Poor Glycemic Control During Radiochemotherapy Contributes to Reduced Local Control and Overall Survival in Patients with Non-Small Cell Lung Cancer

Reporter: Abigail Berman, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2012

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Presenting Author: Mohamad Fakhreddine, MS
Affiliation: University of Texas MD Anderson Cancer Center, Houston, TX

Background

  • Diabetes mellitus (DM) is known to be associated with a higher incidence of malignancies as well as a worse prognosis of cancer patients. There are few studies, however, looking at lung cancer specifically, and glycemic control.
  • Preclinical studies suggest that elevated plasma glucose levels may contribute to radioresistance in part via effects of insulin-like growth factor (IGF) and Akt signaling.
  • Based on this, the authors investigated whether glycemic control during radiation therapy for non-small cell lung cancer (NSCLC) correlates with overall survival (OS) or loco-regional control (LC).
  • This study also was designed to evaluate the benefit of metformin use and outcomes.

Materials and Methods

  • Patients in this retrospective study were selected from an institutional database of patients treated with definitive radiochemotherapy for NSCLC between 1998 and 2011.
  • The total cohort consisted of 352 patients, 145 of which had a diagnosis of type 2 DM and 207 were not diabetic.
  • Glycemic control was defined by four parameters:
  • Diagnosis of DM, type 2
  • Glycosylated hemoglobin (HgbA1c) levels (measured within 3 months before treatment). This data was available in 65 patients.
  • Plasma glucose levels defined as the mean of 2-3 highest measurements during treatment. High average glucose was defined as having above the median value of 136 mg/dL.
  • Diabetic medications during treatment.
  • Data on body mass index (BMI) within 1 month before treatment were also extracted.
  • The following demographic information was extracted: age, gender, smoking status, histology, stage, nodal status, and dose.

Results

  • The median age of 352 patients was 65.3 years. Median follow up was 22.7 months. There were 35 stage I patients, 22 stage II, 130 stage IIIA, 165 stage IIIB. Mean dose was 63.4 Gy.
  • There were statistically significant differences in baseline characteristics including age >65 (27% DM vs 57% non-DM), stage I or II (28% DM vs 8% non-DM), N0 status (27% DM vs 15% non-DM), high average glucose (83% DM vs 28% non-DM).
  • On univariate analysis for overall survival, the following were statistically significant: age >65 (HR 1.38), nodal status (N0 vs N3, HR 1.72), high average glucose (<136, HR 1.42), HgbA1c >6.4% (HR 3.88), metformin use (HR 0.52).
  • Univariate analysis for local control revealed that high average glucose was associated with a HR of 1.64.
  • On multivariate analysis, high average glucose (HR 1.57) and metformin use (HR 0.52) remained statistically significant for overall survival.
  • For local control, multivariate analysis revealed that high average glucose was significantly associated with local failure (HR 1.64).

Author's Conclusions

  • The diagnosis of DMII was associated with younger age and earlier stage of diagnosis.
  • High average glucose was associated with worse overall survival and local control.
  • Metformin was associated with improved overall survival, but not improved local control or glycemic control.
  • Prospective data is needed, taking into account chemotherapy and steroid use.

Clinical Implications

  • This study represents one of the first studies to look at the clinical effects of diabetes in lung cancer and it demonstrates that patients with poorly-controlled diabetes had worse overall survival and local control.
  • There are several limitations to this study:
    • Only one of the parameters indicating poor glycemic control was significantly associated with decreased overall survival and local control. Therefore, it calls into question if there is an association between long-term glycemic control and cancer outcomes.
    • Many of the patients were given dexamethasone for chemotherapy preparation. This study did not take into account whether or not the patients received chemotherapy (and dexamethasone) and therefore this may be an unmeasured confounder.
    • The study did not take into account how long the patients had the diagnosis of diabetes; it would be interesting to explore whether survival also correlates with time since diabetes diagnosis.
  • This is an important hypothesis-generating study. For recommendations to be made about cancer patients’ diet or specific diabetes control guidelines, a prospective study should be conducted.
  • This study has an additional important finding that metformin was associated with improved overall survival. There have been many studies that have shown the beneficial use of metformin in both cancer prevention as well as an adjuvant in treatment.
    • A recent study by Mazzone et al. (BMC Cancer. 2012 Sep 14;12(1):410) showed that the use of metformin is associated with a lower likelihood of developing lung cancer in diabetic patients. Interestingly, they showed that diabetics who develop lung cancer while receiving metformin may have a more aggressive cancer phenotype.
    • The use of metformin is actively being investigated by the NCIC in a prospective randomized trial of the effect of metformin versus placebo on recurrence and survival in early stage breast cancer.
  • Further studies both on the effect of glycemic control on cancer outcomes and metformin as part of cancer treatment are warranted in lung cancer as well as other disease sites.


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