Until now, there has been no effective therapy for metastatic thyroid cancer that is not amenable to surgery and that does not concentrate iodine. Response rates with chemotherapy have been so low that best supportive care has been the standard of care for most patients. Both VEGFR and BRAFV600E
are thought to play a role in the progression of metastatic thyroid cancer.10
Recent preliminary results presented suggest the utility of using newer targeted therapies in treating metastatic thyroid cancer.9-12
Of the targeted therapies that have recently shown promise in metastatic thyroid cancer, only sorafenib targets both VEGFR and BRAF signaling.
In our trial of sorafenib in patients with metastatic iodine-nonavid thyroid cancer, we observed a partial response rate of 23.3% and a stable disease rate of 53.3%. Median PFS time was estimated to be 18 months. The fact that all but two of our patients had fluorodeoxyglucose uptake by their metastatic lesions on positron emission tomography scan highlights the poor prognosis of our patients.26
In the Eastern Cooperative Oncology Group trial of doxorubicin-containing regimens, PFS time for patients with metastatic iodine-nonavid differentiated thyroid cancer was estimated at 2 months for both arms, and median overall survival time was 8 months.6
Thus, our PFS of 18 months may represent a considerable improvement in outcome for these patients. Biologic agents such as sorafenib are associated with prolonged stable disease and modest tumor shrinkage in solid tumors.27,28
Patients in whom the disease steadily progresses develop complications that arise from enlarging masses, primarily in the neck and chest. Thus, stable disease results in a clinical benefit for many patients. Our evaluation used RECIST criteria, which were originally developed to assess responses to cytotoxic drugs. Recently, there has been debate over the use of RECIST for biologic agents like sorafenib that provide benefit less with tumor shrinkage than with stable disease.29
As is evident on the CT scan in , treatment with sorafenib resulted in a vast improvement in tumor burden in the lung, but because subcentimeter lesions are considered nonmeasurable by RECIST criteria, improvement of this kind is not captured in our overall response rate and points to the need for measures of disease-related symptoms and clinical benefit in future studies. Furthermore, as has been documented previously,30
treatment with VEGFR tyrosine kinase inhibitors can result in cavitation of lesions with internal necrosis without a change in size of the lesion. In these cases, newer methods for ascertaining decreases in contrast-enhancing tumor, not just tumor diameter, are likely to more accurately reflect antitumor activity that results in disease control.
Although all subtypes of thyroid cancer were included in our study, our patient population consisted mostly of patients with differentiated thyroid cancer; 27 of 30 patients had either papillary or follicular subtypes. Thus, our results may not be generalizable to other subtypes of thyroid cancer. Notably, the two patients who had progressive disease as their best response had poorly differentiated/anaplastic disease.
Several adverse events previously described with sorafenib occurred at similar rates.31
The severity of hepatic toxicity in the patient whose liver function continued to deteriorate despite cessation of sorafenib has not been previously reported with sorafenib treatment. The patient refused a liver biopsy, and no infectious cause or drug interaction was identified. Adverse effects were usually manageable with brief holidays from treatment and dose reductions as needed. On reintroduction of the drug, toxicities, if recurrent, were less severe. The frequent interruptions in administration or dose reductions of sorafenib did not prevent most patients from achieving stable disease or a partial response. Because of concern for hypothyroidism in patients treated with other biologic therapies,32
we monitored monthly serum TSH in our patients. Because 33% of the patients on study required alterations in dosing of their thyroid hormone replacement therapy, TSH should be monitored in all thyroid cancer patients receiving sorafenib.
Serum thyroglobulin, a key tumor marker for differentiated thyroid cancers,33
decreased precipitously in patients receiving sorafenib. The decrease preceded tumor shrinkage on CT and, therefore, reflects a biologic response in addition to decreased tumor burden. Thus far, we have not been able to elucidate a relationship between thyroglobulin levels and the degree or duration of response. However, secretion of thyroglobulin is likely affected by alterations in cell signaling caused by sorafenib. Therefore, changes in the thyroglobulin levels in the setting of treatment with sorafenib must be interpreted with caution.
A previous trial of sorafenib presented in abstract form in 200634
was the first to suggest its activity in patients with iodine-refractory metastatic thyroid cancer. The importance of VEGFR inhibition is evident by the encouraging results of other VEGFR inhibitors in trials for thyroid cancer.9-12
Although BRAF signaling (a target of sorafenib) is important in thyroid cancer, its therapeutic significance remains unclear. Genotyping and immunohistochemistry experiments are underway in our laboratory to better elucidate the relationship of BRAF activity and outcome with sorafenib treatment.
In conclusion, long-term disease control in patients with advanced thyroid cancer can be obtained with sorafenib, a well-tolerated oral agent. Development of the multikinase inhibitors marks the first significant progress in treating patients with thyroid cancer in more than 30 years. Treatment with sorafenib provided a clinical benefit (partial response + stable disease) rate of 77% in patients with iodine refractory, metastatic thyroid cancer in whom no other options for treatment were available. These promising results suggest that sorafenib warrants further investigation in the treatment of advanced thyroid cancer.