Therapy of malignant thyroid diseases

Data on thyroid carcinoma

Thyroid carcinoma is the most common malignant tumor originating from endocrine glands, although it is rather rare, accounting for approx. 1% of all malignant tumors. In Germany, the annual incidence of thyroid carcinoma is approx. 3 - 5 new cases per 100,000 inhabitants. The mortality rate is approx. 3 - 6/ 1 million p/ year (~ 0.0005%).

Women are affected about twice as often as men, and the incidence increases significantly with increasing age.

Histologically, a distinction is made between so-called differentiated carcinomas (papillary and follicular) and undifferentiated (anaplastic) and medullary carcinomas (C-cell carcinoma) originating from the parafollicular C-cells. The most common carcinoma is papillary with approx. 65%, followed by follicular with approx. 27%. Medullary carcinomas and anaplastic carcinomas are much rarer at less than 5 %.

Papillary and follicular thyroid carcinomas generally occur sporadically, although familial forms are described in around 5% of cases. In contrast, medullary carcinoma occurs more frequently in families (approx. 25 - 30 %) and is inherited in an autosomal dominant manner with almost 100 % penetrance. The cause is a mutation of the so-called RET protooncogene on chromosome 10. Half of these patients with the familial form of C-cell carcinoma develop pheochromocytomas (tumors of the adrenal medulla) as part of the so-called multiple endocrine adenomatosis (MEA or MEN).

There are no known causes for the development of thyroid carcinomas, with one exception, namely exposure to ionizing radiation, particularly in childhood. This includes, for example, external radiation exposure as part of radiotherapy or the incorporation of radioactive iodine. This is impressively documented by the massive increase in the incidence of thyroid cancer in children following the Chernobyl reactor disaster in 1986.

Treatment of thyroid cancer

The treatment of thyroid cancer at the Ludwig Maximilian University of Munich is interdisciplinary and is based on the guidelines of the German Society of Nuclear Medicine, the German Cancer Society, the German Society of Endocrinology (Thyroid Section) and the German Society of Surgery. The therapy usually consists of 3 pillars, namely surgery, radioiodine therapy and lifelong substitution with thyroid hormone.

Primary therapy is always surgical, with total thyroidectomy (= total removal of the thyroid gland) being the first choice for papillary and follicular carcinomas.

Radioiodine therapy

In almost all cases, surgery is followed by ablative radioiodine therapy, the purpose of which is to eliminate (usually benign) residual thyroid tissue or any tumor cells that may be present. The background to radioiodine therapy is that the majority of well-differentiated SD carcinomas show a more or less pronounced iodine metabolism.

Furthermore, radioiodine therapy is indicated for the treatment of local recurrences, lymph node and distant metastases if surgical options have been exhausted.

The purpose of postoperative radioiodine therapy is based on the following considerations:

Radioiodine therapy leads to a reduction in the risk of recurrence, presumably by destroying occult micrometastases.

Only after primary ablative RIT is it possible to reliably detect or exclude radioiodine-storing metastases in a whole-body scintigraphy, as any normal thyroid tissue still present is strongly iodine-avid.

The tumor marker thyroglobulin (hTG) has much better diagnostic value in the absence of normal thyroid tissue.

Radioiodine therapy is carried out with radioactive iodine-131, which is usually administered orally in the form of a capsule and reaches the thyroid cells via the stomach and blood. The radiation effect is mainly achieved by the beta radiation (b-decay) produced during radioactive decay, which has a range of a few millimeters in the tissue. This means that a very high radiation exposure can be achieved in the remaining thyroid tissue. The simultaneously generated gamma radiation enables the activity distribution to be visualized in the so-called post-therapy scintigram.

In order for the radioactive iodine to be absorbed into the thyroid cells in the best possible way, it is necessary for the thyroid gland to be clearly hypothyroid at the time of therapy, because under these circumstances a hormone produced in the pituitary gland (TSH) stimulates the thyroid cells to maximize the uptake of iodine; TSH values > 30 µU/ml are aimed for. This hypothyroidism is usually achieved by abstaining from hormones for approx. 3 weeks after surgery.

Radioiodine therapy is not indicated for patients with medullary or de-differentiated (anaplastic) thyroid carcinoma. Absolute contraindications for radioiodine therapy are pregnancy, i.e. a pregnancy test is mandatory, and breastfeeding. Contraception is recommended for 6 - 12 months after radioiodine therapy in order to avoid the need for a further application of radionuclides.

Carrying out radioiodine therapy

Preparation: Due to the high TSH stimulation required, any existing thyroid hormone medication must be discontinued approx. 4 weeks before radioiodine therapy; after the operation, no thyroid hormone may be administered until the time of radioiodine therapy. Furthermore, strict iodine restriction must be observed (no contrast medium applications, low-iodine diet).

In accordance with legal requirements, radioiodine therapy in Germany can only be carried out on an inpatient basis. During the inpatient stay, the size of the postoperative thyroid remnant is first estimated using a small amount of test activity (figure).

Thyroid hormone replacement is also started on the day of discharge, initially aiming for a TSH value of < 0.1 µU/ml. This is usually achieved with a daily levothyroxine dose of 2.5 µg/kg body weight. In the case of papillary carcinomas with sizes < 2 cm, which are particularly favorable prognostically, complete TSH suppression can later be dispensed with; we recommend a TSH target value of 0.2 - 0.4 µ/ml.

Risks and side effects

Overall, side effects of radioiodine therapy are rare. Temporary inflammation of the thyroid gland and tumor remnants, the salivary glands and the gastric mucosa are sometimes seen. These side effects are usually minor and can be treated well with anti-inflammatory measures (e.g. ice tie) or anti-inflammatory medication. To prevent damage to the salivary glands, care should be taken to ensure sufficient saliva flow, which can be achieved by giving lemon juice, chewing gum or sour sweets. Sufficient fluid intake and frequent emptying of the bladder should also be ensured.

Late side effects are extremely rare and are only seen after repeated high-dose radioiodine therapy. The following are described as late side effects of radioiodine therapy: dose-dependent bone marrow insufficiency with a total activity of usually more than 30 - 40 GBq, a dose-dependent incidence of leukemia (approx. 1%), sicca syndrome (frequency 10 - 20%) and pulmonary fibrosis (< 1%) with extensive lung metastasis.

However, there is no evidence of an increased incidence of genetic damage, i.e. increased malformations or other negative effects in pregnancies following radioiodine therapy.

Aftercare

Although differentiated thyroid carcinomas have a very good prognosis as described, lifelong follow-up care is still necessary, as it is a characteristic of thyroid carcinomas to develop so-called late recurrences relatively frequently. The aim of follow-up care is therefore the early detection of a recurrence or metastasis of the thyroid carcinoma.

The most important parameter in the aftercare of differentiated thyroid carcinomas is thyroglobulin, a substance produced exclusively by thyroid cells. After successful ablation of the residual thyroid tissue, no thyroglobulin may be detected in the patient's blood. If thyroglobulin levels are below the detection limit, further morphological examinations are usually unnecessary. As part of the follow-up examinations, sufficient thyroid hormone substitution must also be checked, as must the calcium level and the blood count.

If a measurable thyroglobulin level reappears, a diagnostic iodine 131 whole-body scintigram (in hypothyroidism) or other nuclear imaging procedures (primarily positron emission tomography) as well as X-ray examination procedures (computer tomography, magnetic resonance imaging) must be used to search for possible recurrences or metastases. Depending on these results, the therapy options are determined, which essentially cover the spectrum of the initial therapy.

Prognosis

The prognosis for differentiated thyroid carcinomas is generally very good, with a 10-year survival rate of between 85 and 90 % for papillary carcinomas and between 75 and 80 % for follicular carcinomas. Local recurrence is seen in 5 - 20 % of cases, metastases in 10 - 15 %. In addition to the tumor stage and histological type (figure), the prognosis depends on the patient's age; younger patients have a significantly better prognosis.

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