Salivary Dysfunctions and Consequences After Radioiodine Treatment for Thyroid Cancer: Protocol for a Self-Controlled Study (START Study)

Introduction

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 [1]. Although incidence rates are steadily increasing, mortality rates have declined slightly in recent decades, and thyroid cancer has an excellent prognosis with a 10-year survival rate of over 90% [1].

Standard treatment for differentiated thyroid cancer is thyroidectomy followed by radioiodine (¹³¹I) ablation [2]. This ¹³¹I complementary therapy aims to destroy thyroid remnant tissues, thus facilitating biological surveillance via the thyroglobulin dosage and reducing the risk of cancer relapse. This therapy also treats possible persistent or metastatic diseases, and enables assessment of disease extension through posttherapy scintigraphy. However, the usefulness of ¹³¹I-therapy is debated, especially for cancers with a low risk of recurrence because of their excellent survival rate, and the possibility of adverse effects of this therapy in the short, medium, and long term [3]. The salivary gland might be a site of inflammation after ¹³¹I-therapy owing to its ability to capture and concentrate iodine [4], and in particular radioactive iodine, which may be symptomatic in the acute phase, and can be followed by chronic salivary dysfunctions [5]. Such dysfunctions are defined as any quantitative or qualitative change in saliva production, such as a decrease in salivary secretion ranging from minor to severe hypofunction [6]. Nevertheless, saliva is crucial for the maintenance of buccal health. Notably, the incidence of salivary dysfunctions is still unclear, ranging from 2% to 67%, due to major methodological differences between studies, including the method and timing of identification of salivary dysfunctions [4].

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 [7]. Quality of life after ¹³¹I-therapy requires special attention because of the good prognosis of differentiated thyroid cancer. In the context of ¹³¹I-therapy for thyroid cancer, few studies have assessed the long-term quality of life at 6 months or later after ¹³¹I-therapy [8-12], whereas it has been shown that salivary dysfunction assessed by a specific questionnaire may occur more than 6 months after therapy for 25% of patients [13]. Moreover, there are inconsistencies in the reported relationships between objective measures of salivary flow (sialometry) and subjective measures of salivary dysfunction (self-questionnaire) [6,11], reinforcing the need to assess salivary dysfunction by creating a composite criterion combining objective and subjective measures.

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 [14], the potential existence of individual genetic sensitivity to ¹³¹I in mediating the relationship between ¹³¹I exposure and salivary dysfunctions is important to study, especially as specific epigenetic changes could lead to increased sensitivity to ionizing radiation [15]. Other risk factors of salivary dysfunctions in the context of thyroid cancer treated by ¹³¹I-therapy are poorly understood. Only one study investigated the relationship between salivary flow and age, gender, or pathological tumor-node-metastasis (TNM) staging, but did not show any significant relationship, potentially owing to a lack of statistical power due to the small number of patients included (N=67) [11], emphasizing the importance of setting up a study with a large number of patients. Increased knowledge of these factors would help to identify the patients at risk of developing salivary dysfunctions, which could possibly help to adapt the treatment and follow-up accordingly.

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.

Methods

Study Design

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 (Figure 1).

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Inclusion and Exclusion Criteria

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.

Ethical Considerations

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) [16].

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.

Conduct of the Study

Schedule

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.

Before Enrollment

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.

Enrollment Visit (T0)

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 Multimedia Appendix 1), and the patients are equipped with thermoluminescent dosimeters (see Dosimetry section below) just before administration of the ¹³¹I-therapy. The dosimeters will be removed by the physician 5 days later, immediately before the posttherapy scan.

Six-Month Follow-up (T6)

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

Eighteen-Month Follow-up (T18)

Patients are called by phone to answer the self-questionnaires with a clinical research associate.

Data Collection

All data are collected using paper versions, and are then entered and recorded on a secure server (Table 1).

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 Multimedia Appendix 1).

Saliva sampling has been performed according to a standardized methodology (see Multimedia Appendix 2).

Dosimetry

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 (Figure 2). They are removed 5 days later, just before the posttherapy scan.

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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 [17]. To validate this method, the response of thermoluminescent dosimeters to iodine does not have to deviate significantly from their response under standard calibration conditions.

Study Endpoints

Primary Endpoint

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 [18,19].

Secondary Endpoints

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.

Statistical Analyses

Sample Size Calculation

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 [4,20,21]. Thus, the number of patients required is distributed as follows: 40 and 80 patients in the groups treated with delivered activities of 1.1 GBq and 3.7 GBq, respectively. Furthermore, to consider potential losses during follow-up, a final number of 130 patients is required.

Descriptive Analyses

The description of the population (means, SDs, and percentages) at baseline (before ¹³¹I-therapy) is presented in this paper. Comparison tests have been performed (t test and χ² tests) between the two groups of patients (1.1 GBq and 3.7 GBq groups) at T0. This is based on medical and individual data collected in the questionnaire, the ¹³¹I dose received precisely at the salivary glands in comparison with the delivered activity, saliva flow descriptions, and responses to the questionnaires.

Planned Analyses

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 (Textbox 1) will then be entered into multivariate models to measure the risk of developing salivary dysfunctions or other outcomes, adjusted for risk factors previously identified.

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).

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.

Results

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 Table 2. The START sample is composed of a large majority of women, with an average age of 47 years (range 18.70-81.80 years). All patients underwent total thyroidectomy with a diagnosis of differentiated thyroid cancer confirmed by pathological examination; the highest proportion in the TNM classification was Tx-T2, followed by Nx-N0, N1, T3, and T4, including approximately 47% of patients with residual thyroid tissue. The ¹³¹I-therapy was performed an average 4.11 (SD 3.91) months after the surgery (range 1-35 months). The majority of the included patients were treated for a papillary thyroid cancer.

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 Multimedia Appendix 3).

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 Multimedia Appendix 3).

Regarding radioiodine activity, the average doses recorded by the thermoluminescent dosimeters are presented in Table 3. Preliminary results based on the numerical calibration of the dosimeters in terms of cumulated activity provide absorbed doses to the salivary glands after application of the S-factor (self-dose) for salivary glands. There were 43 and 127 patients for which dosimeters were readable in the 1.1 GBq group and 3.7 GBq group, respectively. The doses to the salivary glands were approximately 3-times higher in the 3.7 GBq group than in the 1.1 GBq group (Table 3). For the whole group, the dose to the salivary glands per unit administered activity was 0.63 (SD 0.24) Gy/MBq. The ratio of left/right salivary glands cumulated activity was 0.97 (SD 0.15).

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.

Discussion

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 [22]. Regarding dosimetry, it can be observed that the recorded doses are highly correlated to the administered activities, with a strong earlobes left/right symmetry.

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 [4,20,21]. Nevertheless, salivary complications following ¹³¹I-therapy have been poorly studied, and the incidence rate is not very well estimated.

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.