Na[¹³¹I]l

Radiopharmaceutical: Na[¹³¹I]I, Sodium[¹³¹I]iodide, sodium iodide (¹³¹I)

Nuclide: Iodine-131

Activity: fixed activity of Iodine-131 ranging between 1.11 GBq and 7.4 GBq, or Dosimetry based activities depending on the stage of the disease

Administration: Oral or i.v.

Kinetics: After oral administration, 90% of the Iodine-131 is absorbed via the intestine within 1 h. Excretion takes place primarily with the urine but also with the faeces. Purge, if necessary, at high doses to reduce radiation exposure of the gut and to promote the interpretability of the post-therapy scintigram. The maximum uptake in the tumour is reached after approximately 12 to 24 h. The biological half-life can be estimated at 4 days. The effective half-life is 2.7 days. When rhTSH is used for stimulation, different kinetics are expected resulting in a more rapid excretion from the body of circulating Iodine-131. Due to this, side- effects such dysfunction of lacrimal and salivary glands can be minimized.

5.4.1 Mechanism of uptake / drug biology

Administration of Iodine-131 for DTC treatment has been in common use since the 1940s [91]. In comparison to normal thyroid cells, thyroid cancer cells have a reduced expression of the sodium/iodide symporter (NIS), which determines iodine uptake from the blood [103]. Therefore, to improve Iodine-131 uptake, high thyroid-stimulating hormone (TSH) levels are achieved before Iodine-131 treatment by hormone withdrawal or recombinant human TSH (rhTSH) administration.

5.4.2 Patient selection

Patients with:

• Thyroid residues after near total thyroidectomy
• Operated thyroid cancer with aggressive pattern and high risk of recurrence
• Iodine-absorbing recurrences or metastases of DTC;
• Inoperable iodine-absorbing DTC

5.4.3 Exclusion criteria

• Absolute contraindications are pregnancy and breast-feeding.
• A relative contraindication is an insufficiently high serum TSH level (<30 mU/L) after at least 4 weeks of thyroid hormone withdrawal or after rhTSH stimulation. In this situation, treatment should be postponed except in case of hyperfunctioning known distant metastases from DTC

5.4.4 Procedure

Standard care prior to Iodine-131 therapy:

• Stopping levothyroxine Iodine uptake in the thyroid (carcinoma) tissue depends on the TSH level in the serum. To obtain sufficient TSH stimulation (TSH >30 mU/L), the patient should stop taking levothyroxine at least 3 weeks prior to a diagnostic scintigram with radioactive iodine or before treatment with Iodine-131. If the hypothyroid phase is poorly tolerated by the patient, triiodothyronine (Cytomel^®, for example 0.0125 mg t.d.s.) may be given after stopping levothyroxine until 14 days before the Iodine-131 treatment. An alternative for TSH stimulated ablation in low-risk patients is the use of rhTSH. The standard dose is 0.9 mg i.m. per day, administered on day 1 and 2 followed by Iodine-131 therapy on day 3. Recombinant TSH has already been registered for diagnostic use and for ablation; it can also be extremely useful for therapeutic use in selected patients.

Limitation of dietary iodine: An iodine-restricted diet can double the effective tumour dose in favourable circumstances. It is therefore desirable to give patients an iodine-restricted diet from four days 1-2 weeks before treatment with Iodine-131, and iodine-containing medication should be discontinued 4-6 weeks prior to treatment and to continue this for at least one day after administration of Iodine-131 [44].

• Laxatives: To reduce the radiation exposure of the intestine, it is recommended that purging be undertaken (e.g. with magnesium oxide) if patients suffer with constipation (stool less frequently than 1 to 2 times daily). This will also avoid the patient suffering from troublesome bowels during the post-therapeutic whole body scintigram.
• Hydration: To reduce the absorbed dose of Iodine-131 in the bladder wall and surrounding structures (gonads!) the patient must be advised to drink sufficiently (at least 2 l a day) during the admission.
• Pregnancy test: Pregnancy is an absolute contraindication to treatment with Iodine-131. Just as in the case of Iodine-131 therapy for hyperthyroidism, it is necessary in women of childbearing age to exclude pregnancy by means of a pregnancy test before administration of the therapeutic dose.

Standard care after Iodine-131 therapy

• Approximately one week after any ablative or therapeutic activity of Iodine-131, a whole body scintigram must be performed using the ablative / therapeutic activity of Iodine-131. In this way, metastases not yet known can be visualized and the iodide uptake of known metastases evaluated. The use of SPECT/CT acquisitions on neck region and focused on high uptake area is warranted to better characterize abnormal uptake foci [104].
• Usually, discharge from the therapy department is only allowed with a dose rate lower than a fixed threshold, which depends on national legislation (for instance <20 µSv/h at 1m distance from the patient). Special precautions should be taken to avoid radiation exposure to members of the family, and especially to pregnant women and children.
• Pregnancy should be avoided at least 6 months after initial treatment. In female patients with progressive thyroid cancer, it is recommended to prevent pregnancy.

5.4.5 Dosimetry

Several studies, most of them acquiring planar images, have reported absorbed doses to remnants and metastases with values ranging from <10 Gy to 1000 Gy [105–107].

Several studies have investigated correlations between the absorbed doses delivered to remnants and metastases and response, resulting in a wide range of absorbed doses to achieve a successful ablation. For instance, absorbed doses to remnants higher than 49 Gy, 90 Gy, and 300 Gy have been reported [105,107,108]. For metastases, absorbed doses of over 40 Gy and 80 Gy have been documented [107,108].

Currently, in the treatment of DTC there are no well-established values for absorbed doses to remnants and metastases which may be used as prescription values. Thus, this treatment is performed in most cases by administration of a fixed activity of Sodium[¹³¹I]iodide ranging between 1.11 GBq and 7.4 GBq depending on the stage of the disease.

In the case of recurrent or metastatic disease, the administered activity may be calculated based on the absorbed dose constraints of the normal tissue (usually red marrow) [40]. and of the lesions  Initial pre-therapy planning would require a tracer activity of Sodium[¹³¹I]iodide or Sodium [¹²⁴l]iodide [35,38,108].

5.4.6 Effectiveness

The effectiveness of the treatment is usually evaluated by measuring thyroglobulin levels and sometimes also by acquiring a whole-body scan between 6 and 12 months after the treatment. High rates of success, of about 90% or higher, can be expected for treatments with ablative intent as reported in phase III trials [109–111].

In the presence of metastases, the 5-year survival ranges from 78% in patients with single-organ metastasis to 15% in patients with multi-organ metastases [112]. The superiority of Dosimetry based high activities vs fixed activities in metastatic patients on patient outcome should be evaluated; only few retrospective studies are available on this topic [113,114].

5.4.7 Side Effects

Short-term side-effects

• Sialadenitis: Transient sialadenitis occurs quite frequently after a treatment with a high activity of Iodine-131 (±10%). The cause is the high concentration of Iodine-131 in the salivary glands. Symptoms are pain and swelling in the first three days after therapy. Sometimes patients complain about a dry mouth and a metallic taste that may last from several weeks to months. The excretion of Iodine-131 from the salivary glands after the administration of a therapeutic dose is stimulated by allowing patients to eat sweets or other products that stimulate saliva production, but this should be initiated not earlier than 1 day after the administration of Iodine-131.
• Gastrointestinal symptoms: 10%-60% of patients treated with high activity Na[¹³¹I]I  (5500-7400 MBq) will suffer from radiation-induced gastritis, characterized by nausea, sometimes leading to vomiting. These symptoms usually begin 8 h after administration, can last 2 to 3 days and are easily treated with anti-emetics.
• Local effects: A high dose of Iodine-131 can lead to a radiation thyroiditis, if there is still a lot of residual tissue present. This presents a few days after therapy with a painful, sometimes red neck. The pain may spread to the ear. Aspirin is often an effective treatment. In some cases, corticosteroids are indicated.
• Oedema: In the case of brain metastases, Iodine-131 treatment may lead to oedema. Therefore, major cerebral metastases must preferably first be treated neurosurgically with the aid of external radiotherapy. If, after all, Iodine-131 is primarily decided upon, the patient must be pre-treated with corticosteroids, mannitol or glycerol to prevent oedema.
• Myelosuppression: Myelosuppression may occur one month after the administration of Iodine-131. This myelosuppression is mild and reversible. Myelosuppression is more frequently seen in patients with a high cumulative dose and where there is extensive skeletal metastasis.
• Pneumonitis and pulmonary fibrosis are possible concerns in the presence of diffuse lung metastases, and absorbed dose-rate methods have been suggested based on the whole-body retention threshold of 2.96 GBq at 48 hours post-treatment [115].

Long-term side-effects

Emergence of second primary malignancies: There is controversy concerning the effect of Iodine-131 treatment on the occurrence of second primary malignancies in patients with DTC [116]. The necessity of Iodine-131 therapy needs to be balanced against the risks.

5.4.8 Status

Sodium[¹³¹I]iodide is approved in the EU for the treatment of DTC.