Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset

Stokes, William A.; Eguchi, Megan; Amini, Arya; Hararah, Mohammad K.; Ding, Ding; McDermott, Jessica D.; Karam, Sana D.

doi:10.1016/j.oraloncology.2018.06.022

Cited by 18 publications

(24 citation statements)

References 45 publications

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“…Madera et al reached similar conclusions [129]. A retrospective study published by Stokes et al [130] in 2018 found that, HN cancers patients with DM improved greatly after taking metformin. These results suggest that metformin can improve the cancer-specific survival rate in patients with both HN cancer and DM.…”

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confidence: 64%

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Diabetes and its Potential Impact on Head and Neck Oncogenesis

Wang

Zhang

et al. 2020

J. Cancer

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In recent years, the incidence of diabetes mellitus and cancer has increased sharply; indeed, these have become the two most important diseases threatening health and survival. Head and neck (HN) tumors are the sixth most common malignancies in humans. Numerous studies have shown that there are many common risk factors for diabetes mellitus and HN squamous cell carcinoma, including advanced age, poor diet and lifestyle, and environmental factors. However, the mechanism linking the two diseases has not been identified. A number of studies have shown that diabetes affects the development, metastasis, and prognosis of HN cancer, potentially through the associated hyperglycemia, hyperinsulinemia and insulin resistance, or chronic inflammation. More recent studies show that metformin, the first-line drug for the treatment of type 2 diabetes, can significantly reduce the risk of HN tumor development and reduce mortality in diabetic patients. Here, we review recent progress in the study of the relationship between diabetes mellitus and HN carcinogenesis, and its potential mechanisms, in order to provide a scientific basis for the early diagnosis and effective treatment of these diseases.

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confidence: 64%

“…2016 Figueiredo et al (126) People with diabetes have a lower risk of HNC than those without diabetes; metformin use may explain this inverse association. 2018 Stokes et al (130) Metformin improves the cancer-specific survival rate in patients with head and neck cancer and diabetes mellitus.…”

Section: Effect Of Metformin and Other Diabetic Drugs On Hn Tumorsmentioning

confidence: 99%

Diabetes and its Potential Impact on Head and Neck Oncogenesis

Wang

Zhang

et al. 2020

J. Cancer

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“…Time‐dependent modelling has since been applied in some studies to avoid immortal time bias . However, immortal time bias obscured the true association in a recent observational study reporting beneficial effects of metformin on HNC‐specific survival . In addition to accounting for time biases, the choice of a comparison group is critical to minimize bias from disease severity differences, as illustrated in a study evaluating metformin and survival among colorectal cancer patients .…”

Section: Resultsmentioning

confidence: 99%

“…[19][20][21] However, immortal time bias obscured the true association in a recent observational study reporting beneficial effects of metformin on HNC-specific survival. 25 In addition to accounting for time biases, the choice of a comparison group is critical to minimize bias from disease severity differences, as illustrated in a study evaluating metformin and survival among colorectal cancer patients. 21 Patients with any metformin exposure in the year prior to diagnosis had a 31% reduced risk of all-cause mortality compared with patients with diabetes exposed to at least one non-metformin antidiabetic prescription.…”

Section: Re Sults and Discussionmentioning

confidence: 99%

Metformin exposure and survival in head and neck cancer: A large population-based cohort study

et al. 2019

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Summary What is known and objective Observational clinical studies of metformin for prevention and treatment of several cancer types have reported mixed findings. Although preclinical studies have suggested metformin may reduce head and neck cancer (HNC) proliferation, clinical evidence is limited. The objective of this large population‐based study was to evaluate the relationship between metformin exposure following HNC diagnosis and all‐cause mortality. Methods We conducted a retrospective cohort study using the Italian Emilia‐Romagna Regional administrative healthcare database, which includes demographic, hospital and outpatient prescription information for ~4.5 million residents. Included patients were followed from the first hospital discharge (index) during the study period (01/2003‐12/2012) with a diagnosis of HNC. Metformin exposure and select covariates were operationalized in a time‐dependent manner during follow‐up. Cox proportional hazards models estimated the covariate‐adjusted time‐dependent association between metformin exposure and all‐cause mortality. Results and discussion Among 7872 patients diagnosed with HNC, 708 (9.0%) were exposed to metformin after HNC diagnosis, and 3626 (46.1%) died during follow‐up (median follow‐up: 35.2 months). In the covariate‐adjusted model, the all‐cause mortality rate appeared lower (HR: 0.81, 95% CI: 0.61‐1.09) among metformin exposed patients during the 2 years post‐diagnosis, while the all‐cause mortality rate appeared higher (HR: 1.20, 95% CI: 0.94‐1.53) among exposed patients after 2 years post‐diagnosis. Metformin was protective among patients ≤60 years of age (HR for the period of 0‐2 years post‐diagnosis: 0.22, 95% CI 0.09‐0.56; HR for the period ≥2 years post‐diagnosis: 0.56, 95% CI 0.26‐1.22) but not in those >60 years. What is new and conclusion In this population‐based study of metformin in HNC, we found a modest protective association between metformin exposure and all‐cause mortality in the 2‐year post‐diagnosis period. Age appeared to modify the association between metformin and HNC survival.

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“…Lastly, our study also did not investigate the impact of the type of diabetic treatment on survival outcomes. There have been numerous recent studies that have shown an association between metformin therapy in diabetes with improved survival end points in head and neck cancer, with some even suggesting that metformin may be considered an adjunct in the standard treatment of head and neck cancer (Rêgo, Pavan, Elias, De Luca Canto, & Guerra, 2015; Saka Herran, Jane‐Salas, Estrugo Devesa, & Lopez‐Lopez, 2018; Stokes et al., 2018). Conversely, there are also some studies that showed that exogenous insulin usage, especially with increased dosages, is associated with worse all‐cause mortality or cancer‐specific prognosis in other malignancies (Chen, Chubak, et al, 2017; Holden, Jenkins‐Jones, Morgan, Schernthaner, & Currie, 2015; Sonnenblick et al., 2017).…”

Section: Discussionmentioning

confidence: 99%

The impact of preoperative glycated hemoglobin levels on outcomes in oral squamous cell carcinoma

et al. 2020

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Objectives This study aimed to investigate the association between preoperative glycated hemoglobin (HbA1c) levels and the treatment outcomes of oral cavity squamous cell carcinoma (OSCC). Methods Three hundred and fifty‐eight OSCC patients were consecutively enrolled between July 2004 and July 2016. Clinicopathological parameters and survival outcomes were analyzed following HbA1c stratification of 6.5% (HbA1c ≥ 6.5%: n = 74, 20.6%) and 7.0% (HbA1c ≥ 7.0%: n = 53, 14.8%). Results Higher HbA1c levels were associated with elevated body mass index, lower albumin levels, wider surgical margins, and prolonged hospital stays (HbA1c 6.5%: p = .001, .048, .030, .009, respectively; HbA1c 7.0%: p = .092, .032, .009, .015, respectively). Survival rates stratified by HbA1c 6.5% were as follows: locoregional recurrence‐free survival, p = .014; distant metastasis‐free survival, p = .013; second primary cancer‐free survival, p = .015; overall survival, p = .014; disease‐specific survival, p = .002 and HbA1c 7.0%: locoregional recurrence‐free survival, p = .013; distant metastasis‐free survival, p = .013; second primary cancer‐free survival, p = .014; overall survival, p = .015; disease‐specific survival, p = .004. Multivariate analyses identified HbA1c as an independent prognostic factor for overall and disease‐specific survival (HbA1c 6.5%: p = .014 and .002, respectively; HbA1c 7.0%: p = .036 and .013, respectively). Conclusions Oral squamous cell carcinoma patients with higher preoperative HbA1c levels had longer hospitalization and worse survival outcomes.

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Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset

Abstract: HNC patients with diabetes taking metformin experience improved CSS. Prospective investigation of the addition of metformin to standard-of-care HNC therapy is warranted.

Cited by 18 publications

References 45 publications

Diabetes and its Potential Impact on Head and Neck Oncogenesis

Diabetes and its Potential Impact on Head and Neck Oncogenesis

Metformin exposure and survival in head and neck cancer: A large population-based cohort study

The impact of preoperative glycated hemoglobin levels on outcomes in oral squamous cell carcinoma

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