Metformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With Diabetes

Margel, David; Urbach, David R.; Lipscombe, Lorraine L.; Bell, Chaim M.; Kulkarni, Girish S.; Austin, Peter C.; Fleshner, Neil

doi:10.1200/jco.2012.46.7043

Cited by 243 publications

(203 citation statements)

References 35 publications

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“…Despite the promising results of lower mortality among prostate cancer patients exposed to metformin (22), an analysis of 270 men with diabetes, with and without metformin use, revealed no association between metformin use and progression-free, disease-free, or overall survival following treatment with BT (23). Similar results were found in another cohort of 199 diabetes patients, in which diabetes did not affect cancer-specific survival or biochemical progression following BT (24).…”

Section: Discussionsupporting

confidence: 62%

Prostate-specific antigen nadir concentration, hypertension and diabetes as risk factors for biochemical failure after permanent 125I seed brachytherapy for prostate cancer

Kovalainen

Vaarala

2016

Molecular and Clinical Oncology

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Abstract. The aim of this study was to evaluate risk factors for biochemical failure (BF) following permanent prostate seed 125 I brachytherapy for prostate cancer. The study reviewed the medical records of 607 patients with biopsy-proven prostate adenocarcinoma who were treated at Oulu University Hospital between 2001 and 2014. Clinical characteristics at diagnosis, treatment-related data and follow-up data were collected to identify potential risk factors for BF, which was defined using the Phoenix criteria [prostate-specific antigen (PSA) increase >2 µg/l from the PSA nadir concentration, which defined as the lowest PSA concentration observed after BT]. The median follow-up was 81 months. BF was detected in 117 (19.3%) patients. The PSA nadir concentration was associated with BF. The mean times to BF were 114 [95% confidence interval (CI): 112-116] and 55 (95% CI: 47-63) months for patients with PSA nadir concentrations <0.5 and ≥0.5 µg/l, respectively (P<0.001). Patients with underlying hypertension or diabetes tended to develop BF more rapidly. For patients without and with hypertension, the mean times to BF were 104 (95% CI: 100-107) and 98 (95% CI: 93-103) months, respectively (P=0.035). For patients without and with diabetes, the mean times to BF were 103 (95% CI: 100-106) and 89 (95% CI: 77-102) months, respectively (P=0.006). The overall survival and prostate cancer-specific survival rates were 90.3 and 98.0%, respectively. The mean overall survival and prostate-cancer specific survival times were 147 and 158 months, respectively. Therefore, PSA nadir level was identified as a clear risk factor for BF. In addition, BF tended to develop more rapidly among patients with underlying hypertension or diabetes. These risk factors should be considered, and individually tailored follow-up may be useful for identifying patients requiring more intense follow-up for early BF detection.

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Section: Discussionsupporting

confidence: 62%

Prostate-specific antigen nadir concentration, hypertension and diabetes as risk factors for biochemical failure after permanent 125I seed brachytherapy for prostate cancer

Kovalainen

Vaarala

2016

Molecular and Clinical Oncology

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“…Despite a lack of important details of the treatment, a subgroup analysis of 937 patients (24.4% of the entire cohort) who received radiotherapy as primary treatment showed a 48% decrease in prostate cancer-specific mortality (adjusted HR, 0.56; 95% CI: 0.3-0.85; P ¼ 0.09; ref. 36). Other results from a smaller cohort of patients with head and neck cancer treated with postoperative radiotherapy or patients with esophageal cancer treated with neoadjuvant chemoradiation showed that metformin use leads to lower locoregional relapse rates and improved complete pathologic response (30,37).…”

Section: Discussionmentioning

confidence: 99%

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Zannella

Pra

Muaddi

et al. 2013

Clinical Cancer Research

265

208

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Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curativeintent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method.Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P ¼ 0.0106).Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.

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“…However, there has been renewed interest in the effect of this drug on cancer outcomes in patients with prostate cancer. To date, six observational studies have investigated the effects of metformin on cancerrelated mortality, distant metastasis, and all-cause mortality in men diagnosed with prostate cancer (7)(8)(9)(10)(11)(12). In three studies, the use of metformin was associated with strong decreased risks (ranging between 24% and 80% risk reductions) of several prostate cancer outcomes (8,10,11), whereas the other three studies reported nonsignificant findings (7,9,12).…”

Section: Introductionmentioning

confidence: 99%

The Use of Metformin in Patients with Prostate Cancer and the Risk of Death

Bensimon

Yin

Suissa

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Given the conflicting results from observational studies, we assessed whether the use of metformin after a prostate cancer diagnosis is associated with a decreased risk of cancer-specific and all-cause mortality.Methods: This study was conducted linking four databases from the United Kingdom. A cohort of men newly diagnosed with nonmetastatic prostate cancer with a history of treated type II diabetes, between April 1, 1998 and December 31, 2009, was followed until October 1, 2012. Nested case-control analyses were performed for cancer-specific mortality and all-cause mortality, in which exposure was defined as use of metformin during the time to risk-set. Conditional logistic regression was used to estimate adjusted rate ratios (RR) of each outcome with 95% confidence intervals (CI).Results: The cohort consisted of 935 men with prostate cancer and a history of type II diabetes. After a mean follow-up of 3.7 years, 258 deaths occurred, including 112 from prostate cancer. Overall, the post-diagnostic use of metformin was not associated with a decreased risk of cancer-specific mortality (RR, 1.09; 95% CI, 0.51-2.33). In a secondary analysis, a cumulative duration 938 days was associated with an increased risk (RR, 3.20; 95% CI, 1.00-10.24). The post-diagnostic use of metformin was not associated with all-cause mortality (RR, 0.79; 95% CI, 0.50-1.23).Conclusion: The use of metformin after a prostate cancer diagnosis was not associated with an overall decreased risk of cancer-specific and all-cause mortality.Impact: The results of this study do not support a role for metformin in the prevention of prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev; 23(10); 2111-8. Ó2014 AACR.

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Metformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With Diabetes

Abstract: Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men.

Cited by 243 publications

References 35 publications

Prostate-specific antigen nadir concentration, hypertension and diabetes as risk factors for biochemical failure after permanent 125I seed brachytherapy for prostate cancer

Prostate-specific antigen nadir concentration, hypertension and diabetes as risk factors for biochemical failure after permanent 125I seed brachytherapy for prostate cancer

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

The Use of Metformin in Patients with Prostate Cancer and the Risk of Death

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