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Open Access 01-12-2017 | Study protocol

First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial

Authors: Christian Grønhøj, David H. Jensen, Peter V. Glovinski, Siri Beier Jensen, Allan Bardow, Roberto S. Oliveri, Lena Specht, Carsten Thomsen, Sune Darkner, Katalin Kiss, Anne Fischer-Nielsen, Christian von Buchwald

Published in: Trials | Issue 1/2017

Abstract

Background

Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia.

Methods

This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention.

Discussion

The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials.

Trial registration

EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015.

ClinicalTrials.gov, Identifier: NCT02513238. First received on 2 July 2015.

The trial is prospectively registered.

Available only for authorised users

Dawes C. Physiological factors affecting salivary flow rate, oral sugar clearance, and the sensation of dry mouth in man. J Dent Res. [Internet]. 1987;66 Spec No:648–53. Available from: http://ukpmc.ac.uk/abstract/MED/3476629.

Jensen SB, Pedersen AML, Vissink A, Andersen E, Brown CG, Davies AN, et al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer. 2010;18(8):1061–79. doi:10.1007/s00520-010-0837-6. Epub 2010 Mar 25.CrossRefPubMed

Burlage FR, Coppes RP, Meertens H, Stokman MA, Vissink A. Parotid and submandibular/sublingual salivary flow during high dose radiotherapy. Radiother Oncol. 2001;61:271–4.CrossRefPubMed

Bralic M, Muhvic-Urek M, Stemberga V, Golemac M, Jurkovic S, Borcic J, et al. Cell death and cell proliferation in mouse submandibular gland during early post-irradiation phase. Acta Med. Okayama [Internet]. 2005;59:153–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16155641. Accessed 27 Sep 2016.

Vissink a, Jansma J, Spijkervet FKL, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med. [Internet]. 2003;14:199–212. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12799323.

Blanco AI, Chao KSC, El Naqa I, Franklin GE, Zakarian K, Vicic M, et al. Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:1055–69.CrossRefPubMed

Deasy JO, Moiseenko V, Marks L, Chao KSC, Nam J, Eisbruch A. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys. 2010;76:S58–63.CrossRefPubMedPubMedCentral

Ortholan C, Chamorey E, Benezery K, Thariat J, Dassonville O, Poissonnet G, et al. Modeling of salivary production recovery after radiotherapy using mixed models: determination of optimal dose constraint for IMRT planning and construction of convenient tools to predict salivary function. Int J Radiat Oncol Biol Phys. 2009;73:178–86.CrossRefPubMed

Roesink JM, Moerland MA, Hoekstra A, Van Rijk PP, Terhaard CHJ. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: a prospective study of dose-volume response relationships. Int J Radiat Oncol Biol Phys. 2004;58:1451–60.CrossRefPubMed

10.

Lee C, Langen KM, Lu W, Haimerl J, Schnarr E, Ruchala KJ, et al. Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration. Int J Radiat Oncol Biol Phys. 2008;71:1563–71.CrossRefPubMed

11.

Dijkema T, Raaijmakers CPJ, Ten Haken RK, Roesink JM, Braam PM, Houweling AC, et al. Parotid gland function after radiotherapy: the combined Michigan and Utrecht experience. Int J Radiat Oncol Biol Phys. 2010;78:449–53.CrossRefPubMedPubMedCentral

12.

Brennan MT, Elting LS, Spijkervet FKL. Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer. 2010;18(8)979–84.

13.

Murdoch-Kinch CA, Kim HM, Vineberg KA, Ship JA, Eisbruch A. Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72:373–82.CrossRefPubMedPubMedCentral

14.

Cotrim AP, Hyodo F, Matsumoto KI, Sowers AL, Cook JA, Baum BJ, et al. Differential radiation protection of salivary glands versus tumor by tempol with accompanying tissue assessment of tempol by magnetic resonance imaging. Clin Cancer Res. 2007;13:4928–33.CrossRefPubMed

15.

van Luijk P, Pringle S, Deasy JO, Moiseenko V V, Faber H, Hovan A, et al. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci Transl Med. [Internet]. 2015;7:305ra147. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26378247.

16.

Lajer C, Buchwald C, Nauntofte B, Specht L, Bardow A, Jensdottir T. Erosive potential of saliva stimulating tablets with and without fluoride in irradiated head and neck cancer patients. Radiother Oncol. 2009;93:534–8.CrossRefPubMed

17.

Vissink A, Jansma J, Spijkervet FKL, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med. 2003;14:199–212.CrossRefPubMed

18.

Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hematopoietic tissues : cloning in vitro and retransplantation in vivo. Transplantation [Internet]. 1974;17:331–40. Available from: http://journals.lww.com/transplantjournal/Fulltext/1974/04000/STROMAL_CELLS_RESPONSIBLE_FOR_TRANSFERRING_THE.1.aspx.CrossRef

19.

Jensen DH, Oliveri RS, Trojahn Kølle S-F, Fischer-Nielsen A, Specht L, Bardow A, et al. Mesenchymal stem cell therapy for salivary gland dysfunction and xerostomia: a systematic review of preclinical studies. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. [Internet]. 2014;117:335–342.e1. Available from: http://www.sciencedirect.com/science/article/pii/S2212440313016817.

20.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed

21.

Simard EP, Torre LA, Jemal A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. Oral Oncol. 2014;50:387–403.CrossRefPubMed

22.

National Institute of Cancer. Common Terminology Criteria for Adverse Events (CTCAE). NIH Publ. [Internet]. 2010;2009:0–71. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

23.

24.

Coire F, Umemura A. Increase in the cell volume of the rat submandibular gland during postnatal development. Braz J morphol [Internet]. 2003;20:37–42. Available from: http://www.researchgate.net/publication/228920172_Increase_in_the_cell_volume_of_the_rat_submandibular_gland_during_postnatal_development/file/9fcfd51127be57e996.pdf.

25.

Wang Z-H, Yan C, Zhang Z-Y, Zhang C-P, Hu H-S, Kirwan J, et al. Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study. Laryngoscope [Internet]. 2009;119:1966–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19688858. Accessed 27 Sep 2016.

26.

Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU Side Effect Rating Scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. [Internet]. 1987 ;334:1–100. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2887090. Accessed 10 Oct 2016

27.

Pai S, Ghezzi EM, Ship JA. Development of a Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91:311–6.CrossRefPubMed

28.

Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;50:695–704.CrossRefPubMed

29.

Navazesh M, Christensen CM. A comparison of whole mouth resting and stimulated salivary measurement procedures. J Dent Res. 1982;61:1158–62.CrossRefPubMed

30.

Bardow A, Madsen J, Nauntofte B. The bicarbonate concentration in human saliva does not exceed the plasma level under normal physiological conditions. Clin Oral Investig. [Internet]. 2000:245–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11218496. Accessed on 27 Sep 2016.

31.

Bruvo M, Moe D, Kirkeby S, Vorum H, Bardow A. Individual variations in protective effects of experimentally formed salivary pellicles. Caries Res. 2009;43:163–70.CrossRefPubMed

32.

Lexner MO, Bardow A, Hertz JM, Almer L, Nauntofte B, Kreiborg S. Whole saliva in X-linked hypohidrotic ectodermal dysplasia. Int J Paediatr Dent. [Internet]. 2007;17:155–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17397458. Accessed on 27 Sep 2016.

33.

Bian Z-Y, Fan Q-M, Li G, Xu W-T, Tang T-T. Human mesenchymal stem cells promote growth of osteosarcoma: involvement of interleukin-6 in the interaction between human mesenchymal stem cells and Saos-2. Cancer Sci. 2010;101:2554–60.CrossRefPubMed

34.

Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22.CrossRefPubMed

35.

Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol. 2016;1416:123-46. p. 123–46. Available from: http://link.springer.com/10.1007/978-1-4939-3584-0_7. Accessed 13 Oct 2016.

36.

Yagi H, Kitagawa Y. The role of mesenchymal stem cells in cancer development. Front. Genet. 2013;4:261.CrossRefPubMedPubMedCentral

37.

Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells [Internet]. 2011;29:11–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21280155. Accessed 27 Sep 2016.

38.

Colazzo F, Alrashed F, Saratchandra P, Carubelli I, Chester AH, Yacoub MH, et al. Shear stress and VEGF enhance endothelial differentiation of human adipose-derived stem cells. Growth Factors [Internet]. 2014;7194:1–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25112491.

39.

Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, et al. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy [Internet]. 2010;12:576–8. Available from: http://www.sciencedirect.com/science/article/pii/S1465324910704229.CrossRef

40.

Casiraghi F, Remuzzi G, Abbate M, Perico N. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Rev [Internet]. 2013;9:65–79. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22237468.

41.

MacIsaac ZM, Shang H, Agrawal H, Yang N, Parker A, Katz AJ. Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells. Exp Cell Res. 2012;318:416–23.CrossRefPubMed

Title: First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial
Authors: Christian Grønhøj
David H. Jensen
Peter V. Glovinski
Siri Beier Jensen
Allan Bardow
Roberto S. Oliveri
Lena Specht
Carsten Thomsen
Sune Darkner
Katalin Kiss
Anne Fischer-Nielsen
Christian von Buchwald
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Trials / Issue 1/2017
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-017-1856-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial

Abstract

Background

Methods

Discussion

Trial registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

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