Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. The Oncologist 2017;22:165-172Implications for Practice: Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.

Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach.

PURPOSE: The purpose of this study was to investigate the incidence of drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in patients with neuroendocrine tumours (NET) and characterise radiographic patterns of pneumonitis. METHODS: Sixty-six patients (39 males, 27 females, age: 22-79 years) with advanced NET treated with mTOR inhibitor, everolimus, were retrospectively studied. Chest computed tomography scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by an independent review of two radiologists. Extent, distributions, and specific findings were evaluated in cases positive for pneumonitis. Radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia. RESULTS: Drug-related pneumonitis was radiographically detected in 14 patients (21%). Time from the initiation of therapy to pneumonitis was within 6 months of therapy in 10 patients (71%), while it ranged from 1.0 to 27.7 months. Pneumonitis was more common in patients who had never smoked (p=0.03). Lower lungs were more extensively involved than upper and middle lungs. Peripheral and lower distributions were most common (n=8), followed by peripheral and multifocal distributions (n=3). Ground glass and reticular opacities were present in all cases, with consolidation in eight cases. The radiographic pattern of pneumonitis was classified as cryptogenic organising pneumonia (COP) pattern in eight patients, non-specific interstitial pneumonia (NSIP) pattern in five, and hypersensitivity pneumonitis pattern in one patient. CONCLUSION: Drug-related pneumonitis was noted in 21% of the advanced NET patients treated with everolimus. Radiographic pattern of pneumonitis was most commonly COP pattern, followed by NSIP pattern.