Treatment and outcome of patients with Graves’ disease and metastatic differentiated thyroid cancer

There were 1524 patients (354 males and 1170 females, 11–91 years of age, median 51 years) with a differentiated thyroid carcinoma registered by The Cancer Registry of Republic of Slovenia during a 10-year period (from 2010 to 2019). During this period, altogether 28 patients (eight males, 20 females; 49–85 years of age; median 74 years) were treated because of differentiated thyroid cancer and distant metastasis at the time of diagnosis at our Institute. The subject of our retrospective study were four patients (three men, one female; 64–76 years of age, median 73 years) who had Graves’ disease and metastatic thyroid cancer. The Protocol Review Board and Ethics Committee of the Institute of Oncology on 9^th December 2020 (ERID-KSOPKR-0082/2020, ERIDEK-0083/2020, ERIDNPVO-0040/2020) reviewed and approved the study, which was conducted in accordance with the ethical standards prescribed in the Declaration of Helsinki. For retrospective studies, informed consent is not necessary according to the national regulations. The need for consent was waived by the Institutional Review Board and Ethics Committee of the Institute of Oncology Ljubljana.

Thyrotoxicosis with concomitant thyroid cancer was detected in 5 of 28 patients with distant metastases. Anti-TSH-R antibodies were not measured in all our patients. However, anti-TSH-R antibodies were measured in all patients with hyperfunctioning primary tumors or hyperfunctioning metastases. Elevated anti-TSH-R antibodies were detected in 4 of our 28 patients with distant metastases. All four patients with GD had a hyperfunctioning primary tumor as well as hyperfunctioning metastases.

A chart review for each patient with distant metastases was performed. All histological slides of our patients with metastatic differentiated thyroid cancer were examined by the pathologist experienced in thyroid pathomorphology. Distant metastases were diagnosed by clinical examination and additional diagnostic procedures, including lung and/or bone X-ray, ultrasonography, ultrasound guided fine-needle aspiration biopsy, radionuclide investigations with radioiodine and ¹⁸F-FDG PET/CT, computed tomography, and/or nuclear magnetic resonance imaging. The tumor stage, presence of regional and/or distant metastases, as well as residual tumor after surgery were assessed by the 8^th edition of TNM clinical classification according to the UICC criteria from 2017.⁹ Data on patients’ age, gender, disease history, presence of Graves’ disease, extent of cancer, histomorphological characteristics, mode of cancer specific therapy, outcome, and survival were collected. The clinical and pathological characteristics of the tumors are presented in Table 1. The treatment of patients and their outcome are presented in Table 2.

The majority of patients received multimodal treatment. Surgery is the mainstay of the treatment of primary tumors in differentiated thyroid cancer. All surgically treated patients had primary surgery and all other cancer-specific therapies (surgery, radioiodine (RAI) ablation of thyroid remnant, RAI therapy, external beam radiotherapy (EBRT) and/or systemic therapy) at the Institute of Oncology. All patients received therapy with L-thyroxine for TSH suppression.

All patients had a follow-up exam at our Institute at least twice per year. This consisted of obtaining medical history, a physical examination, and determining serum Tg concentration. Imaging with radioiodine scintigraphy and/or ¹⁸F-FDG PET/CT, computed tomography, and/or nuclear magnetic resonance was conducted once a year. It was also conducted whenever Tg concentration increased or clinical symptoms suggested that the disease had progressed.

Cause-specific and overall survival was defined as the period from primary cancer treatment to death or the last follow-up. The median duration of follow-up was 3.33 years (range 0.04–7.83 years).

The Student t-test or the Mann–Whitney U-test was used according to data distribution. The association between categorical variables was tested by the chi-square test or Fisher's exact test, as appropriate. All comparisons were two-sided and a p-value <0.05 was considered statistically significant. The survival curves were calculated according to the Kaplan-Meier method. A multivariate statistical analysis was not performed because of the small number of patients. The statistical package PASW 18 (SPSS Inc., Chicago, IL, USA) was used for the analysis.

A 71-year-old patient with GD was presented to a surgical oncologist because of a 2.3 cm primary papillary thyroid cancer with lung metastases. He had hyperthyroidism and GD after iodine exposure, heart failure, generalized arteriosclerosis, gangrene of the lower extremity, and type 2 diabetes. He had just had a myocardial infarction with stented coronary arteries. Due to the poor general condition and accompanying diseases, we did not decide on surgical intervention or oncological treatment. He died after two months due to deterioration of heart function.

A total thyroidectomy was performed on a 76-year-old patient with hyperthyroidism due to GD and cytological suspicion of papillary thyroid cancer. Before the operation, she received thyrostatic drugs. Histologically, it was a poorly differentiated thyroid carcinoma, 6.5 cm in diameter with extensive capsular invasion, but no vascular invasion or extrathyroidal spread. The metastases were not functionally active. After hormonal withdrawal she received 150 mCi of RAI, which accumulated in the lungs, skeleton, left kidney and right paracolic area. After six months and another six months, she received 152 mCi and 145 mCi of RAI after hormonal withdrawal, which accumulated in the same places. After nine months, she received the 4^th and last 152 mCi of radioiodine and accumulation was less intense. After another nine months, there was no more accumulation in the metastases on RAI whole body scan, and ¹⁸F-FDG PET-CT showed the progression in the 5^th left rib and right iliac bone. The patient was still asymptomatic. The skeletal lesions with a progression of disease were treated with EBRT. Anti-TSH-R levels were elevated all the time. The Tg value fell from 11982 ng/mL before surgery to 9598 ng/mL before the first RAI therapy, and then slowly declined. Titres of anti-Tg antibodies were not increased. At the time of progression 34 months after the first treatment, Tg value was only 280 ng/mL, anti-Tg antibodies were not increased, but TPO antibodies were increasing. Because the patient was asymptomatic, the medical oncologist has not yet decided on systemic treatment and the patient has been on active surveillance for seven months since progression of the disease was diagnosed.

A 75-year-old patient was operated on after preparation with thiamazole for a pathological fracture of Th2 (Figure 1) and spinal stabilization was performed in October 2017. Postoperatively, he was irradiated in the area of the thoracic spine with sensitization with weekly low doses of vinblastine and doxorubicin. In December 2017, a total thyroidectomy was performed. Histological examination showed a 7 × 5.5 cm oncocytic tumor with regressive changes after chemotherapy. In January 2018, T3 hyperthyroidism occurred. In February 2018, the patient received 151 mCi of RAI, which accumulated in many places in the spine. In March 2018, the RAI non-avid tumor in the sternum and in the right iliac bone was treated with EBRT. Because of side effects of bisphosphonates therapy, the patient discontinued this therapy. In August 2018, he had T3 hyperthyroidism again. After preparation with thiamazole, he received 160 mCi of RAI in October 2018. It accumulated in the skeletal metastases. Due to poor accumulation of RAI in Th5, he was referred to a medical oncologist, who did not decide on systemic therapy. In March 2019, he received 161 mCi RAI, the accumulation of RAI in metastases was less intense. In February 2020, he was asymptomatic, but ¹⁸F-FDG PET-CT showed a progression of metastases, so therapy with 166 mCi of RAI was administered. Only some metastases accumulated RAI. In April 2020, MRI showed progression of metastasis in Th5 and again T3 hyperthyroidism was diagnosed, therefore therapy with sorafenib (200 mg + 400 mg) was initiated. Because of the side effects, the dose was reduced to half, which he tolerated better. But after four months, the patient stopped this therapy due to side effects. He was asymptomatic until April 2022. At that time ¹⁸F-FDG PET-CT showed new metastases in the skeleton and T3 hyperthyroidism recurred. Therapy with lenvatinib was initiated on May 2022. For the first time since the beginning of cancer treatment, anti-TSH-R levels fell to the normal level three months after initiation of treatment with lenvatinib. The level of Tg also dropped from 5838 ng/mL in May 2020 to 2360 ng/mL in August 2022.

FIGURE 1.

A 64-year-old male patient had clinical signs of hyperthyroidism and a tumor measuring 9 cm in diameter of the left thyroid lobe, metastatic neck lymph node and metastases in the lungs, mediastinum, and in the 8^th right rib measuring 20 × 5.6 × 4.5 cm, in the left acetabulum measuring 9 × 9 × 3 cm and in the skull measuring 5 × 4 × 2 cm.⁸ The region of the left hip had been irradiated with concomitant doxorubicin 20 mg once weekly. When hyperthyroidism was controlled with thiamazole, a total thyroidectomy was performed. Persistent T3 hyperthyroidism, most likely caused by anti-TSH-R stimulated T3 production in a large metastasis in the 8^th right rib, was cured by rib resection. The patient was treated with three RAI therapies. But after a short interval, the disease progressed despite treatment with RAI and therapy with sorafenib. The patient died due to distant metastases 28 months from the beginning of treatment.

At presentation, 5 of 28 patients had hyperthyroidism and four of them had GD. Two patients with GD had functional metastases.

Papillary carcinoma, Hürthle cell carcinoma, follicular and poorly differentiated thyroid carcinoma were diagnosed in 13, 6, 5 and 4 patients, respectively. Graves’ disease was present in two patients with Hürthle cell carcinoma, one with papillary and one with poorly differentiated thyroid carcinoma (p = 0.28).

The mean age of patients without GD and with GD was 74 years and 71 years, respectively. Age of patients with and without GD was not statistically different (p = 0.36). There was a trend for male predominance in patients with GD (p = 0.06). Mean primary tumor size in patients without GD and with GD was 5.5 and 6.3 cm, respectively (p = 0.36). There was no statistical difference in pT stage (p = 0.52) or pN stage (p = 1.00) between the group of patients without GD and with GD.

Initial sites of metastases were: lungs in 24 cases, bones in 12 cases, mediastinum in eight cases, liver in two cases and skin in one case. Single and multiple organ metastases were present in 14 and 14 patients, respectively. Lung metastases only, bone metastases only and skin metastases only were present in eleven patients, two patients and one patient, respectively. There was no statistical difference in distribution of metastases between patients without GD and with GD.

Palliative treatment was only applied in four cases: in one due to severe comorbidities, and in three due to very advanced cancer. The data on the type of surgery for primary tumors and treatment of distant metastasis are listed in Table 2. Total or near-total thyroidectomy is considered a proper surgical procedure for thyroid cancer; however, it was performed in only 18 of 28 patients. It was not performed because of inoperable tumors (N = 8), very advanced age of the patient, severe comorbidities (N = 1), or if the patient refused surgical procedure (N = 1). Initial treatment in three patients with a locally advanced tumor was neoadjuvant chemotherapy. Tumor size decreased in all patients: by more than 30% in two patients, and by less than 30% in one patient. Metastases in regional lymph nodes were surgically treated as a part of primary surgical procedure by functional radical neck dissection in four patients. Surgical treatment of distant metastases was more common in patients with GD in comparison to those without GD (p = 0.016). Surgical therapy of bone metastases was conducted on two patients: a resection of the 8^th right rib with hormone active metastases in one patient and a resection of metastasis in the 2^nd thoracic vertebra due to pathological fracture and narrowing of the spinal canal in another patient.

RAI was used for the ablation of thyroid remnant tissue in 18 (64%) patients. The ablation dose was 3.4–4.8 GBq (92–129 mCi) of RAI. RAI was used also for treatment of distant metastases with empiric dose of 3.7–7.4 GBq (100–200 mCi) in 14 patients. These 18 patients received altogether 31 therapies with RAI (range 1–4; median 2) and a dose 11.47–24.72 GBq (310–668 mCi; median 535 mCi).

Altogether, six patients were treated with chemotherapy, while kinase inhibitors were used in ten patients. EBRT was done in a total of 13 patients, of whom seven received EBRT to the neck and superior mediastinum.

Patients were followed for 0.04–7.83 (median 3.33) years. Disease-specific survival of our 28 patients ranged from 0.04 to 7.83 years. The 5-year disease-specific and overall survival was 51% and 44%, respectively. The 3-year disease-specific survival of patients with and without Graves’ disease were 67% and 57%, respectively (Figure 2). The length of disease-specific survival in patients with and without Graves’ disease was not statistically different (p = 0.59). The 3-year overall survival of patients with and without Graves’ disease were 50% and 54%, respectively (Figure 3). The length of overall survival in patients with and without Graves’ disease was not statistically different (p=0.99).

FIGURE 2.

FIGURE 3.

In 18 patients who had total thyroidectomy and RAI therapy, the 5-year disease-specific and overall survival was 70% and 61%, respectively. The 3-year disease-specific survival of patients with and without Graves’ disease were 66% and 81%, respectively. The length of disease-specific survival in patients with and without Graves’ disease was not statistically different (p = 0.66). In these 18 patients, the 3-year overall survival of patients with and without Graves’ disease were 66% and 76%, respectively. The length of overall survival in patients with and without Graves’ disease was not statistically different (p = 0.91).

By the end of the study, nine patients were still alive (2.3–7.83 years, median 4.42 years), four patients died of causes unrelated to primary disease, while 15 patients died of thyroid carcinoma. Of the latter, eleven patients died of distant metastases, one of uncontrolled locoregional disease, and the remaining three patients died of distant and locoregional progression of the disease. Two of four patients with Graves’ disease are alive, at the time of writing for 34 and 52 months. Both have slow progression of RAI non-avid metastases; one is on systemic multikinase inhibitor therapy, while the other is still asymptomatic and on active surveillance before initiation of systemic therapy.