title: Radiation-induced hypothyroidism after treatment of head and neck cancer.
abstract: Head and neck cancer is the sixth most common cancer in the world. In Denmark the incidence was 1,287 in 2013 (thyroid cancer excluded). Head and neck cancer is predominantly a loco-regional disease, and radiotherapy (RT) and surgery are major treatment options. Approximately 70% of Danish patients receive definitive RT, and the rest are treated with surgery with or without post-operative RT. Radiation to the normal tissues is inevitable during RT. The current advanced treatment modalities allow precise calculation of radiation doses to normal tissues and there is a potential to distribute the dose to avoid adverse effects from radiation. However, this requires knowledge about the radiation tolerance levels of individual organs. Radiation-induced hypothyroidism (RIHT) is a well-known late effect of radiation to the thyroid gland, which can develop months to years after RT. The reported incidence of RIHT varies considerably, however, and the tolerance level of the thyroid gland is poorly defined. The aim of this PhD project was thus to elucidate these issues. The first study included a cohort of 203 patients with head and neck cancer who were treated with definitive RT and no surgery at Odense University Hospital, Denmark, in 2002-2010. Analysis of patient characteristics, precise radiation doses to the thyroid gland and follow-up assessments of thyroid function after radiotherapy gave an estimated five-year incidence of RIHT of 26%. Significant risk factors for the development of RIHT were a small thyroid volume and a high mean radiation dose to the gland. Two models were developed for predicting the risk of RIHT, taking both the thyroid volume and the mean radiation dose into account. One model was based on the collected data alone, while the other model included an estimated time distribution for the development of RIHT (i.e. latency). Using the model that considered latency, dose constraints for the thyroid gland were proposed for keeping the risk of RIHT after radiotherapy below 25%. This model emerged as the preferred model, and its robustness was tested in the following two studies. The second study aimed at assessing the impact of variation of estimated risk of RIHT due to intra- and inter-observer variability in delineated thyroid gland volume. Fifty treatment plans were randomly chosen for either repeat delineation by the author (intra-observer) or delineation by another radiation oncologist (inter-observer). The variations in delineated thyroid gland volume and mean radiation dose, and the subsequent variation in estimated risk of RIHT were assessed. For the entire study population, the variation in predicted risk of RIHT was small and the model was robust towards observer variations in delineation of the thyroid gland. However, for some patients there were pronounced differences in the estimated risk due to variation in organ delineation, and thus precise delineation is of utmost importance for the individual patient. The third study aimed at studying the robustness of the model in a cohort of head and neck cancer patients treated with definitive RT at the Department of Oncology, Aarhus University Hospital. A total of 198 patients were included after one assessment of thyroid function (blood sample of thyrotropin, TSH) during routine follow-up after radiotherapy. A small thyroid volume and a high mean radiation dose were also found to be significant risk factors for RIHT in this cohort. These factors were included in a new risk model. Direct comparison of the two models was not possible, however, due to a different number of TSH assessments in the two cohorts. It was also not possible to estimate latency on the basis of a single measurement of thyroid function. Nevertheless, when the number of TSH assessments was taken into account, the estimated risk of RIHT was very similar in the two cohorts.
  
  
  CONCLUSIONS
  Hypothyroidism is a frequent late effect after definitive radiotherapy. As the condition has been linked to increased risk of cardiac disease and mortality, and decreased quality of life, it is important to consider the risk of RIHT when planning radiation treatment. The size of the thyroid gland and the radiation dose to the gland are key factors in the development of RIHT, and both these factors should be considered when determining dose constraints for the thyroid gland. A risk of RIHT below 25% is recommended. Furthermore, routine assessment of thyroid gland function should be offered after radiotherapy in the neck area. Finally, the robustness of the risk model should be studied in a longitudinal follow-up of a cohort of patients with repeated thyroid function assessment.
authors.affiliation: m_feen_r@hotmail.com.
authors.forename: Marianne
authors.initials: M
authors.lastname: Feen Rønjom
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D007037:Hypothyroidism / Q000209:etiology*; D011832:Radiation Injuries; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D013961:Thyroid Gland / Q000528:radiation effects*