ABSTRACT
Lung large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive malignancy with a dismal prognosis. This study was designed to depict patterns of distant organ metastatic and to analyze prognosis of LCNEC patients. We gathered data from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. We conducted the Kaplan-Meier method to calculate overall survival (OS) and compare different variables. Cox proportional hazards regression models in univariate and multivariate analyses were employed to further explore prognostic factors. A total of 1335 LCNEC patients were eventually selected from the SEER database, of which 348 patients (26.0%) had single organ metastasis and 197 patients (14.8%) had multiple metastases. Our study indicates that patients with single organ metastasis generally have a poor prognosis, with a median OS of 8 months for both lung and brain metastasis with 1-year survival rates of 33% and 29% respectively. Patients with multiple metastases exhibited the worst prognosis, with a median OS of only 4 months and a 1-year OS of 8%. Multivariate analysis revealed that age, T stage, N stage, chemotherapy and radiation in metastatic patients were independently associated with OS. In conclusion, LCNEC exhibits a high metastatic rate when diagnosed. The most common metastatic organ is the brain in single-site metastatic patients. Patients with single or multiple metastases exhibit a significantly worse prognosis than those with non-organ metastases. In the group of single organ metastases, patients with brain and lung metastases had a better prognosis than those with bone and liver metastases.
ABSTRACT
Peptide receptor radionuclide therapy (177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment. Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)-polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20 MBq mL-1 ) and fluzoparib (50 µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20 MBq mL-1 , 4.4-fold) and fluzoparib (50 µm, 2.1-fold). 177 Lu-DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177 Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177 Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of 177 Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.