Discussion
pneumonitis, NEC, cancers, cardiovascular disease, neutropenia, toxicity, GEP-NET
PNEUMONITIS, CANCERS, NEUTROPENIA, CARDIOVASCULAR DISEASE, DISEASE
To the best of our knowledge, this is the first prospective clinical trial examining everolimus and temozolomide as first-line treatment in metastatic HG GEP-NEN. The study’s primary endpoint was met (DCR at 6 months of 65%), PFS was 10.2 months and OS was 26.4 months. Grade 3–4 toxicity was commonly observed. Dose reductions, dose delay and treatment discontinuation due to toxicity were registered in 26 (70%), 23 (62%), five (14%) patients, respectively, but the quality of life remained stable through the treatment period.The intention of the study was to include high-grade GEP-NEN with a Ki-67 ≤55%. Due to the changing WHO classification, a re-evaluation of morphology and Ki-67 index was performed to separate NET G3 from NEC. NET G3 and NEC are two distinct disease entities, supported by their different responses to platinum-based chemotherapy, survival, and molecular profile [There are limited data on first-line treatment for advanced GEP-NET G3 and mainly retrospective data are available [Comparing our results to previous studies on systemic treatment for GEP-NET G3 are difficult, as these studies include retrospective data, a mixture of different treatment lines, inclusion of non-digestive primaries, and lack of pathological review of HG GEP-NEN according to the 2019 WHO classification. Studies on first-line treatment with platinum/etoposide in NET G3 show a PFS of 5.0–6.9 months [Our findings indicate that everolimus/temozolomide may be considered a treatment option for selected GEP-NET G3 patients. The combination might be an alternative especially for patients with significant cardiovascular disease or a complete lack of dihydropyrimidine dehydrogenase [The optimal way to treat GEP-NEC patients with a Ki-67 < 55% is uncertain, with published studies indicating a poorer response to platinum/etoposide [Elevated CRP at baseline was a significant poor prognostic factor for PFS and OS among all patients and for PFS in the NET G3 subgroup. CRP is a well-known prognostic factor for other cancers and for survival in surgically resected pancreatic G1-G3 NEN [[18F]FDG-PET is known to show a high uptake in GEP-NEC and in the majority of NET G3 patients [The safety profile in our study was consistent with previous reports on everolimus/temozolomide, but with a high number of patients experiencing grade 3–4 toxicity (81%), and the majority needing dose reduction (70%) and/or treatment delay (62%). The rate of haematological toxicity (neutropenia grade 3–4 28% vs. 7% and trombocyopenia grade 3–4 25% vs. 16%) and all grades of pneumonitis (24 % vs. 7%) was higher in our study compared to the prospective data on everolimus/temozolomide provided by Chan et al. [