Regeneron; and serving as a consultant/advisory board member for AstraZeneca, BMS, Debiopharm, Nanobiotix, and Tilos. G.J.H. reports research support to institution from BMS and EMD Serono. R.B.T. reports serving on the data safety monitoring board for Intrexon/PSI and on the advisory board for EMD Serono and Regeneron. N.G.C. reports research funding from Merck, Pfizer, and GlaxoSmithKline. G.R. reports consulting for EMD Serono, Pfizer, Merck, Regeneron, Sanofi, and Castle; and owning stocks in Regeneron and Syros pharmaceuticals.
Pancreatic cancer is one of the most devastating forms of human cancer. The lack of effective clinical treatments for pancreatic cancer has led to one of the lowest five-year survival rates among all cancers. Recently, our laboratory has developed a novel series of isoprenylated coumarin derivatives that have exhibited anti-pancreatic cancer activity exclusively under nutrient-deprived conditions. In this study, we report the effect of the various cell culture medium components on the preferential cytotoxicity of our lead isoprenylated coumarin compound against the pancreatic adenocarcinoma cell line PANC-1. In particular, our findings show a clear link between observed cytotoxicity and glucose deprivation, suggesting that our compound targets a salvage pathway when glycolysis is no longer an option for cancer cell survival. The cytotoxicity of our lead compound was also examined in vitro against two other pancreatic cancer cell lines, BxPC-3 and Capan-2 under both nutrient-rich and nutrient-deprived conditions.
setting have yet to be examined. The purpose of our study is to determine whether NAC followed by CCRT provides an overall survival (OS) benefit, particularly among high-risk patients. Materials/Methods: We queried the national cancer database for patients with NPC and limited the initial 13,929 patients to those treated with either NAC followed by CCRT or CCRT alone; defining NAC followed by CCRT as chemotherapy initiation 21 days prior to RT initiation and CCRT as initiation 20 days prior to and 36 days after RT initiation. After excluding patients with metastatic disease, those treated with surgery or palliative therapy, and without clinical staging, we arrived at a total of 5274 patients. We performed survival analyses using univariate (UVA) and multivariate (MVA) cox proportional analysis to determine if an association between NAC and OS exists. Results: The median survival of the entire patient cohort was 8.9 years, with a median follow up of 3.3 years. Median survival for the NAC plus CCRT group was 9.4 years and 8.8 years in the CCRT alone group. NAC plus CCRT did not affect OS on UVA (HR 1.01; 95% CI [0.90,1.14)]; P Z .870) and MVA (HR 0.89; 95% CI [0.79,1.00]; P Z .053) though trending towards significance. We also stratified patients into risk categories. High-risk included patients with clinical stage IV or keratinizing histology and low all others. NAC plus CCRT improved OS in the highrisk population on MVA (HR 0.86; 95% CI [0.75, 0.98]; P Z.023) but not in the low risk (HR 1.06; 95% CI [0.80, 1.39]; P Z .692). Conclusion: Patients with nonmetastatic NPC treated with NAC plus
patients received adjuvant CRT. On multivariable logistic regression, female sex, younger age, academic treatment facility, higher comorbidity index, and lower clinical T and N stages were associated with higher odds of receiving primary surgery. Three-year OS in the CRT cohort was 90.8% vs. 92.5% in patients receiving primary surgery (log-rank P Z .92). On multivariable Cox regression, upfront surgery was not associated with improved OS when compared with CRT (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.84-1.43, P Z .48). Increasing clinical T and N stage, older age, and non-private insurance were significantly associated with inferior OS. Lack of OS benefit with upfront surgery persisted in a subset analysis of patients with margin-negative resection, with a 3-year OS of 90.1% in patients undergoing CRT vs. 93.5% in primary surgery patients (log-rank P Z .14). Propensity score-matching identified a cohort of 2,618 patients and redemonstrated similar OS (HR, 1.11; 95% CI 0.83-1.49; P Z 0.49). Conclusion: Upfront surgery was not associated with improved OS compared to CRT in this patient cohort. The majority of surgical patients received trimodal therapy with adjuvant CRT. Efforts to improve patient selection in order to minimize the need for trimodal therapy are justified given the lack of observed survival benefit with surgery.
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