current status and controversies of proton therapy in the modern era.

How proton therapy fits into the management of adult intracranial tumors.

Intracranial tumors include a challenging array of primary and secondary parenchymal and extra-axial tumors which cause neurologic morbidity consequential to location, disease extent, and proximity to critical neurologic structures. Radiotherapy can be used in the definitive, adjuvant, or salvage setting either with curative or palliative intent. Proton therapy (PT) is a promising advance due to dosimetric advantages compared to conventional photon radiotherapy with regards to normal tissue sparing, as well as distinct physical properties, which yield radiobiologic benefits. In this review, the principles of efficacy and safety of PT for a variety of intracranial tumors are discussed, drawing upon case series, retrospective and prospective cohort studies, and randomized clinical trials. This manuscript explores the potential advantages of PT, including reduced acute and late treatment-related side effects and improved quality of life. The objective is to provide a comprehensive review of the current evidence and clinical outcomes of PT. Given the lack of consensus and directives for its utilization in patients with intracranial tumors, we aim to provide a guide for its judicious use in clinical practice.

Clinical application of an institutional fractionated stereotactic radiosurgery (FSRS) program for brain metastases delivered with MRIdianⓇ BrainTx™.

Single-fraction stereotactic radiosurgery (SRS) or fractionated SRS (FSRS) are well established strategies for patients with limited brain metastases. A broad spectrum of modern dedicated platforms are currently available for delivering intracranial SRS/FSRS; however, SRS/FSRS delivered using traditional CT-based platforms relies on the need for diagnostic MR images to be coregistered to planning CT scans for target volume delineation. Additionally, the on-board image guidance on traditional platforms yields limited inter-fraction and intra-fraction real-time visualization of the tumor at the time of treatment delivery. MR Linacs are capable of obtaining treatment planning MR and on-table MR sequences to enable visualization of the targets and organs-at-risk and may subsequently help identify anatomical changes prior to treatment that may invoke the need for on table treatment adaptation. Recently, an MR-guided intracranial package (MRIdian A3i BrainTxTM) was released for intracranial treatment with the ability to perform high-resolution MR sequences using a dedicated brain coil and cranial immobilization system. The objective of this report is to provide, through the experience of our first patient treated, a comprehensive overview of the clinical application of our institutional program for FSRS adaptive delivery using MRIdian's A3i BrainTx system-highlights include reviewing the imaging sequence selection, workflow demonstration, and details in its delivery feasibility in clinical practice, and dosimetric outcomes.

Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort.

BACKGROUND: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. METHODS: Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). RESULTS: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. CONCLUSIONS: H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.

Prophylactic Radiotherapy Of MInimally Symptomatic Spinal Disease (PROMISSeD): study protocol for a randomized controlled trial.

BACKGROUND: Early palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year. METHODS: This is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0-2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20-30 Gy of radiation in 2-10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05. DISCUSSION: The results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy. TRIAL REGISTRATION: ClinicalTrials.Gov NCT05534321 . Registered September 9, 2022. TRIAL STATUS: Version 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024.

Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors.

Radiotherapy for ultracentral lung tumors represents a treatment challenge, considering the high rates of high-grade treatment-related toxicities with stereotactic body radiation therapy (SBRT) or hypofractionated schedules. Accelerated hypofractionated magnetic resonance-guided adaptive radiation therapy (MRgART) emerged as a potential game-changer for tumors in these challenging locations, in close proximity to central organs at risk, such as the trachea, proximal bronchial tree, and esophagus. In this series, 13 consecutive patients, predominantly male (n = 9), with a median age of 71 (range (R): 46-85), underwent 195 MRgART fractions (all 60 Gy in 15 fractions) to metastatic (n = 12) or primary ultra-central lung tumors (n = 1). The median gross tumor volumes (GTVs) and planning target volumes (PTVs) were 20.72 cc (R: 0.54-121.65 cc) and 61.53 cc (R: 3.87-211.81 cc), respectively. The median beam-on time per fraction was 14 min. Adapted treatment plans were generated for all fractions, and indications included GTV/PTV undercoverage, OARs exceeding tolerance doses, or both indications in 46%, 18%, and 36% of fractions, respectively. Eight patients received concurrent systemic therapies, including immunotherapy (four), chemotherapy (two), and targeted therapy (two). The crude in-field loco-regional control rate was 92.3%. No CTCAE grade 3+ toxicities were observed. Our results offer promising insights, suggesting that MRgART has the potential to mitigate toxicities, enhance treatment precision, and improve overall patient care in the context of ultracentral lung tumors.

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.

PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

Commissioning Intracranial Stereotactic Radiosurgery for a Magnetic Resonance-Guided Radiation Therapy (MRgRT) System: MR-RT Localization and Dosimetric End-to-End Validation.

PURPOSE: This is the first reporting of the MRIdian A3iTM intracranial package (BrainTxTM) and benchmarks the end-to-end localization and dosimetric accuracy for commissioning an magnetic resonace (MR)-guided stereotactic radiosurgery program. We characterized the localization accuracy between MR and radiation (RT) isocenter through an end-to-end hidden target test, relative dose profile intercomparison, and absolute dose validation. METHODS AND MATERIALS: BrainTx consists of a dedicated head coil, integrated mask immobilization system, and high-resolution MR sequences. Coil and baseplate attenuation was quantified. An in-house phantom (Cranial phantOm foR magNetic rEsonance Localization of a stereotactIc radiosUrgery doSimeter, CORNELIUS) was developed from a mannequin head filled with silicone gel, film, and MR BB with pinprick. A hidden target test evaluated MR-RT localization of the 1×1×1 mm3 TrueFISP MR and relative dose accuracy in film for a 1 cm diameter (International Electrotechnical Commission (IEC)-X/IEC-Y) and 1.5 cm diameter (IEC-Y/IEC-Z) spherical target. Two clinical cases (irregular-shaped target and target abutting brainstem) were mapped to the CORNELIUS phantom for feasibility assessment. A 2-dimensional (2D)-gamma compared calculated and measured dose for spherical and clinical targets with 1 mm/1% and 2 mm/2% criteria, respectively. A small-field chamber (A26MR) measured end-to-end absolute dose for a 1 cm diameter target. RESULTS: Coil and baseplate attenuation were 0.7% and 2.7%, respectively. The displacement of MR to RT localization as defined through the pinprick was 0.49 mm (IEC-X), 0.27 mm (IEC-Y), and 0.51 mm (IEC-Z) (root mean square 0.76 mm). The reproducibility across IEC-Y demonstrated high fidelity (<0.02 mm). Gamma pass rates were 97.1% and 95.4% for 1 cm and 1.5 cm targets, respectively. Dose profiles for an irregular-shaped target and abutting organ-at-risk-target demonstrated pass rates of 99.0% and 92.9%, respectively. The absolute end-to-end dose difference was <1%. CONCLUSIONS: All localization and dosimetric evaluation demonstrated submillimeter accuracy, per the TG-142, TG-101, MPPG 9.a. criteria for SRS/SRT systems, indicating acceptable delivery capabilities with a 1 mm setup margin.

Impact of Apolipoprotein E Genotype on Neurocognitive Function in Patients With Brain Metastases: An Analysis of NRG Oncology's RTOG 0614.

PURPOSE: Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT. METHODS AND MATERIALS: NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed-effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. RESULTS: APOE results were available for 45% of patients (n = 227/508). NCF did not differ by APOE e4 carrier status at baseline. Mixed-effects modeling showed that APOE e4 carriers had worse memory after WBRT compared with APOE e4 noncarriers (Hopkins Verbal Learning Test-Revised total recall [least square mean difference, 0.63; P = .0074], delayed recognition [least square mean difference, 0.75; P = .023]). However, APOE e4 carrier status was not associated with time to NCF failure (hazard ratio, 0.86; 95% CI, 0.60-1.23; P = .40). Memantine delayed the time to NCF failure, regardless of carrier status (hazard ratio, 0.72; 95% CI, 0.52-1.01; P = .054). CONCLUSIONS: APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/- memantine), without acceleration of onset of difference in time to NCF failure.

Dosimetric comparison of magnetic resonance-guided radiation therapy, intensity-modulated proton therapy and volumetric-modulated arc therapy for distal esophageal cancer.

Advances in radiotherapy (RT) technologies permit significant decreases in the dose delivered to organs at risk (OARs) for patients with esophageal cancer (EC). Novel RT modalities such as proton beam therapy (PBT) and magnetic resonance-guided radiotherapy (MRgRT), as well as motion management techniques including breath hold (BH) are expected to further improve the therapeutic ratio. However, to our knowledge, the dosimetric benefits of PBT vs MRgRT vs volumetric-modulated arc therapy (VMAT) have not been directly compared for EC. We performed a retrospective in silico evaluation using the images and datasets of nine distal EC patients who were treated at our institution with a 0.35-Tesla MR linac to 50.4 Gy in 28 fractions in mid-inspiration BH (BH-MRgRT). Comparison free-breathing (FB) intensity-modulated PBT (FB-IMPT) and FB-VMAT plans were retrospectively created using the same prescription dose, target volume coverage goals, and OAR constraints. A 5 mm setup margin was used for all plans. BH-IMPT and BH-VMAT plans were not evaluated as they would not reflect our institutional practice. Planners were blinded to the results of the treatment plans created using different radiation modalities. The primary objective was to compare plan quality, target volume coverage, and OAR doses. All treatment plans met pre-defined target volume coverage and OAR constraints. The median conformity and homogeneity indices between FB-IMPT, BH-MRgRT and FB-VMAT were 1.13, 1.25, and 1.43 (PITV) and 1.04, 1.15, 1.04 (HI), respectively. For FB-IMPT, BH-MRgRT and FB-VMAT the median heart dose metrics were 52.8, 79.3, 146.8 (V30Gy, cc), 35.5, 43.8, 77.5 (V40Gy, cc), 16.9, 16.9, 32.5 (V50Gy, cc) and 6.5, 14.9, 17.3 (mean, Gy), respectively. Lung dose metrics were 8.6, 7.9, 18.5 (V20Gy, %), and 4.3, 6.3, 11.2 (mean, Gy), respectively. The mean liver dose (Gy) was 6.5, 19.6, 22.2 respectively. Both FB-IMPT and BH-MRgRT achieve substantial reductions in heart, lung, and liver dose compared to FB-VMAT. We plan to evaluate dosimetric outcomes across these RT modalities assuming consistent use of BH.

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

Tumor treating fields: narrative review of a promising treatment modality for cancer.

BACKGROUND AND OBJECTIVE: Tumor treating fields (TTFields) therapy have emerged as a potentially effective treatment for various malignancies by delivering low-intensity, intermediate-frequency electrical fields that disrupt many processes inside cells, resulting in the interruption of cell division in cancer cells. Additionally, TTFields therapy has been found to be synergistic with existing therapeutic approaches. In this review, we provide an introduction and background to the primary mechanisms of TTFields and discuss the emerging preclinical and clinical outcomes of this novel cancer treatment technology. METHODS: We performed a literature search on PubMed, ClinicalTrials.Gov, and Google Scholar using the terms 'TTFields' and 'cancer'. We included studies, review articles, and editorials published in English from 1st January 2000 to 1st October 2023. All obtained publications were reviewed and their key references are cross-checked to ensure a balanced and high-quality review. KEY CONTENT AND FINDINGS: Clinical studies reported to date have demonstrated the survival advantage of TTFields therapy in newly diagnosed glioblastoma (GBM), non-small cell lung cancer (NSCLC), and meaningful clinical activity in recurrent GBM (rGBM) and malignant pleural mesothelioma. Moreover, TTFields therapy has exhibited promising safety profiles across a diverse range of cancers including pancreatic cancer, hepatocellular carcinoma (HCC), ovarian cancer, NSCLC, and gastric cancer, when combined with cytotoxic chemotherapy and/or immunotherapy regimens, suggesting broad applicability as an added treatment modality. CONCLUSIONS: Based on preclinical and clinical studies, TTFields therapy show promise as a potential treatment option for patients with a number of different malignancies, offering a favorable safety profile and the potential for significant clinical benefit. Further research is warranted to establish the optimal treatment parameters and identify specific patient subgroups that may derive the greatest advantage from this treatment modality.

Surgically targeted radiation therapy (STaRT) for recurrent brain metastases: Initial clinical experience.

PURPOSE: This study evaluates the outcomes of recurrent brain metastasis treated with resection and brachytherapy using a novel Cesium-131 carrier, termed surgically targeted radiation therapy (STaRT), and compares them to the first course of external beam radiotherapy (EBRT). METHODS: Consecutive patients who underwent STaRT between August 2020 and June 2022 were included. All patients underwent maximal safe resection with pathologic confirmation of viable disease prior to STaRT to 60 Gy to a 5-mm depth from the surface of the resection cavity. Complications were assessed using CTCAE version 5.0. RESULTS: Ten patients with 12 recurrent brain metastases after EBRT (median 15.5 months, range: 4.9-44.7) met the inclusion criteria. The median BED10Gy90% and 95% were 132.2 Gy (113.9-265.1 Gy) and 116.0 Gy (96.8-250.6 Gy), respectively. The median maximum point dose BED10Gy for the target was 1076.0 Gy (range: 120.7-1478.3 Gy). The 6-month and 1-year local control rates were 66.7% and 33.3% for the prior EBRT course; these rates were 100% and 100% for STaRT, respectively (p < 0.001). At a median follow-up of 14.5 months, there was one instance of grade two radiation necrosis. Surgery-attributed complications were observed in two patients including pseudomeningocele and minor headache. CONCLUSIONS: STaRT with Cs-131 presents an alternative approach for operable recurrent brain metastases and was associated with superior local control than the first course of EBRT in this series. Our initial clinical experience shows that STaRT is associated with a high local control rate, modest surgical complication rate, and low radiation necrosis risk in the reirradiation setting.

Online adaptive radiotherapy: Assessment of planning technique and its impact on longitudinal plan quality robustness in pancreatic cancer.

BACKGROUND AND PURPOSE: Planning on a static dataset that reflects the simulation day anatomy is routine for SBRT. We hypothesize the quality of on-table adaptive plans is similar to the baseline plan when delivering stereotactic MR-guided adaptive radiotherapy (SMART) for pancreatic cancer (PCa). MATERIALS AND METHODS: Sixty-seven inoperable PCa patients were prescribed 50 Gy/5-fraction SMART. Baseline planning included: 3-5 mm gastrointestinal (GI) PRV, 50 Gy optimization target (PTVopt) based on GI PRV, conformality rings, and contracted GTV to guide the hotspot. For each adaptation, GI anatomy was re-contoured, followed by re-optimization. Plan quality was evaluated for target coverage (TC = PTVopt V100%/volume), PTV D90% and D80%, homogeneity index (HI = PTVopt D2%/D98%), prescription isodose/target volume (PITV), low-dose conformity (D2cm = maximum dose at 2 cm from PTVopt/Rx dose), and gradient index (R50%=50% Rx isodose volume/PTVopt volume).A novel global planning metric, termed the Pancreas Adaptive Radiotherapy Score (PARTS), was developed and implemented based on GI OAR sparing, PTV/GTV coverage, and conformality. Adaptive robustness (baseline to fraction 1) and stability (difference between two fractions with highest GI PRV variation) were quantified. RESULTS: OAR constraints were met on all baseline (n = 67) and adaptive (n = 318) plans. Coverage for baseline/adaptive plans was mean ± SD at 44.9 ± 5.8 Gy/44.3 ± 5.5 Gy (PTV D80%), 50.1 ± 4.2 Gy/49.1 ± 4.7 Gy (PTVopt D80%), and 80%±18%/74%±18% (TC), respectively. Mean homogeneity and conformality for baseline/adaptive plans were 0.87 ± 0.25/0.81 ± 0.30 (PITV), 3.81 ± 1.87/3.87 ± 2.0 (R50%), 1.53 ± 0.23/1.55 ± 0.23 (HI), and 58%±7%/59%±7% (D2cm), respectively. PARTS was found to be a sensitive metric due to its additive influence of geometry changes on PARTS' sub-metrics. There were no statistical differences (p > 0.05) for stability, except for PARTS (p = 0.04, median difference -0.6%). Statistical differences for robustness when significant were small for most metrics (<2.0% median). Median adaptive re-optimizations were 2. CONCLUSION: We describe a 5-fraction ablative SMART planning approach for PCa that is robust and stable during on-table adaption, due to gradients controlled by a GI PRV technique and the use of rings. These findings are noteworthy given that daily interfraction anatomic GI OAR differences are routine, thus necessitating on-table adaptation. This work supports feasibility towards utilizing a patient-independent, template on-table adaptive approach.