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Simple Summary  Neuroendocrine tumors grade 3 (NET G3) are a newly defined subgroup of neuroendocrine neoplasms. They do not respond well to platinum + etoposide-based chemotherapy. The alternative suggested options have not been analyzed in untreated NET G3 patients so far, therefore the optimal treatment strategy for these tumors is unclear. In our analysis we showed that FOLFOX is the most active regimen holding the highest chance of tumor shrinkage, whereas temozolomide/capecitabine is the most effective, leading to the most durable tumor control.    Abstract  Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE ( n  = 37), 56.4% for FOLFOX ( n  = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) ( n  = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) ( n  = 20), and 16.7% for other ( n  = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX ( p  = 0.333), 12.0 months for TEM/CAP ( p  = 0.093), 4.8 months for STZ/5-FU ( p  = 0.919), and 14.1 months for other ( p  = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months;  p  = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.

Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3)