Strengths and limitations
NEC, GEP-NET
NEOPLASMS
The prospective design of the study and re-evaluation of HE and immunohistochemically stained slides (including Ki-67) by experienced NEN pathologists according to the 2019 WHO classification are major strengths of this study. The main limitations are the trial’s single-arm design, which makes it difficult to compare the results to other treatment regimes, and the limited number of patients due to the infrequency of these neoplasms. Interpretation of the statistical analyses should therefore be done with caution. Further studies are warranted to decide if first-line everolimus and temozolomde may be recommended treatment options for GEP-NET G3. A larger randomised study with CAPTEM as a comparator would have more impact but is, unfortunately, most likely not feasible. The use of everolimus in a first-line treatment regime could possibly impair the use of this drug in second- or third-line settings for NET G3. The recent changes in HG GEP-NEN nomenclature were not in place at the study’s initiation; therefore, this is a combined NET G3 and NEC cohort. After a histopathology review, seven patients had a Ki-67 > 55%. These patients were included in the final analysis, which seems reasonable considering the unknown optimal cut-off for Ki-67 and the interpersonal variability in Ki-67 reporting. Adequate pathological assessment will be essential in future clinical trials to further assess optimal therapeutic options for NET G3 and NEC. Our survival results may be influenced by the selection of patients with performance status ≤1. In this study, the O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation status was not analysed, and NGS analyses are lacking for most patients. Studies have shown conflicting results on the predictive value of MGMT for the benefit of temozolomide treatment; however, a recent study found a correlation to RR for pancreatic NET G1-2 patients [