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H. Kim

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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.10 - Metformin as a Radiosensitizer for Lung Cancer (ID 3306)

      16:15 - 17:45  |  Author(s): H. Kim

      • Abstract
      • Presentation
      • Slides

      In vitro data and early clinical results suggest that metformin, an agent commonly used in diabetes therapy, has direct cancer growth inhibition potential via mammalian target of rapamycin (mTOR) pathway suppression. Furthermore, a number of observational studies have associated lower cancer incidence and a lower risk of nonspecific cancer-related mortality with metformin use. Our first objective is to determine whether the use of metformin is associated with improved local recurrence (LRR) and overall survival (OS) rates in diabetic patients with non-small cell lung cancer (NSCLC) treated with definitive chemoradiation. Based on encouraging retrospective clinical results, we moved on to establish an in-vivo murine model of lung cancer and to evaluate the tumor growth delay from using metformin as a radiosensitizing agent.

      Data from 760 consecutive patient treatment courses from our institution for patients with NSCLC and small cell lung cancer treated with radiation therapy between 6/2008 and 6/2013 were analyzed. All patients with diabetes and stage IIIA and IIIB NSCLC who received metformin during definitive radiotherapy were analyzed to determine clinical outcomes. For the in-vivo murine study, H1299 adenocarcinoma cells were injected in the flanks of nude mice for the subcutaneous tumor model. On day 2, mice began receiving daily intraperitoneal injection of metformin or vehicle for 5 days, after which they underwent irradiation to the flanks of 3Gy X 3 fractions. Tumor measurements were taken every other day and tumor growth delay was plotted. In order to assess the effect of metformin in the lungs as well as in-situ tumor effects, an orthotopic mouse model using bioluminiscence imaging (BLI) will be developed to allow serial lung tumor measurements as well as assessment of metformin effects on the normal lung when combined with irradiation.

      Of 760 patient treatment courses analyzed, 16 distinct patients with stage III NSCLC were identified that received metformin for diabetes while undergoing definitive chemoradiation. Patients were predominantly female (63%) and had stage IIIA disease (69%). They were treated to a median of 66.6/1.8 Gy with concurrent (81%) or sequential (19%) chemotherapy.A dramatic improvement in LLR in patients receiving metformin was seen compared to historical controls. With a median follow-up time of 10.4 months, only 2 local recurrences (9.6 and 14.9 months post-radiotherapy) have occurred. The median disease-free survival and OS have not been reached. From our in vivo murine data, early data supports the use of metformin as a radiosensitizing agent in the treatment of locally advanced NSCLC.

      Our clinical experience demonstrates patients receiving definitive chemoradiation for stage III NSCLC who took metformin for diabetes had improved local control and OS compared with our patients not taking metformin and compared with historical controls. Additional evidence is needed to supporting radiation potentiation effects of metformin in the setting of definitive chemoradiation for locally advanced NSCLC patients. Such findings, along with our clinical retrospective data, will lead to institutional prospective clinical trials, for the first-time, using metformin as a radiosensitizing agent in combination with radiation therapy and chemotherapy in the treatment of lung and potentially other cancers.

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