A randomized phase II trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas.

BACKGROUND: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER: NCT03387592.

Advances in understanding and management of high-grade pancreatic neuroendocrine neoplasm: a comprehensive review.

High-grade (HG) pancreatic neuroendocrine neoplasms (PAN-NENs) are aggressive and have a poor prognosis. Yet, our understanding and treatment approaches for these tumors have rapidly evolved in the past decade, despite a lack of prospective and randomized trials. It is essential to differentiate grade 3 (G3) neuroendocrine tumors (NETs) from neuroendocrine carcinomas (NECs) due to their different prognostic and treatment implications. The molecular landscape of HG PAN-NENs is complex, with mutations in key cancer-related genes, extensive genomic rearrangements, and chromosomal instability. Advanced studies have provided insights into the significant genetic heterogeneity of HG PAN-NENs and potential therapeutic targets. Several therapeutic strategies have emerged from molecular characterization studies. These include agents targeting the mammalian target of rapamycin (mTOR) pathway, DNA repair pathways, and epigenetic modifiers. Moreover, high programmed cell death ligand 1 (PD-L1) expression in some tumors indicates potential for immunotherapy. However, many challenges remain, with a deeper understanding of the genetic and epigenetic alterations in these tumors necessary to develop novel therapeutic strategies and improve patient outcomes. Treatment strategies for HG PAN-NENs vary. Looking to the future, many clinical trials are exploring novel therapies or combinations of known therapies to improve outcomes. It is evident that understanding the molecular landscape of PAN-NECs, alongside personalized therapeutic strategies, is crucial to developing effective treatment options and improving patient outcomes. In this discourse, our emphasis will be on the molecular landscape and available treatment strategies for HG PAN-NECs.

Therapeutic efficacy of platinum/etoposide regimens in the treatment of advanced poorly differentiated neuroendocrine carcinomas of the lung: A retrospective analysis.

Background: Lung neuroendocrine neoplasms (NENs) are rare malignancies developed from bronchial mucosa. Because of its rarity and complex histopathology, there is limited data on the role of chemotherapy in this subset of tumors. Few studies regarding the treatment of poorly differentiated lung NENs, known as neuroendocrine carcinomas (NECs), are available and many limits are detectable as heterogeneity of tumor samples including different origins and different clinical behaviors, moreover, no evidence of therapeutic advances have been achieved along the last thirty years. Method: We performed a retrospective analysis of 70 patients affected by poorly differentiated lung NECs: half of patients underwent a first line therapy with a combination of cisplatin plus etoposide; the remaining patients receiving carboplatin instead of cisplatin, plus etoposide. Results: In our analysis, the outcomes of patients treated with either cisplatin or carboplatin schedule are similar in terms of ORR (44% versus 33%), DCR (75% versus 70%), PFS (6.0 versus 5.0 months) and OS (13.0 versus 10 months). Median number of chemotherapy cycles was 4 (range 1-8). The 18% of patients required a dose reduction. Main toxicities reported were hematological (70.5%), gastrointestinal (26.5%) and fatigue (18%). Conclusion: Survival rate in our study suggests that high grade lung NENs are characterized by an aggressive behavior and a poor prognosis, despite the treatment with platinum/etoposide according to available data. Clinical results of present study contribute to strengthen available data on the usefulness of platinum/etoposide regimen in the treatment of poorly differentiated lung NENs.

Do neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasm of the gastrointestinal tract have the same prognosis? A SEER database analysis of 12,878 cases.

BACKGROUND: Neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal (GI) tract are both rare and malignant; however, it is unclear whether their prognosis is the same. METHODS: In this cross-sectional study, a total of 12,878 patients with NEC or MiNEN in the GI tract were reviewed retrospectively by searching the Surveillance, Epidemiology, and End Results (SEER) program database. Next, we compared the characteristics and survival between patients with NEC or MiNEN and further analyzed the prognostic factors for the patients. RESULTS: The data showed that patients with MiNEN had a worse prognosis as compared with patients with pure NEC in the small intestine (SI) and appendix, whereas there was no significant survival difference between NEC and MiNEN in the other parts of the GI system. On the whole, age ⩾55 years (p < 0.0001), male (p = 0.002), being diagnosed at TNM Stage II-IV (p < 0.0001) or not receiving surgical treatment (p < 0.0001) were the independent negative prognostic factors for NEC patients, whereas age ⩾55 years (p = 0.003), being diagnosed at TNM Stage III-IV (p < 0.001) or not receiving surgical treatment (p < 0.001) were identified as the independent negative prognostic factors for the MiNEN patients. Furthermore, when NECs or MiNENs were classified based on the primary tumor site, the results showed that the prognostic factors for NEC and MiNEN varied between the tumor sites. CONCLUSION: The prognostic differences between NECs and MiNENs in the GI tract are heterogeneous and site-related. Patients with appendiceal or SI MiNEN have a poorer prognosis than patients with pure appendiceal or SI NEC. Therefore, we should pay more attention to patients with MiNEN in the SI and appendix and monitor them more closely.