An Analysis of the Potential Benefits of Metformin on Disease Recurrence in Oral and Oropharyngeal Squamous Cell Carcinoma

Christopher F. Thompson, Marilene B. Wang, Yas Sanaiha, Chi Lai, Tristan Grogan, David Elashoff, Maie A. St. John

Department of Head and Neck Surgery, University of California, Los Angeles, USA.
Department of Medicine Statistics Core, University of California, Los Angeles, USA.
Department of Pathology and Laboratory Medicine, University of Cali- fornia, Los Angeles, USA.

DOI: 10.4236/jct.2013.45109                

Abstract

Objective: Diabetes mellitus type 2 has been associated with increased cancer risk and cancer related mortality. Metformin, one of the most widely used anti-diabetic medications, has been found to have important anticancer properties in addition to hypoglycemic effects. The effects of metformin on clinical outcomes in oral cavity (OC) and oropharyngeal (OP) squamous cell carcinoma (SCC) have not been thoroughly analyzed. The purpose of this study was to evaluate the effects of metformin use on cancer recurrence in diabetic patients with oral cavity and oropharyngeal squamous cell carcinoma. Design: Retrospective review. Setting: Academic tertiary medical center. Patients: Seventy-seven patients with diabetes mellitus type 2 and oral cavity or oropharyngeal squamous cell carcinoma were treated and followed at our tertiary academic institution and the Veterans Affairs Greater Los Angeles Healthcare System from 1998 to 2012. Main Outcome Measure: Cox proportional hazards models and Kaplan-Meier curves were constructed to determine if metformin has an effect on disease recurrence after primary cancer treatment. Results: Metformin does not appear to have a significant effect on disease recurrence in patients with OC/OP SCC and diabetes mellitus type 2 (p = 0.53). Even when including only patients with stage I or II disease, metformin still did not decrease recurrence (p = 0.60). Conclusion: Herein, our data suggest that metformin use does not significantly impact time until recurrence for diabetic patients with OC/OP SCC.

Keywords

Metformin; Head and Neck Cancer; Oral Squamous Cell Carcinoma; Oropharyngeal Squamous Cell Carcinoma

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	H. T. Hoffman, L. H. Karnell, G. F. Funk, et al., “The National Cancer Data Base Report on Cancer of the Head and Neck,” Archives of Otolaryngology—Head and Neck Surgery, Vol. 124, No. 9, 1998, pp. 951-962.
[2]	S. Silverman, “Demographics and Occurrences of Oral and Pharyngeal Cancers. The Outcomes, the Trends, the Challenge,” The Journal of the American Dental Association, Vol. 132, Supplement 7S-11S, 2001, pp. 7s-11s.
[3]	G. L. Day and W. J. Blot, “Second Primary Tumors in Patients with Oral Cancer,” Cancer, Vol. 70, 1992, pp. 14-19. doi:10.1002/1097-0142(19920701)70:1<14::AID-CNCR2820700103>3.0.CO;2-S
[4]	L. G. Morris, A. G. Sikora, R. B. Hayes, S. G. Patel and I. Ganly, “Anatomic Sites at Elevated Risk of Second Primary Cancer after an Index Head and Neck Cancer,” Cancer Causes & Control, Vol. 22, No. 5, 2011, pp. 671-679. doi:10.1007/s10552-011-9739-2
[5]	R. Rattan, R. Ali Fehmi and A. Munkarah, “Metformin: An Emerging New Therapeutic Option for Targeting Cancer Stem Cells and Metastasis,” Journal of Oncology, Vol. 2012, 2012, Article ID: 928127. doi:10.1155/2012/928127
[6]	K. Hosono, H. Endo, M. Sugiyama, et al., “Metformin Suppresses Colorectal Aberrant Crypt Foci in a ShortTerm Clinical Trial,” Cancer Prevention Research (Philadelphia), Vol. 3, No. 9, 2010, pp. 1077-1083. doi:10.1158/1940-6207.CAPR-10-0186
[7]	T. M. Chen, C. C. Lin, P. T. Huang and C. F. Wen, “Metformin Associated with Lower Mortality in Diabetic Patients with Early Stage Hepatocellular Carcinoma after Radiofrequency Ablation,” Journal of Gastroenterology and Hepatology, Vol. 26, No. 5, 2011, pp. 858-865. doi:10.1111/j.1440-1746.2011.06664.x
[8]	N. Sadeghi, J. L. Abbruzzese, S. C. Yeung, M. Hassan and D. Li, “Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer,” Clinical Cancer Research, Vol. 18, No. 10, 2012, pp. 2905-2912. doi:10.1158/1078-0432.CCR-11-2994
[9]	L. Vitale-Cross, A. A. Molinolo, D. Martin, et al., “Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions,” Cancer Prevention Research (Philadelphia), Vol. 5, No. 4, 2012, pp. 562-573. doi:10.1158/1940-6207.CAPR-11-0502
[10]	E. Giovannucci, D. M. Harlan, M. C. Archer, et al., “Diabetes and Cancer: A Consensus Report,” Diabetes Care, Vol. 33, No. 7, 2010, pp. 1674-1685. doi:10.2337/dc10-0666
[11]	R. J. Dowling, P. J. Goodwin and V. Stambolic, “Understanding the Benefit of Metformin Use in Cancer Treatment,” BMC Medicine, Vol. 9, No. 33, 2011, pp. 1-6. doi:10.1186/1741-7015-9-33
[12]	S. Jiralerspong, S. L. Palla, S. H. Giordano, et al., “Metformin and Pathologic Complete Response to Neoadjuvant Chemotherapy in Diabetic Patients with Breast Cancer,” Journal of Clinical Oncology, Vol. 27, No. 20, 2009, pp. 3297-3302. doi:10.1200/JCO.2009.19.6410
[13]	H. P. Chen, J. J. Shieh, C. C. Chang, et al., “Metformin Decreases Hepatocellular Carcinoma Risk in a DoseDependent Manner: Population-Based and in Vitro Studies,” Gut, Vol. 62, No. 4, 2013, pp. 606-615.
[14]	C. H. Tseng, “Diabetes, Metformin Use, and Colon Cancer. A Population-Based Cohort Study in Taiwan,” European Journal of Endocrinology, Vol. 167, No. 3, 2012, pp. 409-416. doi:10.1530/EJE-12-0369
[15]	I. Ben Sahra, Y. Le Marchand-Brustel, J. F. Tanti and F. Bost, “Metformin in Cancer Therapy: A New Perspective for an Old Diabetic Drug,” Vol. 9, No. 5, 2010, pp. 1092-1099.
[16]	M. F. McCarty, “MTORC1 Activity as a Determinant of Cancer Risk-Rationalizing the Cancer-Preventive Effects of Adiponectin, Metformin, Rapamycin, and Low-Protein Vegan Diets,” Medical Hypotheses, Vol. 77, No. 4, 2011, pp. 642-648. doi:10.1016/j.mehy.2011.07.004
[17]	H. D. Skinner, V. C. Sandulache and T. J. Ow, et al., “TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence,” Clinical Cancer Research, Vol. 18, No. 1, 2012, pp. 290-300. doi:10.1158/1078-0432.CCR-11-2260
[18]	S. Sklenicka, S. Gardiner, E. J. Dierks, B. E. Potter and R. B. Bell, “Survival Analysis and Risk Factors for Recurrence in Oral Squamous Cell Carcinoma: Does Surgical Salvage Affect Outcome?” Journal of Oral and Maxillofacial Surgery, Vol. 68, No. 6, 2010, pp. 1270-1275. doi:10.1016/j.joms.2009.11.016
[19]	D. H. Lee, M. J. Kim, J. L. Roh, et al., “Distant Metastases and Survival Prediction in Head and Neck Squamous Cell Carcinoma,” Otolaryngology—Head and Neck Surgery, Vol. 147, No. 5, 2012, pp. 870-875. doi:10.1016/j.joms.2009.11.016