title: Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy.
abstract: We assessed the presence of salivary cytokines, their modulation during chemoradiation therapy (CTRT), and their association with oral mucositis severity in patients with head and neck cancer (HNC).
  
  
  
  The present prospective observational study enrolled 55 patients with locally advanced HNC requiring CTRT. We also studied 10 healthy volunteers and 10 patients with other cancers. The salivary levels of 13 cytokines were analyzed. We constructed a cytokine predictive score of oral mucositis severity.
  
  
  
  The baseline salivary cytokine levels were not associated with the severity of treatment-induced oral mucositis. The cytokine levels overall increased during treatment, especially in patients with worse mucositis. In particular, on univariable analysis, an increase of interleukin (IL)-1β (area under the curve [AUC] 0.733; P=.009), IL-6 (AUC 0.746; P=.005), and tumor necrosis factor-α (AUC 0.710; P=.005) at the third week of treatment was significantly associated with the development of severe oral mucositis. On multivariable analysis, the predictive score based on the IL-1β and IL-6 changes from baseline to week 3 was an early strong predictor of higher grade oral mucositis.
  
  
  
  The treatment of HNC patients with concurrent CTRT induces a significant increase in the salivary levels of IL-1β, IL-6, and tumor necrosis factor-α, all positively associated with the severity of mucosal toxicity. A greater increase of IL-1β and IL-6 3 weeks after treatment initiation is predictive of worse oral mucositis, representing a potential tool for the early identification of patients at risk.
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Paolo.bossi@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Clinical Epidemiology and Trial Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Miceli
authors.affiliation: Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Cova
authors.affiliation: Radiotherapy 2 Unity, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Orlandi
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Resteghini
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Locati
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Alfieri
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Imbimbo
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Granata
authors.affiliation: Clinical Epidemiology and Trial Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Radiotherapy 2 Unity, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Nicola Alessandro
authors.initials: NA
authors.lastname: Iacovelli
authors.affiliation: Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Huber
authors.affiliation: Department of Physics and Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cavallo
authors.affiliation: Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D002277:Carcinoma / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000628:therapy; D000068818:Cetuximab / Q000008:administration & dosage; D059248:Chemoradiotherapy / Q000009:adverse effects*; D002945:Cisplatin / Q000008:administration & dosage; D016207:Cytokines / Q000032:analysis; D000077143:Docetaxel; D019583:Dose Fractionation, Radiation; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000628:therapy; D053583:Interleukin-1beta / Q000032:analysis*; D015850:Interleukin-6 / Q000032:analysis*; D007822:Laryngeal Neoplasms / Q000628:therapy; D009062:Mouth Neoplasms / Q000628:therapy; D009303:Nasopharyngeal Neoplasms / Q000628:therapy; D009959:Oropharyngeal Neoplasms / Q000628:therapy; D011446:Prospective Studies; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods; D012463:Saliva / Q000737:chemistry*; D012720:Severity of Illness Index; D013280:Stomatitis / Q000209:etiology* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D043823:Taxoids; D014409:Tumor Necrosis Factor-alpha; D000077143:Docetaxel; D016190:Carboplatin; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil