Radioiodine therapy in differentiated thyroid carcinoma.

For papillary and follicular thyroid carcinomas, ablative radioiodine therapy with TSH stimulation is given four to six weeks after surgery. Studies show that high standard activity (3.7 GBq vs. 1.1 GBq) is not necessary in patients with low individual risk factor profiles. In contrast, for adjuvant therapy in patients with higher-risk thyroid carcinoma, the recommendation for a higher therapeutic activity of 3.7-7.4 GBq J-131 radioiodine remains. For patients with radioiodine-refractory disease, there are new therapeutic options to complement palliative chemotherapy, for example the use of the tyrosine kinase inhibitor sorafenib.

The first successful radioiodine treatment of metastatic differentiated thyroid carcinoma dates back to 1946. Although this makes radioiodine therapy one of the long-established therapies, it is undergoing a shift toward risk-adapted, individualized therapy with lower J-131 radioiodine treatment activities; it is primarily used to ablate residual thyroid tissue in patients with low-risk thyroid carcinomas.

Due to the iodine storage of differentiated thyroid carcinomas (70% of thyroid carcinomas), there are very good diagnostic and therapeutic options for patients with such disease. Interdisciplinary therapy of thyroid carcinoma is based on teamwork of endocrine surgery, pathology, nuclear medicine, internal oncology, radiation oncology and internal endocrinology. Staging and grading is according to TNM classification, staging according to UICC. Papillary thyroid carcinomas metastasize predominantly to adjacent cervical lymph nodes, but distant metastases are rare in patients younger than 40 years. In follicular thyroid carcinoma, on the other hand, pulmonary and osseous metastases are possible even in smaller tumors; lymph node metastases are rare.

Four to six weeks after surgery, ablative radioiodine therapy under TSH stimulation (thyroxine depletion/rTSH) is performed for papillary and follicular thyroid carcinoma. ^Thyrogen® is approved in Switzerland for thyroglobulin measurement twice in low-risk thyroid carcinoma. Further applications are possible after cost approval by the medical examiner. For ablation in low-risk carcinomas, ^Thyrogen® can be used once.

Radioiodine therapy is indicated for all papillary and follicular thyroid carcinomas, with the exception of papillary thyroid carcinoma ≤1 cm in diameter without risk factors (CAVE: patient’s need for safety). Radioiodine therapy is contraindicated during pregnancy and breastfeeding. In medullary, anaplastic, and oncocytic (<10% radioiodine-storing) thyroid carcinoma, radioiodine therapy yields no benefit except as radioiodine elimination of residual thyroid in oncocytic thyroid carcinoma for thyroglobulin progression. There is rarely an indication for radiotherapy or chemotherapy.

Indications for radioiodine therapy

The following indications exist for radioiodine therapy:

• Ablation of residual thyroid tissue after total or subtotal thyroidectomy with the aim of eliminating residual thyroid tissue remaining postoperatively to provide optimal conditions for tumor follow-up. This consists of I-131 whole-body scintigraphy (no focal uptake in the thyroid lodge), sonography (postoperative baseline sonography), and measurement of serum thyroglobulin (not measurable under stimulation six months after therapy).
• Adjuvant therapy for suspected microscopic residual thyroid carcinoma after surgical resection with the goal of preventing or delaying recurrence of detectable disease, analogous to adjuvant therapy as in solid carcinoma.
• Radioiodine therapy for radioiodine-storing macro-thyroid carcinoma recurrences in combination after surgical resection (always to be considered primary) or lymph node or distant metastases, especially after incomplete resection, or inoperability depending on the individual situation with the goal of curation or palliation.

Applied activity

For ablation of residual thyroid tissue, two studies showed that high standard activity is not necessary in patients with low individual risk factor profiles. Activity administration of 1.1 GBq compared with 3.7 GBq (the latter still commonly practiced) showed an equivalent ablation rate under thyroid hormone deprivation or administration of recombinant human thyroid-stimulating hormone (^Thyrogen®) [1,2]. The toxicity rate in patients treated with 1.1 GBq is also lower, as expected [3]. Successful ablation of residual thyroid tissue was defined in these studies as follows: Normal ultrasound findings of the neck and low thyroglobulin (<1 ng/ml) after Thyrogen® ^stimulation, with or without negative radioiodine scan, less than one year after radioiodine ablation. This definition is not uncontroversial among experts, since thyroglobulin remains measurable if necessary and leads to false positive measurement results – with corresponding follow-up examinations – by residual normal thyroid tissue. On the other hand, it is known that side effects of radioiodine therapy are rare (with early diagnosis and lower therapy activities), but increase with higher cumulative dose.

As long as no prospectively collected late results are available with regard to the described problem, a graduated pragmatic approach is recommended for patients with a low risk profile. In this context, it is important to know the approximate quantifiable residual thyroid volume and the individual risk factors that justify a lower therapeutic activity (than usual so far) for ablation of the residual thyroid tissue, in accordance with the principle “as much as necessary, as little as possible”.

In contrast, for adjuvant therapy in patients with higher-risk thyroid carcinomas, the recommendation for a higher therapy activity of 3.7-7.4 GBq J-131 radioiodine remains (initial or follow-up therapy); therapy is performed using the long-established measures for prophylaxis or minimization of the known side effects of radioiodine therapy [4]. The results of clinical and histopathologic risk analyses are incorporated into the decision of how high the therapy activity should be [5]. Studies are currently underway to use J-124 iodide PET/CT to better objectify the level of treatment activity. This method not only has a higher sensitivity for tumor site detection, but also allows dosimetric calculations for individual optimization of the therapeutic activity to be selected to achieve the desired tumor site dose [6,7]. In contrast, F-18-FDG-PET/CT is used in recurrence diagnosis as a primary staging examination, especially when the tumor marker thyroglobulin rises to detect dedifferentiated (radioiodine-negative) tumor foci.

The results of radioiodine therapy of radioiodine-storing macrothyroid carcinoma recurrences after surgical resection are better with small tumor mass and higher degree of differentiation than with large tumors and lower differentiation. In principle, the radical surgical procedure should always be examined first, or iodine storage should be investigated. This is done with either J-123 or J-131 radioiodine scintigraphy. The planar gamma camera-assisted whole-body overview image is supplemented at most, depending on the problem, by a 2-in-1 SPECT/low-dose CT scan of the body region that is the diagnostic focus [8].  Iodine-storing distant metastases can often be treated curatively or palliatively in the long term by radioiodine therapy. On the discharge day after radioiodine therapy, a post-therapy scan is always performed to document therapeutic radioiodine uptake, for supplemental staging, and in the case of repeat radioiodine therapy, for follow-up assessment.

Preparation of radioiodine therapy

When preparing for radioiodine therapy, the following principles should be observed:

• Iodine contamination prophylaxis, i.e., no use of iodine-containing X-ray contrast medium or disinfectant, no iodine-containing medications, dietary supplements, and cosmetics (especially with algae extracts), temporary low iodine diet.
• Depending on local agreement, four to six weeks of thyroxine abstinence or, under ongoing thyroxine medication, administration of rTSH (^Thyrogen®) twice 24 and 48 hours before radioiodine administration.
• Review dental status prior to planned high-dose radioiodine therapy.

What are the options for radioiodine-refractory disease?

For patients with radioiodine-refractory disease, new therapeutic options now exist to complement palliative chemotherapy. After waiting and watching in stable disease, active therapy is initiated in symptomatic progressive disease. These include re-induction therapy of a radioiodine uptake, for example with selumetinib (potent, highly selective MEK1 inhibitor), which offers the possibility of modular combined re-radioiodine therapy in two-thirds of treated patients [9], assuming sufficient retention of the therapy radioiodine in the tumor lesions, or the use of inhibitors of multiple tyrosine and RAF kinases, for example sorafenib (^Nexavar®) [10]. For the treatment of patients with progressive, locally advanced or metastatic, radioiodine-refractory, differentiated thyroid cancer, sorafenib has been approved in Switzerland since January 1, 2015. .

Literature:

1. Schlumberger M, et al: Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012; 366: 1663-1673.
2. Mallick U, et al: Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 2012; 366: 1674-1685.
3. Cheng W, et al: Low- or high-dose radioiodine remnant ablation for differentiated thyroid carcinoma: a meta-analysis. J Clin Endocrinol Metab 2013; 98: 1353-1360.
4. Luster M, et al: Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-008-0883-1, www.eanm.org/publications/guidelines/gl_radio_ther_259_883.pdf.
5. Pryma DA, Mandel SJ: Radioiodine Therapy for thyroid cancer in the era of risk stratification and alternative targeted therapies. J Nucl Med 2014; 55: 1485-1491,  DOI: 10.2967/jnumed.113.131508.
6. Sgouros G, et al: Three-dimensional radiobiological dosimetry (3D-RD) with 124I PET for 131I therapy of thyroid cancer. Eur J Nucl Med Mol Imaging 2011; 38(suppl 1): S41-S47.
7. Kist JW, et al: Recurrent differentiated thyroid cancer: towards personalized treatment based on evaluation of tumor characteristics with PET (THYROPET Study). BMC Cancer 2014; 14: 405.
8. Grewal RK, et al: The effect of posttherapy 131I SPECT/CT on risk classification and management of patients with differentiated thyroid cancer. J Nucl Med 2010; 51(9): 1361-1367.
9. Ho AL, et al: Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013; 368: 623-632.
10. Wilhelm SM, et al: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7: 3129-3140.
     

InFo ONCOLOGY & HEMATOLOGY 2015; 3(6): 10-12.