Head and neck squamous cell carcinoma accounts for approximately 6.5% of cancer cases with anoverall survival at 5 years of approximately 55%. Recent research has focused on identifying new molecular targets in the context of a precision medicine. It is also necessary to evaluate the host factors associated with a higher risk of recurrence and mortality, or that can modulate treatment tolerance1 . Cancer has in common with diabetes increased insulin and IGF-1 secretion, metabolic alterations and changes in the immune system with the release of pro-infl ammatory cytokines. Historically, cancer has been seen as an abnormality in proliferation, but modern vision includes neoplasms among metabolic diseases. Malignant cells reprogram metabolism in order to provide their nutritional substrate adapted to their needs. Tumor cell causes increased consumption of glucose and glutamine and increased glycolysis2 . Hyperglycemia is defi ned as a blood glucose of more than 126 mg/dL or random blood glucose above 200 mg/dL3 . Factors including diabetes mellitus, obesity, pancreatitis, chronic stress can cause hyperglycemia. Cancer is recognized as a chronic condition also associated with hyperglycemia considered associated with being associated with tumorigenesis or tumor progression. Epidemiological studies have highlighted a link between the presence of diabetes and the development of a large number of solid tumors. Th e most common associations were between diabetes and hepatic and pancreatic cancers, with a higher incidence than the general population4.

Th e study included 25 patients diagnosed with locally advanced, non-metastatic squamous cell carcinoma of the head and neck. Patients were evaluated for tumor staging using pretreatment CT imaging followed by a new CT evaluation after 2-4 cyclesinduction chemotherapy. Induction chemotherapy included plati-num-salt monotherapy, platinum doublets taxanesplatinum doublet (TP), platinum-5-fl uorouracil (PF) or triple platinum-taxane-5-fl uorouracil (TPF). Seven patients received Carboplatin or Cisplatin monotherapy, 14 patients received TP or PF platinum doublet and 4 patients received triple association (TPF) protocol. Subsequently, all patients received curative intent radiotherapy in a total dose of 70Gy in 35 fractions using intensifi ed modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) techniques. Th e RECIST/ RECIST 1.1 criteria were used in all cases to evaluate the imaging response to induction chemotherapy. Response to induction chemotherapy was assessed by imaging methods as complete response, partial response, stationary disease and progressive disease. All patients who did not benefi t from post-induction chemotherapy imaging evaluation (CT or MRI), who received less than 2 cycles and more than 4 cycles of chemotherapy, were excluded from the study. Also excluded were patients who were evaluated at more than 60 days after the last cycle of chemotherapy. Five patients in the study group were diagnosed with diabetes at the time of the cancer diagnosis and one patient was diagnosed after the histopathological confi rmation of the malignant diagnosis. Four of the patients were treated with oral antidiabetics and one patient was treated with insulin. Two of the diabetic patients experienced infectious complications and hospitalization that required delay of the radiotherapy.

All patients developed toxicity during treatment. Radio-mucositis and dysphagia occurred most frequently starting from the 2nd week of treatment, requiring symptomatic treatment in all cases. All patients developed toxicity during treatment. Radio-mucositis and dysphagia occurred most frequently starting from the 2nd week of treatment, requiring symptomatic treatment in all cases. Th ere was 2 grade from 4 acute toxicity (mucositis) after multidisciplinary treatment, one in the non-diabetic patents lot and one in the diabetic patients group. Hematologic toxicity (anemia, lymphopenia, thrombocytopenia) was present in equal proportions among diabetic and non-diabetic patients. radiomucosity and chewing disorder were more prevalent amongst patients with fl oor cancers. A diabetic patient treated with metformin for 2 years presents a high had blood glucose level (>160mg/dl) after iv Dexamethasone administration (4g/day) for 2 weeks. 3 patients, including one diabetic patients, required discontinuation of treatment between 2-6 days due to thrombocytopenia (75.000 per microliter).

Foreman et al. tries to elucidate the controversy over the infl uence of diabetes on the survival of treated patients for head and neck cancers. His analysis demonstrates no diff erent between the diabetic (64%, 95% CI = 58% -71%) and nondiabetic (67%, 95% CI = 65% -69%, P = .078) analyzing overall survival for 5 years5 . Th e impact of comorbidity on tumor and treatmentspecifi c outcomes in head and neck squamous carcinoma was analyzed by Singh et al. but the authors did not identify in a study including 70 diabetic patients radio-chemotherapy treated, an increased rates of treatment-associated complications6 . Charlson comorbidity index was also found to be a valid prognostic indicator in patients with head and neck cancer7 . Th e relationship between the values of salivary mucins and pH and the correlation of the laryngeal cancer etiology has been assessed from the premise that xerostomia is a risk factor by altering the saliva quality and the autoimmune disease has a decrease in the value of pH and salivary fl ow. As a direct consequence decreases the value of spinnbarkeit which measures the ability of the mucous layer to adhere to the epithelium can cause alteration of the mucin layer in the oral cavity. Increasing salivary mucin concentration associated with diabetes leads to the impossibility of creating the mucosal protective layer and by this algorithm diabetes becomes a risk factor for squamous cell head and neck cancers8 . Xerostomia and impaired quality of life by reducing salivary volume and altered saliva quality are identifi ed in many studies. Diabetes mellitus and low metabolic control are associated with adverse eff ects on oral health. Radiotherapy is also causing xerostomia and altered pH and bacterial fl ora of the oral cavity with direct consequences in worsening of radiomucositis and the appearance of dental caries9,10. Hyperglycemia of the patients benefi ting from nutritional support in hospitalization is common, reaching up to 30% in patients receiving enteral nutritional support and in more than half of patients in patients receiving parenteral nutrition11. Corticosteroids are often administered to cancer patients in combination with chemotherapy for antiemetic purposes to prevent vomiting induced by chemotherapy or allergic eff ects. In patients diagnosed with and treated with radiotherapy or radiochemistry for neck cancers, dexamethasone is often used as an anti-edematous drug with a long half-life and an anti-infl ammatory eff ect more than other corticosteroids. Generally administered over long periods of time for patients receiving 2-4 cycles of induction chemotherapy followed by concomitant radiotherapy or radio-chemotherapy for 7 weeks, adverse eff ects are not rare, the most common being hyperlipidemia, adrenal suppression, growth suppression, amenorrhea, gynecomastia12. Hyperglycemia and insulin resistance are commonly associated with the use of corticosteroids downregulation of glucose transporter 4 in muscle, associated with increased insulin required for the uptake of glucose into cells, and with increased hepatic glucose production, blocking inhibition of insulin binding to the cell insulin receptor. Corticosteroids also inhibit the production of insulin by the cells13. Th e use of glucocorticoids may exacerbate pre-diabetes or undiagnosed diabetes and may trigger a hyperglycemic non-ketotic hyperosmolar coma for patents who already have a previously manifested clinical diabetes. Being aware that symptoms of hyperglycemia such as thirst, dry mouth, polyuria, and lethargy are common in tumor pathologies and often associated with oncological treatments, the diagnosis of diabetes present at the onset of oncological treatment is often late14. Family history of diabetes and the patient history of gestational diabetes, older age, obesity, and the steroids doses required are considered predictive factors for glucocorticoid induced diabetes by Clement and collaborators15. Patients with pre-existing diabetes require close monitoring of oral anti-diabetic therapy on corticosteroid therapy but are often inadequate. Patients treated with insulin prior to glucocorticoid administration will often require basal and postprandial doses for appropriate glycemic control16.Th e addition of chemotherapy to radiotherapy in the treatment of locally advanced squamous cell carcinoma has shown signifi cant benefi t in overall survival with the most eloquent evidence for concurrent administration of chemotherapy and radiotherapy. Al Saraf et al. concluded 30 years ago that the combination of Cisplatin and radiotherapy is an eff ective and safe treatment in patients with advanced head and neck cancer and today platinum based chemotherapy is part of all the multidisciplinary therapeutic recommendations for locally advanced head and neck cancers. Concurrent chemo-radiotherapy using weekly Cisplatin at 40mg / m2 per week and the standard dose of 100mg /m2 Cisplatin three-weekly are used concurrently with radiotherapy17,18. Th e use of chemotherapy induction followed by radio-chemotherapy or radiotherapy as the unique treatment method remains a controversial topic. However, the platinum induction regimens and 5-fl uorouracil (PF) -containing induction regimens demonstrated a signifi cant survival benefi t compared to individual loco-regional treatment. Th e triplet combination of Docetaxel, Cisplatin, and 5-fl uorouracil used as an induction regimen has been shown to be more eff ective than platinum-based platinum-based chemotherapy or platinum 5-fl uorouracil. Th e development of a hyperglycemic crisis in head and neck cancer patients benefi ting from platinum-based chemotherapy has also been reported. Huang et al reports from a total of 185 patients, 3.8% who developed type 2 diabetes after initial chemotherapy. 3 patients developed diabetic ketoacidosis and the hyperglycemic crisis in this study group, complications occurring in patients with multiple comorbidities20. Intrinsic factors have been associated with acute skin toxicity in breast cancer radiotherapy21. Diabetes is identifi ed as a risk factor in studies that include pelvic irradiation, especially for prostate cancer patients and just like smoking and hypertension, and atherosclerosis is associated with bowel tardive toxicity23. Th e CT / IRM evaluation of the induction chemotherapy response is poorly correlated with the pathological response especially in the tumors of the oral cavity and the larynx. In these cases, RECIST criteria may not be sensitive suggestive for predicting response after induction chemotherapy24.

Th e study does not show that the presence of diabetes increases the rate of toxicity in head and neck cancers except radiomucositis. However, the association of high blood pressure and type 2 uncontrolled diabetes at the onset of radiotherapy limits the administration of glucocorticoids and aff ects the quality of life of patients. It is necessary to monitor the late toxicity that can be potentiated by microangiopathic diabetic complications and the evaluation of a larger group of patients.An extensive study including the correlation of dosimetric parameters with acute and late toxicities in head and neck cancers with the doses received by diff erent organs is necessary to assess whether there is a need to limit the dose of radiation to the oral cavity and parotid glands below the current recommended limits to prevent xerostomia and oral mucositis.

Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.