[Show abstract][Hide abstract] ABSTRACT: The American Thyroid Association appointed a panel of experts to revise the original guidelines: "Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association", based on a review of the relevant literature.
Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality. The original "Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association" provided abundant source material and an excellent organizational structure that served as the basis for the current revisions.
The primary focus of this revision is on the diagnosis and treatment of patients with sporadic and hereditary MTC.
The panel developed 68 evidence-based recommendations to assist clinicians in the care of patients with MTC. The recommendations are based on what the panel designates to be current, rational, and optimal medical practice.
Thyroid: official journal of the American Thyroid Association 03/2015; 25(6). DOI:10.1089/thy.2014.0335 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Thyroid cancer incidence rates in the United States and globally have increased steadily over the last 40 years, primarily due to a tripling of the incidence of papillary thyroid carcinoma (PTC). Objective: The purpose of this study was to analyze trends in demographic, clinical, pathologic, and molecular characteristics of PTC from 1974 to 2009. Design and Setting: We identified and histologically reviewed 469 consecutive cases of PTC from one US institution from 4 preselected periods (1974 to 1985, 1990 to 1992, 2000, and 2009) and assessed BRAF and RAS point mutations and RET/PTC rearrangements among 341 tumors ≥0.3 cm in size. Changes over time were analyzed using polytomous and binary logistic regression; all analyses were adjusted for age and sex. Results: During this period, the median age of patients at diagnosis increased from 37 to 53 years (P < .001) and the percentage of microcarcinomas (≤1.0 cm) increased from 33% to 51% (P < .001), whereas extrathyroidal extension and advanced tumor stage decreased from 40% to 21% (P = .005) and from 43% to 28% (P = .036), respectively. Changes in tumor histopathology showed a decrease in classic PTC and an increase in the follicular variant (P < .001). The proportion of tumors with a BRAF mutation was stable (∼46%) but increased from 50% to 77% (P = .008) within classic papillary PTCs. The proportion of tumors with RAS mutations increased from 3% to 25% and within follicular pattern tumors from 18% to 44% (P < .001). The proportion of RET/PTC rearrangements decreased from 11% to 2% (P = .038). Conclusions: Similar to US national trends, we found an increasing age at diagnosis and greater detection of smaller-sized intrathyroidal PTCs. However, the overall proportion of BRAF mutations remained stable. Sharply rising percentages of the follicular variant histology and RAS mutations after 2000 suggest new and more recent etiologic factors. The increased incidence is not likely to be due to environmental or therapeutic radiation because the percentage of RET/PTC rearrangements decreased.
The Journal of Clinical Endocrinology and Metabolism 02/2014; 99(2):E276-E285. DOI:10.1210/jc.2013-2503 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Thyroid cancer is usually cured by timely thyroidectomy, however the treatment of patients with advanced disease is challenging, as their tumors are mostly unresponsive to conventional therapies. Recently, the malignancy has attracted much interest for two reasons: the dramatic increase in its incidence over the last three decades, and the discovery of the genetic mutations or chromosomal rearrangements causing most histological types of thyroid cancer. Objective: This update reviews the molecular genetics of thyroid cancer and the clinical trials evaluating kinase inhibitors (KIs), in patients with locally advanced or metastatic disease. The update also reviews studies in other malignancies, which have identified mechanisms of efficacy, and also resistance, to specific KIs. This information has been critical both to the development of effective second-generation drugs and to the design of combinatorial therapeutic regimens. Finally, the update addresses the major challenges facing clinicians who seek to develop more effective therapy for patients with thyroid cancer. Results: PubMed was searched from January 2000 to September 2013 using the terms: thyroid cancer, treatment of thyroid cancer, clinical trials in thyroid cancer, small molecule therapeutics, kinase inhibitors, and next generation sequencing. Conclusions: A new era in cancer therapy has emerged based on the introduction of KIs for the treatment of patients with liquid and solid organ malignancies. Patients with thyroid cancer have benefited from this advance and will continue to do so with the development of drugs having greater specificity and with the implementation of clinical trials of combined therapeutics to overcome drug resistance.
The Journal of Clinical Endocrinology and Metabolism 01/2014; 99(5):jc20132622. DOI:10.1210/jc.2013-2622 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. EXPERIMENTAL DESIGN: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess anti-tumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28 day treatment cycles. The dose could be escalated to 150 mg/m2/d after 2 cycles. Radiographic response to vandetanib was quantified using RECIST(v1.0), biomarker response was measured by comparing post-treatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient reported outcome was used to assess clinical benefit. RESULTS: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n=15) the confirmed objective partial response rate was 47% (exact 95%CI, 21%, 75%). Biomarker partial response was confirmed for calcitonin in twelve subjects and for CEA in eight subjects. CONCLUSIONS: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.
Clinical Cancer Research 06/2013; 19(15). DOI:10.1158/1078-0432.CCR-13-0071 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease.
We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade.
Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells.
The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC.
Clinical Cancer Research 07/2012; 18(13):3532-40. DOI:10.1158/1078-0432.CCR-11-2700 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC.
Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.
Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).
[Show abstract][Hide abstract] ABSTRACT: Most medullary thyroid cancers (MTC) express somatostatin receptors; therefore, (111)In-octreotide somatostatin receptor scintigraphy (SRS) may be useful in detecting sites of metastases in children with MTC.
The aim of the study was to evaluate tumor metastases in children and adolescents with MTC using SRS in comparison to conventional imaging.
A case series was conducted as part of baseline evaluation for cancer treatment protocol at the National Institutes of Health Clinical Center.
Eleven patients with a median age of 15 (range, 9-17) yr participated in the study, 10 with histologically proven, metastatic MTC due to the M918T mutation of the RET protooncogene, and one with a known RET polymorphism.
After receiving 0.086 mCi/kg (111)Indium-pentreotide, patients were examined with a single photon emission computed tomography scan 4 and 24 h after injection. Baseline conventional imaging, including computed tomography (neck, chest, abdomen, ± pelvis, adrenals), magnetic resonance imaging (neck), and bone scan, was performed on all patients.
SRS results were compared with conventional imaging.
Five of the 11 patients had abnormal findings on SRS. Of the 53 total target lesions present in the patients, only 24.5% were accurately identified through SRS.
SRS appears to be less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC. SRS incompletely identified sites of tumor and failed to visualize small sites of tumor or liver and lung metastases, and it has a limited role in the evaluation of metastatic disease in pediatric MTC patients.
The Journal of Clinical Endocrinology and Metabolism 12/2011; 97(2):E207-12. DOI:10.1210/jc.2011-2766 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.
[Show abstract][Hide abstract] ABSTRACT: The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family alpha co-receptors (GFRalpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy.
Clinical Cancer Research 12/2009; 15(23):7119-23. DOI:10.1158/1078-0432.CCR-08-2742 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians.
Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality.
Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and handling of devascularized parathyroid glands), initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy), management of persistent or recurrent MTC (including the role of tumor marker doubling times, and treatment of patients with distant metastases and hormonally active metastases), long-term follow-up and management (including the frequency of follow-up and imaging), and directions for future research.
One hundred twenty-two evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what we believe is current, rational, and optimal medical practice.
Thyroid: official journal of the American Thyroid Association 07/2009; 19(6):565-612. DOI:10.1089/thy.2008.0403 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine Needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational Web site and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document addresses follow-up procedures and therapeutic options for suggested diagnostic categories. Follow-up options for "nondiagnostic" and "benign" thyroid aspirates are given. The value of ultrasound examination in the follow-up of "nondiagnostic" and "benign" thyroid aspirates is discussed. Ultrasound findings requiring reaspiration or surgical resection are described as are the timing and length of clinical and ultrasonographic surveillance for cytologically "benign" nodules. Options for surgical intervention are given for the diagnostic categories of "atypical/borderline," "follicular neoplasm," "suspicious for malignancy" and "malignant" (http://thyroidfna.cancer.gov/pages/info/agenda/).
[Show abstract][Hide abstract] ABSTRACT: The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine-Needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational website and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters regarding training for the performance of thyroid FNA via palpation; training for the performance of thyroid FNA via ultrasound imaging, and credentialing/re-credentialing for the performance of a thyroid FNA. (http://thyroidfna.cancer.gov/pages/info/agenda/)
[Show abstract][Hide abstract] ABSTRACT: Properly performed clinical trials provide a foundation for evidence-based medical practice. The surgeon plays a central role in the management of patients with malignant solid tumors, including thyroid cancer, because operative extirpation of the malignancy is the essential first step in effective therapy. This article discusses the role of the surgeon in the clinical research of thyroid cancer and also reviews the important clinical trials that have influenced the treatment of patients with thyroid cancer. Recent discoveries defining the genetic mutations underlying the various types of thyroid cancers have led to the development of targeted therapies. These chemical compounds, which are now being evaluated in clinical trials, hold great promise for the treatment of patients with locally advanced and distant metastatic disease. The surgical investigator also plays an important role in procuring tumor tissue from patients in clinical trials. The molecular analysis of these tissues is of critical importance in selecting specific therapies and predicting patient response and prognosis.
World Journal of Surgery 05/2007; 31(5):987-95. DOI:10.1007/s00268-006-0908-5 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Since the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that "prophylactic surgery" would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by "prophylactic surgery." CONCLUSIONS: In this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.
World Journal of Surgery 04/2007; 31(3):450-64. DOI:10.1007/s00268-006-0616-1 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple endocrine neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.
Annual Review of Medicine 02/2007; 58:253-65. DOI:10.1146/annurev.med.58.100305.115303 · 15.48 Impact Factor