Dietrich, Jörg

Abstract Background Multi-modality therapy has improved survival for many patients with brain metastases. However, neurocognitive sequelae remain a challenge. While advances in radiotherapy have reduced toxicity, the potential interaction with targeted therapy and immunotherapy and the consequent impact on neurocognitive outcomes remain poorly defined. We appraised the current evidence on neurocognitive outcomes in the era of modern combined-modality therapy. Methods This systematic review adhered to PRISMA guidelines and included clinical trials reporting neurocognitive outcomes in patients with brain metastases receiving radiotherapy ± concurrent systemic therapies. Studies published through December 31, 2024 were identified through PubMed/Medline, EMBASE, and Web of Science using pre-defined MeSH term-based search strings. Results 39 studies from 1997-2024 involving 6,617 patients met inclusion criteria (n = 27 whole-brain radiotherapy [WBRT]; n = 12 radiosurgery), including six studies evaluating combined-modality therapy in 1,161 patients. Baseline cognitive evaluation was performed inconsistently, but neurocognitive deficits were frequently observed prior to treatment. Most randomized trials reported improved cognitive outcomes and quality of life with advanced radiotherapy techniques (e.g., hippocampal avoidance, radiosurgery) vs WBRT. Among 20 randomized trials comparing radiotherapy with or without a concurrent investigational systemic therapy, only four included neurocognitive assessments. There was no evidence of cognitive sequelae with combined-modality therapy, though evaluable trials were limited due to inconsistent reporting of neurocognitive functioning. Conclusion As survival improves in patients with brain metastases, preserved cognition is an important outcome measure. The lack of neurocognitive endpoints in pivotal brain metastasis trials represents a critical evidence gap. The interaction between radiotherapy and novel systemic therapies, and their combined effects on neurocognition, remain unknown. To address this, we recommend 1) integrating sensitive, pragmatic, and tailored neurocognitive assessments into oncology trials to quantify additive toxicity, 2) early and systematically incorporating neuropsychology into care pathways, 3) expanding radiation dose-sparing and radioprotective strategies, and 4) evaluating the utility of cognitive rehabilitation programs.

Abstract Introduction: Primary central nervous system T-cell lymphoma (PCNSTL) is a rare form of PCNSL, comprising 2–8% of cases. Prognostic factors remain undefined, and no standard treatment protocol currently exists. Prior studies have been limited by small sample sizes, incomplete molecular profiling, and poor representation of novel treatment modalities. In this study, we aimed to identify clinicopathologic factors associated with patient (pt) outcomes and delineate the spectrum of treatment regimens used to inform future clinical practice. Methods A multicenter retrospective study was conducted across 15 North American academic institutions. Pts aged ≥18 years with biopsy-confirmed PCNSTL between 2009 and 2025 with no evidence of systemic disease were included. Cases with CNS relapse of systemic T-cell lymphoma were excluded. Baseline characteristics were analyzed using independent t-tests, Fisher's exact tests, or Pearson's chi-square tests. Primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated by Kaplan–Meier, log-rank tests, and Cox regression. Results: Forty-two pts met inclusion criteria. Median age was 57 (range 19–77), 69% were male, and 79% were white. Most (69%) had ECOG 0–1. No patients had HIV, hepatitis B or C, or a history of solid organ transplant. LDH was elevated at diagnosis in 38%, and 24% had B-symptoms. Mean absolute lymphocyte count at diagnosis was 1.82/µL. The most common histologic subtypes were PTCL-NOS (76%), followed by ALK-negative ALCL (12%) and γδ T-cell lymphoma (5%). All patients had parenchymal brain lesions with 57% having multifocal disease. Additionally, CSF involvement was seen in 21%, vitreoretinal involvement in 3%, and deep brain involvement in 34%. Next-generation sequencing was performed in seven pts (17%), with disease-associated variants identified in three cases. Among these, two pts had mutations in TP53, and one had a mutation in DNMT3A. Cytogenetics were obtained in 7 pts with only one exhibiting a complex karyotype. Only one pt was EBV positive by EBER-ISH. Overall, 79% received HD-MTX-based therapy. First-line treatments were mainly HD-MTX alone (38%), HD-MTX + temozolomide (17%), or vincristine + procarbazine (12%). No patients were treated on clinical trials. Median treatment duration was 78 days and median number of treatment cycles was 4 (range 1–9 cycles). One patient received radiation alone; 5% received radiation with systemic therapy. A steroid pre-phase was used in 60%, with 44% exhibiting a clinical response. Overall response rate to first-line treatment was 63% (13 CR, 12 PR). Imaging alone was used in determining response in all patients. Repeated biopsy was not performed. Twelve patients (29%) underwent consolidative autologous transplant, most commonly with thiotepa/carmustine (TT/BCNU, 69%) or BEAM conditioning (25%). Median duration of follow-up was 10.4 months. Sixty-two percent of pts progressed during the study period, with 7% experiencing extra-CNS relapse. Median PFS was 8.2 months. Improved PFS was associated with >3 cycles of therapy (p=0.03) and transplant with TT/BCNU (p=0.0004). At last follow-up, 43% were in remission and 52% were deceased, mostly due to disease progression (77%). Median OS was 17.6 months. One- and two-year OS rates were 58% and 42%, respectively. OS was associated with Nottingham/Barcelona score <2 (p=0.02), >3 treatment cycles (p=0.0008), response to first-line therapy (p=0.0007), and TT/BCNU-based transplant (p=0.0001). IELSG, Taipei, and MSKCC risk scores were not significantly associated with survival, though IELSG approached significance (p=0.09). Discussion: This study is among the largest cohorts of PCNSTL pts compiled to date. PCNSTL remains rare and heterogenous. Treatment across centers largely mirrors management of B-cell PCNSL with high utilization of HD-MTX regimens and TT/BCNU conditioning autologous transplant. Survival outcomes within our cohort are consistent with those previously reported within the literature. Receipt of >3 cycles of therapy, TT/BCNU conditioning and Nottingham/Barcelona scores were associated with longer survival within our cohort. Limitations of our study include its retrospective design and heterogeneity within pt disease characteristics, treatments utilized and disease assessment intervals. Further exploration into pathophysiology and optimal management of this unique entity is needed.

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

Abstract BACKGROUND STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone in patients with recurrent anaplastic astrocytoma (AA). We previously reported an overall survival (OS) and progression free survival (PFS) of the combination in the patients with grade 3 IDH-mutant astrocytoma. Here we report updated OS and PFS outcomes based on additional molecular classification and blinded independent central review (BICR). METHOD Eligibility included: age ≥ 18 years, AA (2016 WHO criteria) with first recurrence ≥ 6 months after radiation, KPS ≥ 70, and no imaging findings consistent with grade 4 glioblastoma. Patients received eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) (Arm A) or lomustine alone (110 mg/m2 Q 6 weeks) (Arm B). Primary endpoint was OS. RESULTS Updated molecular data resulted in re-classification of the 343 AA patients enrolled into 3 WHO 2021 defined tumor subtypes, 196 tumors were IDHmut, CDKN2A/B intact, consistent with diagnosis of astrocytoma, IDHmut, WHO grade 3, 33 tumors had CDKN2A/B loss consistent with astrocytoma, IDHmut, WHO grade 4, 106 tumors were IDHwt consistent with diagnosis of glioblastoma, IDHwt, WHO grade 4. Updated results strengthen initial conclusion that eflornithine plus lomustine resulted in significant survival benefit in the astrocytoma, IDHmut, WHO grade 3 group (mOS 34.9 vs, 23.5 months, HR = 0.64, stratified log rank p =0.0136). PFS with eflornithine was also improved (15.8 vs, 7.2 months, HR = 0.57, stratified log rank p =0.0113). BICR demonstrated a high correlation between investigator and centrally determined PFS (p=0.0305), and high correlation between OS and PFS (p=.0001). CONCLUSION The clinically meaningful OS and PFS benefits observed with eflornithine in the molecularly defined 2021 WHO CNS grade 3 astrocytomas is further confirmed and expanded based on additional molecular classification and BICR of PFS.

Abstract BACKGROUND Recurrent anaplastic astrocytoma (AA), a grade 3 brain cancer, remains an unmet medical need. STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone, originally for patients with recurrent AA. However, as the WHO definition of AA evolved during trial conduct (e.g., excluding IDH wild-type disease), we determined results in both the original ITT population and by revised molecularly defined WHO 2021 diagnoses in pre-planned analyses. METHOD Key eligibility: age ≥ 18, AA (2016 WHO criteria), first recurrence ≥ 6 months after radiation and temozolomide, KPS ≥ 70, no imaging findings consistent with grade 4 glioblastoma. Stratification: IDH, age, resection extent, and geography. Patients were randomized to Arm A: eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) or Arm B: lomustine (110 mg/m2 Q 6 weeks). Primary endpoint was OS. The pre-specified hazard ratio (HR) goal was 0.667 based on projected median OS (mOS) increase to 18 months from 12 months. RESULTS 343 pts (172/171 Arms A/B) were randomized (105 sites, 8 countries). ITT analysis found no difference between arms (mOS 23.4 vs. 20.3 months, HR = 0.94). However, a pre-specified subset analysis in IDH mutant, 2021 WHO-defined grade 3 astrocytoma (n=194), showed significant improvement with eflornithine (mOS 34.9 vs. 23.5 months, HR = 0.64, log rank p = 0.016) and PFS (15.8 vs. 7.2 months, HR = 0.58, log rank p = 0.015). No difference was observed in the IDH wild-type subset. AEs were consistent with historic data. CONCLUSION There was no difference in OS between arms in the ITT analysis. However, medically meaningful and statistically significant OS and PFS benefits were observed with eflornithine in the pre-planned analysis of patients with molecularly defined 2021 WHO CNS grade 3 astrocytoma.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Abstract Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.