Herein, we assessed the incidence and risk factors for late thyroid complications (thyroid dysfunction and tumours) that can occur after radiation therapy. Few studies have focused on both forms of thyroid pathology. Moreover, in this study, we closely followed our patients since they finished their radiation therapy. Thus, we believe that we diagnosed hypothyroidism and thyroid nodules at the most approximate real-time of the development of clinical disease. Furthermore, we were able to establish evidence-based tailored surveillance for cancer survivors.
Hypothyroidism was found to be common late radiation toxicity (56.7%). The prevalence of hypothyroidism was lowest in leukaemia patients and the events occurred after a shorter interval in HNT than in other diagnostic groups. We found that patients who received neck and CSI had higher odds of developing hypothyroidism compared to TBI. The results are in contradiction to a previous study that reported no significant differences between radiation fields. This different outcome may be due to the heterogeneity of the cohorts. In the mentioned study, only 10 Leukaemia patients received TBI and 11 Hodgkin's survivors had neck irradiation. In our study, the risk of hypothyroidism tended to be higher among patients who received higher radiation doses (>35 Gy). Our findings are consistent with those from the US childhood cancer survivor study which reported a 30% risk of thyroid dysfunction for subjects whose thyroid received 35–44 Gy and 50% for radiation dose over 45 Gy. We also found that leukaemia patients had a lower prevalence of hypothyroidism than the CNS tumour group. This finding may be explained by the treatment modalities for each cancer type (mean TBI dose = 13 ± 4 Gy; mean CSI dose = 36 ± 6 Gy). Our results are in accordance with findings from the British childhood cancer survivor study that reported a twofold to threefold greater risk of hypothyroidism for survivors of HD and CNS tumours than leukaemia patients.
Hypothyroidism in survivors of childhood brain tumours can result from either irradiation of the thyroid gland or of the hypothalamic–pituitary gland complex. Many patients could have developed a mixed form of hypothyroidism; however, primary hypothyroidism is usually more prevalent and precocious than central hypothyroidism.[12,13] Studies report rates of thyroid dysfunction ranging from 37% to 74%, which is in line with our results in this diagnostic group (65.3%).
We did not find an increased risk of hypothyroidism among female patients, as has been reported by others.[5,6] The attributable risk of hypothyroidism due to chemotherapy remains controversial. Whereas most authors do not find a significant association, a more recent study reported a modest increase in the risk of thyroid dysfunction with bleomycin and cyclophosphamide. Thyrotoxicosis was not observed in our cohort. Thyroid function was evaluated at least a few months after irradiation, far from the thyroiditis by destruction susceptible period that may occur right after RT.
We observed an 8.5% overall incidence of thyroid cancer in patients aged 17–45 years. According to Cancer Research UK, the incidence rate of thyroid cancer in persons aged 20–44 years is 1–4 per 100,000 in men and 5–12 per 100,000 in women. It is likely that these patients have been subjected to more frequent endocrine surveillance, particularly thyroid ultrasound, at our outpatient clinic.
It has been proposed that the risk for thyroid cancer increases linearly with the dose up to 20–29 Gy and at doses higher than 30 Gy, there is a reduction in dose-response. This is consistent with the cell-killing hypothesis of high dose radiation, in that dead cells cannot give rise to a malignancy, and cell survival decreases exponentially with increasing dose. We found that younger age at diagnosis and irradiation doses under 35 Gy were significantly associated with the development of thyroid malignancies, in line with an updated pooled analysis of 12 studies. Female gender also presented a higher risk for developing thyroid cancer, consistent with previous observations in survivors of childhood acute leukaemia.
Although not statistically significant, patients with leukaemia had a higher incidence of thyroid cancer (20% in this diagnostic group), probably due to the tumorigenic effects of low radiation doses.
Head and neck cancer patients had the lowest incidence of thyroid cancer (one case). Two reasons can contribute to this outcome: these patients were exposed, on average, to higher doses of radiation (>50 Gy) and second, these tumours are often diagnosed in adulthood when the thyroid gland is less radiosensitive.
All cancers observed were PTC and its follicular variants, with a low rate of metastatic disease. This is in line with studies following the Chernobyl accident which depicted a predominance of PTC: thousands of thyroid cancers were reported but only a few deaths. Most young children presented with a solid or follicular subtype, whereas older children had more frequently classical PTC.
New evidence reports an increased risk of thyroid cancer associated with alkylating agents but only in the radiation dose range under 20 Gy. Nevertheless, the effect of chemotherapy on the overall risk of thyroid cancer after low dose radiation is modest.
There are possible limitations associated with our study. Mainly, the heterogeneity of our cohort (different disease types and treatment modalities) and the retrospective nature of the analysis. Also, we did not assess the effects of chemotherapeutic agents on thyroid complications. Nevertheless, our study provides useful information about the risk of hypothyroidism and thyroid cancer after RT, and, thus, may be practical for the follow-up management of these patients.
The US children's oncology guidelines recommend that thyroid examination starts 5 years after RT, with high-risk groups being those treated for cancer at a younger age, female sex, and radiation dose between 10 and 30 Gy. However since most differentiated thyroid cancers have a favourable prognosis, there is still debate regarding both the necessity of routine surveillance and the optimal modality for screening. The International Late Effects of Childhood Cancer Guideline Harmonisation Group recommends that all survivors be counselled about options for thyroid cancer surveillance. Of the two available screening modalities, thyroid ultrasound and neck palpation neither was shown to be superior. Thyroid palpation should occur every 1–2 years. If thyroid ultrasonography is chosen as a screening modality, it should be repeated every 3–5 years. No recommendation is made for how long surveillance should be continued.
In light of our outcomes, we developed a risk-based protocol for surveillance of thyroid complications in cancer survivors followed at our department. Thus, in addition to annual thyroid palpation, we suggest:
Annual screening for thyroid function starting 12 months after RT, with greater emphasis on patients with HNT tumours or high radiation doses.
Ultrasound screening beginning 3–5 years after RT, with further attention to women, younger patients (<20 years), and low radiation doses (<35 Gy).
Patients who underwent neck irradiation at doses ≥70 Gy may not require a routine ultrasound scanning. However, neck palpation can still be performed as surveillance in this group.
Following thyroid nodules diagnosis, we recommend to apply the guidelines of the international societies.[22,23] As the whole gland is at risk after irradiation, we usually offer total thyroidectomy to these patients when there is a surgical indication.
In conclusion, our results further support the evidence for lifelong surveillance of cancer survivors with a history of radiation exposure. They highlight the need for thyroid function and ultrasound screening in accordance with a well-defined risk-based protocol.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Clin Endocrinol. 2022;96(5):728-733. © 2022 Blackwell Publishing