A 66-year-old woman with an 80-gm toxic multinodular goiter underwent thyroidectomy because of compressive symptoms with the surgical pathology showing a 3.5 cm follicular variant of papillary thyroid carcinoma with lymphatic permeation. She was ablated with 99.5 mCi of I-131, and a posttherapy scan showed only four foci of uptake in the thyroid bed. Despite thyroid stimulating hormone suppressive therapy with levothyroxine, her thyroglobulin level remained 2.5 ng/mL and increased to 4.8 ng/mL over the next year.

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Kishore M. Lakshman

Stephanie L. Lee

One year after initial therapy, a hypothyroid whole body I-123 scan with elevated TSH of 35.5 uIU/mL and thyroglobulin of 22.6 ng/mL revealed no abnormal radioiodine uptake. She received 103.3 mCi I-131 for localization purposes, but her posttreatment scan was negative for metastatic disease. Her slowly increasing thyroglobulin level entered an accelerated phase about two years after diagnosis (figure 1). Thorax CT scans showed two to three small inflammatory pulmonary nodules between 2 mm and 3 mm that disappeared and reappeared in different areas of the lung on different scans; a neck MRI was unremarkable. After her thyroglobulin rose to 32.4 ng/mL, a PET/CT showed multiple bilateral hypermetabolic left neck nodes, but after bilateral neck dissection all the lymph nodes were benign and thyroglobulin levels remained elevated.

During the next year, her thyroglobulin levels continued to rise but she remained asymptomatic. A CT thorax almost four years after initial diagnosis showed numerous new pulmonary nodules; the largest measured 6 mm. After stimulation with recombinant human TSH stimulation (40.9 uIU/mL), the thyroglobulin rose to a very high level of 2,008 ng/mL, but both an I-123 whole body scan and PET/CT scan did not show any abnormal uptake. The CT scan demonstrated that the pulmonary nodules had grown, and the largest nodule was 10 mm. The patient had a left upper lobe pulmonary wedge resection that confirmed multifocal metastatic papillary thyroid carcinoma.

The patient was started on sorafenib 400 mg twice a day because of progressive disease demonstrated by new, growing pulmonary nodules and rising thyroglobulin levels. Her largest measurable tumor was just 1 cm in diameter and, therefore, did not meet the Response Evaluation Criteria in Solid Tumors criteria to enter a clinical trial. After two months of treatment, her thyroglobulin level fell from 192 ng/mL to 23 ng/mL and was accompanied by a significant decrease in the size and numbers of the small pulmonary nodules on CT scan (figures 2A and 2B). The largest pulmonary nodule decreased from 10 mm to 4 mm in diameter. Interestingly, with time, her pulmonary nodules have remained stable and smaller than before sorafenib treatment but her thyroglobulin levels have risen to a new plateau close to her original thyroglobulin level (figures 1 and 2A). Repeat PET/CT scans have not revealed any new or progressive disease. Investigators of the phase 2 trials of sorafenib and noniodine avid thyroid carcinoma have suggested using thyroglobulin levels cautiously during therapy as it may no longer reflect tumor burden. We believe that despite the rise in thyroglobulin, this patient’s tumor burden is stable after two years of treatment with sorafenib and has extended her life expectancy.

The above case represents the complexity in treatment of thyroid cancers, especially when they are progressive and iodine nonavid. New therapies on the horizon provide hope for patients with previously untreatable disease.

Activation of receptor tyrosine kinase pathway (Ras-Braf-MEK-MAPK-ERK), whether by rearrangement or gene amplification, appears to be specific for the transformation of thyroid follicular cells into papillary thyroid carcinomas. Activating mutations of the serine/threonine kinase BRAF and genetic rearrangements of the RET tyrosine kinase genes results in a constitutive activation of this signaling pathway accounting for the majority of papillary thyroid carcinoma. Approximately 30% of follicular thyroid carcinomas have an activating mutation of the RAS oncogene. In addition to RAS and RET signaling in thyroid carcinomas, overexpression of vascular endothelial growth factor and platelet-derived growth factor receptors have been described in thyroid carcinomas.

Sorafenib is an oral, small-molecule multityrosine kinase inhibitor that was approved by the FDA in 2005 for the treatment of advanced renal cell carcinoma. The molecular targets of sorafenib include several tyrosine kinases involved in tumorogenesis (Braf kinase, Flt-3, c-Kit and RET) and angiogenesis (VEGFR1, 2 and 3, and PDGFRΒ). Sorafenib inhibits tumor growth and angiogenesis by inhibiting cellular proliferation and inducing apoptosis. The repertoire of tumor types for which sorafenib could be applicable is rapidly expanding due to its multikinase inhibitory profile and its potential effects against cancers with multiple molecular drivers, such as papillary thyroid cancer.

Two medium-sized, open-label, phase-2 trials with sorafenib published in the last year showed exciting results in patients with progressive, metastatic, noniodine responsive thyroid cancer. The two studies demonstrated similar results, with a partial response (30% decrease in measurable disease) in 23% and 15% of patients, respectively, but many other patients showed stable disease. The clinical benefit rates (partial response plus stable disease) in the two studies were 77% and 71% with a progression-free period of 70 weeks and 79 weeks. Adverse events associated with the drug included fatigue, palmar-plantar erythema, stomatitis, musculoskeletal pain and hypertension. One-third of patients required thyroid hormone therapy adjustment, previously described with this type of therapy. One death from liver failure was reported in the two trials. Similar results were reported in an open-label, phase-2 study with motesanib, an inhibitor of VEGF, PDGF and KIT.

These reports show promise for these targeted agents to stabilize the majority of patients with progressive, noniodine responsive metastatic disease who have no other treatment options. Although not specifically approved for thyroid cancers, it may be considered in selected patients with progressive, noniodine responsive metastatic disease who do not qualify for clinical trials. More studies are needed to demonstrate long-term safety and efficacy and to identify new, more effective drugs that will not only stabilize but eradicate advanced thyroid cancers.

It is extremely critical to enroll eligible patients with progressive differentiated and medullary thyroid carcinomas into phase 3 trials with multikinase inhibitors to prove their effectiveness.

Kishore M. Lakshman, MD, MPH, is a Fellow in Endocrinology in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center.

Stephanie L. Lee, MD, PhD, is Associate Chief in the Section of Endocrinology, Diabetes and Nutrition and Associate Professor of Medicine at Boston Medical Center.

For more information:

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