Extract from: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer

The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer

Bryan R. Haugen, M.D.1 (Chair)*,Erik K. Alexander, M.D.2, Keith C. Bible, M.D., Ph.D.3, Gerard M. Doherty, M.D.4, Susan J. Mandel,M.D., M.P.H.5, Yuri E. Nikiforov, M.D., Ph.D.6,Furio Pacini, M.D.7, Gregory W. Randolph, M.D.8, Anna M. Sawka, M.D., Ph.D.9, Martin Schlumberger, M.D.10, Kathryn Schuff, M.D.11, Steven I. Sherman, M.D.12,Julie Ann Sosa, M.D.13, David L. Steward, M.D.14, R. Michael Tuttle, M.D.15,and Leonard Wartofsky, M.D.16

*Authors are listed in alphabetical order and were appointed by ATA to independently formulate the

content of this manuscript. None of the scientific or medical content of the manuscript was dictated by the ATA.

1 University of Colorado School of Medicine, Aurora, Colorado.

2Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusettes.

3The Mayo Clinic, Rochester, Minnesota.

4Boston Medical Center, Boston, Massachusettes.

5 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

6University of Pittsburgh Medical Center, Pittsburgh, Pennsylvannia.

7 The University of Siena, Siena, Italy.

8Massachusettes Eye and Ear Infirmary, Massachusettes General Hospital, Harvard Medical

School, Boston, Massachusettes.

9University Health Network, University of Toronto , Toronto, Canada.

10Institute Gustave Roussy and University Paris Sud, Villejuif, France.

11Oregon Health and Science University, Portland, Oregon.

12University of Texas M.D. Anderson Cancer Center, Houston, Texas.

13Duke University School of Medicine, Durham, North Carolina.

14University of Cincinnati Medical Center, Cincinnati, Ohio.

15Memorial Sloan-Kettering Cancer Center, New York, New York.

16MedStar Washington Hospital Center, Washington, DC.

Running title: ATA Thyroid Nodule/DTC Guidelines

 

Operative approach for a biopsy diagnostic for follicular cell-derived malignancy.

RECOMMENDATION 35

  1. A) For patients with thyroid cancer >4 cm, or with gross extrathyroidal extension (clinical T4), or clinically apparent metastatic disease to nodes (clinical N1) or distant sites (clinical M1), the initial surgical procedure should include a near-total or total thyroidectomy and gross removal of all primary tumor unless there are contraindications to this procedure.

(Strong Recommendation, Moderate-quality evidence)

 

  1. B) For patients with thyroid cancer >1 cm and <4 cm without extrathyroidal extension, and without clinical evidence of any lymph node metastases (cN0), the initial surgical procedure can be either a bilateral procedure (near-total or total thyroidectomy) or a unilateral procedure (lobectomy). Thyroid lobectomy alone may be sufficient initial treatment for low risk papillary and follicular carcinomas; however, the treatment team may choose total thyroidectomy to enable RAI therapy or to enhance follow-up based upon disease features and/or patient preferences.

(Strong Recommendation, Moderate-quality evidence)

 

  1. C) If surgery is chosen for patients with thyroid cancer <1 cm without extrathyroidal extension and cN0, the initial surgical procedure should be a thyroid lobectomy unless there are clear indications to remove the contralateral lobe. Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas in the absence of prior head and neck irradiation, familial thyroid carcinoma, or clinically detectable cervical nodal metastases.

(Strong Recommendation, Moderate-quality evidence)

 

Surgery for thyroid cancer is an important element of a multifaceted treatment approach. The

operation must be compatible with the overall treatment strategy and follow-up plan recommended by the managing team. Consideration should be given to referring patients with high risk features (clinical N1 disease, concern for RLN involvement or grossly invasive disease) to experienced surgeons as both completeness of surgery and experience of the surgeon can have a significant impact on clinical outcomes and complication rates (1-4). Previous guidelines have endorsed total thyroidectomy as the primary initial surgical treatment option for nearly all differentiated thyroid cancers greater than 1 cm with or without evidence of locoregional or distant metastases ( 5). This was based on retrospective data suggesting that a bilateral surgical procedure would improve survival (6), decrease recurrence rates (7-9), allow for routine use of RAI remnant ablation, and facilitate detection of recurrent/persistent disease during follow-up. However, recent data have demonstrated that in properly selected patients, clinical outcomes are very similar following unilateral or bilateral thyroid surgery(10-14). Furthermore, since the requirement for routine use of RAI ablation was one of the major reasons given in support of total thyroidectomy in low to intermediate risk patients, our current more selective approach to RAI ablation in these patients requires a critical reassessment of this indication. In some patients, the presence of the remaining lobe of the gland may obviate the life-long need for exogenous thyroid hormone therapy. Finally, as our follow-up management paradigm has moved away from diagnostic whole body RAI scanning and toward a greater reliance on neck ultrasonography and serial serum Tg measurements (even in patients that did not receive RAI remnant ablation), we must also question whether total thyroidectomy and RAI remnant ablation is required to facilitate follow-up in low to intermediate risk patients.

In an analysis of 52,173 papillary thyroid cancer patients diagnosed between 1985 and 1998 from the National Cancer Data Base (43,227 total thyroidectomy, 8,946 lobectomy), Bilimoria et al. demonstrated a slightly higher 10 year relative overall survival for total thyroidectomy as opposed to thyroid lobectomy (98.4% vs 97.1% respectively, p < 0.05) and a slightly lower 10 year recurrence rate (7.7% vs 9.8% respectively, p 0.05) (6). When analyzed by size of the primary tumor, statistically significant differences in survival and recurrence was seen for all sizes greater than 1 cm based on the extent of initial surgery.    However, data on extra thyroidal extension, completeness of resection and other co-morbid conditions, which could have had a major impact on survival and recurrence risk, were not available.   Therefore, it is unclear how often lobectomy was done based on proper selection of low to intermediate risk patients versus how often lobectomy was done in high risk patients because of co-morbid conditions, inability to obtain a complete resection, or status of the contralateral recurrent laryngeal nerve.    This is an important distinction because thyroid lobectomy patients were found to have extra thyroidal extension in 7% (13), underwent external beam radiation therapy in 1-2% (12) and radioactive iodine therapy in 12-18% (7,13), and had high risk features in 8% (13). Given the small magnitude of differences reported for survival and recurrence between the total thyroidectomy and the lobectomy patients, it is quite possible that the slightly poorer outcomes seen in the lobectomy group could have been significantly influenced by lobectomy patients with concurrent high risk features.    Adam et al. performed an updated analysis of 61,775 patients in the National Cancer Database who underwent thyroid surgery between 1998-2006 (15). They demonstrated that the overall survival advantage seen for patients with 1-4 cm PTC who underwent thyroidectomy in the study by Bilimoria et al. disappeared when further adjustment was made for additional variables related to complexity and severity of illness. This lack of overall survival advantage was also seen when the group was subdivided into patients

with 1-2 cm and 2-4 cm PTC.

Previously, Haigh et al. had analyzed 5,432 papillary thyroid cancer patients from the SEER database (4,612 total thyroidectomy and 820 lobectomy) and found no difference in 10 year overall survival between total thyroidectomy and thyroid lobectomy when risk stratified by the AMES

included 7% with extra thyroidal extension, 1% with distant metastases, 5% with primary tumors

greater than 5 cm, and 8% classified as AMES high risk.

More recently, two additional studies have analyzed the SEER database and both have failed to demonstrate a significant difference in survival when comparing total thyroidectomy with thyroid lobectomy (11,12). Barney et al. included 23,605 differentiated thyroid cancer patients diagnosed between 1983 and 2002 (12, 598 total thyroidectomy, 3,266 lobectomy) and found no difference in 10 year overall survival (90.4% for total thyroidectomy vs 90.8% for lobectomy) or 10 year cause specific survival (96.8% for total thyroidectomy vs 98.6% for lobectomy).   Furthermore, in a multivariate analysis that included age, T, N, M, sex, year of diagnosis, extent of surgery and RAI use, no difference in overall survival or cause specific survival was seen with respect to the extent of initial surgery. Mendelsohn et al. (12) analyzed 22,724 PTC patients diagnosed between 1998 and 2001 (16,760 total thyroidectomy, 5,964 lobectomy) and found no differences in overall survival or disease specific survival when comparing total thyroidectomy with lobectomy. Interestingly, of the patients that had lobectomy, 1.6% received external beam irradiation, 16% had extra thyroidal extension, 9% of tumors were greater than 4 cm, and 20% received RAI ablation (once again indicating that lobectomy was done in some high risk patients).

Consistent with the SEER data analyses, two single center studies also confirm that lobectomy is associated with excellent survival in properly selected patients (10,14). After a median follow-up of 8 years, only 1 disease specific death was seen in a cohort of 889 papillary thyroid cancer patients with T1-T2 tumors treated with either total thyroidectomy (n=528) or lobectomy (n=361) (14). Furthermore, Matsuzu et al. reported a cause specific survival rate of 98% after a median of 17 years of follow-up in properly select PTC patients treated with lobectomy and ipsilateral neck dissection (10).

Given the propensity for PTC to be multifocal (often involving both lobes), it is not surprising that some studies have demonstrated a lower risk of loco-regional disease recurrence following total thyroidectomy as compared to thyroid lobectomy (7-9).  However, with proper patient selection, loco-regional recurrence rates of less than 1-4% and completion thyroidectomy rates of less than 10% can be achieved following thyroid lobectomy (14-16).

Furthermore, the few recurrences that develop during long-term follow-up are readily detected

and appropriately treated with no impact on survival (10;14;16).

Therefore, we conclude that in properly selected low to intermediate risk patients (patients with unifocal tumors < 4 cm, and no evidence of extra thyroidal extension or lymph node metastases by examination or imaging), the extent of initial thyroid surgery probably has little impact on disease specific survival.  While recurrence rates can be quite low in these patients, it is likely that the lowest rates of recurrence during long-term follow-up would be associated with a total thyroidectomy.    But since salvage therapy is quite effective in the few patients that recur after thyroid lobectomy, a conservative management approach to completion surgery, accepting a slightly higher risk of loco-regional recurrence, is an acceptable management strategy. Finally, a more selective use of RAI coupled with a greater reliance on neck US and serial serum Tg measurements for detection of recurrent disease is likely to significantly decrease the mandate for total thyroidectomies in low and intermediate risk patients done solely to facilitate RAI remnant ablation and follow-up.

Near-total or total thyroidectomy is necessary if the overall strategy is to include RAI therapy post-operatively, and thus is recommended if the primary thyroid carcinoma is >4 cm, if there is gross extra-thyroidal extension, or if regional or distant metastases are clinically present.

For tumors that are between 1 and 4 cm in size, either a bilateral thyroidectomy (total or neartotal)

or a unilateral procedure (thyroid lobectomy) may be suitable as treatment plan. Older age (>45 years), contralateral thyroid nodules, a personal history of radiation therapy to the head and neck, or familial DTC may be criteria for recommending a bilateral procedure either because of plans for RAI therapy, to facilitate follow-up strategies, or to address suspicions of bilateral disease (10,14, 17,18).

The relationship between surgeon volume and patient outcomes has been studied extensively over the last 20 years.  Institutional studies examining outcomes following thyroidectomy by high-volume surgeons have been published demonstrating overall safety.    In one of the first studies examining the relationship between surgeon volume and thyroidectomy outcomes at a state level, Sosa et al. found a strong association between higher surgeon volume and favorable patient outcomes, especially with regard to recurrent laryngeal nerve injury and wound complications (1). This was especially pronounced for patients undergoing total thyroidectomy for thyroid cancer. Others have made similar observations (2 ;19;20).    In a recent study of patients undergoing thyroidectomy in the Health Care Utilization Project Nationwide Inpatient Sample (HCUP-NIS), surgeons were divided into low- (<10 cases/yr; encompassing 6072 surgeons), intermediate- (10-100 cases/yr; 11,544 surgeons), and highvolume (>100 cases/yr; 4009 surgeons) categories (21).

Over 80% of thyroid resections were performed by low- and intermediate-volume surgeons. On average, high-volume surgeons had the lowest complication rates for patients who underwent total thyroidectomy for cancer at 7.5%; intermediate-volume surgeons had a rate of 13.4%, and low-volume surgeons 18.9%, (p<0.001).

From robust population level data such as these, it can be concluded that referral of patients to high-volume thyroid surgeons is associated, on average, with superior outcomes. However, such referral is not always possible, given the relative scarcity of high-volume surgeons and their geographic distribution. In addition, there are some data suggesting that other factors, such as surgeon age, should be considered (22).      Therefore, conclusions at a population level cannot always be applied to individual surgeons and patient circumstances. It may, however, be reasonable to consider sending patients with more extensive disease and concern for grossly invasive disease to a high volume surgeon experienced in the management of advanced thyroid cancer.

It is worth noting that even high-volume surgeons have a higher overall post-operative complication rate when performing total thyroidectomy compared to lobectomy (23). Using the HCUP-NIS, these authors found that high-volume thyroid surgeons had a complication rate of 7.6% following thyroid lobectomy but a rate of 14.5% following total thyroidectomy. For low volume surgeons, the complication rates were 11.8% and 24.1%, respectively. Therefore, patients should carefully weigh the relative benefits and risks of total thyroidectomy vs. thyroid lobectomy, even when surgery is performed by high-volume surgeons.

 

[B8] Lymph node dissection

RECOMMENDATION 36

  1. A) Therapeutic central-compartment (level VI) neck dissection for patients with clinically

involved central nodes should accompany total thyroidectomy to provide clearance of disease

from the central neck.

(Strong Recommendation, Moderate-quality evidence)

 

  1. B) Prophylactic central-compartment neck dissection (ipsilateral or bilateral) should be considered in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes (cN0) who have advanced primary tumors (T3 or T4), clinically involved lateral neck nodes (cN1b), or if the information will be used to plan further steps in therapy.

(Weak Recommendation, Low-quality evidence)

 

  1. C) Thyroidectomy without prophylactic central neck dissection may be is appropriate for small (T1 or T2), noninvasive, clinically node-negative PTC (cN0) and for most follicular cancers.

(Strong Recommendation, Moderate-quality evidence)

 

RECOMMENDATION 37

Therapeutic lateral neck compartmental lymph node dissection should be performed for

patients with biopsy-proven metastatic lateral cervical lymphadenopathy.

(Strong Recommendation, Moderate-quality evidence)

Regional lymph node metastases are present at the time of diagnosis in a majority of patients with papillary carcinomas and a lesser proportion of patients with follicular carcinomas (24;25,26). Although PTC lymph node metastases are reported by some to have no clinically important effect on outcome in low risk patients, a study of the SEER database found, among 9904 patients with PTC, that lymph node metastases, age >45 years, distant metastasis, and large tumor size significantly predicted poor overall survival outcome on multivariate analysis (27).

All-cause survival at 14 years was 82% for PTC without lymph node metastases and 79% with

nodal metastases (p < 0.05). Another SEER registry study concluded that cervical lymph node

metastases conferred an independent risk of decreased survival, but only in patients with

follicular cancer and patients with papillary cancer over age 45 years (28).

However, characteristics of the lymph node metastases can further discriminate the risk of recurrence to the patient, especially in those patients with clinically evident metastasis, multiple metastases, larger metastases, and/or extracapsular nodal extension (29,30), compared to those with more limited microscopic nodal disease (26).

A recent comprehensive analysis of the National Cancer Data Base and SEER, however, showed a small but significantly increased risk of death for patients younger than 45 years with lymph node metastases compared with those younger patients without involved lymph nodes, and that incrementally more metastatic lymph nodes up to six involved nodes confers additional mortality risk in this age group (31). This study underlines the importance of rigorous preoperative screening for nodal metastases and potentially raises questions about current thyroid cancer staging systems. Common to all of these studies is the conclusion that the effect of the presence or absence of lymph node metastases on overall survival, if present, is small and probably most significant in older patients.

The cervical node sites are well-defined (32 ), and the most common site of nodal metastases is in the central neck which is cervical level VI. A recent consensus conference statement describes the relevant anatomy of the central neck compartment, delineates the nodal subgroups within the central compartment commonly involved with thyroid cancer, and defines the terminology relevant to central compartment neck dissection (33). In many patients, lymph node metastases in this area do not appear abnormal on preoperative imaging ( 25;34 -37) or by inspection at the time of surgery (26), defining a cN0 group.

The role of therapeutic lymph node dissection for treatment of thyroid cancer node metastases is well accepted for cN1 disease (27;38-40). However, the value of routine prophylactic level VI (central) neck dissection for cN0 disease remains unclear. Central compartment dissection (therapeutic or prophylactic) can be achieved with low morbidity by experienced thyroid surgeons (41-43). Value for an individual patient depends upon the utility of the staging information to the treatment team in specific patient circumstances (43,44).

Based on limited and imperfect data, prophylactic dissection has been suggested to improve

disease-specific survival (45) local recurrence (36;46), and post-treatment thyroglobulin levels (36;47). It has also been used to inform the use of adjuvant RAI (35;39,42; 46,48) and improve the accuracy of the estimates of risk of recurrence (48-50). However, in several studies, prophylactic dissection has shown no improvement in long-term patient outcome, while increasing the likelihood of temporary morbidity, including hypocalcemia, although prophylactic dissection may decrease the need for repeated radioiodine treatments (25;38;39;41;51-55).

The removal of cN0 level VI lymph nodes detects a substantial number of patients with pN1 disease; however, the direct effect of this on long-term outcome is small at best (55,56).

The use of staging information for the planning of adjuvant therapy depends upon whether this

information will affect the team-based decision-making for the individual patient. For these

reasons, groups may elect to include prophylactic dissection for patients with some prognostic

features associated with an increased risk of metastasis and recurrence (older or very young age,

larger tumor size, multifocal disease, extrathyroidal extension, known lateral node metastases) to

contribute to decision-making and disease control (36;43;47). Alternatively, some groups may apply prophylactic level VI dissection to patients with better prognostic features if the patient is to have a bilateral thyroidectomy, and if the nodal staging information will be used to inform the decision regarding use of adjuvant therapy (35;42;48). Finally, for some groups it appears reasonable to use a selective approach that applies level VI lymph node dissection at the time of initial operation only to patients with clinically evident disease based on preoperative physical exam, preoperative radiographic evaluation or intraoperative demonstration of detectable disease (cN1) (26;51;58).

The information from prophylactic central neck dissection must be used cautiously for staging information. Since microscopic nodal positivity occurs frequently, prophylactic dissection often converts patients from clinical N0 to pathologic N1a, upstaging many patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to stage III (25;34 – 39). However, microscopic nodal positivity does not carry the recurrence risk of macroscopic clinically detectable disease (26). Thus microscopic nodal upstaging may lead to excess radioactive iodine utilization and patient follow-up. Alternatively, the demonstration of uninvolved lymph nodes by prophylactic dissection may decrease the use of radioiodine for some groups (35;42;48). These effects may account for some of the existing extreme variability in utilization of radioactive iodine for thyroid cancer (59).

Studies of the BRAF V600E mutation have suggested an association between presence of the mutation and the risk of nodal disease (60-62) although results across all patients with papillary thyroid carcinoma are mixed (63-66). However, the presence of a BRAF V600E mutation has a limited positive predictive value for recurrence and therefore BRAF V600E mutation status in the primary tumor should not impact on the decision for prophylactic central neck dissection (67).

The above recommendations should be interpreted in light of available surgical expertise.

For patients with small, noninvasive, cN0 tumors, the balance of risk and benefit may favor

thyroid lobectomy and close intraoperative inspection of the central compartment, with the plan

adjusted to total thyroidectomy with compartmental dissection only in the presence of involved

lymph nodes.

Lymph nodes in the lateral neck (compartments II–V, ), level VII (anterior mediastinum), and rarely in Level I may also be involved by thyroid cancer (26;68,69).

For those patients in whom nodal disease is evident clinically on preoperative US and nodal

FNA cytology or Tg measurement, or at the time of surgery, surgical resection by compartmental

node dissection may reduce the risk of recurrence and possibly mortality (70-72).

 

[B9] Completion thyroidectomy

 

RECOMMENDATION 38

  1. A) Completion thyroidectomy should be offered to those patients for whom a bilateral thyroidectomy would have been recommended had the diagnosis been available before the initial

surgery. Therapeutic central neck lymph node dissection should be included if the lymph nodes

are clinically involved. Thyroid lobectomy alone may be sufficient treatment for low risk

papillary and follicular carcinomas.

(Strong Recommendation, Moderate-quality evidence)

 

  1. B) Radioactive iodine ablation in lieu of completion thyroidectomy is not recommended

routinely; however, it may be used to ablate the remnant lobe in selected cases.

(Weak Recommendation, Low-quality evidence)

Completion thyroidectomy may be necessary when the diagnosis of malignancy is made

following lobectomy for an indeterminate or nondiagnostic biopsy. In addition some patients

with malignancy may require completion thyroidectomy to provide complete resection of

multicentric disease, and to allow for efficient RAI therapy. However, since intrathyroidal PTC

or low risk FTC can be managed with either lobectomy or total thyroidectomy   (See Recommendation 35B), a completion thyroidectomy is not always required. The surgical risks

of two-stage thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to

those of a near-total or total thyroidectomy (73-75). The marginal utility of prophylactic lymph node dissection for cN0 disease argues against its application in re-operations.

Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (76;77). There are limited data regarding the long-term outcomes of this approach. The data suggest similar clinical outcomes with a slightly higher proportion of patients with persistent detectable thyroglobulin. This approach may be helpful in patients for whom completion thyroidectomy carries some increased risk and for whom a delay in the length of time required to achieve destruction of the normal thyroid, which follows RAI (as opposed to surgical resection), is acceptable. In one unblinded, multi-center, randomized controlled equivalence trial comparing dose activities in achieving successful ablation of a remaining lobe in patients with T1b or T2 primary tumor, who had surgical contraindications or declined completion thyroidectomy, the remnant ablation success rate was significantly higher using 100 mCi (75% success rate. 1 mCi = 37 MBq), compared to 30 mCi (54%), although mild to moderate short-term neck pain was more frequently reported in the high dose group (66%) compared to the low dose group (51%) (77). Prednisone treatment for neck pain was used more frequently in the high dose group (36% of patients) compared to the low dose activity group.

 

[B36] What is the role of radioactive iodine (RAI) (including remnant ablation,

adjuvant therapy, or therapy of persistent disease) after thyroidectomy, in the primary

management of differentiated thyroid cancer?

 

RECOMMENDATION 51

  1. A) RAI remnant ablation is not routinely recommended after thyroidectomy for ATA low

risk DTC patients. Consideration of specific features of the individual patient that could

modulate recurrence risk, disease follow-up implications, and patient preferences, are relevant to

RAI decision-making.

(Weak recommendation, Low-quality evidence)

 

  1. B) RAI remnant ablation is not routinely recommended after lobectomy or total thyroidectomy for patients with unifocal papillary microcarcinoma, in the absence of other adverse features.

(Strong recommendation, Moderate-quality evidence)

 

  1. C) RAI remnant ablation is not routinely recommended after thyroidectomy for patients with multi-focal papillary microcarcinoma, in absence of other adverse features. Consideration of specific features of the individual patient that could modulate recurrence risk, disease follow up implications, and patient preferences, are relevant to RAI decision-making.

(Weak recommendation, Low-quality evidence)

 

  1. D) RAI adjuvant therapy should be considered after total thyroidectomy in ATA intermediate risk level differentiated thyroid cancer patients.

(Weak recommendation, Lowquality evidence)

 

  1. E) RAI adjuvant therapy is routinely recommended after total thyroidectomy for ATA high risk differentiated thyroid cancer patients

(Strong recommendation, moderate-quality evidence)

 

Depending on the post-operative risk stratification of the individual patient, the primary goal of post-operative administration of radioactive iodine (RAI) after total thyroidectomy may include:

1) RAI remnant ablation (to facilitate detection of recurrent disease and initial staging

by tests such as thyroglobulin measurements or whole body RAI scans),

2) RAI adjuvant therapy (intended to improve disease-free survival by theoretically destroying suspected, but unproven residual disease, especially in those at increased risk of disease recurrence),

or 3) RAI therapy (intended to improve disease-specific and disease-free survival by treating persistent disease in higher risk patients). Additional considerations in RAI decision-making may include: patient co-morbidities (and the potential impact of therapeutic doses of RAI or preparation for the procedure), feasible or preferred disease surveillance procedures, patient preferences (the

latter being particularly important when clear data on therapeutic efficacy are lacking), or others.

It is important to note that in patients with low risk DTC, disease surveillance may be accomplished without RAI ablation using neck ultrasound and thyroglobulin with thyroglobulin antibody measurements while on thyroid hormone therapy.

We categorized the results of our review according to the ATA Risk of Recurrence Risk stratification (outlined in a preceding section of these guidelines). However, given that the ATA

risk classification is relatively new and the majority of studies examining therapeutic efficacy of

post-surgical RAI remnant ablation or therapy (adjuvant or for persistent disease), have been

performed with attention to traditional mortality risk stratification systems such as the AJCC/TNM system, MACIS, National Thyroid Cancer Treatment Cooperative Study Group (NTCTCSG), or others, it was necessary to extrapolate the results of many studies according to estimated ATA risk level. We have also categorized some of the results of our evidence review according to the AJCC/TNM risk of mortality stratification system, as this system has been in use longer in our field . Evaluation of post-operative disease status and recommendations for radioiodine remnant ablation and adjuvant therapy can be found in algorithms in Figures 5-8.

 

ATA Low Risk: Studies examining the impact of RAI remnant ablation/adjuvant therapy on long-term thyroid cancer outcomes in ATA low risk patients are subject to limitations due to their observational nature (and potential for bias), as well as limited statistical power to detect relatively uncommon events (such as disease-related mortality). By definition, the risk of disease-specific mortality is low, the risk of persistent/recurrent disease is low (around 3%), and there is no demonstration that delayed discovery and treatment of persistent disease may decrease the chance of cure in these patients. In a retrospective multi-center registry study, 1298 differentiated thyroid cancer patients categorized as ATA low risk level, were followed for a median of 10.3 years, and there was no significant effect of RAI remnant ablation adjuvant therapy on overall or disease-free survival, using respective multivariate and stratified propensity analysis techniques (80). Prospective data from the National Thyroid Cancer Treatment Cooperative Study Group (NTCTCSG) suggest that overall disease-specific and disease-free survival are not improved by RAI treatment in NTCTCSG Stage I and II patients (i.e. patients aged <45 years with no distant metastases or patients aged ≥45 years with a primary tumor < 4 cm in diameter, no extra-thyroidal extension, and no nodal metastases), also using multivariate analyses and propensity analyses (81;82). In two systematic reviews examining results of multivariate adjusted analyses, with a focus on low risk differentiated thyroid cancer using classic clinic-pathologic staging systems such as TNM/AJCC, the majority of studies did not show a significant effect of RAI remnant ablation adjuvant therapy in reducing thyroid cancerrelated death, and conflicting findings of studies relating to outcomes of disease recurrence (83;84). A more recent systematic review of the literature supported the findings of the earlier systematic reviews (85). It is important to note that in the studies summarized in this section on ATA low risk disease (or equivalent), patients with multifocal papillary thyroid cancer were generally included (if no other adverse features meeting criteria for upstaging were noted).

To date, there is little evidence to suggest that RAI may improve disease-specific mortality in low

risk differentiated thyroid cancer patients, and there is some conflicting evidence on effect on

recurrence, with newer data using the ATA risk system, suggesting lack of a significant effect.

Furthermore, the majority of the best available observational evidence suggests that RAI remnant

ablation adjuvant therapy is unlikely to improve disease-specific or disease-free survival in

papillary microcarcinoma (< 1 cm, uni- or multi-focal), in absence of other higher risk features

( 86-91). In a recent retrospective analysis of of 704 papillary microcarcinoma patients whose initial risk level was ATA low or intermediate who were followed for a median of 64 months, there was no significant reduction in recurrence rates in patients treated with RAI compared to those not treated with RAI using a propensity score analysis (87). With respect to microcarcinomas of follicular cancer and Hürthle cell cancer, a recent SEER registry secondary data analysis suggested no disease-specific survival benefit in patients treated with RAI in a multivariate analysis adjusted for age, histology, disease extent, type of surgery and external beam radiation (the total number of patients in this study was 564) (92). A limitation of interpreting these data on follicular and Hürthle cell microcarcinomas is that some of the patients in the study had some adverse features and were not all considered low risk, however the authors adjusted for relevant variables in their multivariate analysis (92). The role of RAI remnant ablation adjuvant therapy in ATA low risk DTC should be clarified in the future, following completion of RCTs, such as the Iodine or Not (IoN) trial for low and intermediate risk patients (93) and ESTIMABL2 for low risk patients.

 

ATA Intermediate Risk: We did not find studies specifically examining RAI treatment efficacy

in the ATA Intermediate risk group, thus, results of studies using alternative classification

systems were extracted as they applied to this risk category. Multivariate adjusted analyses from

SEER suggest that post-surgical RAI treatment is associated with improved overall survival for

aggressive papillary thyroid cancer histologies such as: tall cell, diffuse sclerosing, and insular

variants (95;96). Furthermore, multivariate adjusted analyses from SEER suggest that RAI

treatment is associated with improved overall survival in node-positive adult patients with PTC

or pT3 node-negative PTC, where the primary tumor is >4 cm or there is evidence of microscopic extrathyroidal extension (97). It is however important to note that in this SEER study the overall survival rate was very high in node-positive or pT3-node negative PTC patients aged<45 years, such that 99% and 98% of such individuals were alive after a median follow-up period of 6.8 years, with or without RAI treatment, respectively. The clinical significance of this approximately 1% absolute risk difference could be questioned. In contrast, in the same study, for individuals aged ≥65 years, assuming the same median study follow-up period of 6.8 years, 73% of T3-node negative or node-positive PTC patients treated with RAI and 69% of those not treated with RAI were alive (96); in this older subgroup, the absolute risk difference would be estimated to be about 4%.

There is some supportive evidence from multivariate and propensity analyses that there may be a benefit of adjuvant RAI treatment in improving overall and disease-specific survival as well as disease-free survival in patients with nodal metastases aged ≥45 years, as such patients would be included in the NTCTCSG stage III category (82). Furthermore, in a single center retrospective study from Hong Kong examining data from a subgroup of 421 patients with node positive papillary thyroid cancer, lymph node failure-free survival was improved with postsurgical

radioactive iodine treatment, with the greatest treatment benefits observed in patients with N1b disease, as well as with lymph nodes >1 cm in diameter (97). RAI therapeutic efficacy in patients <45 years of age with nodal metastases are unclear, as such patients are categorized as Stage I by the NTCTCSG system and no significant benefit of RAI treatment was observed for the Stage I group in that study, with no specific subgroup analysis reported according to node positivity (81). A single-center retrospective study from the Mayo Clinic examining 20-year cause-specific mortality and recurrence rate, suggested no significant benefit in papillary thyroid cancer patients with a MACIS score of <6 who had positive lymph nodes, using respective univariate analyses (17); given that age is incorporated in the MACIS score, it is possible that age was a contributing factor in the results of that analysis. In a subgroup of 352 patients with microscopic extra-thyroidal extension from a single center retrospective study, post-surgical radioactive iodine treatment was associated with a reduction in rate of local relapse (97). However, in the NTCTCSG study, microscopic extra-glandular invasion would be classified as NTCTCSG stage I for those < 45 years of age and II for those ≥45 years of age, and those stages were associated with lack of clear benefit of RAI. In a recent systematic review, Lamartina et al. reported conflicting results on the impact of RAI treatment on disease recurrence, specifically indicating that 11 non-randomized studies suggested a benefit, whereas 13 studies did not show a significant benefit (85). For patients with ATA intermediate risk DTC, limited risk-group specific data examining RAI efficacy is available, but existing data suggest that the greatest potential benefit may be observed with adverse thyroid cancer histologies, increasing volume of nodal disease, lymph node disease outside the central neck, and advancing patient age. Benefits on survival or recurrence can be expected primarily in patients

with higher risk of recurrent or persistent disease that is iodine-avid. More studies are needed,

including RCTs, to characterize RAI treatment efficacy in ATA intermediate risk patients. The

adjuvant therapeutic efficacy of RAI treatment in improving long-term thyroid cancer outcomes

in the situation of isolated microscopic central neck nodal disease in absence of other adverse

features is unknown, so the relatively good overall prognosis of this group (as outlined in the

preceding section of these guidelines) as well as the uncertainty RAI therapeutic efficacy for this

subgroup, are important considerations in RAI decision-making. Clearly more research is needed to understand the therapeutic efficacy in various subgroups of patients in the ATA intermediate risk category.

 

ATA High Risk: A prospective multicenter study reported a significant improvement in overall and disease-specific mortality, as well as disease-free survival in NTCTCSG stage III and IV patients, after statistical adjustment using multivariate and propensity stratified analyses (81). Furthermore, prospectively collected data from the SEER cancer registry suggest that post-surgical RAI therapy is associated with improved overall survival in patients with papillary thyroid cancer with distant metastases (when distant metastases combined with age >45 years, tumor size > 2cm, and positive lymph nodes at primary diagnosis) (98). Data from SEER also suggest that overall survival in patients with follicular thyroid cancer with distant metastases more than doubled in patients receiving post-surgical RAI treatment (98). Thus, routine postsurgical RAI treatment is recommended in patients with ATA high risk DTC.

 

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