5‑Fluoruracil (5-FU) and its oral prodrug capecitabine are mainstays in combined chemoradiotherapy regimens. They are metabolized by dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants of the DPYD gene cause a reduction in DPYD activity, leading to possibly severe toxicities. Therefore, patients receiving 5‑FU-/capecitabine-based chemoradiotherapy should be tested for DPYD variants. However, there are limited clinical data on treatment adjustments and tolerability in patients with decreased DPYP activity receiving combined chemoradiotherapy. Therefore, a retrospective analysis of the toxicity profiles of patients with decreased DPYD activity treated at our center was conducted. For all patients receiving 5‑FU-/capecitabine-based chemo(radio)therapy at our department, DPYD activity was routinely tested. Genotyping of four DPYD variants (DPYD*2A, DPYD*13, c.2846A > T, and haplotype B3) was conducted according to the recommendation of the German Society for Hematooncology (DGHO) using TaqMan hydrolysis polymerase chain reaction (PCR; QuantStudy 3, Thermo FisherScientific, Darmstadt). DPYD variants and activity score as well as clinical data (tumor entity, treatment protocol, dose adjustments, and toxicity according to the Common Terminology Criteria for Adverse Events [CTCAE]) were assessed and reported. Of 261 tested patients, 21 exhibited DPYD variants, 18 of whom received chemoradiotherapy. All but one patient was treated for rectal or anal carcinoma. The observed rate of DPYD variants was 8.0

Abstract BACKGROUND Despite multimodal treatment (resection, radiation therapy, alkylating chemotherapy and/or tumor-treating fields), the treatment of progressive CNS WHO Grade 3 astrocytoma and glioblastoma remains challenging. Re-irradiation (Re-RT) might be considered in the course of the disease. Optimal fractionation/dose prescription schedules are still under investigation, underlining a gap in clinical data in this regard. Here, we retrospectively analyzed post-progression survival (PPS) and progression-free survival (PFS) in a single center cohort. MATERIAL AND METHODS Patients receiving Re-RT with 20 Gy in 5 fractions (4 Gy per fraction; corresponding to 35 Gy in an equivalent dose normalized to 2 Gy (EQD2)) upon progression of recurrent astrocytoma glioblastoma or grade 3 astrocytoma (12/2020-12/2022) were included. Planning target volume for Re-RT was gross tumor volume = (T1 with contrast) + 5 mm. Clinical endpoints included PPS, PFS since start of Re-RT, therapy in case of further progression, bevacizumab therapy, MGMT promotor methylation (MGMT meth), and IDH status. RESULTS To date, 40 patients were analyzed (27 male); median age 62.25 a, range 31-83 a; 34 GBM IDHwt, 6 other), 15 of who showed MGMT meth (24 w/o MGMT meth, 1 not determined). Primary therapy was 60 Gy with concomitant temozolomide (TMZ), TMZ + lomustine, or study medication in 30, 54.0 Gy + adjuvant TMZ in 3, and 40.05 Gy + TMZ in 7 patients. Patients received heterogenous systemic therapies and 0-3 treatment lines prior to Re-RT (median 1 prior treatment modality). Re-RT was considered in localized non-resectable progression. Median time between first line therapy and first progression was 10.8 months and between first line therapy and Re-RT 16.7 months, respectively. Seven patients received an integrated boost of up to 30 Gy. Median PFS was 2.6 months (range <1-10.4 months); with 7,6 months PPS (range <1 - 22.4 months). 19 patients (47.5%) received bevacizumab during further course of the disease. Following Re-RT, 16 patients (40%) received further tumor-directed therapy. CONCLUSION This is a heterogenous single-center cohort. PFS after Re-RT was 2.6 months, and PPS was 7.6 months, respectively, published data reporting 6-12 months PPS after re-irradiation (EQD2 ranging between 48-60 Gy) despite a comparatively low and conservative cumulative dose of 20 Gy (35 Gy EQD2). Treatment time was only 5 days. Thus, re-irradiation with 4 Gy x 5 could be an option in a palliative setting and could be included in interdisciplinary treatment discussions for progressive CNS WHO grade 3 astrocytoma and glioblastoma.

Abstract Background Recently, a molecular signature describing the mesenchymal / proneural features of primary stem-cell-enriched glioblastoma cultures was identified correlating with invasiveness, radiation sensitivity and patient-outcome. However, generating and characterizing primary cultures is time-consuming and this might hamper translation into clinical concepts. The aim of this study was to evaluate the use of standard preoperative MR imaging (T1ce and T2FLAIR sequences) to predict the molecular signature and thus enable the development of clinical treatment concepts based on the molecular properties of the individual tumors. Material and Methods For 16 patients, for whom primary stem cell enriched cultures had been characterized for their mesenchymal / proneural signature and radiation sensitivity, tumor volume (hyperintense volume in T1ce), necrosis (hypointense volume inside the tumor volume) and edema (hyperintense volume in T2FLAIR) were contoured for volumetric analysis. Volume parameters were used to calculate ratios (edema/tumor and necrosis/tumor) and a MRI signature, which was then correlated with molecular parameters and patient outcome stratified by MGMT promoter methylation. Results As expected, the prognosis of patients with MGMT-promoter-methylated tumors was better (n.s.) compared to those with unmethylated MGMT promoters. Neither molecular nor imaging data were significantly different between these subgroups. In the subgroup of patients with unmethylated MGMT promoter, volumetric imaging parameters correlated with the molecular signature and cellular radiation sensitivity of the stem cell enriched cultures. This association was much weaker in the subgroup with methylated MGMT promoter. Conclusion In the subgroup of patients with unmethylated MGMT promoter, volumetric parameters on preoperative standard MR imaging might hint at the molecular properties of the respective tumor and its radiation sensitivity. This might be a clinically applicable method to stratify treatment according to molecular stem cell subtype without tissue culture and molecular analysis.