Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors

Abstract

Introduction Recent classification of neuroendocrine neoplasms has defined well‐differentiated high‐grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well‐described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. Materials and Methods This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients’ demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression‐free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki‐67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum‐etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96–16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. Conclusion Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short‐lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. Implications for Practice High‐grade well‐differentiated neuroendocrine tumors (NET G3) are considered a different entity from low‐grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well‐differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review

“…We acknowledge the potential confounding effect of patients with panNEN, who made up 67% of the current cohort but only 25% of the study cited above [3]. Some significant series of patients with NENs treated with CAPTEM have been published, but they have each reported on fewer numbers of patients with G3 disease [18, 24–30]. Although the data regarding CAPTEM in grade 1–2 well‐differentiated GEPNENs have shown significant promise, grade 3 NENs are a clinically and genetically distinct group with a much worse prognosis.…”

Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?

“…It can be argued that this subgroup might include some G3-WD-NETs. In fact, similar to G3-WD-NETs [27], the majority of non-SC EP-NECs with a Ki-67 index of <55% from the present study were of pancreatic origin (52.2%) (Other sites of origin were stomach (13.0%), CUP (8.7%), colon (8.7%), small bowel (8.7%), ovary (4.3%) and biliary tract (4.3%)). Despite the exclusion of equivocal cases (NEC vs. G3-WD-NET) by pathologists, there is still the possibility that some tumours with a low proliferative rate (20% < Ki-67 < 50-55%) were misclassified as NECs rather than G3-WD-NETs, especially those with a non-SC morphology.…”

Clinicopathological and molecular profile of grade 3 gastroenteropancreatic neuroendocrine neoplasms

“…Increasing data suggest that therapies used for G2 NET could also be used for G3 NET, particularly those with Ki‐67 < 50%. Retrospective series have reported median progression‐free survival times of 6 months with everolimus, 24 16 months with PRRT 25 and 9 months with capecitabine plus temozolomide 26 . On the other hand, platin may not be the best option for G3 NET, as demonstrated indirectly with the lower response rate of high‐grade NEN with lower Ki‐67 in the pivotal Nordic study 2 …”