Investigation of metformin as a radiation sensitizer in pancreatic cancer.

253 Background: Clinical study demonstrates that diabetic patients taking metformin while undergoing chemotherapy and/or radiation for localized pancreatic cancer have improved overall survival compared to diabetics not taking metformin or non-diabetic patients (Sadeghi, Clin Cancer Res 2012). Metformin may act as a radiosensitizer through direct effects on cancer cells and/or indirect effects on the host, such as the inhibition of hepatic gluconeogenesis or inflammation (Pollak, Clin Cancer Res 2012). In vitro study demonstrates that the direct effects of metformin include suppression of mTOR, G2/M cell cycle arrest, and toxicity to cancer stem cells with resultant increase in chemo and radiosensitivity, though some of these studies employed supra-physiologic doses of metformin (1-10mM) instead of physiologic doses (10uM) (Song, Sci Rep 2012; Sanli, IJROBP 2010). Methods: MiaPaCa-2 human pancreatic cancer cells were grown in physiologic (5mM) or supra-physiologic (25mM) glucose media. After exposure to metformin (10uM or 10mM) for 3-7 days in cell culture, phosphorylation of AMPK, a target of metformin, was measured by western blot and radiation survival was determined by clonogenic survival assay. Results: MiaPaCa-2 cells grown in 5mM glucose media with metformin have higher levels of AMPK phosphorylation than those grown in 25mM glucose media or without metformin. Radiation clonogenic survival was similar between cells exposed to any of the treatment conditions, including differences in glucose concentration and/or presence of metformin. Conclusions: MiaPaCa-2 pancreatic cancer cells do not demonstrate enhanced radiosensitivity to metformin in vitro. Future studies will investigate whether K-Ras wild-type cell lines exhibit enhanced radiosensitivity to metformin in vitro and whether metformin acts as a radiosensitizer in vivo

Radiotherapy dose–response analysis for diffuse large B-cell lymphoma with a complete response to chemotherapy

Abstract Objective To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). Methods Patients with stage I-IV DLBCL treated from 1995–2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In-field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose. Results 105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R-CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30 Gy (range, 12–40 Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5 Gy, p  Conclusion In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response.</p