Thyroid cancer epidemiology and prognostic variables.

Thyroid cancer comprises a broad spectrum of diseases with variable prognoses. Although most patients with this disease have excellent overall survival, there are some who do not fare so well. With the worldwide increase in incidence, the need to identify which tumours pose the greatest risk to patients is more acute than ever. This paper will discuss this rising trend in incidence with an analysis of the possible reasons for the increase. In addition, the paper will explore the factors that portend a worse prognosis for the individual patient. Finally, the limitations of the current staging systems will be discussed, with particular emphasis on why they are not as informative in the management of patients with thyroid cancer.

Cost-effectiveness of using recombinant human TSH prior to radioiodine ablation for thyroid cancer, compared with treating patients in a hypothyroid state: the German perspective.

OBJECTIVE: This investigation evaluated the cost-effectiveness of radioiodine remnant ablation following preparation with recombinant human TSH (rhTSH), compared with the standard preparation, whereby patients are rendered hypothyroid. DESIGN: The economic evaluation relates to patients with well differentiated thyroid cancer who have undergone thyroidectomy, but have no metastases. The evaluation takes a societal perspective, considering costs and benefits to all parties. The benefits were expressed in units of quality-adjusted life years (QALY), so differences in life expectancy were captured with consideration of quality of life. METHODS: A lifetime Markov model with Monte Carlo simulation of 100,000 patients was used to assess cost per QALY gained. The clinical inputs were sourced from a multi-centre, randomised controlled trial comparing remnant ablation success after rhTSH-preparation with hypothyroid preparation. The model applied German unit costs, however, the structure is generalisable to other jurisdictions. The additional cost of rhTSH procurement and administration is considered relative to the clinical benefits and cost offsets. These included avoidance of hypothyroidism, increased work productivity, earlier discharge from radioprotection and a theoretical reduction in the risk of secondary malignancy. The latter two benefits relate to faster radioiodine clearance after rhTSH preparation. RESULTS: The additional benefits of rhTSH (0.0495 QALY) are obtained with an incremental societal cost of 47 euro, equating to an incremental cost per QALYof 958 euro. Sensitivity analyses had only a modest impact upon cost-effectiveness, with all one-way sensitivity results remaining under 15,000 euro/QALY. CONCLUSIONS: The use of rhTSH prior to radioiodine ablation represents good value-for-money with the benefits to patient and society obtained at modest net cost.

A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma.

Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin.

The incidence of differentiated thyroid cancer (DTC) has increased in many places around the world over the past three decades, yet this has been associated with a significant decrease in DTC mortality rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse rates remain high, in the order of 20-40%, depending upon the patient's age and tumor stage at the time of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment, but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumors that are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 ((131)I), followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regression modeling of 1510 patients without distant metastases at the time of initial treatment and including surgical and (131)I treatment, the likelihood of death from DTC is increased by several factors, including age >45 years, tumor size >1.0 cm, local tumor invasion or regional lymph-node metastases, follicular histology, and delay of treatment >12 months. Cancer mortality is favorably and independently affected by female sex, total or near-total thyroidectomy, (131)I treatment and levothyroxine suppression of TSH. Treatments with (131)I to ablate thyroid remnants and residual disease are independent prognostic variables favorably influencing distant tumor relapse and cancer death rates. Delay in treatment of persistent disease has a profound impact on outcome. Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New paradigms, however, provide alternative pathways to prepare patients for (131)I treatment and to optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease can now be identified within the first year after initial treatment by recombinant human (rh)TSH-stimulated serum Tg concentrations greater than 2 microg/l, without performing DxWBS. These new follow-up paradigms promptly identify patients with lung metastases that are not evident on routine imaging, but which respond to (131)I treatment. In addition, rhTSH can be given to prepare patients for (131)I remnant ablation or (131)I treatment for metastases, especially those who are unable to withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH fails to increase.

Sodium iodide symporter in health and disease.

Radioiodine-concentrating activity in thyroid tissues has allowed the use of radioiodine as a diagnostic and therapeutic agent for patients with thyroid disorders such as well-differentiated thyroid cancer. However, some extrathyroidal tissues also take up radioiodine, contributing to unwanted side effects of radioiodine therapy. Now that the molecule that mediates radioiodine uptake, the sodium iodide symporter (NIS), has been cloned and characterized, it may be possible to develop novel strategies to differentially modulate NIS expression and/or activity, enhancing it in target tissues and impeding it in others. In addition to restoring NIS expression/activity to ensure sufficient radioiodine uptake for the diagnosis and treatment of advanced thyroid cancers, we envision that it may be possible to selectively increase or confer NIS expression/activity in tumors of nonthyroidal tissues to facilitate the use of radioiodine in their diagnosis and treatment. We also consider the molecular basis of thyroid and nonthyroid disorders that may be complicated by NIS deregulation. Finally, we explore the use of NIS as an imaging reporter gene to monitor the expression profile of the transgene in transgenic mouse animal models and in patients undergoing gene therapy clinical trials.

Using recombinant human TSH in the management of well-differentiated thyroid cancer: current strategies and future directions.

Mortality rates from thyroid cancer have fallen significantly in recent decades, almost certainly as the result of earlier diagnosis and improved treatment of differentiated (papillary and follicular) thyroid cancer. Enhanced survival is likely a result of early diagnosis and therapy applied at a disease stage when treatment is most effective. In the United States and Europe, most patients at high risk for relapse and death from thyroid cancer are treated with total or near-total thyroidectomy and receive radioiodine ablation of residual normal or malignant thyroid tissue, followed by treatment with thyroid hormone, a strategy that cures more than 80% of patients. Still, some die of the disease and nearly 15% have local recurrences, while another 5% to 10% develop distant metastases. Over 50% of recurrences appear in the first five years, but distant metastases may surface years, and sometimes decades, after initial therapy. Much has been learned about risk stratification to predict recurrence and death from thyroid cancer but individual patients continue to have adverse outcomes not always foreseen by a low tumor stage. Follow-up must accordingly be meticulous and prolonged. The National Cancer Center Network (NCCN) has recently established consensus practice guidelines that give explicit advice about the diagnosis and management of benign and malignant thyroid tumors, including paradigms for long-term follow-up and the treatment of recurrent disease. The guidelines confirm that diagnostic scanning with 131I and measurement of serum thyroglobulin (Tg) levels are the mainstay of follow-up, offering the opportunity to detect recurrent or persistent cancer at very early stages. These guidelines advocate TSH-stimulated serum Tg measurements, done either during thyroid hormone withdrawal or stimulation with recombinant human TSH (rhTSH, Thyrogen), that often identify the presence of cancer well before diagnostic whole-body scanning or other imaging studies can spot the tumor, which offers the opportunity to treat recurrent disease at an early stage. The use of rhTSH adds a new dimension to long-term follow-up that avoids putting patients through the symptoms of hypothyroidism, and offers the opportunity to follow some patients with rhTSH-stimulated serum Tg levels without performing 131I whole-body scans. A multicenter international study has shown that serum Tg measurements alone are not as sensitive in the identification of patients with persistent or recurrent tumor as are rhTSH-stimulated serum Tg determinations. Although not yet approved for preparation of patients for 131I therapy, rhTSH has been used successfully in a compassionate use program for this purpose in a relatively large number of patients. Formal clinical investigations now planned to provide guidelines for the use of rhTSH for therapeutic 131I portend a new set of effective therapeutic paradigms for the management of differentiated thyroid cancer.

Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands.

The observation that radioiodide uptake (RAIU) activity, mediated by the Na+/I- symporter (NIS), is significantly increased in lactating breast suggests that RAIU and NIS expression in mammary gland are modulated by hormones involved in active lactation. We showed that both the NIS expression level and RAIU in rat mammary gland are maximal during active lactation compared to those in the mammary glands of virgin and pregnant rats as well as the involuting mammary gland. In the lactating mammary gland, NIS is clustered on the basolateral membrane of alveolar cells as a lesser glycosylated form than NIS in thyroid. The RAIU of lactating mammary gland was partially inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of PRL release. These findings suggest that RAIU and NIS expression in mammary gland are at least in part modulated by oxytocin and PRL. Indeed, we showed that NIS messenger ribonucleic acid level was increased in a dose-dependent manner by oxytocin and PRL in histocultured human breast tumors.

Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study.

BACKGROUND: The American College of Surgeons Commission on Cancer (CoC) has conducted national Patient Care Evaluation (PCE) studies since 1976. METHODS: Over 1500 hospitals with CoC-approved cancer programs were invited to participate in this prospective cohort study of U.S. thyroid carcinoma cases treated in 1996. Follow-up will be conducted through the National Cancer Data Base. RESULTS: Of the 5584 cases of thyroid carcinoma, 81% were papillary, 10% follicular, 3.6% Hürthle cell, 0.5% familial medullary, 2.7% sporadic medullary, and 1.7% undifferentiated/anaplastic. Demographics and suspected risk factors were analyzed. Fine-needle aspiration of the thyroid gland (53%) or a neck lymph node (7%), thyroid nuclear scan (39%), and ultrasound (38%) constituted the most frequently utilized diagnostic modalities. The vast majority of patients with differentiated thyroid carcinoma presented with American Joint Committee on Cancer Stage I and II disease and relatively small tumors. For all histologies, near-total or total thyroidectomy constituted the dominant surgical treatment. No lymph nodes were examined in a substantial proportion of cases. Residual tumor after the surgical event could be documented in 11% of cases, hypocalcemia in 10% of cases, and recurrent laryngeal nerve injury in 1.3% of cases. Complications were most frequently associated with total thyroidectomy combined with lymph node dissection. Thirty-day mortality was 0.3%; when undifferentiated/anaplastic cancer cases were eliminated, it decreased to 0.2%. Adjuvant treatment, probably underreported in this study, consisted of hormonal suppression (50% overall) and radioiodine (50% overall). CONCLUSIONS: In addition to offering information concerning risk factors and symptoms, the current PCE study compliments the survival information from previous NCDB reports and offers a surveillance snapshot of current management of thyroid carcinoma in the U.S. Identified opportunities for improvement of care include 1) more frequent use of fine-needle aspiration cytology in making a diagnosis; 2) more frequent use of laryngoscopy in evaluating patients preoperatively, especially those with voice change; and 3) improved lymph node resection and analysis to improve staging and, in some situations, outcomes.

Hypothyroidism after treatment for nonthyroid head and neck cancer.

OBJECTIVES: To determine the incidence of posttreatment hypothyroidism in patients treated with surgery with or without radiotherapy for advanced-stage nonthyroid head and neck cancer and to make recommendations for its detection. DESIGN: A prospective study to assess the incidence and time frame of occurrence of hypothyroidism in patients by primary tumor site and treatment modality. Thyroid function tests were performed preoperatively, at the first postoperative visit, and then approximately every 6 months. Patients were followed up for up to 3 years. SETTING: Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. PATIENTS: A total of 251 patients with nonthyroid head and neck cancer were originally enrolled; 198 patients with evaluable data were studied to determine the incidence of posttreatment hypothyroidism. Approximately 80% of the patients had advanced stage (III or IV) or recurrent cancer. RESULTS: The overall incidence of posttreatment hypothyroidism was 15% in 198 patients followed up for a mean of approximately 12 months. Hypothyroidism developed in 12% of patients treated with nonlaryngeal surgery and radiotherapy. The group undergoing total laryngectomy (with thyroid lobectomy) and radiotherapy had a 61% incidence of hypothyroidism. The average time to detection of hypothyroidism was 8.2 months. CONCLUSIONS: Approximately 15% of patients treated for advanced head and neck cancer with surgery and radiotherapy will develop hypothyroidism. Those treated with total laryngectomy and radiotherapy are at greatest risk.

Long-term outcome of patients with differentiated thyroid carcinoma: effect of therapy.

OBJECTIVE: To present an overview of current therapeutic practices and results in patients with differentiated thyroid carcinoma. METHODS: Personal series of patients and selected studies reported in the literature are reviewed relative to outcome (tumor recurrence and cancer-related mortality) after treatment of differentiated thyroid cancer. RESULTS: In the United States, thyroid carcinoma ranks 14th in incidence among the major malignant tumors. Although many factors influence the long-term outcome with papillary and follicular thyroid carcinoma, the patient's age at the time of diagnosis, tumor stage, and initial treatment are the most important. The risk of death from thyroid cancer becomes substantially greater after age 40 years and increases dramatically after 60 years of age. Tumor recurrence is more prevalent before age 20 and after age 60 years. Delay in therapy for more than a year after initial manifestation also has been shown to have an adverse effect on outcome. The optimal initial treatment is usually near-total thyroidectomy and surgical excision of extrathyroidal tumor, when possible. For complete ablation of residual thyroid tissue, radioactive iodine therapy is usually necessary and should be followed by thyroid hormone suppression of serum thyrotropin concentrations. A schedule of 6-month follow-up intervals is recommended, until the serum thyroglobulin is undetectable and 131I whole-body scanning shows no uptake in the neck or extrathyroidal sites. CONCLUSION: An aggressive approach to management of differentiated thyroid carcinoma is likely to render about 90% of patients permanently free of disease.