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Following radioiodine (131I) therapy of differentiated thyroid cancer, the salivary glands may become inflamed, leading to dysfunctions and decreases in patients’ nutritional status and quality of life. The incidence of these dysfunctions after 131I-therapy is poorly known, and no clinical or genetic factors have been identified to date to define at-risk patients, which would allow the delivered activity to be adapted to the expected risk of salivary dysfunctions.
The aims of this study are to estimate the incidence of salivary dysfunctions, and consequences on the quality of life and nutritional status for patients after 131I-therapy; to characterize at-risk patients of developing posttreatment dysfunctions using clinical, biomolecular, and biochemical factors; and to validate a dosimetric method to calculate the dose received at the salivary gland level for analyzing the dose-response relationship between absorbed doses to salivary glands and salivary dysfunctions.
This prospective study aims to include patients for whom 131I-therapy is indicated as part of the treatment for differentiated thyroid cancer in a Paris hospital (40 and 80 patients in the 1.1 GBq and 3.7 GBq groups, respectively). The follow-up is based on three scheduled visits: at inclusion (T0, immediately before 131I-therapy), and at 6 months (T6) and 18 months (T18) posttreatment. For each visit, questionnaires on salivary dysfunctions (validated French tool), quality of life (Hospital Anxiety and Depression scale, Medical Outcomes Study 36-Item Short Form Survey), and nutritional status (visual analog scale) are administered by a trained clinical research associate. At T0 and T6, saliva samples and individual measurements of the salivary flow, without and with salivary glands stimulation, are performed. External thermoluminescent dosimeters are positioned on the skin opposite the salivary glands and at the sternal fork immediately before 131I administration and removed after 5 days. From the doses recorded by the dosimeters, an estimation of the dose received at the salivary glands will be carried out using physical and computational phantoms. Genetic and epigenetic analyses will be performed to search for potential biomarkers of the predisposition to develop salivary dysfunctions after 131I-therapy.
A total of 139 patients (99 women, 71.2%; mean age 47.4, SD 14.3 years) were enrolled in the study between September 2020 and April 2021 (45 and 94 patients in the 1.1 GBq and 3.7G Bq groups, respectively). T6 follow-up is complete and T18 follow-up is currently underway. Statistical analyses will assess the links between salivary dysfunctions and absorbed doses to the salivary glands, accounting for associated factors. Moreover, impacts on the patients’ quality of life will be analyzed.
To our knowledge, this study is the first to investigate the risk of salivary dysfunctions (using both objective and subjective indicators) in relation to organ (salivary glands) doses, based on individual dosimeter records and dose reconstructions. The results will allow the identification of patients at risk of salivary dysfunctions and will permit clinicians to propose a more adapted follow-up and/or countermeasures to adverse effects.
ClinicalTrials.gov NCT04876287; https://clinicaltrials.gov/ct2/show/NCT04876287
DERR1-10.2196/35565
Approximately 10,600 new cases of thyroid cancer were diagnosed in France in 2018, and this incidence has increased by an average of 4.4% per year between 1990 and 2018 [
Standard treatment for differentiated thyroid cancer is thyroidectomy followed by radioiodine (131I) ablation [
Salivary dysfunctions may lead to an increased risk of inflammation and/or oral infection, a change in the taste of food, and difficulties in swallowing and digestion. Lacrimal gland dysfunctions (one of the diagnostic criteria for Sjögren syndrome) have also been reported after 131I-therapy, suggesting that some patients may develop simultaneous lacrimal and salivary gland dysfunctions in the years following 131I-therapy [
Additionally, the dose-response relationships between 131I-therapy and the incidence of salivary and lachrymal dysfunctions have been rarely studied, and the administered activity is typically used as a proxy for the dose absorbed by the salivary glands. However, the administered activity does not accurately reflect the dose received by the salivary glands due to the variation in iodine uptake ability of the salivary gland, which could be modified by the size of the thyroid remnant tissues or a potential iodine deficiency of the patient before treatment, along with the inherent interpatient variability affecting the entire biokinetics of iodine. The use of an adapted dosimetric method using thermoluminescent dosimeters and anthropomorphic phantoms would make it possible to better estimate the dose-response relationship by estimating the absorbed dose to the salivary gland.
Finally, while a strong interrelationship between epigenetic processes and genetic factors associated with dry mouth syndrome has been shown [
In this context, the Salivary dysfuncTions After Radioiodine Treatment (START) study was launched in September 2020, with the following objectives: (1) to estimate the mid- and long-term incidence of salivary dysfunctions in patients with thyroid cancer treated with 131I, using objective, subjective, and mixed criteria; (2) to highlight risk factors of posttreatment salivary dysfunctions using clinical, pathological, biomolecular, and biochemical factors; (3) to validate a dosimetric method to calculate the dose absorbed by the salivary gland; (4) to estimate the dose-response relationship between exposure of the salivary glands to 131I and salivary dysfunctions; and (5) to investigate the consequences of salivary dysfunctions on the quality of life and nutritional status of patients.
START is a prospective self-controlled study that includes patients with thyroid cancer who underwent thyroidectomy and are candidates for complementary 131I-therapy. This research program aims to enroll 120 patients from the nuclear medicine department of Pitié-Salpêtrière Hospital (Paris, France), divided into two groups of 40 and 80 patients treated with 131I activity of 1.1 GBq and 3.7 GBq, respectively, thus expecting a high number of patients with salivary dysfunctions to provide good statistical power for the analyses.
All consecutive patients awaiting 131I-therapy are systematically invited to participate in the study. They are enrolled just prior to the 131I capsule administration (ie, 1 to 3 months after thyroidectomy), and have three follow-up points: at enrollment (T0), and at 6 months (T6) and 18 months (T18) after 131I-therapy (
Timeline summarizing the study's outline. T0: enrollment; T6: 6 months after radioiodine (131I) therapy; T18: 18 months after radioiodine therapy.
To be included, patients must have undergone thyroidectomy for the treatment of a differentiated thyroid cancer, be a candidate for complementary 131I-therapy, be over 18 years of age, be willing to participate in the study, and have signed a consent form. Patients who have previously been treated with 131I or who are likely to be treated with multiple 131I therapies within 18 months of inclusion are excluded.
This study will be conducted in accordance with the Declaration of Helsinki (amended at the 64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the principles of “Good Clinical Practice” and the Medical Research Involving Human Subjects Act (WMO) [
Approvals from the local ethical committee have been received (Comité de Protection de Personnes Sud Mediterranée III, ID 20.01.24.56149; and Agence Nationale de Sécurité des Médicaments, ID 2020-A00208-31). The protocol is registered and will be posted on the ClinicalTrials.gov public website under the number NCT04876287.
Patients included in the study must sign a consent form in which they certify that they have understood the objectives and procedures of the research in which they will participate. They certify that they have had time to think and ask questions to come to an informed decision to participate, and they are aware that this study is not mandatory in the context of their therapy and that they can withdraw at any time.
The START study is expected to be carried out from September 2020 until October 2022, including three measuring points for each patient: at enrollment, and at 6 and 18 months later.
The investigating physician in the nuclear medicine department enables first contact with patients during the postsurgery consultation. During this first visit, the physician introduces the START study and its objectives to the patients for whom 131I-therapy is planned, informs them about the nature of the constraints and the expected benefits of the research, and answers all of the patient’s questions. The physician ensures that patients meet the inclusion criteria. If the inclusion criteria are fulfilled, a study information leaflet detailing the protocol is given to the patient with the consent form.
The enrollment visit occurs when an eligible patient has given consent to participate in the study. This visit takes place at the hospital during the consultation prior to the complementary 131I-therapy (on the day of treatment, approximately 2 months after surgery) in a face-to-face manner with a clinical research associate. Clinical and personal data and saliva samples are collected, self-administered questionnaires are provided to patients (see Data Collection section below and
The 6-month follow-up takes place during the posttherapy consultation at the Thyroid and Endocrine Tumors Unit, Institute of Endocrinology (E3M), Pitié-Salpêtrière Hospital (Paris, France), in a face-to-face manner with a clinical research associate. During this visit, clinical and personal data collection, saliva samples, and self-questionnaires are again carried out
Patients are called by phone to answer the self-questionnaires with a clinical research associate.
All data are collected using paper versions, and are then entered and recorded on a secure server (
All questionnaires are completed at each measuring point of the study for each patient. Questionnaires have been selected on the basis of ease and speed of administration by an interviewer, peer-validated, and on the fact that they are the most widely used questionnaires in this type of research (see
Saliva sampling has been performed according to a standardized methodology (see
Summary of data collection.
Data type | Qualitative data | Quantitative data |
Thyroid cancer information (collected only at the enrollment visit) | Size of the postsurgery remnant, tumor histology, pTNMa staging, Tgb stimulation protocol, family history of thyroid cancer, patient history of cancer or comorbidities, prescribed activity of 131I (1.1 or 3.7 GBq) | Surgery to therapy duration (months) |
Clinical data | Self-rated menopausal status, all medications used during the last 3 months, tobacco and alcohol consumption, self-palpation of the salivary glands (normal, painful, or swollen), self-reported oral carries or infections, observed cracked lips, self-reported use of a saliva substitute, sialagogue | Age, height, weight |
Questionnaires | Salivary complaints questionnaire; eye dryness, OSDIc questionnaire; questions about nutrition; anxiety and depressive symptoms (HADd scale) | Physical and mental composite scores about quality of life (MOS SF-36e) |
Saliva samples | Not applicable | Weight (precision 0.01 mg), volume (precision 0.01 mL), electrolyte concentrations (mmol/L: sodium, potassium, chloride, amylase, and total protein composition), genetic and epigenetic variant proportions |
apTNM: pathological tumor-node-metastasis.
bTg: thyroglobulin.
cOSDI: Ocular Surface Disease Index.
dHAD: Hospital Anxiety and Depression.
eMOS SF-36: Medical Outcome Study Short Form 36 items.
Immediately before therapy, three thermoluminescent dosimeters (7LiF: Mg,Ti, Thermo Scientific DXT-RAD dosimeter model: DXT-700, provider: APVL) are placed under each earlobe (at the salivary glands level) and at the sternal fork level, protected by an adhesive plastic film (
Thermoluminescent dosimeter position.
Subsequently, the dose received specifically by the salivary glands will be estimated from the dosimeter readings. This requires the development of a specific calibration protocol that allows relating the dosimeter readings to the cumulative activity in the salivary glands and thyroid residues, using computational human models [
The primary endpoint is a composite criterion combining objective (salivary flow dysfunctions with and/or without stimulation) and subjective (reporting discomfort, pain in the parotid area, difficulty swallowing, or eye dryness) criteria at T6. Salivary flow dysfunctions are defined as an unstimulated salivary flow <0.2 mL/min and/or a stimulated salivary flow <0.7 mL/min [
Secondary endpoints are defined as follows: change in quality-of-life score between T0, T6, and T18; change in nutrition between T0, T6, and T18; change in chemical saliva composition between T0 and T6; change in anxiety and depression symptoms between T0, T6, and T18; genetic and/or epigenetic variant identification that may modify the risk of salivary dysfunctions after 131I-therapy; identification of individual factors associated with salivary dysfunctions at T6 and T18; and dose-response analysis between the 131I-dose received precisely at the salivary glands and salivary dysfunctions at T6 and T18.
A minimum of 120 patients is required to complete the START study. This number is based on a statistical power of 80% with an α risk of 5%, and with theoretical percentages from the literature of salivary dysfunctions of 30% and 60% for the 1.1 GBq and 3.7 GBq therapy groups, respectively [
The description of the population (means, SDs, and percentages) at baseline (before 131I-therapy) is presented in this paper. Comparison tests have been performed (
Paired comparison tests will be used to assess differences in data between T0 and T6. Correlations, principal component analyses, and multiple correspondence analyses will be used to study the factors (objective and subjective) common to patients with salivary dysfunctions after 131I-therapy.
All factors significant at a 10% threshold in univariate analyses using different regression models (
The mixed regression models, adjusted for confounders, performed to investigate the temporal evolution for the different outcomes, will be set up using a random intercept for each patient with a first-order autoregressive covariance structure to account for repeated measurements.
The different scores to the questionnaires for quality of life, nutrition, and symptoms of depression and anxiety assessments are calculated and classes are created according to the recommendations for each questionnaire and for each visit (T0, T6, and T18).
Categorical
Dry mouth sensation after treatment, dry eye (Ocular Surface Disease Index), Hospital Anxiety and Depression (HAD) anxiety scale, HAD depression scale, changes in nutrition, composite outcome (sum of dysfunctions)
Continuous
Unstimulated saliva flow (mL/min), stimulated saliva flow (mL/min), saliva pH, electrolyte concentrations in saliva (mmol/L), physical composite score (Medical Outcome Study Short Form 36 items [MOS SF-36]), mental composite score (MOS SF-36), genetic and/or epigenetic variants
Categorical
Continuous
Correlations,
Dose received by the salivary glands, administered dose
Gender, self-rated menopausal status, age, BMI, histology, thyroid remnant tissue, pathological tumor-node-metastasis staging, thyroglobulin stimulation protocol, salivary comorbidities, medication intake, tobacco and alcohol consumption, surgery to therapy duration (months), family history of thyroid cancer
All statistical analyses will be performed using SAS statistical software for Windows (SAS Institute, Cary, NC). An α level of .05 will be accepted as significant.
Patient enrollment took place from September 2020 to April 2021, with a total of 139 patients enrolled, including 45 and 94 patients treated with 1.1 and 3.7 GBq 131I, respectively.
Characteristics of the study participants are displayed in
Concerning the saliva samples, the mean pH was 7.34 (SD 0.48; range 6.00-8.50), with flow rates of 0.76 (SD 0.46; range 0.04-3.00) mL/min and 2.13 (SD 0.88; range 0.40-4.82) mL/min for unstimulated and stimulated saliva, respectively.
Statistically significant differences between the 1.1 and 3.7 GBq treated groups were found in saliva pH and nonstimulated saliva volume.
At the enrollment visit, among all 139 patients, 19 (13.6%) patients had suspicious or obvious symptoms of depression, whereas 67 (48.2%) patients had suspicious or obvious symptoms of anxiety according to the Hospital Anxiety Depression scale (see Table S1 in
When asked if patients experienced changes after thyroid removal surgery, 25 (18.0%) had the sensation of a dry mouth, 48 (34.5%) said they drink more often, and 27 (19.4%) were eating less salty foods.
Regarding lifestyle habits, among the 139 patients, 95 (68.3%) had never smoked, compared to 28 (20.1%) exsmokers and 16 (11.5%) current smokers; 87 (62.6%) never drink alcohol, compared to 45 (32.4%) being occasional drinkers (1-7 drinks/week) and 7 (5.0%) being regular drinkers (7-14 drinks/week) (see Table S1 in
Regarding radioiodine activity, the average doses recorded by the thermoluminescent dosimeters are presented in
Characteristics of the study population.
Characteristics | 1.1 GBq group (n=45) | 3.7 GBq group (n=94) | Total (N=139) | ||||||
|
.24 | ||||||||
|
Women | 35 (78) | 64 (68) | 99 (71.2) |
|
||||
|
Men | 10 (22) | 30 (32) | 40 (28.8) |
|
||||
Age (years), mean (SD) | 47.16 (13.86) | 47.02 (14.36) | 47.07 (14.15) | .96 | |||||
BMI, mean (SD) | 26.88 (5.93) | 27.14 (6.12) | 27.06 (6.04) | .82 | |||||
|
.02 | ||||||||
|
Follicular | 2 (4) | 18 (19) | 20 (14.4) |
|
||||
|
Papillary | 43 (96) | 76 (81) | 119 (85.6) |
|
||||
|
<.001 | ||||||||
|
Tx-T2 | 44 (100) | 59 (63) | 103 (74.6) |
|
||||
|
T3 | 0 (0) | 33 (35) | 33 (23.9) |
|
||||
|
T4 | 0 (0) | 2 (2) | 2 (1.5) |
|
||||
|
Nx-N0 | 38 (84) | 40 (43) | 78 (56.1) |
|
||||
|
N1 | 7 (16) | 54 (57) | 61 (43.9) |
|
||||
|
<.001 | ||||||||
|
L-thyroxin replacement stop | 0 (0) | 49 (52) | 49 (35.2) |
|
||||
|
rTSHd | 45 (100) | 45 (48) | 90 (64.8) |
|
||||
|
.07 | ||||||||
|
No | 29 (64) | 45 (48) | 74 (53.2) |
|
||||
|
Yes | 16 (36) | 49 (52) | 65 (46.8) |
|
||||
|
.66 | ||||||||
|
No | 37 (82) | 80 (85) | 117 (84.2) |
|
||||
|
Yes | 8 (18) | 14 (15) | 22 (15.8) |
|
||||
|
.19 | ||||||||
|
No | 31 (69) | 66 (70) | 97 (69.8) |
|
||||
|
Type 2 diabetes | 3 (7) | 2 (2) | 5 (3.6) |
|
||||
|
Dyslipidemia | 3 (7) | 3 (3) | 6 (4.3) |
|
||||
|
Diagnosed hypertension | 6 (13) | 22 (23) | 28 (20.1) |
|
||||
|
Sjögren syndrome | 0 (0) | 1 (1) | 1 (0.7) |
|
||||
|
Brain tumors | 1 (2) | 0 (0) | 1 (0.7) |
|
||||
|
Other | 1 (2) | 0 (0) | 1 (0.7) |
|
||||
|
.15 | ||||||||
|
No | 41 (91) | 91 (97) | 132 (95.0) |
|
||||
|
Yes | 4 (9) | 3 (3) | 7 (5.0) |
|
||||
Delay between surgery and RAIe therapy (months), mean (SD) | 4.98 (5.15) | 3.69 (3.09) | 4.11 (3.91) | .07 | |||||
Unstimulated saliva flow (mL/min), mean (SD) | 3.13 (1.82) | 4.12 (2.47) | 3.8 (2.32) | .02 | |||||
Stimulated saliva flow (mL/min), mean (SD) | 9.65 (3.18) | 11.12 (4.83) | 10.65 (4.41) | .07 | |||||
|
.67 | ||||||||
|
Yes | 9 (20) | 16 (17) | 25 (18.0) |
|
||||
|
No | 36 (80) | 78 (83) | 114 (82.0) |
|
||||
|
7.2 (0.42) | 7.41 (0.50) | 7.34 (0.48) | .02 | |||||
|
|
|
|
.29 | |||||
|
Normal | 34 (79) | 78 (86) | 112 (83.6) |
|
||||
|
Light | 3 (7) | 8 (9) | 11 (8.2) |
|
||||
|
Mild | 4 (9) | 2 (2) | 6 (4.5) |
|
||||
|
Severe | 2 (5) | 3 (3) | 5 (3.7) |
|
a
bpTNM: pathological tumor-node-metastasis.
cTSH: thyroid-stimulating hormone.
drTSH: recombinant thyroid-stimulating hormone.
eRAI: radioactive iodine.
fOSDI: Ocular Surface Disease Index.
Dosimetry description.
Variables | 1.1 GBq group (n=45) | 3.7 GBq group (n=94) |
Recorded doses at the left earlobe [Hp(0.07), mSv], mean (SD) | 30.07 (9.81) | 104.38 (35.43) |
Recorded doses at the right earlobe [Hp(0.07), mSv], mean (SD) | 30.74 (8.88) | 107.72 (42.66) |
Recorded doses at the sternal fork [Hp(0.07), mSv], mean (SD) | 49.88 (31.47) | 173.33 (94.2) |
Absorbed doses to the salivary glands (mGy), mean (SD)a | 702.00 (310.00) | 2316.00 (784.00) |
aN=127.
Further results should be published in 2022. These will be based on comparisons of data from questionnaires and saliva samples between T0 and T6. Individual factors associated with salivary dysfunctions will be presented, as well as the dose-response relationship between absorbed doses to the salivary glands and salivary dysfunctions at T6 and T18.
Since many patients treated with 131I for thyroid cancer report salivary disorders, interfering with their quality of life, the START study was launched to detect and evaluate early and mid-term radiation-induced toxicity after 131I-therapy based on a prospective self-controlled study of patients with thyroid cancer. As an original multidisciplinary approach, the START study was designed to combine both objective and subjective parameters of quality of life with clinical and genetic information based on precise dosimetry, which better reflects the heterogeneity of the dose absorbed by the salivary glands. The use of several dosimeters makes it possible to discriminate the contribution coming from the thyroid remnants, after calibration under representative geometrical conditions. This approach further avoids having to perform several imaging examinations for the patients, and to integrate, de facto, the temporal variations of the activity in the salivary glands.
Moreover, this study will be the first to evaluate the genetic and epigenetic variants involved in salivary dysfunctions in patients treated with 131I, which may help to understand some of the biological mechanisms involved in radiation-induced sensitivity. These results should help to better estimate the individualized risk of long-term salivary dysfunctions after 131I-therapy, and thus allow the consideration of potential adverse effects in the choice of treatment.
As the study is still ongoing, this paper presents the protocol and objectives of the START study, as well as descriptive analyses of the included population and the doses recorded by the dosimeters. It is noteworthy that the sex ratio in the study reflects that of the population treated in nuclear medicine departments, which allows for an accurate estimation of the incidence of salivary disorders [
The START study is carried out in collaboration with the Pitié-Salpêtrière Hospital Group, which is the largest European center for the treatment of thyroid cancer, with 10 to 12 patients per week treated with 131I-therapy in the nuclear medicine department. The main limitation of this study is the potentially small number of patients presenting posttherapy salivary dysfunctions. However, the number of subjects to be included was calculated on the basis of 80% statistical power with a first-order risk of 5% and percentages of salivary dysfunctions estimated from the literature [
This study will help to deepen knowledge on the risks of salivary dysfunctions after 131I-therapy, as well as provide a better understanding of involved genetic factors. The findings will help target patients at risk of developing salivary dysfunctions and possibly adapt the treatment, thus improving the quality of life and nutritional status of patients with thyroid cancer.
Questionnaires.
Saliva sampling.
Table S1.
radioiodine
Salivary dysfuncTions After Radioiodine Treatment
baseline enrollment
6-month follow-up
18-month follow-up
tumor-node-metastasis staging
The START study is supported by an internal Institut de Radioprotection et de Sûreté Nucléaire fund set up to enhance exploratory research projects. The authors would like to express their gratitude to all the patients included in this study and all the medical staff for their valuable assistance. The authors also extend thanks to Ilma Choffel de Witte for her proofreading and correction of the English language.
None declared.