11C-methionine in the diagnostics and management of glioblastoma patients with rapid early progression: nonrandomized, open label, prospective clinical trial (GlioMET).

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The treatment of GBM consists of a combination of surgery and subsequent oncological therapy, i.e., radiotherapy, chemotherapy, or their combination. If postoperative oncological therapy involves irradiation, magnetic resonance imaging (MRI) is used for radiotherapy treatment planning. Unfortunately, in some cases, a very early worsening (progression) or return (recurrence) of the disease is observed several weeks after the surgery and is called rapid early progression (REP). Radiotherapy planning is currently based on MRI for target volumes definitions in many radiotherapy facilities. However, patients with REP may benefit from targeting radiotherapy with other imaging modalities. The purpose of the presented clinical trial is to evaluate the utility of 11C-methionine in optimizing radiotherapy for glioblastoma patients with REP. METHODS: This study is a nonrandomized, open-label, parallel-setting, prospective, monocentric clinical trial. The main aim of this study was to refine the diagnosis in patients with GBM with REP and to optimize subsequent radiotherapy planning. Glioblastoma patients who develop REP within approximately 6 weeks after surgery will undergo 11C-methionine positron emission tomography (PET/CT) examinations. Target volumes for radiotherapy are defined using both standard planning T1-weighted contrast-enhanced MRI and PET/CT. The primary outcome is progression-free survival defined using RANO criteria and compared to a historical cohort with REP treated without PET/CT optimization of radiotherapy. DISCUSSION: PET is one of the most modern methods of molecular imaging. 11C-Methionine is an example of a radiolabelled (carbon 11) amino acid commonly used in the diagnosis of brain tumors and in the evaluation of response to treatment. Optimized radiotherapy may also have the potential to cover those regions with a high risk of subsequent progression, which would not be identified using standard-of-care MRI for radiotherapy planning. This is one of the first study focused on radiotherapy optimization for subgroup of patinets with REP. TRIAL REGISTRATION: NCT05608395, registered on 8.11.2022 in clinicaltrials.gov; EudraCT Number: 2020-000640-64, registered on 26.5.2020 in clinicaltrialsregister.eu. Protocol ID: MOU-2020-01, version 3.2, date 18.09.2020.

Adjuvant radiotherapy after brain metastasectomy: analysis of consecutive cohort of 118 patients from real world practice.

Background: The aim of this retrospective study is to analyze a consecutive cohort of brain metastasis (BM) patients treated off clinical trials through combination of surgery and radiotherapy over the last 15 years in a tertiary neurooncology center. Materials and methods: All BM patients operated between 2007-2019 received adjuvant linac-based radiotherapy categorized to whole brain radiotherapy (WBRT) and tumor bed stereotactic radiotherapy. Survival outcomes and local control was analyzed. Results: In total, 118 patients were enrolled, those with stereotactic radiotherapy (41%) had better baseline characteristics mirrored in longer overall survival (OS) [18 vs. 7.1 months, p < 0.001; hazard ratio (HR) 0.47, p = 0.004] with median follow-up of 58 months. Cumulative incidence for local, distant, and extracranial control was not significantly different between groups, with 12-month cumulative control of 22% vs. 18%, 44% vs. 29%, and 35% vs. 32% for stereotactic and WBRT group, respectively. WBRT was an independent factor for better distal brain control. Conclusions: Real world data demonstrating significantly better overall survival in patients treated with postoperative targeted radiotherapy compared with postoperative WBRT is presented, with no significant difference in cumulative incidence for local or distant brain control. The majority of patients with targeted radiotherapy had a fractionated dose schedule with outcomes comparable to single-dose radiation trials of postoperative targeted radiotherapy.

Unilateral hippocampal sparing during whole brain radiotherapy for multiple brain metastases: narrative and critical review.

Background: The landscape of brain metastases radiotherapy is evolving, with a shift away from whole-brain radiotherapy (WBRT) toward targeted stereotactic approaches aimed at preserving neurocognitive functions and maintaining overall quality of life. For patients with multiple metastases, especially in cases where targeted radiotherapy is no longer feasible due to widespread dissemination, the concept of hippocampal sparing radiotherapy (HA_WBRT) gains prominence. Methods: In this narrative review we explore the role of the hippocampi in memory formation and the implications of their postradiotherapy lateral damage. We also consider the potential advantages of selectively sparing one hippocampus during whole-brain radiotherapy (WBRT). Additionally, by systematic evaluation of relevant papers published on PubMed database over last 20 years, we provide a comprehensive overview of the various changes that can occur in the left or right hippocampus as a consequence of radiotherapy. Results: While it is important to note that various neurocognitive functions are interconnected throughout the brain, we can discern certain specialized roles of the hippocampi. The left hippocampus appears to play a predominant role in verbal memory, whereas the right hippocampus is associated more with visuospatial memory. Additionally, the anterior part of the hippocampus is more involved in episodic memory and emotional processing, while the posterior part is primarily responsible for spatial memory and pattern separation. Notably, a substantial body of evidence demonstrates a significant correlation between post-radiotherapy changes in the left hippocampus and subsequent cognitive decline in patients. Conclusion: In the context of individualized palliative radiotherapy, sparing the unilateral (specifically, the left, which is dominant in most individuals) hippocampus could expand the repertoire of strategies available for adapted WBRT in cases involving multiple brain metastases where stereotactic radiotherapy is not a viable option. Prospective ongoing studies assessing various memory-sparing radiotherapy techniques will define new standard of radiotherapy care of patients with multiple brain metastases.

Toxicity of external beam accelerated partial-breast irradiation (APBI) in adjuvant therapy of early-stage breast cancer: prospective randomized study.

BACKGROUND: Accelerated partial breast irradiation (APBI) is an alternative breast-conserving therapy approach where radiation is delivered in less time compared to whole breast irradiation (WBI), resulting in improved patient convenience, less toxicity, and cost savings. This prospective randomized study compares the external beam APBI with commonly used moderate hypofractionated WBI in terms of feasibility, safety, tolerance, and cosmetic effects. METHODS: Early breast cancer patients after partial mastectomy were equally randomized into two arms- external APBI and moderate hypofractionated WBI. External beam technique using available technical innovations commonly used in targeted hypofractionated radiotherapy to minimize irradiated volumes was used (cone beam computed tomography navigation to clips in the tumor bed, deep inspiration breath hold technique, volumetric modulated arc therapy dose application, using flattening filter free beams and the six degrees of freedom robotic treatment couch). Cosmetics results and toxicity were evaluated using questionnaires, CTCAE criteria, and photo documentation. RESULTS: The analysis of 84 patients with a median age of 64 years showed significantly fewer acute adverse events in the APBI arm regarding skin reactions, local and general symptoms during a median follow-up of 37 months (range 21-45 months). A significant difference in favor of the APBI arm in grade ≥ 2 late skin toxicity was observed (p = 0.026). Late toxicity in the breast area (deformation, edema, fibrosis, and pain), affecting the quality of life and cosmetic effect, occurred in 61% and 17% of patients in WBI and APBI arms, respectively. The cosmetic effect was more favorable in the APBI arm, especially 6 to 12 months after the radiotherapy. CONCLUSION: External APBI demonstrated better feasibility and less toxicity than the standard regimen in the adjuvant setting for treating early breast cancer patients. The presented study confirmed the level of evidence for establishing the external APBI in daily clinical practice. TRIAL REGISTRATION: NCT06007118.

Challenges with hippocampal MR spectroscopy as a surrogate for pre-radiotherapy assessment of neurocognitive impairment in patients with brain metastasis.

AIM: Patients with multiple brain metastases (BM) benefit from hippocampal-avoiding whole brain radiotherapy (HA-WBRT), the challenging and less available form of WBRT. This study explores potential of pre-radiotherapy (pre-RT) hippocampal magnetic resonance spectroscopy (MRS) measuring hippocampal neuronal density as an imaging surrogate and predictive tool for assessing neurocognitive functions (NCF). METHODS: 43 BM patients underwent pre-RT hippocampal MRS. N-acetyl aspartate (NAA) concentration, a marker for neuronal density (weighted by creatine (Cr) and choline (Cho) concentrations), and neurocognitive function (NCF) tests (HVLT and BVMT) performed by certified psychologists were evaluated. Clinical variables and NAA concentrations were correlated with pre-RT NCFs. RESULTS: HVLT and BVMT subtests showed pre-RT deterioration except for BVMT recognition. Significantly better NCFs were observed in women in HVLT subsets. Significantly higher NAA/Cr + Cho was measured in women (median 0.63 vs. 0.55; P=0.048) in the left hippocampus (no difference in the right hippocampus). In men, a positive correlation (0.51, P=0.018) between total brain volume and HVLT-TR, between left hippocampal NAA/Cr + Cho and HVLT-R (0.45, P=0.063), and between right hippocampal NAA/Cr + Cho and BVMT-recognition (0.49, P=0.054) was observed. In women, a borderline significant negative correlation was observed between left hippocampal NAA/Cr + Cho and BVMT-TR (-0.43, P=0.076) and between right NAA/Cr + Cho and HVLT-DR (-0.42, P=0.051). CONCLUSION: Borderline statistically significant correlations were observed with speculative interpretation underlying the challenges of hippocampal MRS as a surrogate for neurocognitive impairment. Further studies need to be done to ascertain the opportunities for imaging predictors of benefit from memory sparing radiotherapy.

Hippocampal subfield volumetric changes after radiotherapy for brain metastases.

Background: Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus. Method: Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after 4 months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions. Results: The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5 mm3, median volume 137 vs. 135 mm3; P = .027), the region of the presumed location of neuronal progenitors. Conclusions: Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy.

Controversies in neuro-oncology: Focal proton versus photon radiation therapy for adult brain tumors.

Radiation therapy (RT) plays a fundamental role in the treatment of malignant and benign brain tumors. Current state-of-the-art photon- and proton-based RT combines more conformal dose distribution of target volumes and accurate dose delivery while limiting the adverse radiation effects. PubMed was systematically searched from from 2000 to October 2023 to identify studies reporting outcomes related to treatment of central nervous system (CNS)/skull base tumors with PT in adults. Several studies have demonstrated that proton therapy (PT) provides a reduced dose to healthy brain parenchyma compared with photon-based (xRT) radiation techniques. However, whether dosimetric advantages translate into superior clinical outcomes for different adult brain tumors remains an open question. This review aims at critically reviewing the recent studies on PT in adult patients with brain tumors, including glioma, meningiomas, and chordomas, to explore its potential benefits compared with xRT.

Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study.

BACKGROUND: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. METHODS: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0-2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union's Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. DISCUSSION: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023.