Abstract
Background:
Rosiglitazone is a peroxisome proliferator–activated receptor (PPAR) gamma agonist that has shown promise as both an antiproliferative and redifferentiating agent for the treatment of thyroid cancer in preclinical studies. We investigated the efficacy and side effects of rosiglitazone therapy in patients with differentiated thyroid cancer of follicular cell origin that fails to take up radioiodine or is unresectable.
Methods:
Twenty patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks).
Results:
Five of 20 patients had a positive radioiodine scan after rosiglitazone treatment. Four patients had radioiodine uptake in the neck and one patient had uptake in the pelvis. Unstimulated thyroglobulin levels after rosiglitazone treatment increased in five patients, remained stable in 12 patients, and decreased in three patients. Seven patients had progressive disease on follow-up cross-sectional imaging; six patients in the size and number of lung metastasis and two patients in the size of the neck tumors. Overall, five patients had a partial response (decreased thyroglobulin or positive radioiodine uptake), three patients had stable disease (no change in thyroglobulin and radioiodine uptake status), and 12 patients had disease progression (increased thyroglobulin). By RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up. The mean follow-up time after protocol treatment was 12 months (median 12 months).
Conclusions:
Our findings suggest that rosiglitazone therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with differentiated thyroid cancer but this did not result in clinically significant response on long-term follow-up. Moreover, no patients had response to rosiglitazone therapy by anatomic imaging studies.
Introduction
Redifferentiating agents such as peroxisome proliferator–activated receptor (PPAR) gamma agonists, histone deacetylase (HDAC) inhibitors, and demethylating agents have a direct antineoplastic effect and induce increased radioiodine uptake in preclinical models of thyroid cancer (2 –9). Specifically, PPAR gamma agonists prevent tumorigenesis in transgenic mouse models, inhibit cellular proliferation by causing cell cycle arrest and apoptosis, induce redifferentiation, and inhibit angiogenesis (5,7,10,11). In differentiated thyroid cancer, PPAR gamma expression is dysregulated (12 –14). Furthermore, a chromosomal rearrangement of the PAX8 gene with PPAR gamma (PAX8/PPAR gamma) has been observed in about 50% of follicular thyroid cancer and 17% of follicular adenoma (13,15). The PAX8/PPAR gamma rearrangement likely results in loss of the tumor suppressor function of wild-type PPAR gamma (15,16). Rosiglitazone is a potent PPAR gamma agonist, which belongs to the thiazolinedione class of drugs. The thiazolinediones activate the PPAR gamma receptor and their antineoplastic and redifferentiation effects are being studied in a variety of human cancers (17 –20).
In the present study, we investigated the efficacy and side effects of rosiglitazone therapy in patients with differentiated thyroid cancer of follicular cell origin that fails to take up radioiodine or is unresectable.
Methods
Patient selection
The study entry criteria are summarized in Table 1. All patients were required to have histologically proven differentiated thyroid cancer of follicular cell origin. Patients were also required to have persistent or recurrent differentiated thyroid cancer as indicated by an increasing serum thyroglobulin level and negative radioiodine scans or unresectable tumor. The study was approved by the Committee on Human Research at the University of California, San Francisco. Written informed consent was obtained from all patients prior to starting protocol treatment. This trial was registered with the National Institute of Health (ClinicalTrials.gov) public trials registry. Before study entry, all patients had a complete history and physical examination, a noncontrast chest computed tomography scan, a neck and mediastinal magnetic resonance imaging, and a neck ultrasound.
TSH, thyrotropin.
Treatment
Rosiglitazone (Avandia, GlaxoSmithKline, Philadelphia, PA) 4 mg was given orally every day for 7 days and then the dosage was increased to 8 mg every day for 49 days. At the beginning of rosiglitazone treatment, thyroxine was discontinued; the patients were started on triiodothyronine 25 μg orally twice a day for 6 weeks. For the last 2 weeks of rosiglitazone treatment, triiodothyronine was discontinued and a low iodine diet was begun. The 24-hour urinary iodine level was measured and was lower than 30 μg/L in all patients before radioiodine (131I) scanning (reference range 42‱350 μg/L; performed at Quest Diagnostics-Nichols, San Juan Capistrano, CA). After 8 weeks of rosiglitazone treatment, a whole body 131I scan was performed with 3–4 mCi of 131I.
Assessment of toxicity and response
Patients were monitored biweekly by physical examination and laboratory tests for toxicity and side effects of the study drug (cold-like symptoms and headache, hypoglycemia, congestive heart failure, peripheral edema, hepatotoxicity, and anemia). Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) 2.0.16.
The primary endpoint of the study was to determine radioiodine uptake status and thyroglobulin levels before and after rosiglitazone treatment. The secondary endpoint was to measure rosiglitazone-associated side effects. After completion of the protocol treatment and radioiodine ablation, assessment of response to rosiglitazone therapy was performed based on the following criteria. A complete response was defined as increased radioiodine uptake on whole body scan and thyroglobulin levels lower than 10 ng/mL off thyroid hormone. A partial response was classified as either increased radioiodine uptake or a decreased thyroglobulin level. Stable disease was defined as no change in radioiodine uptake status or no change in thyroglobulin level. Progressive disease was characterized as an increase in measurable tumor mass or thyroglobulin level, or both. Serum basal and stimulated thyroglobulin levels were measured at entry, stimulated after 8 weeks of rosiglitazone treatment, and basal thyroglobulin levels at 3 months, 6 months, and 1 year follow-up. The target enrollment for this study was 20 subjects and the results in the first 10 patients enrolled have been previously reported (21). An analysis of the overall response rate (combining complete and partial responses) was computed in patients who completed treatment. At 3 months follow-up after entry and treatment with rosiglitazone and radioiodine ablation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) guideline to determine response (22).
Results
Twenty-one patients were enrolled in the study and 20 patients completed the treatment. Patient clinical characteristics are summarized in Table 2. Sixteen patients had papillary thyroid cancer, one patient had follicular thyroid cancer, two patients had Hürthle cell cancer, and one patient had follicular variant of papillary thyroid cancer. The mean follow-up time after protocol treatment was 12 months (median 12 months).
The intended treatment dose was 200 ± 20 mCi in all patients except one patient who received 50 mCi due to a low body weight.
Five of 20 patients had a positive radioiodine scan after rosiglitazone treatment. Four patients had radioiodine uptake in the neck and one patient had uptake in the pelvis. One of the five patients with uptake in the neck had known diffuse lung metastasis, which was not radioiodine positive after rosiglitazone treatment. Unstimulated thyroglobulin levels after rosiglitazone treatment increased in five patients, remained stable in 12 patients, and decreased in three patients. Seven of 13 patients had progressive disease on follow-up cross-sectional imaging; six patients in the size and number of lung metastasis and two patients in the size of the neck tumors. Overall, five patients had a partial response, three patients had stable disease, and 12 patients had disease progression. By RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up.
No patient developed any toxicity or adverse event associated with rosiglitazone treatment. One patient had to withdraw from the study due to narcotic overdose. One patient 1 month after rosiglitazone treatment and radioiodine therapy was found to have extensive choroidal retinal atrophy in both eyes. The patient had previously known blind spots and this was likely a chronic condition not associated with rosiglitazone and radioiodine therapy. Another patient developed bleeding at his tracheotomy site from mechanical erosion in the great vessels.
Discussion
There have been limited effective treatment alternatives for patients with advanced and progressive differentiated thyroid cancer who fail conventional therapy with surgery, radioiodine, and thyroid hormone for TSH suppression. In preclinical studies, redifferentiating agents in thyroid cancer have been studied as possible treatment alternatives for advanced thyroid cancer. Redifferentiating agents such as PPAR gamma agonists have direct antineoplastic effects and may make tumors radioiodine sensitive. Although PPAR gamma agonists such as rosiglitazone showed promise as treatment for advanced or progressive differentiated thyroid cancer in preclinical models of thyroid cancer, we found partial response in only 25% of patients who received rosiglitazone therapy for 8 weeks.
Response to therapy in patients with differentiated thyroid cancer has been evaluated using serum thyroglobulin levels which is an excellent marker for recurrent or persistent disease and is often elevated before there is even any evidence of disease on cross-sectional imaging. It is, however, unclear whether redifferentiating agents could increase thyroglobulin levels as a result of increasing expression of this gene, which is a differentiation marker of thyroid cancers of follicular cell origin, or should decrease the serum levels as a result of a decrease in tumor burden. We used the latter rationale when defining response because ultimately tumor burden should be decreased on long-term follow-up. We also used radioiodine uptake status as a response criteria because one of the main advantages of redifferentiation therapy in thyroid cancer is to make radioiodine-resistant tumors responsive. Although we had five patients who had positive uptake of 131I, the amount of uptake was clinically insignificant and one patient who had cervical uptake did not have uptake in the lung metastasis. Using RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up.
Our previous report in the first 10 patients enrolled in the study suggested that the radioiodine uptake status and serum thyroglobulin levels after rosiglitazone treatment were not related to the amount of PPAR gamma expression level in the tumor (21). A recent study suggests that the level of PPAR gamma in papillary thyroid cancer by immunohistochemistry was related to whether there was uptake after rosiglitazone therapy (23). It is unclear if the level of PPAR gamma expression in tumor determines whether rosiglitazone therapy would induce (131I) uptake because the existing tumor burden would need to be sampled and not the previous or primary tumor samples, given that differentiated thyroid cancers have a heterogeneous cell population and genetic alterations.
There are several limitations to our study. The dose used for rosiglitazone may be ineffective. Preclinical studies, however, show the serum concentrations that have antineoplastic and redifferentiating effects in vitro could be achieved in serum with an oral dose of 8 mg of rosiglitazone (7,10). The study cohort may also be relatively too small to detect a partial or complete response that is 20% or less. Lastly, the definition of using radioiodine uptake status as a response criteria may not be justified as the long-term effect or clinical significance that would result from such a response is unclear. This is the reason we also determined the response rate by using the RECIST criteria at 3 months follow-up, which was disappointing.
In summary, we found that rosiglitazone therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with differentiated thyroid cancer but this did not result in clinically significant response on long-term follow-up. Moreover, no patients had response to rosiglitazone therapy by anatomic imaging studies.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.