Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer.

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.

A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer.

BACKGROUND: Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that has been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of human cancers including thyroid cancer. METHODS: Ten 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). The levels of PPARgamma receptor mRNA and protein expression were determined in the patient's neoplasm. RESULTS: Of 10 patients, 4 had positive radioiodine scans after rosiglitazone therapy with uptake in the neck in 3 patients and in the pelvis in 1 patient. After treatment, the serum thyroglobulin level decreased in 2 patients, increased in 5 patients, and was stable in 3 patients. No patient developed clinically important toxicity associated with rosiglitazone treatment. We found no relationship in the level of PPARgamma mRNA and protein expression in patients who had radioiodine uptake compared with those who did not. CONCLUSIONS: Our findings suggest that rosiglitazone treatment may induce radioiodine uptake in some patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. We found no relationship between the expression level of the PPARgamma mRNA and protein in the neoplasm and radioiodine uptake status after rosiglitazone therapy, questioning the potential pathway of effect.

Extent of disease and practice patterns for medullary thyroid cancer.

BACKGROUND: There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC. STUDY DESIGN: Patients with MTC (n=1,070) were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I=1973 to 1979, group II=1980 to 1986, group III=1987 to 1993, and group IV=1994 to 2000) were compared for changes in demographics, extent of disease, and treatment. RESULTS: Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p=0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p < 0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually. CONCLUSIONS: There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment.

Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is rare but is one of the most aggressive human malignancies. Several prognostic factors have been observed in patients with ATC, and some experts advocate aggressive multimodal therapy in selected patients. However, it is unclear whether such an approach significantly improves survival. The authors analyzed prognostic factors and treatment outcomes in patients with ATC reported in the National Cancer Institute's Surveillance, Epidemiology, and End Results data base. METHODS: The cohort consisted of 516 patients with ATC reported to 12 population-based cancer registries between 1973 and 2000. Demographic, pathologic, and treatment data were used for univariate and multivariate survival analyses. RESULTS: The mean patient age at diagnosis was 71.3 years, and there were 171 men and 345 women. Eight percent of patients had intrathyroidal tumors, 38% had extrathyroidal tumors and/or lymph node invasion, and 43% of patients had distant metastasis. The average tumor size was 6.4 cm (range, 1-15 cm). Sixty-four percent of patients underwent surgical resection of their primary tumor, and 63% received external beam radiotherapy. The overall cause-specific mortality rate was 68.4% at 6 months and 80.7% at 12 months. Univariate analysis showed that age < 60 years, female gender, intrathyroidal tumor, external beam radiotherapy, surgical resection, and combined surgical resection of tumor and radiotherapy were associated with a lower cause-specific mortality. On multivariate analysis, only age < 60 years, an intrathyroidal tumor, and the combined use of surgical and external beam radiation therapy were identified as independent predictors of lower cause-specific mortality. CONCLUSIONS: Although most patients with ATC had an extremely poor prognosis, patients < 60 years old with intrathyroidal tumors survived longer. Surgical resection with external beam radiotherapy for ATC was associated with lower cause-specific mortality.

Follicular thyroid carcinoma: histology and prognosis.

BACKGROUND: Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy after papillary thyroid carcinoma. The authors studied the clinical course of 132 patients with FTC to determine whether there was a direct relation between the histologic degree of invasion, tumor recurrence, and patient survival. METHODS: The 132 patients in the study population underwent 182 thyroid carcinoma-related operations, and their mean follow-up was 7.5 years (median:,6 years; range, 0-39 years). The following criteria were used to define malignant follicular neoplasms: 1) minimally invasive, tumor invasion through the entire thickness of the tumor capsule; 2) moderately invasive, tumor with angioinvasion (with or without capsular invasion); and 3) widely invasive, broad area or areas of transcapsular invasion of thyroid and extrathyroidal tissue. Forty-five of 119 patients (37.8%) presented with minimally invasive FTC (capsular invasion only), 50 patients (42%) presented with moderately invasive FTC (angioinvasion with or without capsular invasion), and 24 patients (20%) presented with widely invasive FTC. At presentation, 12 patients (9%) had distant metastases, and 8 patients (6%) had lymph node metastases. RESULTS: Excluding 12 patients who presented with distant metastases, 21 patients (16%) developed recurrent metastases 6 months after their initial treatment. Among 45 patients with capsular invasion only, 6 patients (13%) developed recurrent or persistent disease, and 5 patients (11%) died. Of the 50 patients who had angioinvasion with or without capsular invasion, 10 patients (20%) developed recurrent or persistent disease, and 7 patients (14%) died. Patients who had angioinvasion with or without capsular invasion had a less favorable prognosis compared with patients who had capsular invasion only (P < 0.0001). Among patients who had widely invasive FTC, 9 of 24 patients (38%) developed recurrent disease, and 8 patients (33%) died; in addition, 7 of the other 24 patients (29%) had persistent disease and died. The overall death rate for patients with widely invasive FTC was 62%. Patients with persistent disease had a poorer prognosis compared with patients who had recurrent disease (P < 0.0001). Twenty-eight patients (21%) in the entire group died of FTC. CONCLUSIONS: In the current retrospective investigation, the authors demonstrate that patients with minimally invasive FTC (capsular invasion only) had a slightly better survival rate at 5 years (98%) compared with patients who had angioinvasion with or without capsular invasion (80%) and had better survival compared with patients who had widely invasive FTC (38%). Other (but not all) reports in the literature support the findings that FTC with angioinvasion is more aggressive than FTC with only capsular invasion yet is less aggressive than widely invasive FTC. The authors conclude that FTC no longer should be classified as either minimally invasive or widely invasive; rather, they recommend classifying FTC as minimally invasive, moderately invasive, or widely invasive, because prognosis varies according to these groupings.