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  • br T Fransgaard et al br Fig STROBE flow diagram

    2020-08-05


    T. Fransgaard et al.
    Fig. 1. STROBE flow diagram.
    *Patients undergoing surgery for colorectal cancer with curative intent in the period January 1. 2003–July 1. 2015 ** n = 58 metformin, n = 69 other antidiabetic medication, n = 45 treatment with a combination of the different antidiabetic medication.
    4. Discussion
    The study showed no association between diabetes and response to chemo-radiotherapy in respect to DFS, RFS or all-cause mortality. Metformin use had no influence on the outcomes.
    Current treatment standards for locally advanced rectal cancer in-volve neoadjuvant chemo-radiotherapy followed by resection. Response to the treatment is variable, and complete response leaving no residual tumor is achieved in 10–30% of the patients [34]. The factors influencing the tumor response are not well understood. Diabetes have been suggested to reduce the response to chemo-radiotherapy due to the microvascular disease limiting the drug delivery of radio sensitizing agents to the tissue as well as create a hypoxic environment that may decrease sensitivity to radiation [21]. Only a few studies have in-vestigated this in patients with rectal cancer [21,22]. One study in-cluded 110 patients of whom only 17 had diabetes and found higher local progression rates and fewer had pathological complete response (pCR) in the diabetes group compared with the non-diabetes group [21]. Another study including only 19 patients with diabetes and 82 not diagnosed with diabetes found no difference in regard to pCR [22], which is in accordance with the findings of the present study. None of the two studies assessed DFS, RFS or all-cause mortality.
    Metabolic syndrome (three of the following conditions: abdominal obesity, high fasting glucose, hypertension, hyperlipidemia or hyper-triglyceridemia) and type 2 diabetes are closely related. Studies have shown that metabolic syndrome related factors such as obesity, hy-perinsulinemia, Methoctramine and hypercholesterolemia can increase the risk of developing cancers as well as diminish response to therapies [35]. A recent study has shown that presence of risk factors for meta-bolic syndrome and especially hypertension is related to poorer re-sponse to chemo-radiotherapy in patients with rectal cancer [22]. In the present study, patients with diabetes are propensity score matched with  Surgical Oncology 28 (2019) 62–66
    Table 1a
    Patient Characteristics at time of diagnosis.
    Diabetes Non-diabetes
    Sex
    Data were expressed as No./% unless otherwise indicated. Abbreviations BMI:
    Body Mass Index. *P-value calculated using Chi-Square test.
    non-diabetes patients taking among other things comorbidity and BMI into account. Due to the limited sample size the previous study showing a decreased response to chemo-radiotherapy in patients with diabetes were not able to adjust for possible confounders simultaneously and the factors of age, gender and BMI were examined individually. Perhaps this is the reason for the conflicting results with our study. Comorbidity plays a large role in patients with diabetes, which needs to be adjusted for when examining treatment responses in patients diagnosed with diabetes.
    In multiple cancers, tumor hypoxia is a negative prognostic factor causing resistance to radiotherapy. Oxygen is consumed by proximal tumor cells causing hypoxia in tumor cells distal to blood vessels. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia [23]. Metformin is thought to de-crease tumor hypoxia and consequently increase response to chemo-radiotherapy. Although the mechanisms are not completely understood the major mechanism of the radio sensitizing effect is through inhibi-tion of mitochondrial complex 1 and the mitochondrial electron transport chain and hence oxygen consumption [24,36]. A few studies have investigated the association between metformin and response to
    T. Fransgaard et al.
    Table 1b
    Patient Characteristics at time of diagnosis, antidiabetic treatment.
    Metformin Non-diabetes
    Sex
    Data were expressed as No./% unless otherwise indicated. Abbreviations BMI:
    Body Mass Index. *P-value calculated using Chi-Square test.
    chemo-radiotherapy in patients with rectal cancer. Both studies as-sessed pCR as well as long-term effects such as DFS and all-cause mortality [24,25]. The studies showed conflicting results in terms of both DFS, all-cause mortality and pCR. The present study support the findings of no significant difference in terms of DFS, RFS and all-cause mortality between metformin users and non-diabetes patients. No in-formation regarding tumor regression grade or pCR were available for this study, but even though metformin should improve tumor regres-sion grade and pCR the impact seems not to be pronounced enough to influence DFS, RFS and all-cause mortality.