Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer:A Double-Blind Randomized Controlled Trial

BACKGROUND: Radiotherapy for head and neck cancer (HNC) frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of parotid glands of rats, mice, and patients critically depends on dose to its stem cells, mainly located in the gland's main ducts (stem cell rich (SCR) region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiotherapy preserves parotid gland function better than currently-used whole parotid gland sparing radiotherapy. METHODS: HNC patients (n=102) treated with definitive radiotherapy were randomized between standard parotid sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared to pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment. RESULTS: Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy (p=0.004) and ipsilateral 26 and 16 Gy (p=0.001), standard and SCS arm respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% (p=0.01), standard and SCS arm respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared to 2 (4.9%) in the standard arm (p=1.00). However, a trend towards better relative parotid gland salivary function in favor of SCS radiotherapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including complaints of alteration in diet. CONCLUSIONS: No significant better parotid function was observed in SCS radiotherapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive for development of parotid gland function related xerostomia endpoints, than dose to the entire parotid gland

Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 2:Advanced delineation guidelines for FSUs

Background and purpose: In a separate article (PART 1), a rationale and explanation of the physiology-and-anatomy-based concept of Functional Swallowing Units (FSUs) was presented. FSUs are swallowing muscles not included in the set of commonly defined swallowing organs at risk (SWOARs). They are involved in three crucial swallowing components: hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion. This paper is a continuation of PART 1 and it provides detailed computed tomography (CT)-based delineation guidelines for FSUs, which presumably are also at risk of radiationinduced dysphagia. Material and methods: Following analysis of swallowing physiology and human anatomy, presented in PART 1, CT-based delineation guidelines for defined FSUs were created. Delineation was performed by the first author and revised by a panel of experts. Results and conclusions: Detailed delineation guidelines are presented for seven FSUs involved in HLE, TBR and tongue motion. The guidelines are supplemented by CT and MRI-based exemplary illustrations and complete CT/MRI-based delineation atlases (available online). This paper provides information essential to the implementation of the FSU concept in radiation practice, and supports uniform contouring, data collection and further improvement of swallowing sparing radiation-based strategies. (C) 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Head and neck intensity modulated radiation therapy leads to an increase of opportunistic oral pathogens

Objectives: The introduction of intensity modulated radiation therapy (IMRT) has led to new possibilities in the treatment of head and neck cancer (HNC). Limited information is available on how this more advanced radiation technique affects the oral microflora. In a prospective study we assessed the effects of various advanced treatments for HNC on the oral microflora, as well as the effects of elimination of oral foci of infection. Materials and methods: All consecutive dentate patients >18 years, diagnosed with a primary oral or oropharynx carcinoma and seen for a pre-treatment dental screening (May 2011-May 2013) were included. Patients were grouped by oncologic treatment: surgery (SURG), IMRT (IMRT) or IMRT +chemotherapy (CHIMRT). Dental screening data, demographic data, subgingival biofilm samples, oral lavages and whole saliva samples were obtained to microbiologically analyze the effects of cancer treatments (1-year follow-up). Results: This study included 82 patients (29 SURG, 26 IMRT and 27 CHIMRT). The trends in changes in prevalence and proportions of microorganisms were comparable in the IMRT and CHIMRT group. However, relative to the SURG group, increased prevalence of enteric rods, staphylococci and Candida species was observed in the IMRT and CHIMRT groups. In these groups, elimination of oral foci decreased the frequency of detection of pathogens such as Porphyromonas gingivalis, Tannerella forsythia and Streptococcus mutans. Conclusion: Different treatments in HNC patients result in different changes in the oral microflora. Opportunistic pathogens such as staphylococci, enteric rods and Candida sp. tend to increase in prevalence after IMRT with or without chemotherapy, but not after surgical intervention. (C) 2016 Elsevier Ltd. All rights reserved

Patients with advanced periodontal disease before intensity-modulated radiation therapy are prone to develop bone healing problems: a 2-year prospective follow-up study

PURPOSE: Intensity-modulated radiation therapy (IMRT) has changed radiation treatment of head and neck cancer (HNC). However, it is still unclear if and how IMRT changes oral morbidity outcomes. In this prospective study, we assessed the outcome of reducing post-IMRT sequelae by means of pre-radiation dental screening and eliminating oral foci. METHODS: All consecutive dentate patients > 18 years, diagnosed with primary oral or oropharyngeal carcinoma, referred for pre-treatment dental screening between May 2011 and May 2013, were included and followed for 2 years. Patients were treated with IMRT or IMRT with chemotherapy (CHIMRT). Dental screening data, demographic data, and data on oral sequelae during follow-up were recorded. Diagnosed oral foci were treated before start of the radiation therapy. RESULTS: Oral foci were found in 44/56 (79%) patients, consisting predominantly of periodontal breakdown. Bone healing problems after radiotherapy occurred more often in patients with periodontal pockets ≥ 6 mm at baseline (19 vs. 4% in patients with pockets < 6 mm). Osteoradionecrosis developed in 4/56 patients (7%) during follow-up. In line with this observation, multiple logistic regression analysis showed that the periodontal inflamed surface area, which is higher in patients with more severe periodontal disease, predicted that a patient has a higher risk on developing osteoradionecrosis or bone healing problems (p = 0.028). CONCLUSIONS: Patients with severe periodontal disease before IMRT/CHIMRT are more prone to develop bone healing problems post-radiotherapy

Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 1: Physiology and anatomy

BACKGROUND AND PURPOSE: When optimising radiotherapy treatments today, the pharyngeal constrictor muscles and the larynx are usually regarded as the swallowing organs at risk (SWOARs). The purpose of this study was to identify and describe additional, previously undefined groups of muscles (functional units) involved in crucial components of swallowing (hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion), and to emphasise their relevance in radiation-induced dysphagia. MATERIAL AND METHODS: Based on available literature on human anatomy and swallowing physiology, the functional units of muscles involved in HLE, TBR and tongue motion have been identified and described. RESULTS AND CONCLUSION: Functional swallowing units (FSUs) were defined as groups of swallowing muscles sharing their function, that are in close proximity to each other. Seven FSUs involved in HLE, TBR and tongue motion were identified: floor of mouth, thyrohyoid muscles, posterior digastric/stylohyoid muscles complex, longitudinal pharyngeal muscles, hyoglossus/styloglossus muscles complex, genioglossus muscles, intrinsic tongue muscles. The swallowing physiology and anatomy of the FSUs described in this paper will lead to a greater understanding of radiation-induced dysphagia mechanisms and, consequently, to an improvement in the development of swallowing sparing strategies. This article (PART 1) serves as the theoretical foundation for a subsequent article (PART 2), which provides detailed delineation guidelines for FSUs

Stem cell sparing radiotherapy for head and neck cancer patients: a double-blind randomized controlled trial

BACKGROUND Radiotherapy for head and neck cancer (HNC) frequently leads to salivary gland damage and xerostomia. Previously it was demonstrated in rats, mice and patients that the radiation response of parotid glands critically depends on dose to its stem cells, mainly located in the main salivary gland ducts. Therefore, reducing dose to these High Stem Cell Density (HSCD) regions may prevent xerostomia. METHODS To test this hypothesis, 102 HNC patients treated with definitive radiotherapy with or without systemic treatment, were included in a double-blind randomized, controlled trial (RCT) (ClinicalTrials.gov number NCT01955239). Patients were randomized between standard parotid sparing and novel stem cell sparing (SCS) techniques. Primary and secondary endpoints were reduction of saliva production &lt;25% from baseline (FLOW12M) and patient-rated daytime xerostomia (XER12M) twelve months after treatment. RESULTS Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only mean dose to the HSCD regions differed significantly between the arms (contralateral 16 and 11 Gy (p = 0.004) and ipsilateral 26 and 16 Gy (p = 0.001), standard and SCS arm respectively). One FLOW12M occurred in the SCS arm, compared with three in the standard arm (p = 0.72). Relative parotid gland salivary function was consistently better in the SCS arm, albeit not reaching statistical significance. Prevalence of XER12M did not differ significantly (42% and 37% (p = 0.86), respectively). Nonetheless, multivariable analysis showed mean dose to the contralateral HSCD region was the most important dosimetric predictor for XER12M. CONCLUSIONS In this double-blind RCT, a trend of better parotid function was shown for patients treated with SCS radiotherapy. No significant reduction of XER12M was present. However, the contralateral HSCD region dose was the strongest dosimetric predictor, suggesting dose to the HSCD region is more important for development of xerostomia than dose to the entire parotid gland