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N-Acetylcysteine Rinse for Thick Secretion and Mucositis of Head and Neck Chemoradiotherapy (Alliance MC13C2)

A Double-Blind Randomized Clinical Trial



      To determine whether N-acetylcysteine rinse was safe and could improve thickened secretions and dry mouth during and after radiotherapy.

      Patients and Methods

      We designed a prospective pilot double-blind, placebo-controlled randomized clinical trial (Alliance MC13C2). Adult patients (age ≥18 years) were enrolled if they underwent chemoradiotherapy (≥60 Gy). Patients initiated testing rinse within 3 days of starting radiotherapy. With swish-and-spit, they received 10% N-acetylcysteine (2500 mg daily) or placebo rinse solution 5 times daily during radiotherapy and 2 weeks postradiotherapy. The primary aim was to evaluate N-acetylcysteine in improvement of saliva viscosity with the Groningen Radiotherapy-Induced Xerostomia questionnaire. Secondary aims included evaluating xerostomia improvement by the same questionnaire and with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck-35 Questions survey and adverse-event profiles. The type I error rate was 20%.


      Thirty-two patients undergoing chemoradiotherapy were enrolled. Baseline characteristics were balanced for placebo (n=17) and N-acetylcysteine (n=15). N-acetylcysteine was better for improving sticky saliva (area under curve, P=.12). Scores of multiple secondary end points favored N-acetylcysteine, including sticky saliva daytime (P=.04), daytime and total xerostomia (both P=.02), pain (P=.18), and trouble with social eating (P=.15). Repeated measures models confirmed the findings. Taste was a major dissatisifer for N-acetylcysteine rinse; however, both testing rinses were safe and well tolerated overall.


      Our pilot data showed that N-acetylcysteine rinse was safe and provided strong evidence of potential efficacy for improving thickened saliva and xerostomia by patient-reported outcome. A confirmatory phase 3 trial is required.

      Trial Registration

      Abbreviations and Acronyms:

      AUC (area under the curve), COPD (chronic obstructive pulmonary disease), CRT (chemoradiotherapy), EORTC QLQ H&N35 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck-35 Questions), GRIX (Groningen Radiation-Induced Xerostomia), IL (interleukin), NF-κB (nuclear factor κ–light-chain enhancer of activated B cells), PRO (patient-reported outcome), RT (radiotherapy)
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        • Adelstein D.J.
        • Li Y.
        • Adams G.L.
        • et al.
        An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer.
        J Clin Oncol. 2003; 21: 92-98
        • Denis F.
        • Garaud P.
        • Bardet E.
        • et al.
        Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.
        J Clin Oncol. 2004; 22: 69-76
        • O'Neill M.
        • Heron D.E.
        • Flickinger J.C.
        • Smith R.
        • Ferris R.L.
        • Gibson M.
        Posttreatment quality-of-life assessment in patients with head and neck cancer treated with intensity-modulated radiation therapy.
        Am J Clin Oncol. 2011; 34: 478-482
        • Jaguar G.C.
        • Prado J.D.
        • Campanhã D.
        • Alves F.A.
        Clinical features and preventive therapies of radiation-induced xerostomia in head and neck cancer patient: a literature review.
        Appl Cancer Res. 2017; 37: 31
        • Aihara M.
        • Dobashi K.
        • Akiyama M.
        • Naruse I.
        • Nakazawa T.
        • Mori M.
        Effects of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages.
        Respiration. 2000; 67: 662-671
        • Cu A.
        • Ye Q.
        • Sarria R.
        • Nakamura S.
        • Guzman J.
        • Costabel U.
        N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro.
        Sarcoidosis Vasc Diffuse Lung Dis. 2009; 26: 147-154
        • Gosset P.
        • Wallaert B.
        • Tonnel A.B.
        • Fourneau C.
        Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages.
        Eur Respir J. 1999; 14: 98-105
        • Li Y.Q.
        • Zhang Z.X.
        • Xu Y.J.
        • et al.
        N-Acetyl-L-cysteine and pyrrolidine dithiocarbamate inhibited nuclear factor-kappaB activation in alveolar macrophages by different mechanisms.
        Acta Pharmacol Sin. 2006; 27: 339-346
        • Moon C.
        • Lee Y.J.
        • Park H.J.
        • Chong Y.H.
        • Kang J.L.
        N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation.
        Am J Respir Crit Care Med. 2010; 181: 374-387
        • Tirouvanziam R.
        • Conrad C.K.
        • Bottiglieri T.
        • Herzenberg L.A.
        • Moss R.B.
        • Herzenberg L.A.
        High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis.
        Proc Natl Acad Sci USA. 2006; 103: 4628-4633
        • Stephan U.
        • Bowing B.
        • Goering U.
        • et al.
        Acetylcysteine in the oral mucolytic treatment of cystic fibrosis.
        Eur J Respir Dis Suppl. 1980; 111: 127-131
        • Suk J.S.
        • Boylan N.J.
        • Trehan K.
        • et al.
        N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles.
        Mol Ther. 2011; 19: 1981-1989
        • Decramer M.
        • Rutten-van Molken M.
        • Dekhuijzen P.N.
        • et al.
        Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.
        Lancet. 2005; 365: 1552-1560
        • Demedts M.
        • Behr J.
        • Buhl R.
        • et al.
        High-dose acetylcysteine in idiopathic pulmonary fibrosis.
        N Engl J Med. 2005; 353: 2229-2242
        • Edwards G.F.
        • Steel A.E.
        • Scott J.K.
        • Jordan J.W.
        S-carboxymethylcysteine in the fluidification of sputum and treatment of chronic airway obstruction.
        Chest. 1976; 70: 506-513
        • Poole P.
        • Black P.N.
        • Cates C.J.
        Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.
        Cochrane Database Syst Rev. 2012; : CD001287
        • Suter P.M.
        • Domenighetti G.
        • Schaller M.D.
        • Laverriere M.C.
        • Ritz R.
        • Perret C.
        N-acetylcysteine enhances recovery from acute lung injury in man: a randomized, double-blind, placebo-controlled clinical study.
        Chest. 1994; 105: 190-194
        • Zheng J.P.
        • Kang J.
        • Huang S.G.
        • et al.
        Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.
        Lancet. 2008; 371: 2013-2018
        • Chambers M.S.
        • Welsh D.V.
        • Scrimger R.A.
        • et al.
        RK-0202 for radiation-induced oral mucositis.
        J Clin Oncol. 2006; 24
        • Pocock S.J.
        • Simon R.
        Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.
        Biometrics. 1975; 31: 103-115
        • Beetz I.
        • Burlage F.R.
        • Bijl H.P.
        • et al.
        The Groningen Radiotherapy-Induced Xerostomia questionnaire: development and validation of a new questionnaire.
        Radiother Oncol. 2010; 97: 127-131
        • Singer S.
        • Wollbruck D.
        • Wulke C.
        • et al.
        Validation of the EORTC QLQ-C30 and EORTC QLQ-H&N35 in patients with laryngeal cancer after surgery.
        Head Neck. 2009; 31: 64-76
        • Bjordal K.
        • Ahlner-Elmqvist M.
        • Tollesson E.
        • et al.
        Development of a European Organization for Research and Treatment of Cancer (EORTC) questionnaire module to be used in quality of life assessments in head and neck cancer patients. EORTC Quality of Life Study Group.
        Acta Oncol. 1994; 33: 879-885
        • Sloan J.A.
        • Vargas-Chanes D.
        • Kamath C.C.
        • et al.
        Detecting worms, ducks and elephants: a simple approach for defining clinically relevant effects in quality-of-life measures.
        J Cancer Integr Med. 2003; 1: 41-47
        • Allaveisi F.
        • Hashemi B.
        • Mortazavi S.M.
        Radioprotective effect of N-acetyl-L-cysteine free radical scavenger on compressive mechanical properties of the gamma sterilized cortical bone of bovine femur.
        Cell Tissue Bank. 2015; 16: 97-108
        • Yuta A.
        • Baraniuk J.N.
        Therapeutic approaches to mucus hypersecretion.
        Curr Allergy Asthma Rep. 2005; 5: 243-251
        • Ishibashi Y.
        • Takayama G.
        • Inouye Y.
        • Taniguchi A.
        Carbocisteine normalizes the viscous property of mucus through regulation of fucosylated and sialylated sugar chain on airway mucins.
        Eur J Pharmacol. 2010; 641: 226-228
        • Warde P.
        • O'Sullivan B.
        • Aslanidis J.
        • et al.
        A phase III placebo-controlled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer.
        Int J Radiat Oncol Biol Phys. 2002; 54: 9-13
        • Fisher J.
        • Scott C.
        • Scarantino C.W.
        • et al.
        Phase III quality-of-life study results: impact on patients' quality of life to reducing xerostomia after radiotherapy for head-and-neck cancer–RTOG 97-09.
        Int J Radiat Oncol Biol Phys. 2003; 56: 832-836
        • Riley P.
        • Glenny A.M.
        • Hua F.
        • Worthington H.V.
        Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.
        Cochrane Database Syst Rev. 2017; 7: CD012744
        • Dauletbaev N.
        • Fischer P.
        • Aulbach B.
        • et al.
        A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis.
        Eur J Med Res. 2009; 14: 352-358
        • Loprinzi C.L.
        • Barton D.L.
        • Jatoi A.
        • et al.
        Symptom control trials: a 20-year experience.
        J Support Oncol. 2007; 5 (128): 119-125
        • Basch E.
        • Deal A.M.
        • Dueck A.C.
        • et al.
        Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.
        JAMA. 2017; 318: 197-198