Steven I. Sherman

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Associations guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial

BACKGROUND Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). INTERPRETATION Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer

BACKGROUND Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131). METHODS In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety. RESULTS The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related. CONCLUSIONS Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer

PURPOSE XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. PATIENTS AND METHODS A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. RESULTS Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. CONCLUSION Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).

Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer.

BACKGROUND Cervical recurrence occurs in up to 30% of patients with differentiated thyroid carcinoma. We retrospectively compared preoperative transcutaneous ultrasonography and physical examination (PE) results in the detection of local-regional metastases (lymph node and soft tissue) in patients with thyroid cancer. METHODS Data were collected retrospectively from the medical records of patients with thyroid carcinoma who underwent preoperative ultrasonography. Patients were divided into 3 groups: group 1, those undergoing primary thyroid/neck surgery; group 2, those undergoing reoperation for persistent disease; and group 3, those undergoing reoperation for recurrent thyroid carcinoma. For each group, we recorded the frequencies with which ultrasonography detected disease in a neck compartment (central or lateral) that was normal on PE. RESULTS Two hundred twelve patients underwent operation for primary, persistent, or recurrent papillary (n=130), medullary (n=61), or follicular/Hürthle cell (n=21) carcinoma. Ultrasonography detected additional sites of metastatic disease not appreciated on PE in 21 (20%) of 107 group 1 patients, 9 (32%) of 28 group 2 patients, and 52 (68%) of 77 group 3 patients. The surgical procedure performed was altered by the information obtained from preoperative ultrasonography in 82 (39%) of the 212 patients. Of the 107 group 1 patients, cervical recurrence has been detected in only 6 (6%) at a median follow-up of 36 months, in spite of 67 (63%) having tumors larger than 2 cm or lymph node metastases. CONCLUSIONS Preoperative high-quality ultrasonography detected lymph node or soft-tissue metastases in neck compartments believed to be uninvolved by PE in 39% of patients. Ultrasound findings altered the operative procedure in these patients, facilitating complete resection of disease and potentially minimizing local-regional recurrence.

Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer

PURPOSE This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). PATIENTS AND METHODS Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers. RESULTS Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease > or = 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. CONCLUSION Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.

Central hypothyroidism associated with retinoid X receptor-selective ligands.

BACKGROUND The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism. METHODS We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter. RESULTS The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid. CONCLUSIONS Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.

Outcome after Treatment of High-Risk Papillary and Non-Hurthle-Cell Follicular Thyroid Carcinoma

The treatment of thyroid cancer has been investigated extensively, but disagreement remains about the degree of aggressiveness needed in its management. Despite the general perception that the prognosis is excellent, 9% of patients with thyroid cancer die of the disease [1]. Patients with the less differentiated types of thyroid cancer or those presenting at a more advanced stage face higher mortality rates [2, 3]. In addition, the recurrence rate after surgery is more than 20% in persons with differentiated thyroid cancer [2]. Therefore, the ability to define the most effective therapeutic interventions on the basis of patient stratification by histologic type and stage of cancer at initial presentation should improve survival and decrease recurrence rates. The initial treatment for thyroid cancer is surgery, but the extent of surgery needed to improve outcome remains controversial [4-6]. Some studies have shown that more extensive thyroid resection reduces the recurrence rate but has a less definite effect on survival [2, 7]. More extensive surgery may be associated with a higher prevalence of complications, usually hypoparathyroidism or recurrent laryngeal nerve damage (or both), in 3% to 15% of patients [8-10]. The indications for postoperative ablative radioiodine therapy and the required administered activity are also under debate. Multifocality and lymph node involvement at presentation in 46% of persons with papillary thyroid cancer (of whom 25% face persistent or recurrent disease) argue in favor of this therapy [2, 11, 12], despite the risk for sialoadenitis, gastrointestinal symptoms, occasional bone marrow suppression, and possible second cancers [13]. The role of external radiation in the treatment of differentiated thyroid cancer is also highly controversial. Increased recurrence [14], no therapeutic benefit [15-17], and improved local control [18, 19] have all been reported. The National Thyroid Cancer Treatment Cooperative Study Registry was established in 1986 to define clinical practice and to address the effectiveness of therapies on morbidity and mortality by prospectively enrolling a large population of patients from multiple institutions. Patients have been stratified by uniform criteria and followed prospectively from the time of initial diagnosis and treatment. This 9-year report from the registry describes outcomes in patients with high-risk, differentiated thyroid cancer, a group of patients expected to have substantial morbidity and mortality in this time period. Methods A total of 1607 patients in whom thyroid cancer was diagnosed on or after 1 January 1987 were prospectively enrolled in the registry by the 14 participating institutions. No more than 20% of cases came from any single institution or city. Data forwarded to the registry were coded, and individual identifiers, such as name and Social Security number, were kept confidentially by the principal investigator at each institution. Because the patients therapy was not altered by participation in the registry, requirements for informed consent were determined by the institutional review boards at each participating institution, and their mandates were followed. Age, sex, ethnic background, histologic diagnosis, size of primary tumor, multifocality, local invasiveness, and regional or distant metastases were documented. The histologic diagnosis was established at each institution. All variants of papillary cancer, including so-called mixed papillary and follicular carcinomas, were included in the papillary group. Analyses for papillary carcinomas that included and excluded the more aggressive tall-cell variant were performed. The Hurthle cell (oxyphilic) variant of follicular carcinoma was excluded from the follicular group. Patients were stratified on the basis of pathologic diagnosis, age, tumor size, local invasiveness, and extent of metastases at the time of first surgical intervention as determined by gross and histologic findings at surgery, whole-body radioiodine scans, chest radiographs, and other radiologic studies. This stratification system was established empirically before initiation of the registry by a group of experienced clinicians on the basis of information available in 1985. The criteria for categorization as high risk are noted in Table 1. Patients with preoperative vocal cord paresis or with postoperative hypocalcemia or vocal cord paresis that persisted 2 months or less were not designated as having these complications of surgery. The extent of initial surgery, use of postoperative radioiodine therapy, and application of external radiation therapy were analyzed for impact on outcome. With rare exceptions, all patients received thyroxine therapy. Table 1. Criteria for Stratification to High-Risk Groups Outcomes were death due to thyroid cancer or to complications of its treatment, progression (defined as a patient alive with progressive thyroid cancer or dead because of thyroid cancer or complications of its treatment at last follow-up), and disease-free survival (defined as a patient alive with no known residual thyroid cancer or free of thyroid cancer at the time of death from other causes). Statistical Analysis All data were extracted by using a computer-based integrated data management package (Med-log, Information Analysis Corporation, Incline Village, Nevada). Cox proportional-hazards models were performed to determine whether each predictor variable was associated on univariate analysis (Table 2) with survival, progression, and disease-free survival (SAS Institute, Cary, North Carolina). The hazard model was also used to identify the set of predictor variables that best explained the probabilities of overall survival, cancer-specific mortality, progression of disease, or disease-free survival (Table 3). A P value of 0.05 or less was considered statistically significant. Risk ratios obtained from the Cox proportional-hazards analyses are given with 95% CIs. Risk ratios less than 1 indicate improved outcome, and those greater than 1 indicate a worsened outcome. Table 2. Variables Associated with Mortality, Progression, and Disease-Free Survival (by Univariate Analysis) Table 3. Variables That Best Predict Overall Mortality, Cancer-Specific Mortality, Progression of Disease, or Disease-Free Survival (by Multivariate Analysis) Results Follow-up Three hundred three patients with papillary carcinoma and 82 patients with follicular carcinoma were considered to have high-risk thyroid cancer. Twenty patients (5.2%) were lost to follow-up. An additional 64 patients were not included in the survival analyses because no information on patient status was available (n = 60), no cause of death was recorded (n = 2), or patients were alive with no cancer status reported (n = 2). Demographic characteristics of the two groups were similar regardless of whether these cases were included. Patients were followed for a mean of 3.1 years after the date of surgery; 35% were men. The mean (SD) age at entry was 57 15 years. Sex and Age Compared with men, women with papillary cancer had a lower risk for overall mortality (risk ratio [RR], 0.03 [95% CI, 0.23 to 0.92]) but not cancer-specific mortality. Older age did not affect outcome in patients with papillary carcinoma or those with follicular carcinoma, but an age effect might be masked by the fact that age was a factor in defining these high-risk patients. Histologic Type Only 18 patients with papillary cancer had the tall-cell variant (P not significant by multivariate analysis). By univariate analysis, radioiodine therapy was associated with reduced disease progression (risk ratio, 0.10 [CI, 0.01 to 0.72]; P = 0.02). Thyroid Surgery The first surgical procedure on the thyroid and any surgical therapy of the thyroid that occurred within the next 4 months were classified as initial thyroid surgery. Data were not sufficient to allow analysis of the effect of modified neck dissections on complication rates. Of 300 patients with papillary cancer, 256 (85.3%) had a total or near-total thyroidectomy as initial thyroid surgery, 10 (3.3%) had bilateral subtotal thyroidectomy, 26 (8.7%) had lobectomy, 1 (0.3%) had lumpectomy, 4 (1.3%) had biopsy only, and 3 (1.0%) had nonspecified surgery. Of 80 patients with follicular cancer, 57 (71.3%) had total or near-total thyroidectomy as initial thyroid surgery, 2 (2.5%) had bilateral subtotal thyroidectomy, 13 (16.3%) had lobectomy, 4 (5.0%) had lumpectomy, and 4 (5.0%) had biopsy only. The charts of all patients with reported surgical complications were reviewed. The complication rate of initial surgery varied among centers. The overall rate of some type of complication was 14.4% (52 of 360 patients). Specific data on complications were available for 286 of 303 patients with papillary cancer and 74 of 82 patients with follicular thyroid cancer. Hypoparathyroidism alone occurred in 19 of 286 (6.6%) patients with papillary cancer and 3 of 74 (4.0%) patients with follicular cancer. Vocal cord palsy alone was noted in 17 of 286 (5.9%) patients with papillary cancer and 6 of 74 (8.0%) patients with follicular cancer. Combined hypoparathyroidism and vocal cord palsy occurred in 4 of 286 (1.4%) patients with papillary cancer and no patients with follicular cancer. Data were not sufficient to allow analysis of any effect of modified neck dissections on complication rates. Overall mortality from papillary cancer improved with total or near-total thyroidectomy compared with other surgical procedures (RR, 0.41 [CI, 0.20 to 0.85]) (Table 2). Progression of disease and disease-free survival were not improved by more extensive surgery, and surgery did not affect mortality, progression, or disease-free survival in patients with follicular cancer by univariate (Table 2) or multivariate (Table 3) analyses. Radioiodine Therapy Postoperative radioiodine therapy with iodine-131 was administered to 258 of 302 (85.4%) patients with papillary cancer; the init