Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy.

PURPOSE: After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). METHODS AND MATERIALS: In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival. RESULTS: In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival. CONCLUSIONS: The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Opportunities and Alternatives of Modern Radiation Oncology and Surgery for the Management of Resectable Brain Metastases.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

Influence of radiation treatment technique (IMRT vs. 3D-RT) on acute toxicity and prognostic factors for survival for anal cancer.

We compared our institutional experience with intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-RT) for definitive treatment of primary anal cancer. We performed a single-institution retrospective review of all patients with anal squamous cell carcinoma treated with definitive (chemo) radiotherapy with curative intent from 2004 through 2018. We assessed several prognostic factors in respect to relevant survival endpoints. In addition, acute toxicities were determined and compared between IMRT and 3D-RT patients. This study included 94 patients (58 IMRT, 36 3D-RT). Mean follow up for all patients, for IMRT and 3D-RT patients was 61 months (range 6-176), 46 months (range 6-118), and 85 months (range 6-176), respectively. 5-year overall survival (OS) was 86%, disease-free survival (DFS) was 72%, and colostomy-free survival (CFS) was 75% in the IMRT cohort. In the 3D-RT cohort, OS was 87%, DFS was 71%, and CFS was 81% (all p > 0.05). Male gender and Karnofsky Index (KI) were revealed as independent prognostic factors for 5-year OS (p = 0.017; p = 0.023). UICC stage was an independent prognostic factor for DFS and CFS (p = 0.023; p = 0.042). In addition, the pre-treatment leukocyte count was an independent prognostic factor for CFS (p = 0.042). Acute grade ≥ 3 toxicity was not significantly different between IMRT and 3D-RT patients, but the IMRT cohort had favorable outcomes. This study confirmed IMRT as the primary definitive treatment of anal cancer. With similar survival rates, IMRT had the potential to reduce acute toxicity by sparing organs at risk. Promising prognostic factors such as BMI, KI, and leucocyte and hemoglobin levels should be further investigated.

nTMS-derived DTI-based motor fiber tracking in radiotherapy treatment planning of high-grade gliomas for avoidance of motor structures.

BACKGROUND: Management of high-grade gliomas (HGGs) close to motor areas is challenging due to the risk of treatment-related morbidity. Thus, for resection, functional mapping of the corticospinal tract (CST) with navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTTMS) is increasingly used. This study investigated the application of DTI-FTTMS in adjuvant radiation therapy (RT) planning of HGGs for CST avoidance. METHODS: The preoperative DTI-FTTMS-based CST reconstructions of 35 patients harboring HGGs were incorporated into the RT planning system and merged with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Intensity-modulated RT (IMRT) plans were optimized to preserve PRV-FTTMS. Segments within the planning target volume (PTV) were not spared (overlap). RESULTS: With plan optimization, mean dose (Dmean) of PRV-FTTMS can be reduced by 17.1% on average (range 0.1-37.9%), thus from 25.5 Gy to 21.2 Gy (p < 0.001). For PRV-FTTMS segments beyond the PTV dose, reduction is possible by 26.8% (range 0.1-43.9%, Dmean 17.4 Gy vs. 12.5 Gy, p < 0.001). Considering only portions within the 50% isodose level, Dmean is decreased by 46.7% from 38.6 Gy to 20.5 Gy (range 19.1-62.8%, p < 0.001). PTV coverage was not affected: V95% and V90% were 96.4 ± 3.1% and 98.0 ± 3.9% vs. 96.1 ± 3.5% (p = 0.34) and 98.3 ± 2.9% (p = 0.58). Dose constraints for organs at risk (OARs) were all met. CONCLUSION: This study demonstrates that DTI-FTTMS can be utilized in the RT planning of HGGs for CST sparing. However, the degree of dose reduction depends on the overlap with the PTV. The functional benefit needs to be investigated in future prospective clinical trials.

Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience.

BACKGROUND: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. METHOD: Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16-30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan-Meyer analysis were applied. RESULTS: The mean follow-up time was 10.8 months (range, 0-39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3-100%), 71.4% (95%-CI 50.2-92.6%) and 58.0% (95%-CI 34.1-81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. CONCLUSION: In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis.

Dose Reduction to Motor Structures in Adjuvant Fractionated Stereotactic Radiotherapy of Brain Metastases: nTMS-Derived DTI-Based Motor Fiber Tracking in Treatment Planning.

Background: Resection of brain metastases (BM) close to motor structures is challenging for treatment. Navigated transcranial magnetic stimulation (nTMS) motor mapping, combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTmot.TMS), is a valuable tool in neurosurgery to preserve motor function. This study aimed to assess the practicability of DTI-FTmot.TMS for local adjuvant radiotherapy (RT) planning of BM. Methods: Presurgically generated DTI-FTmot.TMS-based corticospinal tract (CST) reconstructions (FTmot.TMS) of 24 patients with 25 BM resected during later surgery were incorporated into the RT planning system. Completed fractionated stereotactic intensity-modulated RT (IMRT) plans were retrospectively analyzed and adapted to preserve FTmot.TMS. Results: In regular plans, mean dose (Dmean) of complete FTmot.TMS was 5.2 ± 2.4 Gy. Regarding planning risk volume (PRV-FTTMS) portions outside of the planning target volume (PTV) within the 17.5 Gy (50%) isodose line, the DTI-FTmot.TMS Dmean was significantly reduced by 33.0% (range, 5.9−57.6%) from 23.4 ± 3.3 Gy to 15.9 ± 4.7 Gy (p < 0.001). There was no significant decline in the effective treatment dose, with PTV Dmean 35.6 ± 0.9 Gy vs. 36.0 ± 1.2 Gy (p = 0.063) after adaption. Conclusions: The DTI-FTmot.TMS-based CST reconstructions could be implemented in adjuvant IMRT planning of BM. A significant dose reduction regarding motor structures within critical dose levels seems possible.

Patient-Reported Outcome (PRO) as an Addition to Long-Term Results after High-Precision Stereotactic Radiotherapy in Patients with Secreting and Non-Secreting Pituitary Adenomas: A Retrospective Cohort Study up to 17-Years Follow-Up.

High-precision radiotherapy has been established as a valid and effective treatment option in patients with pituitary adenomas. We report on outcome after fractionated stereotactic radiotherapy (FSRT) in correlation with patient-reported outcomes (PROs). We analyzed 69 patients treated between 2000 and 2019. FSRT was delivered with a median total dose of 54 Gy (single fraction: 1.8 Gy). PRO questionnaires were sent to 28 patients. Median overall survival was 17.2 years; mean local control was 15.6 years (median not reached). Median follow-up was 5.8 years. Twenty (71%) patients participated in the PRO assessment. Physicians reported symptoms grade ≥3 in 6 cases (9%). Of all, 35 (51%) patients suffered from hypopituitarism at baseline, and during follow-up, new or progressive hypopituitarism was observed in 11 cases (16%). Patients reported 10 cases of severe side effects. Most of these symptoms were already graded as CTCAE (Common Terminology Criteria for Adverse Events) grade 2 by a physician in a previous follow-up exam. PROs are an essential measure and only correlate to a certain extent with the physician-reported outcomes. For high-precision radiotherapy of pituitary adenomas, they confirm excellent overall outcomes and low toxicity. In the future, the integration of PROs paired with high-end treatment will further improve outcomes.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors (NepoMUC): a phase I dose escalation trial.

BACKGROUND: More than 25% of patients with solid cancers develop intracerebral metastases. Aside of surgery, radiation therapy (RT) is a mainstay in the treatment of intracerebral metastases. Postoperative fractionated stereotactic RT (FSRT) to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recurrence. However, FSRT has to be delayed until a sufficient wound healing is attained; hence systemic therapy might be postponed. Neoadjuvant stereotactic radiosurgery (SRS) might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy. Here, we conducted a study to find the maximum tolerated dose (MTD) of neoadjuvant SRS for intracerebral metastases. METHODS: This is a single-center, phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital, Technical University of Munich. The rule-based traditional 3 + 3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied. The primary endpoint is the MTD for which no dose-limiting toxicities (DLT) occur. The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 continuously during the study until the first follow-up visit (4-6 weeks after surgery). Secondary endpoints include local control rate, survival, immunological tumor characteristics, quality of life (QoL), CTCAE grade of late clinical, neurological, and neurocognitive toxicities. In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS. Depending on the occurrence of DLT up to 72 patients will be enrolled. The recruitment phase will last for 24 months. DISCUSSION: Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity, such as better target volume definition with subsequent higher efficiency of eliminating tumor cells, and lower damage to surrounding healthy tissue, and much-needed systemic chemotherapy could be initiated more rapidly. Trial registration The local ethical review committee of Technical University of Munich (199/18S) approved this study on September 05, 2018. This trial was registered on German Clinical Trials Register (DRKS00016613; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016613) on January 29, 2019.

Application of presurgical navigated transcranial magnetic stimulation motor mapping for adjuvant radiotherapy planning in patients with high-grade gliomas.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is applied in neurosurgical routine to detect motor-eloquent brain areas for safe resection of high-grade gliomas (HGGs). However, in radiation therapy (RT) planning, the primary motor cortex is not respected yet in target volume delineation. This study evaluates the implementation of nTMS motor mapping in RT planning in patients harboring motor-eloquent HGGs with the aim of reducing dose applications to the motor cortex. METHODS: nTMS motor maps of 30 patients diagnosed with motor-eloquent HGGs were fused with RT planning imaging and volumetric modulated RT plans were optimized using nTMS motor maps as an organ at risk (OAR). Doses to nTMS motor maps were evaluated using dose-volume histogram (DVH) parameters. RESULTS: Mean dose (Dmean) to the nTMS motor maps was 42.3 Gy (3.7-61.1 Gy) and was significantly reduced by 14.3% to 37.0 Gy (3.6-55.8 Gy, p < 0.05) when constraining the dose to nTMS motor areas to 45 Gy. Areas within the planning target volume (PTV) were not spared (overlap). Yet, the dose to PTV was not compromised. Even with an additional dose escalation (70 Gy) to the tumor area, nTMS motor maps can be spared by 4.6 ±â€¯3.5 Gy (12.8%, p < 0.05). CONCLUSIONS: nTMS motor maps can be easily implemented in standard RT planning and applied for target contouring in RT of HGGs. Doses to motor-eloquent areas can be significantly reduced when considering nTMS motor maps without affecting treatment doses to the PTV. Thus, nTMS could be used as a valuable tool in RT planning.

The Role of Particle Therapy for the Treatment of Skull Base Tumors and Tumors of the Central Nervous System (CNS).

Radiation therapy (RT) is a mainstay in the interdisciplinary treatment of brain tumors of the skull base and brain. Technical innovations during the past 2 decades have allowed for increasingly precise treatment with better sparing of adjacent healthy tissues to prevent treatment-related side effects that influence patients' quality of life. Particle therapy with protons and charged ions offer favorable kinetics with sharp dose deposition in a well-defined depth (Bragg-Peak) and a steep radiation fall-off beyond that maximum. This review highlights the role of particle therapy in the management of primary brain tumors and tumors of the skull base.

The Role of Navigated Transcranial Magnetic Stimulation Motor Mapping in Adjuvant Radiotherapy Planning in Patients With Supratentorial Brain Metastases.

Purpose: In radiotherapy (RT) of brain tumors, the primary motor cortex is not regularly considered in target volume delineation, although decline in motor function is possible due to radiation. Non-invasive identification of motor-eloquent brain areas is currently mostly restricted to functional magnetic resonance imaging (fMRI), which has shown to lack precision for this purpose. Navigated transcranial magnetic stimulation (nTMS) is a novel tool to identify motor-eloquent brain areas. This study aims to integrate nTMS motor maps in RT planning and evaluates the influence on dosage modulations in patients harboring brain metastases. Materials and Methods: Preoperative nTMS motor maps of 30 patients diagnosed with motor-eloquent brain metastases were fused with conventional planning imaging and transferred to the RT planning software. RT plans of eleven patients were optimized by contouring nTMS motor maps as organs at risk (OARs). Dose modulation analyses were performed using dose-volume histogram (DVH) parameters. Results: By constraining the dose applied to the nTMS motor maps outside the planning target volume (PTV) to 15 Gy, the mean dose (Dmean) to the nTMS motor maps was significantly reduced by 18.1% from 23.0 Gy (16.9-30.4 Gy) to 18.9 Gy (13.5-28.8 Gy, p < 0.05). The Dmean of the PTV increased by 0.6 ± 0.3 Gy (1.7%). Conclusion: Implementing nTMS motor maps in standard RT planning is feasible in patients suffering from intracranial metastases. A significant reduction of the dose applied to the nTMS motor maps can be achieved without impairing treatment doses to the PTV. Thus, nTMS might provide a valuable tool for safer application of RT in patients harboring motor-eloquent brain metastases.

Tumor necrosis factor-α enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling.

BACKGROUND AND PURPOSE: We sought to demonstrate that tumor necrosis factor (TNF)-α, via sphingosine-1-phosphate signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. METHODS: We performed intravital fluorescence microscopy to measure blood flow and capillary diameter in anesthetized guinea pigs. To measure capillary diameter ex vivo, capillary beds from the gerbil spiral ligament were isolated from the cochlear lateral wall and maintained in an organ bath. Isolated gerbil spiral modiolar arteries, maintained and transfected in organ culture, were used to measure calcium sensitivity (calcium-tone relationship). In a clinical study, a total of 12 adult patients presenting with typical symptoms of sudden hearing loss who were not responsive or only partially responsive to prednisolone treatment were identified and selected for etanercept treatment. Etanercept (25 mg s.c.) was self-administered twice a week for 12 weeks. RESULTS: TNF-α induced a proconstrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing sphingosine-1-phosphate receptor 2 subtype signaling (by 1 µmol/L JTE013) attenuated the effects of TNF-α in all models. TNF-α activated sphingosine kinase 1 (Sk1) and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1(G82D)) eliminated both baseline spiral modiolar artery calcium sensitivity and TNF-α effects, whereas a nonphosphorylatable Sk1 mutant (Sk1(S225A)) blocked the effects of TNF-α only. A small group of etanercept-treated, hearing loss patients recovered according to a 1-phase exponential decay (half-life=1.56 ± 0.20 weeks), which matched the kinetics predicted for a vascular origin. CONCLUSIONS: TNF-α indeed reduces cochlear blood flow via activation of vascular sphingosine-1-phosphate signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis, and treatment.