This is a multi-centric prospective one arm, phase II clinical trial evaluating the risk of dental complication (normal tissue complication probability (NTCP), especially the probability of fractures and dental caries.
The study design is illustrated in Fig. 1
Study objectives and statistical analyses
This study primarily aims to model the risk of dental complications post-RT, focusing on the normal tissue complication probability (NTCP), specifically the likelihood of fractures and dental caries.
In addition to this primary goal, the study has several secondary objectives:
Firstly, we aim to validate our "predictive dose model" for radiotherapy by considering the tumor's location and the TNM stage. This validation process aims to refine and enhance the accuracy of our predictive model.
Secondly, our intention is to integrate our predictive dose model with dental NTCP. This integration seeks to personalize decisions regarding teeth avulsion before the initiation of RT. By aligning the predictive dose model with dental complications, we aim to optimize treatment planning, minimizing unnecessary dental interventions while ensuring the efficacy of RT.
Lastly, we seek to explore the impact of (partial or total) edentulousness and RT on the overall quality of life of the subjects. Understanding how tooth loss and its interaction with RT affect patients' well-being is crucial for comprehensive treatment considerations and patient-centered care.
Overall, this study aims to not only predict and mitigate dental complications following RT but also to refine treatment strategies, personalize dental interventions, and assess the holistic impact on patients' quality of life.
Sample size calculation
The study's primary objective is to construct a comprehensive model for Normal Tissue Complication Probability (NTCP). Previous research projects suggest an anticipated NTCP rate of approximately 20% per tooth, serving as the unit of analysis. The model will consider several factors for inclusion, including the actual dose to the tooth, parotid glands, pre-RT clinical tooth status, and the cT and cN stages. Up to five variables could potentially form the basis of the final model. To achieve this, a minimum of 50 teeth with complications and a total of 250 teeth must be documented. Considering an average of 10 teeth per subject, the study aims to encompass at least 25 assessable subjects.
Subjects and their respective teeth will be considered evaluable if they maintain follow-up for 36 months post-RT and if all necessary data are accessible for assessing both administered and predicted RT doses. Accounting for an expected 10% rate of screening failure and 30% rate of unevaluable subjects, the study aims to enroll approximately 40 subjects to ensure a sufficient evaluable cohort for analysis.
Patients’ characteristics
Patients with newly diagnosed and histologically confirmed primary HNSCC planned for curative intent RT will be included. The recruiting centers are the Jules Bordet Institute, Centre Hospitalier Universitaire Saint- Pierre and Hôpital Erasme—Clinique Universitaire de Bruxelles.
The inclusion and exclusion criteria are summarized in Table 1.
Study interventions
Dental avulsion:
Before initiating RT, each subject undergoes a meticulous dental assessment. If necessary, dental avulsions are conducted for teeth at risk of compromising long-term survival and situated in areas expected to receive more than 40 Gy, potentially leading to osteoradionecrosis of the jaw. Avulsions are scheduled at least 2 weeks before the start of RT to allow mucosal healing.
Tooth avulsion is performed for all teeth within irradiation fields identified "at risk" according to our developed "predictive model." This includes teeth meeting at least one of the following criteria, indicating compromised long-term viability:
- Tooth mobility score > 2 (Miller’s score, 1985)
- Caries severity score > 4 (ICDAS II, 2005)
- Dutch periodontal screening index (DPSI) score > 2
- Periapical lesion
- Root fracture
- Furcation caries (in multi-rooted teeth)
- Coronary reconstruction exceeding 1/3 of its total surface (except inlay, only and total crown if there are not sign of caries or lack of sealing) In addition, dental avulsions are sometimes also necessary for a more adequate prosthetic rehabilitation.
For all of subjects, a dental decalcification and afterwards, a dental splint will be performed before the start of RT.
Following completion of RT, subjects receive thorough clinical follow-ups, including dental evaluations every 6 months over a period of 36 months. These evaluations aim to promptly identify and address any potential dental concerns that may arise post-treatment. Each session includes a comprehensive stomatological examination and two bitewing radiographs. Additionally, an annual orthopantomogram provides a comprehensive overview of dental health. If necessary, periapical X-rays are conducted to investigate specific dental complaints or to further examine any identified abnormalities in the orthopantomogram.
Patient-reported outcomes
Quality of life questionnaires (EORTC: QLQ-C30 and QLQH&N43) will be completed at screening, at week 3, 7 and at the end of RT treatment. During the follow-up period, those questionnaires will be filled on month 3, 6, 12, 24 and 36 months (end of study). In addition, the Xerostomia questionnaire will be completed once a week during RT treatment and at month 3, 6, 12, 24 and 36 during follow-up visits.
Radiotherapy treatment:
All subjects will be treated by simultaneous integrated boost (SIB) intensity modulated RT (IMRT) / volumetric modulated arc therapy (VMAT).
The dose prescription for various situations can be found in Table 2.
The total radiation dose and fractionation scheme vary based on whether radiotherapy is administered as a standalone treatment or as post-operative therapy with or without extranodal extension and involved margins.
Toxicity evaluation
A comprehensive clinical assessment will be conducted to evaluate toxicity, distinguishing between acute occurrences during RT and up to 3 months post-RT, and late toxicity beyond this period. The intensity of all adverse events will be carefully graded on a 5-point scale (grades 1 to 5) using the National Cancer Institute (NCI)–Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) grading scale.
In this study, specific adverse events of special interest included xerostomia, dental decay, dental fracture, swallowing disorders, tooth abscess, toothache, dental mobility, oral cavity ulceration, and periodontal disease. The severity and frequency of these events will be meticulously assessed, providing valuable insights into the impact of RT on various aspects of oral health.
Clinical outcome evaluation
Several efficacy parameters are assessed to evaluate dental outcomes, including dental decay, fracture, mobility, periodontopathy, endodontopathy, and osteoradionecrosis-free dental avulsion. These parameters will be useful as crucial benchmarks to judge the effectiveness of the "predictive model."
The evaluation of these parameters aimed to validate the model's efficiency. If the dental check-ups, guided by our predictive model, revealed minimal issues post-RT, it would substantiate the legitimacy of extracting fewer teeth before RT. This approach intended to enhance the patient's quality of life by minimizing unnecessary dental interventions while ensuring effective treatment outcomes. The detailed dental outcomes, along with clinical and radiological examinations, are provided in Table 3.
Ancillary and post-trial care
Any patient suffering from a complication due to trial participation will be provided with medical and surgical care as per institutional standards. The participant centers will ensure post-trial care and long-term follow-up for all patients participating in the trial.
Data monitoring
To ensure this trial’s quality assurance, the clinical research physician is assisted by a research team. This team ensures safety, eligibility, treatment compliance and data management (for which the electronic data capture system OpenClinica will be used). Regular monitoring will be performed and observations will be documented.