A Single-centre, Double-blinded, Randomised, Placebo-controlled, Phase II Study to Investigate the Safety and Efficacy of Mesenchymal Stem Cell for Radiation-induced Hyposalivation and Xerostomia in Previous Head and Neck Cancer Patients (MESRIX-III)

Background:

Xerostomia is the diagnosis of the subjective feeling of dry mouth. Xerostomia can coexist with or exist without a reduced production of saliva, although xerostomia is first perceived when unstimulated whole saliva flow rate is reduced by more than 40-50%. In this context, a subnormal or pathologically reduced saliva production (hyposalivation) will severely diminish the quality of life and lead to severe dental decay. The two main causes of grave xerostomia are Sjögren's syndrome and radiation therapy for head and neck cancer. Radiation therapy plays a central role in the curative treatment of most upper head and neck cancers, either as a single modality or in combination with chemotherapy and/or surgery, and the prevalence of xerostomia after head and neck radiation ranges from 74 to 85%.

Radiation therapy increases local tumor control significantly along with the chance of survival, but despite the more advanced methods of radiation therapy, Intensity-Modulated radiation therapy (IMRT), a significant proportion of the radiation is deposited in the healthy tissue surrounding the tumor. The decrease of saliva secretion after radiation therapy predisposes the patients to a variety of conditions. These are either directly or indirectly a result of the decreased production of saliva and include xerostomia, impairment of the normal oral functions (talking, chewing, and swallowing) due to insufficient wetting, and reduced lubrication of mucosal surfaces and the ingested food which impairs nutrition. Furthermore, the oral mucosa can become dry, making the oral mucosa vulnerable, which may lead to frictional trauma and ulceration. In addition, a reduced salivary flow results in a reduced "rinsing" of the entire oral cavity, thus leading to microbial overgrowth, which in addition to other factors may result in rapid dental decay, dental erosion, and oral candidiasis (thrush).

Stem cells have been identified as a potential treatment modality for a wide variety of disorders by their ability to differentiate into many functional cell types. For more than ten years, researchers have investigated the potential of mesenchymal stem cells (MSCs) as an approach to restoring the function of salivary glands after radiotherapy damage and several groups have addressed the use of MSCs or adipose-derived mesenchymal stem cells (ASCs) in preclinical studies of radiation-induced salivary gland dysfunction.

The research group has completed an encouraging randomized-controlled pilot study (MESRIX-I) with 30 patients assessing the safety and efficacy of ex-vivo expanded autologous ASCs for radiation-induced xerostomia in an effort to regenerate the function of the salivary glands (EudraCT nb:2014-004349-29). The results of this study show most importantly that the treatment is safe without any serious adverse events (SAE) and no systemic reactions, and secondly, the patients treated with stem cells have a promising enhanced production of saliva of 33%-50%. Furthermore, the research group has shown that the stem cell group gained vital quality of life measures compared with the placebo group in the form of diminished trouble in eating.