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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
MO05.10 - Metformin as a Radiosensitizer for Lung Cancer (ID 3306)
16:15 - 17:45 | Author(s): M.N. Corradetti
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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P3.08 - Poster Session 3 - Radiotherapy (ID 199)
- Event: WCLC 2013
- Type: Poster Session
- Track: Radiation Oncology + Radiotherapy
- Presentations: 1
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P3.08-027 - Radiation Pneumonitis in IMRT vs. 3D Conformal Radiation Therapy (ID 3161)
09:30 - 16:30 | Author(s): M.N. Corradetti
Radiation pneumonitis is a common cause of morbidity and is a radiation dose-limiting toxicity in patients with locally advanced NSCLC treated with definitive radiotherapy. NSCLC patients are increasingly receiving intensity modulated radiation therapy (IMRT), in part in an attempt to reduce irradiation doses to organs at risk, like the lungs. It is unclear whether the incidence of pneumonitis in IMRT patients differs from that in patients receiving the more commonly available 3D conformal radiation therapy (3DCRT). This retrospective study reports on outcomes at the University of Pennsylvania.
All consecutive patients with non-metastatic locally advanced NSCLC treated with curative intent at the University of Pennsylvania between January 2003 and October 2011 with 3DCRT (n=208) and IMRT (n=58) were graded for post-treatment radiation pneumonitis using Common Toxicity Criteria (CTC) and SWOG criteria in this IRB-approved study. Any short- or long-course initiation of prednisone for dyspnea 1-10 months following treatment was scored as grade 3 pneumonitis. Associations between type of treatment and clinical and demographic factors and outcomes were assessed using Χ and non-parametric equality-of-medians tests. Logistic regression was used to determine predictors of pneumonitis.
Patient characteristics, including age, gender, race, marital status, smoking history and pulmonary function were well balanced across treatment groups (p = 0.18 – 0.97). Patients also had similar tumor TNM-stage, histology, differentiation, and involved lobe (p = 0.26 – 0.62). No differences in the proportion receiving concurrent chemotherapy, radiation prescription, lung V5, lung V20 and mean lung doses, or planning target volume (PTV) were identified (p >0.05 for all). Pneumonitis rates did not differ between the IMRT and 3DCRT patients. In 3DCRT patients, 54% had grade 2+ and 27% had grade 3+ CTC pneumonitis compared to 59% and 34% in IMRT patients, respectively (p >0.05). Additionally, 45% and 17% of 3DCRT patients had grade 2+ and 3+ SWOG pneumonitis compared to 45% and 16% in IMRT patients, respectively (p> 0.05). Lower lung lobe, single marital status, pack-years smoked, low pre-treatment pulmonary function DLCO status, increased lung V5, increased lung V20 and mean lung dose all associated with pneumonitis on univariate logistic regression for both 3DCRT and IMRT patients (p <0.05 for all). A multivariate analysis was performed but yielded no significant results.
Our findings suggest that treatment with IMRT is associated with similar rates of pneumonitis as treatment with 3DCRT for locally advanced NSCLC patients treated with definitive radiation therapy. As opposed to treatment modality, several factors were identified that were associated with pneumonitis risk, included lung lobe, marital and smoking status, pre-treatment lung function, and irradiation dose received by the lung. Thus, care should be taken to limit the lung V5, lung V20, and mean lung doses when administering curative-intent radiotherapy, regardless of treatment with IMRT or 3DCRT.