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BRIEF REPORT |
Divisions of Hematology and Oncology (E.M., M.D.R., L.K., P.S., D.A., M.H.S.), Endocrinology, Metabolism, and Diabetes (R.T.K., M.D.R.), Nuclear Medicine (R.T.K.), and Human Cancer Genetics (M.D.R.); Departments of Internal Medicine (E.M., R.T.K., M.D.R., L.K., P.S., D.A., M.H.S.) and Radiology (R.T.K.), The Ohio State University Thyroid Cancer Unit (R.T.K., M.D.R., P.S., D.A., M.H.S.), The Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio 43210; and Departments of Endocrine Neoplasia and Hormonal Disorders (M.J.K, N.B., S.I.S.), Thoracic/Head and Neck Medical Oncology (M.K.), and Diagnostic Radiology (R.M.), University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
Address all correspondence and requests for reprints to: Manisha H. Shah, M.D., A 438 Starling-Loving Hall, 320 West 10th Avenue, Columbus, Ohio 43210. E-mail: manisha.shah{at}osumc.edu.
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Abstract |
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Objective: The objective of the study was to evaluate the efficacy of celecoxib, a selective COX-2 inhibitor, in treating patients with progressive metastatic differentiated thyroid cancer (DTC) and to explore the relationship of clinical response to tumor COX-2 expression with immunohistochemistry in a subset of patients.
Design: The study was a prospective phase II trial with Fleming single-stage design powered at 80% with a 5% rejection error to detect more than 20% progression-free survival at 12 months.
Setting: Ambulatory patients were from tertiary referral academic medical centers.
Patients: Patients in the study had progressive metastatic DTC and had failed prior standard therapy.
Intervention: Patients were treated with celecoxib 400 mg orally twice a day for 12 months.
Main Outcome Measure: The main outcome measure was progression-free survival at 12 months of treatment using Response Evaluation Criteria in Solid Tumors and/or serum thyroglobulin.
Results: Twenty-three of 32 patients experienced progressive disease or stopped therapy due to toxicity, thus fulfilling the intent-to-treat study endpoint for celecoxib failure. One patient achieved partial response, and one patient completed 12 months of therapy progression-free. The patient with partial response was on therapy along with seven other patients when the study was terminated.
Conclusions: Celecoxib 400 mg orally twice per day fails to halt progressive metastatic DTC in most patients.
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Introduction |
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Activation of cyclooxygenase-2 (COX-2), an enzyme overexpressed in many cancers, promotes tumor development and progression. Indeed, selective inhibition of COX-2 reduces formation and progression of tumors in both animal models and humans. Expression of COX-2 mRNA and protein levels are increased in thyroid cancer tissue compared with nonneoplastic and benign thyroid tissues (8, 9, 10). Furthermore, in vitro studies demonstrated that expression of either RET/PTC1 or RET/PTC3 (two common oncogenes in human PTC) in rat PCCL3 thyroid cells increased COX-2 mRNA levels (11). Based on these observations, we performed a phase II trial of high-dose celecoxib, a selective COX-2 inhibitor, in patients with progressive metastatic DTC who had failed prior standard therapy including RAI131 and looked for a correlation between clinical response and COX-2 protein expression in a subset of these patients.
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Subjects and Methods |
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Eligibility criteria
Patients with histologically confirmed PTC, FTC, HTC, or insular thyroid carcinoma who failed or did not qualify for standard therapy including RAI131 were eligible. Patients were required to have measurable metastatic disease (including neck lymph nodes) and/or elevated serum thyroglobulin (Tg) levels with negative anti-Tg antibodies. Disease progression based on either measurable disease or serum Tg levels was required during the preceding 1 yr. Surgery and chemotherapy within 1 month, RAI131 therapy within 6 months, and external beam radiation within 3 months before study entry were not allowed. Patients receiving conventional doses of celecoxib or rofecoxib for arthritis or dysmenorrhea had this therapy withheld for at least 2 wk before study entry. Patients were required to have adequate organ function and an Eastern Cooperative Oncology Group performance status of 0–2. Patients with endoscopic evidence of an active gastric/duodenal ulcer, gastric/duodenal perforation, or upper GI bleeding within the past 6 months were excluded.
Study design
Oral celecoxib 400 mg twice a day was administered for 12 months. TSH suppressive therapy was maintained in all patients. History, physical examination, toxicity assessment, complete blood counts, and serum chemistries were performed at baseline and every 4 wk during therapy. Tumor response evaluation using computed tomography scan and serum Tg (along with TSH and anti-Tg antibody) was performed within 28 d before beginning treatment, every 12 wk during treatment, and 4–8 wk after treatment completion.
Objective response was assessed according to Response Evaluation Criteria in Solid Tumors (12), and adverse events were graded using the revised National Cancer Institute Common Toxicity Criteria version 2.0 (13). The following criteria were used to define clinical response for serum Tg level: complete response (CR) was the decrease to undetectable levels in the absence of anti-Tg antibodies; partial response (PR) was a 20% or more decrease in serum Tg level on two different occasions drawn at 4-wk intervals; progressive disease (PD) was a 20% or more increase in serum Tg level on two different occasions drawn at 4-wk intervals; and stable disease (SD) was neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD.
Tg assays
Serum Tg measurements were performed by the same laboratory using the same method for each individual patient, although more than one Tg assay [Nichols chemiluminescence immunometric (catalog no. 60-4240) or Advantage Tg assay (catalog no. 62-7035)] was used between patients. Serum samples were frozen and reassayed with the latest Tg sample if deemed necessary.
Immunohistochemistry (IHC)
Paraffin-embedded tumor tissue blocks collected at the time of prior surgery or biopsy were obtained. COX-2 analysis by IHC was performed using the methods previously described (14). Three sections per tumor sample were assessed, and all the samples were processed at the same time. Slides were read by two evaluators who were blinded to the clinical status. Slides were scored on a 0 to +4 scale, with 0 indicating negative and +4 indicating intensely positive tissue staining for COX-2.
Statistical analysis
The primary objective of this open-label, Fleming single-stage phase II trial was to evaluate the efficacy of celecoxib in patients with progressive metastatic DTC by assessing progression-free survival at 12 months. Based on historic controls, we estimated that celecoxib would be considered ineffective if the proportion of patients rendered progression-free after 12 months of therapy was less than 20%. The drug would be recommended for further study, with a 5% rejection error and a power of 80%, if 13 or more of the 35 total patients were progression-free at 12 months.
A secondary objective of this study was to correlate clinical response with COX-2 protein expression tumor samples. The small sample size in this phase II trial was expected to limit our ability to perform inferential tests, and, thus, these tests were performed in an exploratory manner.
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Results |
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Thirty-two patients were accrued between March 2003 and September 2004 from The Ohio State University Comprehensive Cancer Center (n = 25) and University of Texas M.D. Anderson Cancer Center (n = 7). Median age was 65 (42–89) yr, and 19 patients were female. Histological subtypes included PTC (n = 21), FTC (n = 7), HTC (n = 3), and insular thyroid carcinoma (n = 1). Although the most common metastatic sites were the lung (n = 29) and lymph nodes (n = 16), few patients had bony (n = 8) and liver (n = 2) involvement. Evaluation of response to therapy was based on changes in Tg levels in the absence of measurable disease (n = 8), on changes in target lesions alone (n = 6), and on the combination of Tg levels and target lesions in the remaining 18 patients.
Treatment administered
Study accrual was closed on November 18, 2004 after the primary endpoint of the study had been reached. At that time, 23 of 32 patients were off study: 20 with disease progression and three due to toxicities (Fig. 1A
); thus, fewer than 13 patients could be progression-free at 12 months even if the study was fully recruited to 35 patients. The median duration of therapy for all 32 patients was 13 wk (range, 2–52). Eight patients were still receiving therapy for 10–45 wk when the Food and Drug Administration, National Cancer Institute, and Pfizer Inc. released information regarding the increased risk of cardiovascular complications with high doses of celecoxib (15). In light of this new information and the fact that the study was negative in regard to its primary endpoint, the decision was made to terminate treatment in those eight patients and close the study on December 17, 2004.
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All efficacy data are reported using the intent-to-treat analysis and are presented in Fig. 1A
. Only one (3%) patient completed 12 months of therapy and was progression-free at 12 months. The response to therapy in this PTC patient was based solely on changes in target lesions in lungs and lymph nodes, as interfering anti-Tg antibodies prevented Tg response assessment. In regard to the overall best response, no CR was observed. One (3%) patient with PTC achieved PR at 6 months according to the target lesions and Tg, and the PR was maintained at 9 months according to PR of the target lesions and non-PD Tg (Fig. 1B). This patient stopped treatment after 9 months as a result of study termination.
Adverse events
All adverse events with possible, probable, or definite attribution to celecoxib are reported in Table 1. No grade 4 adverse events or thromboembolic, cardiac, or gastrointestinal bleed events were observed. Injury or excision of parathyroid tissue at the time of thyroidectomy and RAI131 treatment appear to account for the high rates of preexisting hypocalcemia and lymphopenia, respectively. New occurrences of hypocalcemia or lymphopenia were uncommon and mild.
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The sample size was limited by occurrence of objective responses in only two patients (one patient had PR and other patient had SD up to 12 months). We performed COX-2 protein expression studies in tumor tissue obtained from two responders and three randomly selected nonresponder PTC patients on this study. There was no difference in cytoplasmic COX-2 expression among three tumor sections per given patient. However, heterogeneity was observed within all positive staining samples. High COX-2 expression was observed in both responders with overall scores of +3. In two of the three nonresponders examined, COX-2 expression was largely negative with overall scores of +1. However, the third nonresponder patient had an overall score of +2–3.
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Discussion |
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). Biases against finding a celecoxib effect include accrual of five patients with PD despite use of celecoxib (or related agents) at much lower dosages in the months before study enrollment, as this allowance may have selected for patients with celecoxib-resistant disease. The rationale for including these patients was that celecoxib at a dose of 400 mg twice daily was associated with significant regression of colorectal adenomas in patients with familial adenomatous polyposis, an effect not seen with 100 mg twice daily (16). Although the study is negative in respect to the primary endpoint, achievement of a durable PR and a prolonged SD for 12 months in two patients is intriguing given the well-tolerated nature of celecoxib. However, achievement of transient (less than 1-yr duration) SD in about one third of our patients cannot be definitively attributed to celecoxib, given the single-arm study design and relatively slow-growing nature of this disease. High COX-2 expression in the tumors was observed in both responders as well as one of the three nonresponders examined in our study. Given the small sample size, the small number of responders, and the subjective nature of IHC interpretation, we cannot draw any conclusions regarding the correlation between COX-2 protein expression and tumor response.
The lack of significant CR or PR could indicate either that celecoxib is more cytostatic than cytocidal or that it is ineffective against metastatic DTC. In most preclinical studies, selective COX-2 inhibitors reduced tumor growth as opposed to induction of tumor regression (17). Similar to other carcinomas, it is also possible that activation of the COX-2 enzyme is required in the early stages of cancer progression rather than in advanced stages.
Finally, successful accrual and timely completion of our phase II clinical trial in this relatively uncommon patient population of refractory progressive DTC demonstrates feasibility of such trials. With the recent discovery of novel targets in DTC, we anticipate a rapid increase in phase II clinical trials in the near future.
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Acknowledgments |
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Footnotes |
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First Published Online March 7, 2006
1 E.M. and R.T.K. are co-first authors. 
Abbreviations: COX-2, Cyclooxygenase-2; CR, complete response; DTC, differentiated thyroid cancer; FTC, follicular thyroid carcinoma; HTC, Hürthle thyroid cell carcinoma; IHC, immunohistochemistry; PD, progressive disease; PR, partial response; PTC, papillary thyroid carcinoma; RAI131, radioactive iodine; SD, stable disease; Tg, thyroglobulin.
Received November 15, 2005.
Accepted March 1, 2006.
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References |
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This article has been cited by other articles:
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  J. A Woyach and M. H Shah New therapeutic advances in the management of progressive thyroid cancer Endocr. Relat. Cancer, September 1, 2009; 16(3): 715 - 731. [Abstract] [Full Text] [PDF]
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