The Effect of Metformin Use during Docetaxel Chemotherapy on Prostate Cancer Specific and Overall Survival of Diabetic Patients with Castration Resistant Prostate Cancer
Abstract
Purpose:
Docetaxel is the first line chemotherapy currently used to treat patients with symptomatic metastatic castration resistant prostate cancer. Although it provides survival benefits, it is associated with significant side effects. Novel therapeutic options are needed for patients with metastatic castration resistant prostate cancer and an approach is combining docetaxel with chemosensitizing agents. Metformin has been shown to improve the survival of patients with breast, lung and endometrial cancer receiving chemotherapy, and enhance chemotherapeutic efficacy in breast cancer and colon cancer cells. However, to our knowledge the chemosensitizing effect of metformin in prostate cancer has not been explored. Therefore, the hypothesis for our study was that diabetic patients with metastatic castration resistant prostate cancer who were administered metformin during docetaxel chemotherapy would have improved prostate cancer specific and overall survival.
Materials and Methods:
This retrospective cohort study used data from several Ontario administrative health care databases. Men older than 65 years diagnosed with metastatic castration resistant prostate cancer and treated with docetaxel were stratified into groups based on diabetes status and use of antidiabetic medications. We evaluated the effect of metformin use with docetaxel on prostate cancer specific survival and overall survival using Kaplan-Meier survival curves, the log rank test and multivariate Cox proportional HRs.
Results:
Survival curves showed that metformin use with docetaxel did not improve prostate cancer specific survival (p = 0.9562) or overall survival (p = 0.9927). HRs showed no significant effect of metformin use with docetaxel on prostate cancer specific survival (HR = 0.96, p = 0.66) or overall survival (HR = 0.94, p = 0.39).
Conclusions:
Metformin use during docetaxel chemotherapy did not significantly improve prostate cancer specific or overall survival in diabetic patients with metastatic castration resistant prostate cancer. This study indicates that metformin may not be an effective chemosensitizer for metastatic castration resistant prostate cancer.
References
- 1 : Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol2014; 32: 3436. Google Scholar
- 2 : The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer2012; 12: 159. Google Scholar
- 3 : Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis2015; 18: 303. Google Scholar
- 4 : Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res2009; 69: 7507. Google Scholar
- 5 : Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res2011; 71: 3196. Google Scholar
- 6 : Effects of metformin on CD133+ colorectal cancer cells in diabetic patients. PLoS One2013; 8: e81264. Google Scholar
- 7 : Metformin: a potential therapeutic agent for recurrent colon cancer. PLoS One2014; 9: e84369. Google Scholar
- 8 : Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol2009; 27: 3297. Google Scholar
- 9 : Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer2011; 117: 5103. Google Scholar
- 10 : Association of metformin use with outcomes in advanced endometrial cancer treated with chemotherapy. PLoS One2016; 11: e0147145. Google Scholar
- 11 : Metformin use and prostate cancer risk. Eur Urol2014; 66: 1012. Google Scholar
- 12 : The influence of antidiabetic medications on the development and progression of prostate cancer. Cancer Epidemiol2012; 36: e243. Google Scholar
- 13 : Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol2013; 31: 3069. Google Scholar
- 14 : Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol2013; 63: 709. Google Scholar
- 15 : An application of capture-recapture methods to the estimation of completeness of cancer registration. J Clin Epidemiol1988; 41: 495. Google Scholar
- 16 : Using cancer registry data: agreement in cause-of-death data between the Ontario Cancer Registry and a longitudinal study of breast cancer patients. Chronic Dis Can2009; 30: 16. Google Scholar
- 17 : Diabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care2002; 25: 512. Google Scholar
- 18 : Coding accuracy of administrative drug claims in the Ontario Drug Benefit database. Can J Clin Pharmacol2003; 10: 67. Google Scholar
- 19 :
A summary of studies on the quality of health care administrative databases in Canada . In: The ICES Practice Atlas, 2nd ed. Edited by . Ottawa: Canadian Medical Association1996: 339. Google Scholar - 20 : Canadian Institute for Health Information Discharge Abstract Database: A Validation Study. ICES Investigative Report, June 2006. Toronto: Institute for Clinical Evaluative Sciences2006. Google Scholar
- 21 : Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care2012; 35: 2665. Google Scholar
- 22 : Association between metformin use and risk of prostate cancer and its grade. J Natl Cancer Inst2013; 105: 1123. Google Scholar
- 23 : Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev2011; 20: 337. Google Scholar
- 24 : The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol Biomarkers Prev2014; 23: 2111. Google Scholar
- 25 : Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila)2014; 7: 867. Google Scholar
- 26 : Influence of concurrent medications on outcomes of men with prostate cancer included in the TAX 327 study. Can Urol Assoc J2013; 7: E74. Google Scholar
- 27 : Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med2004; 351: 1502. Google Scholar
- 28 : Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst2006; 98: 1819. Google Scholar
- 29 : Statin use and reduced cancer-related mortality. N Engl J Med2012; 367: 1792. Google Scholar
- 30 : Castration-resistant prostate cancer: AUA Guideline. J Urol2013; 190: 429. Link, Google Scholar
