Fernanda Vaisman

Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy

To validate the American Thyroid Association (ATA) initial risk of recurrence scheme and the Memorial Sloan Kettering Cancer Center (MSKCC) response to therapy re‐stratification approach in a large cohort of patients with differentiated thyroid cancer (DTC) treated outside of the United States.

In Differentiated Thyroid Cancer, an Incomplete Structural Response to Therapy Is Associated with Significantly Worse Clinical Outcomes Than Only an Incomplete Thyroglobulin Response

BACKGROUND We previously demonstrated the clinical utility of using response to therapy variables obtained during the first 2 years of follow-up to actively modify initial risk estimates which were obtained using standard clinic-pathologic staging systems. While our proposed dynamic risk stratification system accurately reclassified patients who demonstrated an excellent response to therapy as low-risk patients, it grouped patients with either biochemical or structural evidence of disease into a single incomplete response to therapy cohort. This cohort included a wide variety of patients ranging from very minor thyroglobulin (Tg) elevations in the absence of structurally identifiable disease to widespread, progressive structural disease. Here we determined whether subdivision of the incomplete response to therapy category more precisely predicted clinical outcomes. We hypothesized that patients with an incomplete response to therapy based on persistently abnormal Tg values alone would have better clinical outcomes than patients having structurally identifiable disease. METHODS Following total thyroidectomy and radioactive iodine (RAI) ablation, 192 adult thyroid cancer patients were retrospectively identified as having either a biochemical incomplete response (abnormal Tg without structural evidence of disease) or structural incomplete response (structurally identifiable disease with or without abnormal Tg) as the best response to initial therapy within the first 24 months after RAI ablation. Clinical outcomes evaluated included structural disease progression, biochemical disease progression, and overall survival. RESULTS Sixty-three patients (33%) had a biochemical incomplete response while 129 (67%) had a structural incomplete response. Eleven to 156 months after evaluation of their responses (mean=70 months), patients with structural incomplete response were significantly more likely to have structural evidence of disease at final follow-up (37% vs. 17%, p=0.0004), structural progression (52% vs. 5%, p<0.001), biochemical progression (45% vs. 11%, p<0.001), and death from disease (38% vs. 0%, p<0.0001) than patients demonstrating a biochemical incomplete response. Overall survival was significantly better in patients with either a biochemical incomplete response or a loco-regional structural incomplete response than patients demonstrating a structural incomplete response with distant metastasis (Kaplan-Meier analysis, p<0.0001). CONCLUSIONS A structural incomplete response to initial therapy is associated with significantly worse clinical outcome than a biochemical incomplete response to therapy.

Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine

CONTEXT Although response to therapy assessment is a validated tool for dynamic risk stratification in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TT) and radioactive iodine therapy (RAI), it has not been well studied in patients treated with lobectomy or TT without RAI. Because these responses to therapy definitions are heavily dependent on serum thyroglobulin (Tg) levels, modifications of the original definitions were needed to appropriately classify patients treated without RAI. OBJECTIVE This study aimed to validate the response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI. DESIGN AND SETTING This was a retrospective study, which took place at a referral center. PATIENTS A total of 507 adults with DTC were treated with lobectomy (n = 187) or TT (n = 320) without RAI. They had a median age of 43.7 y, 88% were female, 85.4% had low risk, and 14.6% intermediate risk. MAIN OUTCOME MEASURE Main outcome measured was recurrent/persistent structural evidence of disease (SED) during a median followup period of 100.5 months (24-510). RESULTS Recurrent/persistent SED was observed in 0% of the patients with excellent response to therapy (nonstimulated Tg for TT < 0.2 ng/mL and for lobectomy < 30 ng/mL, undetectable Tg antibodies [TgAb] and negative imaging; n = 326); 1.3% with indeterminate response (nonstimulated Tg for TT 0.2-5 ng/mL, stable or declining TgAb and/or nonspecific imaging findings; n = 2/152); 31.6% of the patients with biochemical incomplete response (nonstimulated Tg for TT > 5 ng/mL and for lobectomy > 30 ng/mL and/or increasing Tg with similar TSH levels and/or increasing TgAb and negative imaging; n = 6/19) and all (100%) patients with structural incomplete response (n = 10/10) (P < .0001). Initial American Thyroid Association risk estimates were significantly modified based on response to therapy assessment. CONCLUSIONS Our data validate the newly proposed response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI as an effective tool to modify initial risk estimates of recurrent/persistent SED and better tailor followup and future therapeutic approaches. This study provides further evidence to support a selective use of RAI in DTC.

An International Multi-Institutional Validation of Age 55 Years as a Cutoff for Risk Stratification in the AJCC/UICC Staging System for Well-Differentiated Thyroid Cancer

BACKGROUND Age is a critical factor in outcome for patients with well-differentiated thyroid cancer. Currently, age 45 years is used as a cutoff in staging, although there is increasing evidence to suggest this may be too low. The aim of this study was to assess the potential for changing the cut point for the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system from 45 years to 55 years based on a combined international patient cohort supplied by individual institutions. METHODS A total of 9484 patients were included from 10 institutions. Tumor (T), nodes (N), and metastasis (M) data and age were provided for each patient. The group was stratified by AJCC/UICC stage using age 45 years and age 55 years as cutoffs. The Kaplan-Meier method was used to calculate outcomes for disease-specific survival (DSS). Concordance probability estimates (CPE) were calculated to compare the degree of concordance for each model. RESULTS Using age 45 years as a cutoff, 10-year DSS rates for stage I-IV were 99.7%, 97.3%, 96.6%, and 76.3%, respectively. Using age 55 years as a cutoff, 10-year DSS rates for stage I-IV were 99.5%, 94.7%, 94.1%, and 67.6%, respectively. The change resulted in 12% of patients being downstaged, and the downstaged group had a 10-year DSS of 97.6%. The change resulted in an increase in CPE from 0.90 to 0.92. CONCLUSIONS A change in the cutoff age in the current AJCC/UICC staging system from 45 years to 55 years would lead to a downstaging of 12% of patients, and would improve the statistical validity of the model. Such a change would be clinically relevant for thousands of patients worldwide by preventing overstaging of patients with low-risk disease while providing a more realistic estimate of prognosis for those who remain high risk.

Survival from Differentiated Thyroid Cancer: What Has Age Got to Do with It?

BACKGROUND In most staging systems, 45 years of age is used to differentiate low risk thyroid cancer from high risk thyroid cancer. However, recent studies have questioned both the precise 45 year age point and the concept of using a binary cut off as accurate predictors of disease specific mortality. METHODS A cohort of 3664 thyroid cancer patients that received surgery and adjuvant treatment at Memorial Sloan Kettering Cancer Center (MSKCC) from the years 1985 to 2010 were analyzed to determine the significance of age at diagnosis as a categorical variable at a variety of age cutoffs (5 year intervals between 30 and 70 years of age). The unadjusted and adjusted hazard ratio for the association between disease-specific survival and age was determined using a Cox proportional hazards model adjusted for other predictive variables sex, histology, and pathological T, N, and M status. Furthermore, predictive nomograms of disease-specific mortality were created and validated on an external dataset of 4551 patients to evaluate the impact of age at diagnosis as both a categorical and continuous variable. RESULTS In the MSKCC cohort, with a median follow-up time of 54 months (range 1-332), there were 59 deaths from thyroid cancer with a 10 year disease-specific survival of 96%. Adjusted hazard ratios for all age cutoffs from age 30 to age 70 years were significant. There was no specific cutoff age which risk stratifies patients with differentiated thyroid cancer (DTC). Categorizing age into five strata (<40, 40-49, 50-59, 60-69 and >70 years) showed a 37-fold increase in hazard ratio from age <40 years to age >70 years. A predictive nomogram using age as a continuous variable with other predictive variables had a high concordance index of 96%. Validation on the external cohort had a concordance index of 73%. CONCLUSIONS Mortality from DTC increases progressively with advancing age. There is no specific cutoff age which risk stratifies patients with DTC. A predictive nomogram using age as a continuous variable may be a more appropriate tool for stratifying patients with DTC and for predicting outcome.

Thyroid carcinoma in children and adolescents-systematic review of the literature.

Thyroid cancer in children and adolescents is usually a major concern for physicians, patients, and parents. Controversies regarding the aggressiveness of the clinical presentation and the ideal therapeutic approach remain among the scientific community. The current recommendations and staging systems are based on data generated by studies in adults, and this might lead to overtreating in some cases as well as undertreating in others. Understanding the differences in the biology, clinical course, and outcomes in this population is crucial for therapeutic decisions. This paper evaluates the biology, clinical presentation, recurrences, and overall survival as well as the staging systems in children and adolescents with differentiated thyroid cancer.

Preablation stimulated thyroglobulin is a good predictor of successful ablation in patients with differentiated thyroid cancer.

PURPOSE To evaluate the predictive capacity of clinical and laboratory variables in relation to the success of ablation. The variables studied were as follows: thyroglobulin (Tg) in hypothyroidism, before ablation; age; gender; type of carcinoma (papillary or follicular); the tumor stage; the administered activity of I; and the whole-body scan 7 days after ablation. MATERIALS AND METHODS Retrospective review of the medical records of all patients who were admitted to the therapeutic room to undergo treatment with I, from 1998 to 2007. Of the records reviewed, 96 patients fulfilled the inclusion criteria and had no exclusion criteria. A negative whole-body scan and Tg in hypothyroidism <2 ng/mL, after 6 to 12 months of treatment, were considered as successful ablation. RESULTS The dosage of Tg in hypothyroidism, measured before the ablation, was the only independent predictor of ablation success in multivariate analysis (P < 0.0001), and the optimal cutoff for this cohort was 18 ng/mL. On univariate analysis, the high-risk staging was predictor of ablation failure. CONCLUSION The measurement of Tg in hypothyroidism before ablation might be useful if added to the routine evaluation of patients before I treatment because it was a good predictor of successful ablation.

Prognostic factors of a good response to initial therapy in children and adolescents with differentiated thyroid cancer

BACKGROUND Therapeutic approaches in pediatric populations are based on adult data because there is a lack of appropriate data for children. Consequently, there are many controversies regarding the proper treatment of pediatric patients. OBJECTIVE The present study was designed to evaluate patients with differentiated thyroid carcinoma diagnosed before 20 years of age and to determine the factors associated with the response to the initial therapy. METHODS Sixty-five patients, treated in two tertiary-care referral centers in Rio de Janeiro between 1980 and 2005 were evaluated. Information about clinical presentation and the response to initial treatment was analyzed and patients had their risk stratified in Tumor-Node- Metastasis; Age-Metastasis-Extracapsular-Size; distant Metastasis-Age-Completeness of primary tumor resection-local Invasion-Size and American-Thyroid-Association classification RESULTS Patients ages ranged from 4 to 20 years (median 14). The mean follow-up was 12,6 years. Lymph node metastasis was found in 61.5% and indicated a poor response to initial therapy, with a significant impact on time for achieving disease free status (p = 0.014 for response to initial therapy and p<0,0001 for disease-free status in follow-up). Distant metastasis was a predictor of a poor response to initial therapy in these patients (p = 0.014). The risk stratification systems we analyzed were useful for high-risk patients because they had a high sensitivity and negative predictive value in determining the response to initial therapy. CONCLUSIONS Metastases, both lymph nodal and distant, are important predictors of the persistence of disease after initial therapy in children and adolescents with differentiated thyroid cancer.

Thyroid Lobectomy Is Associated with Excellent Clinical Outcomes in Properly Selected Differentiated Thyroid Cancer Patients with Primary Tumors Greater Than 1 cm

Background and Objective. An individualized risk-based approach to the treatment of thyroid cancer is being extensively discussed in the recent literature. However, controversies about the ideal surgical approach remain an important issue with regard to the impact on prognosis and follow-up strategies. This study was designed to describe clinical outcomes in a cohort of low and intermediate risk thyroid cancer patients treated with thyroid lobectomy. Methods. Retrospective review of 70 patients who underwent lobectomy. Results. After a median follow-up of 11 years, 5 patients (5/70, 7.1%) recurred and 5 had a completion for benign lesions, while 60 patients (86%) continued to be observed without evidence for disease recurrence. Suspicious ultrasound findings were significantly more common in patients that had structural disease recurrence (100% versus 4.3%, P < 0.001). Furthermore, a rising suppressed Tg value over time was also associated with structural disease recurrence (80% versus 21.5%, P = 0.01). After additional therapy, 99% of the patients had no evidence of disease. Conclusions. Properly selected thyroid cancer patients can be treated with lobectomy with excellent clinical outcomes.

How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study.

Background: Studies from every continent have shown that only around 50% of the patients subjected to thyroid hormone replacement have TSH in the normal range. However, to date, there are no consistent data about Brazil. Objectives: To evaluate levothyroxine (LT4) replacement treatment in patients with primary hypothyroidism followed in referral centers in Brazil. Methods: Patients with primary hypothyroidism followed in referral centers (University Hospitals from Universidade Federal do Rio de Janeiro — UFRJ, Unicamp, Universidade Federal do Paraná — UFPR and Universidade Federal do Ceará-UFC) answered a questionnaire that inquired about clinical and biochemical conditions, social-economic status, life quality and clinicians’ orientations as well as their understanding about the information given. Serum TSH was checked close to the interview. Results: 2292 consecutive patients met the inclusion criteria. Mean age 51.2 yr and TSH values between 0.4 and 4.0 mUI/l were considered to be within the reference range. Among all patients taking thyroid medication, 42.7% had an abnormal serum TSH (28.3% were undertreated and 14.4% were overtreated). Approximately all patients (99%) took LT4 in the morning but less than 30 min before breakfast (85.4%). Regarding the clinicians’ orientations: 97.5% of the patients were instructed to take the medication daily, and 92.6% to take 30 min before breakfast (92.6%). However, only 52.1% were told not to take LT4 along with other medication. Conclusions: Our study found that a significant number of patients taking thyroid hormones were not in the therapeutic range. Clinicians should, therefore, consider monitoring patients on thyroid replacement more frequently and being more precise on giving recommendations about the correct use of LT4.