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1. Introduction r> Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgical removal of the tumor is the only curative treat-ment, but still 30–40% of patients with potentially curable CRC relapses . Diabetes mellitus and colorectal cancer share several risk factors including obesity and physical inactivity, and diabetes is proven to be an independent risk factor for developing colorectal cancer .
Metformin is the drug of choice for treatment of type 2 diabetes, and several studies indicate that metformin-users may both have a de-creased risk of developing certain cancers including colorectal cancer [3–5] and have potential survival benefits [4,6–12]. The antineoplastic molecular action of metformin is believed to work through the inhibi-tion of the mammalian target of the rapamycin (mTOR) pathway .
This pathway has a central role in regulating basic cell behaviors such as regulation of protein synthesis and cell growth as well as cell sur-vival, metabolism, and cytoskeletal organization [14–16]. Studies show that metformin has an antineoplastic eﬀect and can inhibit cancer cell growth [13,17].
The standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy followed by total mesorectal excision. This improves resectability, achieves better chance of sphincter pre-servation and reduces the risk of local recurrence [18–20]. Tumor re-sponse to neoadjuvant radiotherapy is an important factor for local recurrence and survival, and the presence of tumor hypoxia is a nega-tive prognostic factor. It has been suggested that patients with diabetes have lower response to neoadjuvant chemo-radiotherapy than non-diabetes patients. These studies have, however, been limited by small
∗ Corresponding author. Zealand University Hospital, Department of Surgery, Lykkebækvej 1, 4600, Køge, Denmark. E-mail address: [email protected] (T. Fransgaard).
T. Fransgaard et al.
sample sizes and lack of long-term outcomes [21,22]. Besides the sus-pected antineoplastic eﬀects exerted through the mTOR pathway, metformin directly inhibits the complex I activity in the mitochondrial 丝裂霉素C transport chain. This could lead to an increase in the response to radiotherapy through inhibition of tumor cell oxygen consumption and improved tumor oxygenation . This is supported by studies suggesting that patients with metformin-treated diabetes have im-proved response rates for radiotherapy in several malignancies  Only a few studies have investigated the radio sensitizing eﬀect of metformin in rectal cancer [24,25].
The aim of the study was to investigate, in a nationwide study, if diabetes and especially metformin use during neoadjuvant chemo-radiotherapy aﬀects the oncological outcomes in patients with rectal cancer.
Through the national clinical register of the Danish Colorectal Cancer Group (DCCG), patients undergoing neoadjuvant chemo-radio-therapy and curative intended resection for rectal cancer in Denmark between January 1, 2003 and July 1, 2015 were identified.
The DCCG includes 98.6% of all patients diagnosed with colorectal cancer and contains detailed information regarding demographic fac-tors, comorbidity, and peri- and postoperative treatment . In the Danish National Patient Register (NPR) all hospital contacts including outpatient visits are registered . Information regarding hospital admission such as date of admission and discharge, procedure codes and diagnoses was obtained from the NPR. A unique personal identi-fication number (CPR-number) is assigned to all Danish residents and information on immigration, emigration, and mortality among all re-sidents are recorded in the Danish Civil Registration System. This system is complete, and loss to follow up is minimal . The unique CPR-number makes it possible to link the registers used. The Danish Pathology Register (DPR)  have recorded standard data on biolo-gical specimens and coded these using the Danish version of the Sys-temized Nomenclature of Medicine (SNOMED). SNOMED codes can be used to document pathological diagnosed recurrences. All incident cancer cases in the Danish population since 1943 are registered in The Danish Cancer Registry (DCR) . The study population was linked to the DCR in order to be able to identify patients with a history of cancer. Since 1995, prescribed drugs dispensed at the Danish community pharmacies have been registered in the Danish National Prescription Registry (DNPR) . All redeemed prescriptions, including WHO de-fined daily doses (DDD) and date of dispensing, were identified. In-dication and prescribed dose are not recorded in the DNPR.