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same serum specimendiffer among assay methods (316). Therefore, the Tg cutoff may differ signiﬁcantly among medical centers and labora- tories. Further, the clinical signiﬁcance of minimallyATA THYROID NODULE/DTC GUIDELINES 67
detectable Tg levels is unclear, especially if only detected following TSH stimulation. However, receiver operating curves have shown that a Tg level on thyroid hormone around0.2–0.3 ng/mL portends the best sensitivity and speciﬁcity fordetecting persistent disease. In these patients, the trend in se- rum Tg over time will typically identify patients with clinically signiﬁcant residual disease. A rising unstimulated or stimu-lated serum Tg indicates disease that is likely to become clinically apparent (618,795). Thyroglobulin doubling time may have utility as a predictor of recurrence, analogous to theuse of calcitonin doubling time for MTC (622,796). [C7] Anti-Tg antibodies The presence of anti-Tg antibodies, which occur in ap- proximately 25% of thyroid cancer patients (797) and 10% of the general population (798), will falsely lower serum Tg determinations in immunometric assays (799). The use ofrecovery assays in this setting to detect signiﬁcant interfer- ence is controversial (799,800). Serum anti-Tg antibody should be
measured in conjunction with serum Tg assay by animmunometric method. Although assay standardization against the International Reference Preparation 65/93 has been recommended (608), wide-ranging variability in assayresults and analytical sensitivity of the assay remains (801,802). Use of recovery methods for anti-Tg antibody may suffer variable interferences (608). Anti-Tg antibody mayrise transiently postoperatively as an apparent immune re-action to the surgery itself and may also rise after ablation therapy (611). Anti-Tg antibodies should be measured in a different assay if the routine anti-Tg antibody assay is neg-ative in a patient with surgically proven Hashimoto thy- roiditis (775). It may be useful to measure anti-Tg antibodies shortly after thyroidectomy and prior to ablation becausehigh levels may herald the likelihood of recurrence in patients without Hashimoto thyroiditis (801). Similarly, recurrent or progressive disease is suggested in those patients initiallypositive for anti-Tg antibodies who then become negative butsubsequently have rising levels of anti-Tg antibodies.
Falling levels of anti-Tg antibodies may indicate successful therapy (614,801). Thus, serial serum anti-Tg antibody quantiﬁcationusing the same methodology may serve as an imprecise surrogate marker of residual normal thyroid tissue, Ha- shimoto thyroiditis, or tumor (608,609,615). Following totalthyroidectomy and RAI remnant ablation, anti-Tg antibodies usually disappear over a median of about 3 years in patients without evidence of persistent disease (611,615,616). Severalstudies demonstrate an increased risk of recurrence/persistent disease associated either with a new appearance of anti-Tg antibodies or rising titers (609–614). From a clinical per-spective, anti-Tg antibody levels that are declining over timeare considered a good prognostic sign, while rising antibody levels, in the absence of an acute injury to the thyroid (release of antigen by surgery or RAI treatment), signiﬁcantly in-creases the risk that the patient will subsequently be diag- nosed with persistent or recurrent thyroid cancer. The recent development of liquid chromatography-tandem mass spectrometry assay of
Tg holds promise for accurate Tg measurement in the presence of Tg autoantibodies (803– 805), but further studies will be required to validate the assaysin terms of functional sensitivity, correlations with immu- noassay results, and patient outcomes, reﬂecting either ex- cellent response or persistent disease (806).[C8] What is the role of serum Tg measurement in patients who have not undergone RAI remnant ablation? &RECOMMENDATION 64 Periodic serum Tg measurements on thyroid hormone therapy should be considered during follow-up of patients with DTC who have undergone less than total thyroidec-tomy and in patients who have had a total thyroidectomybut not RAI ablation. While speciﬁc cutoff levels of Tg that optimally distinguish normal residual thyroid tissue from persistent thyroid cancer are unknown, rising Tgvalues over time are suspicious for growing thyroid tissue or cancer. (Strong recommendation, Low-quality evidence) In low- and intermediate-risk patients who underwent a total thyroidectomy without remnant ablation or
adjuvant therapy, the same strategy of follow-up is used, based onserum Tg determination on LT 4treatment and on neck US at 9–12 months. In most of these patients, neck US does not reveal any suspicious ﬁndings and the serum Tg is <1 ng/mL on LT 4treatment, is low ( <2 ng/mL) and will remain at a low level, or will decrease without any additional therapy over time (545). There is no need for rhTSH stimulation because Tg will increase to a value above 1 ng/mL in 50% of thecases, even in individuals without residual cancer, with the magnitude of increase being related to the size of normal thyroid remnants (783). These patients are followed on anannual basis with serum TSH and Tg determination. In the few patients with a serum Tg that remains elevated over time, especially for those with a rising Tg, remnant ab-lation or adjuvant therapy with 131I
may be considered with a posttherapy WBS if neck US is negative. There is no evidence in these low-risk patients that a delayed treatment over the postoperative treatment may adversely affect the outcome. A cohort of 80 consecutive patients with very low-risk PTMC who had undergone near-total thyroidectomy without postoperative RAI treatment were studied over 5 years (783).The rhTSH-stimulated serum Tg levels were £1 ng/mL in 45 patients (56%) and >1 ng/mL in 35 (44%) patients in whom rhTSH-stimulated Tg levels were as high as 25 ng/mL. Thediagnostic WBS revealed uptake in the thyroid bed butshowed no pathological uptake in any patient, and thyroid bed uptake correlated with the rhTSH-stimulated serum Tg levels (p<0.0001). Neck ultrasonography identiﬁed lymph node metastases in both Tg-positive and Tg-negative patients. The authors concluded that for follow-up of this group of patients: (i) diagnostic WBS was ineffective at detecting metastases;(ii) neck ultrasonography as the main
surveillance tool was highly sensitive in detecting lymph node metastases; and (iii) detectable rhTSH-stimulated serum Tg levels mainly de-pended upon the size of thyroid remnants, which suggests that serum Tg determination should be performed primarily on thyroid hormone therapy when using a sensitive Tg assay(functional sensitivity £0.2 ng/mL). In a series of 290 low-risk patients who had not undergone remnant ablation (545), se- rum Tg levels on LT 4became undetectable ( <1 ng/mL) within 5–7 years in 95% of the cohort and was <0.1 ng/mL in 80% of a subset of these patients, using a sensitive assay to conﬁrm the utility of Tg measurements on thyroid hormone treatment68 HAUGEN ET AL.
for routine follow-up. The frequency of follow-up is uncertain in patients who have not received RAI ablation and have sufﬁcient residual thyroid tissue to produce measurable levelsof serum Tg, the magnitude of which will depend upon themass of residual tissue and the degree of TSH suppression. It appears reasonable to consider periodic measurements of Tg as surveillance for a trend in rising values. [C9] What is the role of US and other imaging techniques (RAI SPECT/CT, CT, MRI, PET-CT)during follow-up? [C10] Cervical ultrasonography &RECOMMENDATION 65 (A) Following surgery, cervical US to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6–12 months and then periodically, depending on the patient’s risk for recurrent disease and Tgstatus. (Strong recommendation, Moderate-quality evidence)(B) If a positive result would change management, ultra- sonographically suspicious lymph nodes ‡8–10 mm (see Recommendation 71) in the smallest diameter should be biopsied for
cytology with Tg measurement in the needlewashout ﬂuid. (Strong recommendation, Low-quality evidence)(C) Suspicious lymph nodes less than 8–10 mm in smallest diameter may be followed without biopsy with consider- ation for FNA or intervention if there is growth or if thenode threatens vital structures. (Weak recommendation, Low-quality evidence)(D) Low-risk patients who have had remnant ablation, negative cervical US, and a low serum Tg on thyroid hormone therapy in a sensitive assay ( <0.2 ng/mL) or after TSH stimulation (Tg <1 ng/mL) can be followed primarily with clinical examination and Tg measurements on thyroid hormone replacement. (Weak recommendation, Low-quality evidence) Cervical ultrasonography is performed with a high- frequency probe ( ‡10 MHz) and is highly sensitive in the detection of cervical metastases in patients with DTC(290,783,807). These studies primarily evaluate patients with PTC, and the utility of neck US for monitoring patients with low-risk FTC is not well-established. Neck US should
in-terrogate all lymph node compartments and the thyroid bed.Frequently, US does not distinguish thyroid bed recurrences from benign nodules (629,808). When an abnormality is found during the year after surgery in patients without anyother suspicious ﬁndings, including low serum Tg on thyroid hormone therapy, follow-up may be performed with neck US. A correlation performed between US ﬁndings and pathology at surgery (292) has shown for lymph nodes >7m m i n t h e smallest diameter that a cystic appearance or hyperechoic punctuations in a context of thyroid cancer should be consideredas malignant; lymph nodes with a hyperechoic hilum are re-assuring; the type of vascularization (central: reassuring; pe- ripheral: concerning) has a high sensitivity/speciﬁcity; a roundshape, a hypoechoic appearance or the loss of the hyperechoic hilum by themselves does not justify a FNA biopsy (FNAB). Interpretation of neck US should take into account all other clinical and biological data. In
fact, the risk of recurrence isclosely related to the initial lymph node status: most lymph node recurrences occur in already involved compartments; the risk increases with a higher number of N1 and a highernumber of N1 with extracapsular extension (338) and with macroscopic rather than microscopic lymph node metastases (335,809). In low- and intermediate-risk patients, the risk of lymph node recurrence is low ( <2%) in patients with undetectable serum Tg a n di sm u c hh i g h e ri nt h o s ew i t hd e t e c t a b l e / e l e v a t e ds e r u mT g .In fact, 1 g of neoplastic thyroid tissue will increase the serumTg by*1 ng/mL during LT 4treatment and by approximately 2–10 ng/mL following TSH stimulation (788,800). Neck US can detect N1 as small as 2–3 mm
in diameter (in patients inwhom serum Tg may be low or undetectable), but beneﬁts of their early discovery ( <8–10 mm) is not demonstrated. FNAB for cytology and Tg measurement in the aspirate ﬂuid is performed for suspicious lymph nodes ‡8–10 mm in their smallest diameter. US guidance may improve the results of FNAB, in particular for small lymph nodes and those locateddeep in the neck. However, FNAB cytology misses thyroid cancer in a signiﬁcant proportion (up to 20%) of patients. The combination of cytology and serum Tg determination in theaspirate ﬂuid increases sensitivity (303,810,811). In cases oflymph node metastases, the Tg concentration in the aspirate ﬂuid is often elevated ( >10 ng/mL), and concentrations above this level are highly suspicious (296,298,301). A Tg concentration inthe aspirate ﬂuid between 1 and 10 ng/mL is moderately suspi- cious for malignancy, and comparison of the Tg measurement in the aspirate ﬂuid and
the serum should be considered in thesepatients. Also, up to half of the FNAB performed for suspicious US ﬁndings are benign, demonstrating that selection of patients for FNAB needs to be improved (296,298,812). Nonsuspiciousand small nodes ( <8–10 mm in the smallest diameter) can be m o n i t o r e dw i t hn e c kU S . [C11] Diagnostic whole-body RAI scans &RECOMMENDATION 66 After the ﬁrst posttreatment WBS performed followingRAI remnant ablation or adjuvant therapy, low-risk and intermediate-risk patients (lower risk features) with an undetectable Tg on thyroid hormone with negative anti-Tg antibodies and a negative US (excellent response to ther- apy) do not require routine diagnostic WBS during follow-up. (Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 67 (A) Diagnostic WBS, either following thyroid hormone withdrawal or rhTSH, 6–12 months after adjuvant RAI therapy can be useful in the follow-up of patients with high or intermediate
risk (higher risk features) of persistentdisease (see risk stratiﬁcation system, section [B19]) and should be done with123I or low activity131I. (Strong recommendation, Low-quality evidence)B) SPECT/CT RAI imaging is preferred over planar im- aging in patients with uptake on planar imaging to betterATA THYROID NODULE/DTC GUIDELINES 69
anatomically localize the RAI uptake and distinguish be- tween likely tumors and nonspeciﬁc uptake (Weak recommendation, Moderate-quality evidence) Following RAI ablation or adjuvant therapy, when the posttherapy scan does not reveal uptake outside the thyroid bed, subsequent diagnostic WBSs have low sensitivity and are usu- ally not necessary in low-risk patients who are clinically free of residual tumor and have an undetectable serum Tg level onthyroid hormone and negative cervical US (583,785,813,814). A diagnostic WBS may be indicated in three primary clinical settings: (i) patients with abnormal uptake outside thethyroid bed on posttherapy WBS, (ii) patients with poorlyinformative postablation WBS because of large thyroid remnants with high uptake of 131I(>2% of the administered activity at the time of WBS) that may hamper the visuali-zation of lower uptake in neck lymph nodes, and (iii) patients with Tg antibodies, at risk of false-negative Tg measurement, even when neck US does not show
any suspicious ﬁndings.Iodine 123 is preferred over 131I in these rare indications for diagnostic WBS, because it delivers lower radiation doses to the body and provides better quality images. Iodine 131 or123I whole-body scintigraphy includes planar images or images using a dual-head SPECT gamma camera of the whole body and spot images of the neck, mediastinum, andon any abnormal focus of RAI uptake. It may be performedafter the administration of either a diagnostic (usually 2–5 mCi) or a therapeutic activity (30–150 mCi) of RAI. Because of the lack of anatomical landmarks on planar images, it is oftendifﬁcult to differentiate uptake in normal thyroid remnants from lymph node metastases (especially when thyroid rem- nants are large), uptake in lung metastases from rib lesions, oraccumulation of RAI in intestine or bladder from a pelvic bone lesion. Hybrid cameras combine a dual-head SPECT gamma camera with a CT scanner in one gantry. This
allows directsuperimposition of functional and anatomical imaging. Theradiation dose delivered to the patient by the low-dose CT scan is 2–5 mSv, a dose that is much lower than the dose delivered by the administration of 100 mCi of 131I (around 50 mSv). Whole-body SPECT/CT performed after the administra- tion of a diagnostic or a therapeutic activity (30 mCi or more) of RAI is associated with (i) an increased number of patientswith a diagnosis of metastatic lymph node and (ii) a de- creased frequency of equivocal ﬁndings (739,743,815–818). Furthermore, the CT portion of the SPECT/CT provides ad-ditional information on non–iodine-avid lesions; SPECT-CT changed tumor risk classiﬁcations in 25% of the patients according to the International Union Against Cancer classi-ﬁcation and in 6% of the patients according to the ATA risk ofrecurrence classiﬁcation; the SPECT-CT changed treatment management in 24 to 35% of patients, by decreasing the rate of equivocal ﬁndings. Finally,
SPECT-CT avoids the need forfurther cross-sectional imaging studies such as contrast CT or MRI. Neoplastic lesions with low uptake of RAI or without any uptake may be a cause of false negative SPECT-CT. Iodine 124 emits positrons, allowing PET/CT imaging in DTC patients. It is used as a dosimetric and also as a diagnostic tool to localize disease. In fact, for each neoplastic focus 124IP E T / C T permits an accurate measureme nt of its volume as well as the uptake and half-life of124I in it, therefore allowing a reliable individual dosimetric assessment for each neoplastic focus.The sensitivity of124I-PET for the detection of residual thyroid tissue and/or metastatic DTC was reported to be higher than that of a diagnostic131I planar WBS (99% vs. 66%) (819–821). Iodine 124 PET/CT has not yet beencompared with131I SPECT/CT in a large series of patients with DTC. Furthermore,124I is not yet widely available
for clinical use and is primarily a research tool at this time. [C12]18FDG-PET scanning &RECOMMENDATION 68 (A)18FDG-PET scanning should be considered in high- risk DTC patients with elevated serum Tg (generally >10 ng/mL) with negative RAI imaging (Strong recommendation, Moderate-quality evidence)(B) 18FDG-PET scanning may also be considered as (i) a part of initial staging in poorly differentiated thyroidcancers and invasive Hu ¨rthle cell carcinomas, especially those with other evidence of disease on imaging or because of elevated serum Tg levels, (ii) a prognostic tool in pa-tients with metastatic disease to identify lesions and pa- tients at highest risk for rapid disease progression and disease-speciﬁc mortality, and (iii) an evaluation of post-treatment response following systemic or local therapy ofmetastatic or locally invasive disease. (Weak recommendation, Low-quality evidence) 18FDG-PET/CT is primarily considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) with negative RAI imaging. In a meta-analysis of 25
studies that included 789 patients, the sensitivity of18FDG-PET/CT was 83% (ranging from 50% to 100%) and the speciﬁcity was 84% (ranging from 42% to 100%) in non–131I-avid DTC (822). Factors inﬂuencing18FDG-PET/CT sensitivity in- cluded tumor dedifferentiation, larger tumor burden, and to alesser extent, TSH stimulation. 18FDG-PET is more sensitive in patients with an aggres- sive histological subtype, including poorly differentiated, tallcell, and Hu ¨rthle cell thyroid cancer.18FDG uptake on PET in metastatic DTC patients is a major negative predictive factor for response to RAI treatment and an independent prognosticfactor for survival (823,824). It can also identify lesions with high18FDG uptake (standardized uptake value) that may be more aggressive and should be targeted for therapy or closemonitoring. It is complementary to131IW B S ,e v e ni nt h e presence of detectable131I uptake in metastases, because18FDG uptake may be present in neoplastic foci with no131Iu p t a k e
. In patients with a TSH-stimulated Tg £10 ng/mL, the sensitivity of18FDG is low, ranging from <10% to 30%. It is therefore recommended to consider18FDG-PET only in DTC patients with a stimulated Tg level ‡10 ng/mL. Of course, this level needs to be adapted and lowered in case of aggressive pathological variant of thyroid cancer that may produce low amounts of serum Tg. Furthermore, in patients with unde-tectable Tg levels but with persistent Tg antibodies the level of serum Tg cannot be reliably assessed and18FDG-PET may localize disease in some of these patients. The sensitivity of18FDG-PET scanning may be slightly in- creased with TSH stimulation. A multicentric prospective study on 63 patients showed an increase in the number of lesions70 HAUGEN ET AL.
detected on the18FDG-PET/CT performed after rhTSH stimulation compared to the18FDG-PET/CT performed on thyroid hormone treatment and without TSH stimulation(825). However, the sensitivity for detecting patients with atleast one tumor site was not improved by the rhTSH stim- ulation. In this study, the lesions found only by rhTSH-PET c o n t r i b u t e da d e q u a t e l yt oa na l t e r e dt h e r a p e u t i cp l a ni nf o u rpatients (6%), and the clinical beneﬁt of identifying these additional small foci remains to be proven. Its clinical b e n e ﬁ tm i g h tb eh i g h e ri np a t i e n t sw i t hn o r m a ln e c ka n dchest CT scan and normal
neck ultrasonography. A meta- analysis on seven studies including the previous study and comprising 168 patients conﬁrmed these results and showedthat 18FDG-PET/CT performed following TSH stimulation altered clinical management in only 9% of patients. Fur- thermore, false positives can be seen with18FDG-PET im- aging with or without TSH stimulation (825). Results of18FDG-PET/CT might alter the indications for 131I treatment or the decision for surgical removal of small tumor foci with18FDG uptake. The frequency of false- positive lesions varies among series from 0% to 39%, and this high number justiﬁes a FNAB with cytology and Tg mea- surement in the aspirate ﬂuid in cases in which surgery isplanned, based on18FDG-PET results. The higher sensitivity of neck ultrasonography for the detection of small metastatic lymph nodes should be noted, with18FDG-PET being more sensitive for some locations such as the retropharyngeal orthe retro-clavicular regions (825). To date, there is no evidence that TSH
stimulation im- proves the prognostic value of18FDG-PET imaging. [C13] CT and MRI &RECOMMENDATION 69 (A) Cross-sectional imaging of the neck and upper chest (CT, MRI) with IV contrast should be considered (i) in the setting of bulky and widely distributed recurrent nodal disease whereUS may not completely delineate disease, (ii) in the assess-ment of possible invasive recurrent disease where potential aerodigestive tract invasion requires complete assessment, or ( i i i )w h e nn e c kU Si sf e l tt ob ei n a d e q u a t e l yv i s u a l i z i n gpossible neck nodal disease (high Tg, negative neck US). (Strong recommendation, Moderate-quality evidence)(B) CT imaging of the chest without IV contrast (imag- ing pulmonary parenchyma) or with IV contrast (to in- clude the mediastinum) should be considered in high riskDTC patients with elevated serum Tg
(generally >10 ng/ mL) or rising Tg antibodies with or without negative RAI imaging. (Strong recommendation, Moderate-quality evidence)(C) Imaging of other organs including MRI brain, MR skeletal survey, and/or CT or MRI of the abdomen shouldbe considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) and negative neck and chest imaging who have symptoms referable to those or-gans or who are being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be at risk for complications of tumor swelling. (Strong recommendation, Low-quality evidence)In patients with elevated or rising Tg or anti-Tg antibodies and NED on neck US or RAI imaging (if performed), CT imaging of the neck and chest should be considered. Thefrequency of positive anatomic imaging increases with higherserum Tg levels above 10 ng/mL. CT is the most frequently recommended ﬁrst-line technique to search for lymph node metastases in patients with squamous cell carcinoma of
thehead and neck, and an injection of contrast medium is man- datory for the analysis of the neck and mediastinum (826). Radioiodine can be administered 4–8 weeks following theinjection of contrast medium, because at that time a majority of the iodine contamination has disappeared in most patients (315). If there is a concern, a random urine iodine (and cre-atinine) prior to initiation of a LID and RAI testing or treat-ment can be measured to make sure the urine iodine is not high. Diagnostic CT scan may complement neck US for the detection of macrometastases in the central compartment, inthe mediastinum, and behind the trachea (307–309), and it is the most sensitive tool for the detection of micrometastases in the lungs. Before revision surgery is contemplated, pre-sumptive recurrent neck targets must be deﬁned by high- resolution radiographic anatomic studies such as US or spiral axial CT scan to complement 18FDG-PET/CT or
RAI im- aging and must be carefully deﬁned to allow for adequate preoperative mapping and deﬁnitive surgical localization. In addition to nodal assessment axial scanning, includingCT scan with contrast has utility in the evaluation of locallyrecurrent invasive disease and relationships with vessels. Such patients may present with hoarseness, vocal cord pa- ralysis on laryngeal exam, progressive dysphagia or massﬁxation to surrounding structures, respiratory symptoms including stridor or hemoptysis, and lesions with rapid pro- gression/enlargement. Such lesions are incompletely evalu-ated with US alone, and axial CT scanning with contrast medium is indicated. The use of MRI has also been advocated for imaging the neck and the mediastinum. It is performed with and withoutinjection of gadolinium chelate as a contrast medium and does not require any injection of iodine contrast medium. The performance of MRI for imaging the neck and mediastinumhas not been directly compared with CT on large numbers of thyroid
cancer patients (827–829). Compared to CT scan, it may better delineate any involvement of the aerodigestivetract (830,831). It is often used as second-line imaging tech- nique in patients with demonstrated or suspicious lesions on CT scan in order to better delineate these lesions. In the lowerpart of the neck, movements of the aerodigestive axis during the procedure that may last several minutes will decrease the quality of images (414). Endoscopy of the trachea and oresophagus, with or without ultrasonography, looking for ev-idence of intraluminal extension can also be helpful in cases of suspected aerodigestive tract invasion. MRI is less sensitive than CT scan for the detection of lung micronodules. Finally, whether these imaging techniques (CT and MRI) should be performed for diagnostic purposes or whether an 18FDG-PET/CT scan should be performed as the ﬁrst-line imaging procedure for diagnosis is still a matter of debate. In the past, CT scan with
injection of contrast medium was more sensitive for the detection of lymph node metastases (832),but with modern PET/CT equipment, the CT scan of the PET/ CT is as reliable as a CT scan used for radiology, and many lesions can be found on18FDG-PET/CT scanning, even if noATA THYROID NODULE/DTC GUIDELINES 71
injection of contrast medium has been performed (833,834). Delineation between lymph node metastases or local recur- rence and vessels or the aerodigestive axis is often not wellvisualized on18FDG-PET/CT in the absence of contrast in- jection, and if necessary other imaging techniques (CT and MRI with contrast medium) may be performed especially for a preoperative work-up. As a result, most patients with ex-tensive disease should be considered for18FDG-PET/CT and CT imaging with contrast, and some patients will also be considered for MRI. This imaging strategy is applied in patients with elevated serum Tg ( >5–10 ng/mL) and no other evidence of disease (neck and chest imaging), starting with a18FDG-PET/CT (822,833). In the past an empiric treatment was used in suchpatients, but recent studies have shown that18FDG-PET/CT imaging is more sensitive and should be performed as the ﬁrst-line approach, with empiric RAI treatment being con-sidered only for those patients with no detectable18FDG
uptake (833). [C14] Using ongoing risk stratiﬁcation (response to thera- py) to guide disease long-term surveillance and therapeutic management decisions Ongoing risk stratiﬁcation allows the clinician to continue to provide individualized management recommendations as the risk estimates evolve over time. While the speciﬁc detailsof how surveillance and therapeutic strategies should be modiﬁed over time as a function of response to therapy re- classiﬁcation within each ATA risk category remains to bedeﬁned, we do endorse the following concepts (more details in Table 13). Excellent response: An excellent response to therapy should lead to a decrease in the intensity and frequency offollow-up and the degree of TSH suppression (this change in management will be most apparent in ATA intermediate- and high-risk patients). Biochemical incomplete response: If associated with stable or declining serum Tg values, a biochemical incom- plete response should lead to continued observation withongoing TSH suppression in most patients. Rising Tg
or anti- Tg antibody values should prompt additional imaging and potentially additional therapies. Structural incomplete response: A structural incomplete response may lead to additional treatments or ongoing ob- servation depending on multiple clinico-pathologic factorsincluding the size, location, rate of growth, RAI avidity, 18FDG avidity, and speciﬁc pathology of the structural lesions. Indeterminate response: An indeterminate response should lead to continued observation with appropriate serialimaging of the nonspeciﬁc lesions and serum Tg monitoring. Nonspeciﬁc ﬁndings that become suspicious over time or rising Tg or anti-Tg antibody levels can be further evaluatedwith additional imaging or biopsy. [C15] What is the role of TSH suppression during thyroid hormone therapy in the long-term follow-up of DTC? &RECOMMENDATION 70 (A) In patients with a structural incomplete response to therapy, the serum TSH should be maintained below0.1 mU/L indeﬁnitely in the absence of speciﬁc contrain- dications. (Strong recommendation, Moderate-quality evidence) (B) In patients with a biochemical
incomplete response to therapy, the serum TSH should be maintained between 0.1 and 0.5 mU/L, taking into account the initial ATA riskclassiﬁcation, Tg level, Tg trend over time, and risk of TSH suppression. (Weak recommendation, Low-quality evidence)(C) In patients who presented with high-risk disease but have an excellent (clinically and biochemically free ofdisease) or indeterminate response to therapy, consider-ation should be given to maintaining thyroid hormone therapy to achieve serum TSH levels of 0.1–0.5 mU/L for up to 5 years after which the degree of TSH suppressioncan by reduced with continued surveillance for recurrence. (Weak recommendation, Low-quality evidence)(D) In patients with an excellent (clinically and bio- chemically free of disease) or indeterminate response to therapy, especially those at low risk for recurrence, theserum TSH may be kept within the low reference range (0.5–2 mU/L). (Strong recommendation, Moderate-quality evidence) (E) In patients who have not undergone remnant ablation or adjuvant therapy
who demonstrate an excellent or in- determinate response to therapy with a normal neck US,and low or undetectable suppressed serum Tg, and Tg or anti-Tg antibodies that are not rising, the serum TSH can be allowed to rise to the low reference range (0.5–2 mU/L). (Weak recommendation, Low-quality evidence) A meta-analysis has suggested an association between thyroid hormone suppression therapy and reduction of majoradverse clinical events (745). The appropriate degree of TSHsuppression by thyroid hormone therapy is still unknown, es- pecially in high-risk patients rendered free of disease. A con- stantly suppressed TSH (0.05 mU/L) was found in one study tobe associated with a longer relapse-free survival than when serum TSH levels were always 1 mU/L or greater, and the degree of TSH suppression was an independent predictor ofrecurrence in multivariate analysis (749). Conversely, another large study found that disease stage, patient age, and 131I therapy independently predicted disease progression,
but thedegree of TSH suppression did not (275). A third study showedthat during LT 4therapy the mean Tg levels were signiﬁcantly higher when TSH levels were normal than when TSH levels were suppressed ( <0.5 mU/L) but only in patients with local or distant recurrence (835). A fourth study of 2936 patients found that overall survival improved signiﬁcantly when the TSH was suppressed to <0.1 mU/L in patients with NTCTCSG stage III or IV disease and to a range of 0.1 mU/L to about 0.5 mU/L in patients with NTCTCSG stage II disease; however, there was no incremental beneﬁt from suppressing TSH to undetectablelevels in stage II patients, and suppression of TSH was of no beneﬁt in patients with stage I disease (671), and higher de- grees of suppression to TSH of <0.03 mU/L provided no ad- ditional beneﬁt (746). Another study found that a serum TSH72 HAUGEN ET AL.
threshold of 2 mU/L differentiated best between patients free of disease and those with relapse or cancer-related mortality, which remained signiﬁcant when age and tumor stage wereincluded in a multivariate analysis (750). A prospective studyshowed that disease-free survival for low-risk patients without TSH suppression was not inferior to patients with TSH sup- pression (836). No prospective studies have been performedexamining the risk of recurrence and death from thyroid cancer associated with varying serum TSH levels, based on the cri- teria outlined above in [C14] for the absence of tumor at 6–12months post surgery and RAI ablation. A recent observational study demonstrated increased risk of all-cause and cardiovascular mortality in DTC patients com-pared to a control population (837). The authors also showedthat survival in the DTC patients was lower when the serum TSH was <0.02 mU/L, which is particularly relevant in patients with an excellent response to therapy in whom overtreatmentshould
be avoided. An approach to balancing the risks of thy- roxine suppression against the risks of tumor recurrence or progression has been presented in a recent review (747). Thisreview helped to deﬁne patients at low, intermediate, and high risk of complications from TSH suppression therapy. Table 15 provides recommendations for TSH ranges based on responseto thyroid cancer therapy weighed against risks of LT 4therapy,which is adapted from the review by Biondi and Cooper (747). In patients at high risk of adverse effects on heart and bone by TSH suppression therapy, the beneﬁts of TSH suppressionshould be weighed against the potential risks. In peri- andpostmenopausal women at risk for bone loss, adjunctive ther- apy with calcium supplements, vitamin D, and other bone- enhancing agents (bisphosphonates, denosumab, etc.) shouldbe considered. b-Adrenergic blocking drugs may be considered in older patients to obviate increases in left ventricular mass and tachycardia (838,839). There are inadequate
data to make a strong recommendation regarding the intensity and duration of TSH suppression in the biochemical incomplete response to therapy category. Thiscategory encompasses a variety of patients with low serum Tglevels (median nonstimulated Tg 3.6 ng/mL) having been initially classiﬁed as ATA low risk (16%–24%), ATA inter- mediate risk (47%–64%), or ATA high risk (18%–21%)(539,607). Furthermore, the risk of development of structurally identiﬁable disease within this cohort is not uniform but rather is related to the ongoing behavior of residual disease as re-ﬂected by both the magnitude of the Tg elevation and to the rate of rise of the serum Tg or anti-Tg antibodies. Based on weak data and expert opinion, we recommend a goal TSH of0.1–0.5 mIU/L for the majority of patients with a biochemical Table 15.Thyrotropin Targets for Long-Term Thyroid Hormone Therapy ATA THYROID NODULE/DTC GUIDELINES 73
incomplete response, recognizing that less intense TSH sup- pression (0.5–2.0 mIU/L) may be appropriate for ATA low- risk patients with stable nonstimulated Tg values near thethreshold for excellent response (e.g., nonstimulated Tg valuesin the 1–2 ng/mL range), while more intense TSH suppression (<0.1 mIU/L) may be desired in the setting of more elevated or rapidly rising Tg values. [C16] What is the most appropriate management of DTC patients with metastatic disease? Metastases may be discovered at the time of initial disease staging or may be identiﬁed during longitudinal follow-up. Ifmetastases are found following initial therapy, some patientsmay subsequently experience a reduction in tumor burden with additional treatments that may offer a survival or palliative beneﬁt (840–844). The preferred hierarchy of treatment formetastatic disease (in order) is surgical excision of loco- regional disease in potentially curable patients, 131I therapy for RAI-responsive disease, external beam radiation therapy orother directed treatment modalities such
as thermal ablation, TSH-suppressive thyroid hormone therapy for patients with stable or slowly progressive asymptomatic disease, and sys-temic therapy with kinase inhibitors (preferably by use of FDA-approved drugs or participation in clinical trials), espe- cially for patients with signiﬁcantly progressive macroscopicrefractory disease. Clinical trials or kinase inhibitor therapymay be tried before external beam radiation therapy in special circumstances, in part because of the morbidity of external beam radiation and its relative lack of efﬁcacy. However, lo-calized treatments with thermal (radiofrequency or cryo-) ab- lation (845), ethanol ablation (846), or chemo-embolization (847) may be beneﬁcial in patients with a single or a fewmetastases and in those with metastases at high risk of local complications; the treatments should be performed in such patients before the initiation of any systemic treatment. Thesemodalities may control treated metastases, may avoid localcomplications, and may delay initiation of systemic treatment. Additionally, surgical therapy in selected incurable patients
is important to prevent complications in targeted areas, such asthe CNS and central neck compartment. Conversely, conser- vative intervention with TSH-suppressive thyroid hormone therapy may be appropriate for selected patients with stableasymptomatic local metastatic disease and most patients with stable asymptomatic non-CNS distant metastatic disease. [C17] What is the optimal directed approach to patients with suspected structural neck recurrence? &RECOMMENDATION 71 Therapeutic compartmental central and/or lateral neck dis- section in a previously operated compartment, sparing unin-volved vital structures, should be performed for patients with biopsy-proven persistent or recurrent disease for central neck nodes ‡8 mm and lateral neck nodes ‡10 mm in the smallest dimension that can be localized on anatomic imaging. (Strong recommendation, Moderate-quality evidence) Persistent or recurrent nodal disease may result in local invasion and is the source of considerable patient and phy-sician anxiety (848). However, several observational studies suggest that low-volume recurrent nodal disease can be in-
dolent and can be managed through active surveillance, al-though not all lesions in these series are documented asmalignant (629,849). Bulky or invasive recurrent disease is best treated surgically (319,850–853). The judgment to offer surgery for recurrent nodal disease in the neck is made with equipoise in two opposing decision elements: (i) the risks of revision surgery (which are typically higher than primary surgery due to scarring from previoussurgery (854) balanced with (ii) the fact that surgical resec- tion generally represents the optimal treatment of macro- scopic gross nodal disease over other treatment options. Animportant element in this decision-making process is theavailability of surgical expertise speciﬁcally in the perfor- mance of revision thyroid cancer nodal surgery, which is a discrete surgical skill set. The decision to treat cervical nodalrecurrence surgically should be made with an appreciation of distant disease presence and progression but may be under- taken even in the setting
of known distant metastasis forpalliation of symptoms and prevention of aerodigestive tract obstruction. The decision for treatment and surgery speciﬁ- cally is best derived through collaborative team approachinvolving surgery, endocrinology, and importantly the pa- tient and family (855). Therefore, cytologic conﬁrmation of disease can be deferred if the ﬁndings of the FNA will notlead to additional evaluation or treatment. While we gener-ally recommend cytologic conﬁrmation of abnormal radio- graphic ﬁndings prior to surgical resection, we recognize that this may not be necessary (or possible) in every case (e.g.,radiographic ﬁndings with a very high likelihood of malig- nancy, or the speciﬁc location of the lymph node makes it difﬁcult/impossible to biopsy). [C18] Nodal size threshold Surgery is considered with the recognition of clinically apparent, macroscopic nodal disease through radiographicanalysis including US (Table 7) and/or axial (CT) scanningrather than through isolated Tg elevation (309,335,856). Given the risks of revision nodal surgery, a
clearly deﬁned preoperative radiographic target is mandatory. The risks ofsurgery relate in part to the exact location of the target node(s) and whether the compartment in question has been previously dissected such as recurrent central neck nodesafter primary thyroidectomy. This target must be deﬁned by high-resolution radiographic anatomic studies such as US or spiral CT scan with contrast, as a complement to 18FDG-PET/ CT or RAI-SPECT/CT when performed, to allow for ade- quate preoperative mapping and deﬁnitive surgical localiza- tion (309,856). Ultrasound-guided FNA for cytology with Tgmeasurement in the aspiration sample can be performed inthe setting of radiographically suspicious nodal recurrence keeping in mind that Tg rinsing may be positive with thyroid bed persistent benign thyroid remnant tissue if the patient hasnot been treated with RAI. Charcoal tattooing under US guidance may help the surgeon to localize the lymph node to be removed during surgery (344). Malignant central neck nodes
‡8 mm and lateral neck nodes ‡10 mm in the smallest dimension that have undergone FNAB and can be localized on anatomic imaging (US with orwithout axial CT) can be considered surgical targets74 HAUGEN ET AL.
(309,857–859). Short-axis nodal diameter measurement is optimally employed in surgical decision-making for nodal malignancy. Smaller lesions are probably best managed withactive surveillance (observation) with serial cross-sectionalimaging, reserving FNA and subsequent intervention for documented structural disease progression. However, multi- ple factors in addition to size should be taken into accountwhen considering surgical options, including proximity of given malignant nodes to adjacent vital structures and the functional status of the vocal cords. Patient comorbidities,motivation, and emotional concerns should also be taken into account along with primary tumor factors (high-grade histology, Tg doubling time, RAI avidity, 18FDG-PET avidity, and presence of molecular markers associated with aggressivebehavior). Through thorough patient and multidisciplinary collaborative discussions, metastatic nodes >8–10 mm can be carefully observed in properly selected patients with serialclinical and radiographic follow-up, with surgery being of- fered if they progress during follow-up and conservative follow-up being maintained if they are stable over time. [C19] Extent
of nodal surgery Because of the increased risk of recurrence with focal ‘‘berry-picking’’ techniques, compartmental surgery is rec- ommended (860,861). Planned compartmental dissection should be adjusted and be more limited depending on thesurgeon’s judgment of procedural safety as it relates toscarring/distortion of anatomy (from prior surgery and/or past radiation therapy) and the perception of impending complications. Typical revision lateral neck dissection in-volves levels II, III, and IV, while revision central neck dis- section includes at least one paratracheal region with prelaryngeal and pretracheal subcompartments. Bilateralcentral neck dissection is offered only when dictated by disease distribution because of the risks of bilateral nerve injury and permanent hypoparathyroidism. Basal Tg decreases by 60%–90% after compartmental dissection for recurrent nodal disease in modern series, but only 30%–50% of patients have unmeasurable basal Tg after such surgery, and it is difﬁcult to predict who will respondto surgery with Tg reduction (627,628,634,858,862–876). However, most series
suggest surgery results in a high clearance rate of structural disease in over 80% of patients(859,875). [C20] Ethanol injection Percutaneous ethanol injection for patients with metastatic lymph nodes is gaining interest as a nonsurgical directed therapy for patients with recurrent DTC. Most of the studieslimited PEI to patients who had undergone previous neckdissections and RAI treatment, those who had FNA-proven DTC in the lymph node, and those with no known distant metastases. One of the ﬁrst studies examining the effectiveness of local metastatic lymph node control by PEI treated 14 pa- tients with 29 lymph nodes (846). Twelve of the 14 patientshad good loco-regional control in this study with short-term follow-up (mean 18 months). The largest study to date treated 63 patients with 109 metastatic lymph nodes be-tween the years 2004 and 2009 (878). Ninety-two lymph nodes (84%) were successfully ablated in this retrospective study with a mean follow-up of
38 months, and most re-quired one to three treatment sessions. Minor complications included brief discomfort at the PEI site, and there were no major complications. A recent study retrospectively reviewed 25 patients who had 37 lymph nodes ablated between the years 1994 and 2012, with a relatively long follow-up of a mean of 65 months (879). All lymph nodes were successfully ablatedin one to ﬁve treatment sessions by lack of ﬂow on US. Most of the lymph nodes decreased in size and 46% completely disappeared. Serum Tg levels were reduced inmost patients and brought into an acceptable range (<2.4 ng/mL) in 82% of patients with negative anti-Tg antibodies. There were no serious or long-term complica-tions. Another recent study also demonstrated safety andefﬁcacy of PEI in 21 patients with 41 metastatic lymph nodes (880). These investigat ors treated patients with only one session, and 24% of patients had a recurrence at
the site of the injection. Limitations of many of the studies included small numbers of patients, relatively short-term follow-up, and many pa-tients with small lymph nodes ( <5–8 mm). A general consensus from studies and reviews is that PEI should be considered in patients who are poor surgical can-didates. Many patients will likely need more than one treat- ment session and lymph nodes >2 cm may be difﬁcult to treat with PEI. Focal PEI treatment does represent a nonsurgicalform of berry picking. Formal neck compartmental dissectionis still the ﬁrst-line therapy in DTC patients with clinically apparent or progressive lymph node metastases. When de- ciding for the optimal strategy of care for a patient’s lymphnode metastases, previous treatment modalities should also be taken into consideration. [C21] Radiofrequency or laser ablation The use of radiofrequency ablation (RFA) with local anes- thesia in the treatment of recurrent thyroid cancer has beenassociated with a
mean volume reduction that ranges betweenapproximately 55% and 95% (881,882) and complete disap- pearance of the metastatic foci in 40%–60% of the cases (845,882,883). As with alcohol ablation, multiple treatmentsessions are often required. Complications include discomfort, pain, skin burn, and changes in the voice (884). Similar to alcohol ablation techniques, it appears that RFA may be mostuseful in high-risk surgical patients or in patients refusing additional surgery, rather than as a standard alternative to surgical resection of metastatic disease (883–885). More re-cently, preliminary ﬁndings using US-guided laser ablation for treatment of cervical lymph node metastases have been re- ported (886). [C22] Other therapeutic options Empiric RAI therapy for structurally identiﬁable disease that is not RAI avid by diagnostic scanning is very unlikely tohave a signiﬁcant tumoricidal effect and is therefore not generally recommended (887). Stereotactic radiotherapy (SBRT) can be successfully used to treat isolated metastaticdisease foci, but it has no
role in most patients with resectable lymph node metastases. EBRT using modern techniques such as intensity modulated radiotherapy and sterotactic radiation,is considered for loco-regional recurrence that is not surgi- cally resectable or with extranodal extension or involvement of soft tissues, particularly in patients with no evidence ofATA THYROID NODULE/DTC GUIDELINES 75
distant disease. Efﬁcacy has been suggested only in retro- spective studies on limited numbers of patients (888,889). Likewise, systemic therapies (such as cytotoxic chemother-apy or kinase inhibitors) for loco-regional disease are con-sidered only after all surgical and radiation therapy options have been exhausted. [C23] What is the surgical management of aerodigestive invasion? &RECOMMENDATION 72 When technically feasible, surgery for aerodigestive in- vasive disease is recommended in combination with RAI and/or EBRT.(Strong Recommendation, Moderate-quality evidence) For tumors that invade the upper aerodigestive tract, surgery combined with additional therapy such as131I and/or external beam radiation therapy is generally advised (890,891). Patient outcome is related to complete resection of all gross diseasewith the preservation of function, with techniques rangingfrom shaving a tumor off the trachea or esophagus for super- ﬁcial invasion, to more aggressive techniques when the trachea is more deeply invaded (e.g., direct intraluminal invasion),including tracheal resection and anastomosis or laryngophar- yngoesophagectomy
(892–894). Surgical decision-making can be complex and must balance oncologic surgical completenesswith preservation of upper aerodigestive track head and neck function. In some circumstances such surgery represents a possible attempt for cure, and in other circumstances it offerssigniﬁcant regional neck palliation in patients with distant metastasis with impending asphyxiation or signiﬁcant he- moptysis (414,891). [C24] How should RAI therapy be considered for loco-regional or distant metastatic disease? For regional nodal metastases discovered on diagnostic WBS, RAI may be employed in patients with low-volume disease or in combination with surgery, although surgery istypically preferred in the presence of bulky disease or disease amenable to surgery. Radioiodine is also used adjunctively following surgery for regional nodal disease or aerodigestiveinvasion if residual RAI-avid disease is present or suspected. Signiﬁcant variation exists nationally in the United States in regard to RAI use, irrespective of the degree of disease or riskof recurrence (895,896). However, there
are no randomized, controlled clinical trials demonstrating better patient out- comes after RAI therapy. One retrospective analysis indi-cated that a delay in RAI therapy of 6 months or more wasassociated with disease progression and reduced survival (897). In one study of 45 patients with persistent serum Tg elevation after reoperation for loco-regional recurrence, ad-juvant RAI therapy demonstrated no beneﬁt (898). [C25] Administered activity of131I for loco-regional or metastatic disease &RECOMMENDATION 73 (A) Although there are theoretical advantages to dosi- metric approaches to the treatment of loco-regional ormetastatic disease, no recommendation can be made about the superiority of one method of RAI administration over another (empiric high activity versus blood and/or bodydosimetry versus lesional dosimetry). (No recommendation, Insufﬁcient evidence)(B) Empirically administered amounts of 131I exceeding 150 mCi that often potentially exceed the maximum tolerable tissue dose should be avoided in patients over age 70 years. (Strong recommendation, Moderate-quality evidence) Despite the
apparent effectiveness of131I therapy in many patients, the optimal therapeutic activity remains uncertain and controversial (895,899). There are three approaches to 131I therapy: empiric ﬁxed amounts, therapy determined by the upper limit of blood and body dosimetry (900–907), and quantitative tumor or lesional dosimetry (908,909). Dosi- metric methods are often reserved for patients with distantmetastases or unusual situations such as renal insufﬁciency (910,911), children (912,913), the elderly, and those with extensive pulmonary metastases (914). Comparison of out-comes among these methods from published series is difﬁcult (895,897,900). No prospective randomized trial to address the optimal therapeutic approach has been published. Oneretrospective study concluded that patients with loco-regional disease were more likely to respond after dosimetric therapy than after empiric treatment (915). Another study demonstrated improved efﬁcacy of administration of dosi-metric maximal activity after failure of empiric dosage (916). Arguments in favor of higher activities cite a positive rela- tionship between the
total 131I uptake per tumor mass and outcome (908), while others have not conﬁrmed this rela- tionship (917). In the future, the use of123Io r131I with modern SPECT/CT or124I PET-based dosimetry may facil- itate whole-body and lesional dosimetry (918–920). In cer- tain settings (e.g., in the patients with radiation-induced thyroid cancer seen after the Chernobyl accident), RAItreatment may be associated with good outcomes even inhigh-risk patients with metastatic disease (921). The efﬁcacy of RAI therapy is related to the mean radiation dose delivered to neoplastic foci and also to the radiosensi-tivity of tumor tissue (922). The radiosensitivity is higher in patients who are younger, with small metastases from well- differentiated papillary or follicular carcinoma and with up-take of RAI but no or low 18FDG uptake. The maximum tolerated radiation absorbed dose (MTRD), commonly deﬁned as 200 rads (cGy) to the blood, is poten-tially exceeded in a signiﬁcant number of patients
undergoingempiric treatment with various amounts of 131I. In one study (923) 1%–22% of patients treated with131I according to dosimetry calculations would have theoretically exceededthe MTRD had they been empirically treated with 100–300 mCi of131I. Another study (924) found that an empirically administered131I activity of 200 mCi would exceed the MTRD in 8%–15% of patients younger than age 70 and 22%– 38% of patients aged 70 years and older. Administering 250 mCi empirically would have exceeded the MTRD in 22% of patientsyounger than 70 and 50% of patients 70 and older. These esti- mates imply the need for caution in administering empiric ac- tivities higher than 100–150 mCi in certain populations such aselderly patients and patients with renal insufﬁciency.76 HAUGEN ET AL.
[C26] Use of rhTSH (Thyrogen) to prepare patients for131I therapy for loco-regional or metastatic disease &RECOMMENDATION 74 There are currently insufﬁcient outcome data to recom- mend rhTSH-mediated therapy for all patients with distant metastatic disease being treated with131I. (No Recommendation, Insufﬁcient evidence) &RECOMMENDATION 75 Recombinant human TSH–mediated therapy may be indi- cated in selected patients with underlying comorbidities making iatrogenic hypothyroidism potentially risky, in pa-tients with pituitary disease whose serum TSH cannot be raised, or in patients in whom a delay in therapy might be deleterious. Such patients should be given the same or higheractivity that would have been given had they been prepared with hypothyroidism or a dosimetrically determined activity. (Strong Recommendation, Low-quality evidence) No randomized trial comparing thyroid hormone with- drawal therapy to rhTSH-mediated therapy for treatment of distant metastatic disease has been reported, but there is a growing body of nonrandomized studies exploring the use ofrhTSH to
prepare patients for therapy of metastatic disease (713,925–934). One small comparative study showed that the radiation dose to metastatic foci is lower with rhTSH thanthat following withdrawal (935). Many of these case reports and series report disease stabilization or improvement in some patients following rhTSH-mediated 131I therapy, but whether the efﬁcacy of this preparation is comparable tothyroid hormone withdrawal is unknown. Extreme or pro- longed elevations of TSH from either thyroid hormone withdrawal or rhTSH may acutely stimulate tumor growthand mass of metastases (930,936–938). With metastatic deposits in the brain or in close relation to the spinal cord or the superior vena cava, such swelling may severely com-promise neurologic function or produce a superior vena cava syndrome, respectively. When distant metastases are evident, MRI of the brain and spine is recommended todetect the presence of critical metastases prior to treatment (see sections [C28] and [C39]). When metastases are de- tected,
institution of temporary high-dose corticosteroidtherapy is recommended for trying to limit the risk of acutetumor swelling and compromised function. Dexamethasone has been employed in doses of 2–4 mg every 8 hours starting 6–12 hours prior to rhTSH and RAI dosing or after 10–12days of thyroid hormone withdrawal, with the steroids continued in a tapering dosage schedule for 1 week post therapy, for 48–72 hours after rhTSH administration, or for72 hours after re-institution of thyroxine therapy when thyroid hormone withdrawal was employed (927). In pa- tients with these critical metastases, consideration should begiven to preparation with either a reduced dose of rhTSH orto attenuating the degree and duration of endogenous TSH elevation after thyroid hormone withdrawal while moni- toring serum TSH levels. This can be achieved by thetemporary addition of LT 3therapy to thyroxine replace- ment. Satisfactory RAI treatment with either empiric or dosimetric activities should be feasible after achieving TSHlevels
of 30–50 mU/L. When thyroid hormone withdrawal has been employed, LT 4therapy should recommence once the dose of RAI is administered in order to reduce the du-ration of TSH elevation. [C27] Use of lithium in131I therapy &RECOMMENDATION 76 Since there are no outcome data that demonstrate a betteroutcome of patients treated with lithium as an adjunct to 131I therapy, the data are insufﬁcient to recommend lithium therapy. (No recommendation, Insufﬁcient evidence) Lithium inhibits iodine release from the thyroid without impairing iodine uptake, thus enhancing131I retention in normal thyroid and tumor cells (939). One study (940) found that lithium increased the estimated131I radiation dose in metastatic tumors on average by more than 2-fold, but pri- marily in those tumors that rapidly cleared iodine. On the other hand, a different study was unable to document anyclinical advantage of lithium therapy on outcome in patients with metastatic disease, despite an increase in RAI
uptake in tumor deposits (941). Lithium use may be associated withadverse events and needs to be precisely managed. [C28] How should distant metastatic disease to various organs be treated? The overall approach to treatment of distant metastatic thyroid cancer is based upon the following observations andoncologic principles: 1. Morbidity and mortality are increased in patients with distant metastases, but individual prognosis depends upon factors including histology of the primary tumor, distribution and number of sites of metastasis (e.g., brain,bone, lung), tumor burden, age at diagnosis of metasta- ses, and 18FDG and RAI avidity (842,933,942–948). 2. Improved survival is associated with responsiveness to directed therapy (surgery, EBRT, thermal ablation, etc.) and/or RAI (842,933,942–948). 3. In the absence of demonstrated survival beneﬁt, cer- tain interventions can provide signiﬁcant palliation orreduce morbidity (847,949–951). 4. Treatment of a speciﬁc metastatic area must be con- sidered in light of the patient’s performance status andother sites
of disease; for example, 5%–20% of pa- tients with distant metastases die from progressive cervical disease (948,952). 5. Longitudinal re-evaluation of patient status and con- tinuing reassessment of potential beneﬁt and risk of intervention are required. 6. In the setting of overall poor anticipated outcome of patients with radiographically evident or symptomatic metastases that do not respond to RAI, the complexity of multidisciplinary treatment considerations and theavailability of prospective clinical trials should en- courage the clinician to refer such patients to tertiary centers with particular expertise. 7. Mutation proﬁling of metastatic tumor (to detect abnor- malities in genes such as BRAF ,TERT ,RAS,o rPAX8/ATA THYROID NODULE/DTC GUIDELINES 77
PPAR c) has not yet deﬁnitively proven to be of value for estimating patient prognosis or for predicting response to treatments such as anti-angiogenic kinase inhibitors,although the presence of certain mutations such asBRAF V600EorPAX8/PPAR care required for some clinical trials. Thus, routine mutation proﬁling cannot be rec- ommended at this time outside of research settings. There is little if any beneﬁt derived from the treatment of RAI-refractory DTC with RAI (953). Although RAI-refractory tumors often may harbor BRAFV600Emutations and RAI-avid tumors are overrepresented with RAS muta- tions, RAI therapy has not been shown to be more effective inpatients with RAS mutations (954). [C29] Treatment of pulmonary metastases &RECOMMENDATION 77 (A) Pulmonary micrometastases should be treated with RAI therapy and RAI therapy should be repeated every 6– 12 months as long as disease continues to concentrate RAI and respond clinically because the highest rates of com-plete remission are reported in these
subgroups. (Strong recommendation, Moderate-quality evidence)(B) The selection of RAI activity to administer for pulmonary micrometastases can be empiric (100–200 mCi, or 100–150 mCi for patients ‡70 years old) or estimated by dosimetry to limit whole-body retention to80 mCi at 48 hours and 200 cGy to the bone marrow. (Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 78 Radioiodine-avid macronodular metastases may be treated with RAI and treatment may be repeated when objective beneﬁt is demonstrated (decrease in the size of the lesions, decreasing Tg), but complete remission is not common andsurvival remains poor. The selection of RAI activity to administer can be made empirically (100–200 mCi) or by lesional dosimetry or whole-body dosimetry if available inorder to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to the bone marrow. (Weak recommendation, Low-quality evidence) In the management of the patient with pulmonary metastases, key criteria for therapeutic decisions include (i)
size of meta- static lesions (macronodular typically detected by chest radi- ography, micronodular typically detected by CT, lesions beneaththe resolution of CT); (ii) avidity for RAI and, if applicable,response to prior RAI therapy; and (iii) stability (or lack thereof) of metastatic lesions. Pulmonary pneumonitis and ﬁbrosis are rare complications of high-dose RAI treatment. Dosimetric ap-proaches to therapy with a limit of 80 mCi whole-body retention at 48 hours and 200 cGy to the bone marrow should be con- sidered in patients with diffuse 131I pulmonary uptake (955). If pulmonary ﬁbrosis is suspected, then appropriate periodic pul- monary function testing and consultation should be obtained. The presence of pulmonary ﬁbrosis may limit the ability tofurther treat metastatic disease with RAI (956). Patients with pulmonary micrometastases ( <2 mm, gener- ally not seen on anatomic imaging) that are RAI avid have thehighest rates of complete remission after treatment with RAI (942,947,957,958). These
patients should be treated with RAI therapy repeatedly every 6–12 months as long as diseasecontinues to concentrate RAI and respond clinically. A precise deﬁnition of ‘‘responding clinically’’ is not fea- sible given the wide variation in disease presentation and re- sponse to therapy. A meaningful response to RAI treatment isgenerally associated with a signiﬁcant reduction in serum Tg and/or in the size or rate of growth of metastases or struc- turally apparent disease. In contrast, a reduction in serum Tgand in RAI uptake with no concomitant decrease or with an increase in tumor size suggests refractoriness to RAI therapy. In the presence of widespread metastases, especially when inbone, additional RAI may temporarily stabilize progression,but it is unlikely to result in cure. The risks of bone marrow suppression or pulmonary ﬁbrosis should generate caution when repeated doses of RAI are being considered. Absoluteneutrophil count and platelet counts are the usual markers
of bone marrow suppression, and pulmonary function testing including diffusing capacity of the lungs for carbon monoxidecan be markers of pulmonary toxicity. Other approaches (see sections [C36–C41]) should be considered once maximal cumulative tolerable radiation doses have been administered. Macronodular pulmonary metastases may also be treated with RAI if demonstrated to be iodine avid. How many doses of RAI to give and how often to give RAI is a decision that must beindividualized based on the disease response to treatment, age ofthe patient, and the presence or absence of other metastatic le- sions (942,947). The presence of signiﬁcant side effects includ- ing bone marrow suppression and salivary gland damage maytemper enthusiasm for additional RAI therapy (959), and risk of second malignancies after RAI treatment remains controversial (766,960,961). Patients with solitary pulmonary DTC metastasesmay be considered for surgical resection, although the potential beneﬁt weighed against the risk of surgery is unclear.
The likelihood of signiﬁcant long-term beneﬁt of 131I treatment in patients with elevated Tg and negative diagnosticRAI scans is very low. (962,963). While some reduction in serum Tg may be observed after such empiric therapy, one analysis concluded that there was no good evidence either foror against such treatment (964). In one small retrospective series of patients with structural disease but negative diag- nostic 131I WBSs, additional RAI therapy was associated with stability of disease in 44%, but progression of structural dis- ease occurred in 56% of the patients (887). [C30] RAI treatment of bone metastases &RECOMMENDATION 79 (A) RAI therapy of iodine-avid bone metastases has been associated with improved survival and should be em-ployed, although RAI is rarely curative. (Strong recommendation, Moderate-quality evidence)(B) The RAI activity administered can be given empiri- cally (100–200 mCi) or determined by dosimetry. (Weak recommendation, Low-quality evidence) RAI therapy for patients with bone metastases
is rarely curative, but some patients with RAI-avid bone metastases may beneﬁt from this therapy (842,947). A dosimetrically78 HAUGEN ET AL.
determined administered dose of RAI may be beneﬁcial for patients with bone metastases (908), although this is not proven in controlled studies. Patients undergoing RAI ther-apy for bone metastases should also be considered for di-rected therapy of bone metastases that are visible on anatomical imaging (section [C38]). This may include sur- gery, external beam radiation therapy, and other focal treat-ment modalities. These patients should also be considered for systemic therapy with bone-directed agents (section [C47]). [C31] When should empiric RAI therapy be considered for Tg-positive, RAI diagnosticscan–negative patients? &RECOMMENDATION 80 In the absence of structurally evident disease, patients with stimulated serum Tg <10 ng/mL with thyroid hormone withdrawal or <5 ng/mL with rhTSH (indeterminate re- sponse) can be followed without empiric RAI therapy oncontinued thyroid hormone therapy alone, reserving addi- tional therapies for those with rising serum Tg levels over time or other evidence of structural disease progression. (Weak recommendation,
Low-quality evidence) &RECOMMENDATION 81 Empiric (100–200 mCi) or dosimetrically determined RAI therapy may be considered in patients with more signiﬁ-cantly elevated serum Tg levels (see Recommendation 80), rapidly rising serum Tg levels, or rising ant-Tg antibody levels, in whom imaging (anatomic neck/chest imaging and/or 18FDG-PET/CT) has failed to reveal a tumor source that is amenable to directed therapy. The risk of high cumulative administered activities of RAI must be balanced againstuncertain long-term beneﬁts. If empiric RAI therapy is gi-ven and the posttherapy scan is negative, the patient should be considered to have RAI-refractory disease and no further RAI therapy should be administered. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 82 If persistent nonresectable disease is localized after an empiric dose of RAI, and there is objective evidence of signiﬁcant tumor reduction, then consideration can be made for RAI therapy to be repeated until the tumor hasbeen eradicated or the tumor no longer
responds to treat-ment. The risk of repeated therapeutic doses of RAI must be balanced against uncertain long-term beneﬁts. (Weak recommendation, Low-quality evidence) Factors to consider when selecting patients for empiric RAI therapy include the level of serum Tg elevation and the results of 18FDG-PET scanning, if performed. Since tumors that are18FDG-PET positive generally do not concentrate RAI (965), RAI therapy is much less likely to be efﬁcacious (965,966) and it is unlikely to alter the poorer outcome in such patients (823). Because of this, it is reasonable to per-form18FDG-PET/CT scanning prior to consideration of empiric RAI therapy (967). The cutoff value of serum Tg above which a patient should be treated with an empiric dose of RAI is not clear. Most studieshave reported primarily on patients with Tg levels after T 4 withdrawal of 10 ng/mL or higher; it has been suggested that a corresponding level after rhTSH stimulation would
be 5 ng/mL(321,782,962,968,969). Patients with a suppressed (624) orstimulated (970) serum Tg of 5 ng/mL or higher are unlikely to demonstrate a decline without therapy, and they have higher rates of subsequent structural recurrence than those with lowerserum Tg levels (970). In addition, a rising serum Tg indicates disease that is likely to become clinically apparent, particularly if it is rapidly rising (622,971,972). If serum Tg levels suggest residual or recurrent disease, but diagnostic RAI WBS imaging is n egative and structural imag- ing does not reveal disease that is amenable to directed therapy(surgical, thermal ablation, EBRT, alcohol ablation, see section[ C 1 7a n dC 3 8 ] ) ,t h e ne m p i r i ct h e r a p yw i t hR A I( 1 0 0 – 2 0 0m C i ) or dosimetrically determined RAI activities can be considered for
two purposes: (i) to aid in disease localization, and/or (ii) astherapy for nonsurgical disease. This approach may identify the location of persistent disease in approximately 50% of patients (968,973,974), although the reported range of success is wide.From a therapeutic perspective, over half of patients experi- ence a fall in serum Tg after empiric RAI therapy in patients with negative diagnostic WBS (963,969,975,976); however,there is no evidence for improved survival with empiric therapy in this setting (782,962,968). Further, there is evidence that Tg levels may decline without speciﬁc therapy in a signiﬁcantproportion of patients with Tg levels <10 ng/mL (539,618– 620,624,782,970–972,975,977–979). The most compelling ev- idence for beneﬁt from empiric RAI therapy is for pulmonary metastases, which are not amenable to surgical management orEBRT (782,844,980). [C32] What is the management of complications of RAI therapy? &RECOMMENDATION 83 The evidence is insufﬁcient to recommend for or against the routine use of measures
to prevent salivary glanddamage after RAI therapy. (No recommendation, Low-quality evidence) &RECOMMENDATION 84 Patients with xerostomia are at increased risk of dental caries and should discuss preventive strategies with theirdental/oral health professional. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 85 Surgical correction should be considered for nasolacrimal outﬂow obstruction, which often presents as excessivetearing (epiphora) but also predisposes to infection. (Strong recommendation, Low-quality evidence) While RAI appears to be a reasonably safe therapy, it is associated with a cumulative dos e-related low risk of early- and late-onset complications such as salivary gland damage, dental caries (981), nasolacrimal duct obstruction (982), and secondary malignancies (762,763,961,983,984), and it may likely con-tribute to long-term dysphagia (985). Therefore, it is important to ensure that the beneﬁts of RAI therapy, especially repeated courses, outweigh the potential risks. There is probably no doseATA THYROID NODULE/DTC GUIDELINES 79
of RAI that is completely safe, nor is there any maximum cu- mulative dose that could not be used in selected situations. However, with higher individual and cumulative doses there areincreased risks of side effects as discussed previously. For acute transient loss of taste or change in taste and sialadentitis, recommended measures to prevent damage to the salivary glands have included hydration, sour candies,amifostine, and cholinergic agents (986), but evidence is insufﬁcient to recommend for or against these modalities. One study suggested sour candy may actually increase sali-vary gland damage when given within 1 hour of RAI therapy, as compared to its use until 24 hours post therapy (987). Another study showed that the use of lemon slices within20 min of 124I administration resulted in increased radiation absorbed dose to the salivary glands (988). A different study suggested that early use and multiple administered doses of lemon juice transiently decreased
radiation exposure to theparotid glands (989), so the exact role and details of use of sialagogues to prevent salivary gland damage remains un- certain. Patients with painful sialadenitis may receive painrelief from local application of ice. For chronic salivary gland complications, such as dry mouth and dental caries, cholin- ergic agents may increase salivary ﬂow (986). Interventionalsialendoscopy has been shown in a number of small studies to be an effective treatment in patients with RAI-induced sia- ladenitis that is unresponsive to medical therapy (990–992). [C33] How should patients who have received RAI therapy be monitored for risk of secondarymalignancies? &RECOMMENDATION 86 Although patients should be counseled on the risks of second primary malignancy with RAI treatment for DTC, the absolute increase in risk of developing a second pri- mary malignancy attributable to RAI treatment is consid-ered small and does not warrant speciﬁc screening to anyextent greater than age-appropriate general population
health screening. (Weak recommendation, Low-quality evidence) Most long-term follow-up studies variably report a very low risk of secondary malignancies (bone and soft tissue malig-nancies, including breast, colorectal, kidney, and salivary cancers, and leukemia) in long-term survivors (762,763). A meta-analysis of two large multicenter studies showed that theRR of second malignancies was signiﬁcantly increased at 1.19 ([95% CI 1.04–1.36], p<0.010), relative to thyroid cancer survivors not treated with RAI, although the absolute increasein second primary malignancy risk attributable to RAI is con-sidered to be small (961). The risk of leukemia was also sig- niﬁcantly increased in thyroid cancer survivors treated with RAI, with a RR of 2.5 ([95% CI 1.13–5.53], p<0.024) (961). Studies on T1N0 PTC from the SEER registry suggested that the excess risk of leukemia after RAI treatment was greater in young individuals compared with older individuals. The excessrisk of leukemia was signiﬁcantly greater in patients aged <45 years
(standardized incidence rate of 5.32 [95% CI 2.75–9.30] for those aged <45 years versus 2.26 [95% CI 1.43–3.39] in older individuals) (766). The risk of secondary malignancies is dose related (763), with an excess absolute risk of 14.4 solid cancers and of 0.8 leukemias per gigabecquerel (1 GBq =27mCi) of 131I at 10,000 person-years of follow-up. Cumulative 131I activities above 500–600 mCi are associated with a sig- niﬁcant increase in risk. In theory, the risk of second primarymalignancies increases with higher administered activities.There is no direct evidence of increased risk of secondary malignancies after a single administration of 30–100 mCi in comparison to the observed risk of second primary cancer inthyroid cancer patients who have not been treated with 131I. The risk is clearly increased in patients who have been treated with a large cumulative activity that is higher than 600 mCi (763),which suggests a dose–effect relationship. This is an
argument for using the minimal activity necessary to treat each patient. There appears to be an increased risk of breast cancer in womenwith thyroid cancer (762,983,993). It is unclear whether this isdue to screening bias, RAI therapy, or other factors. An ele- vated risk of breast cancer with 131I was not observed in another study (764). The use of laxatives may decrease radiation ex-posure of the bowel, particularly in patients treated after pro- longed withdrawal of thyroid hormone, and vigorous oral hydration will reduce exposure of the bladder and gonads (22). [C34] What other testing should patients receiving RAI therapy undergo? &RECOMMENDATION 87 Patients receiving therapeutic doses of RAI should have baseline complete blood c ount and assessment of renal function. (Weak recommendation, Low-quality evidence) Published data indicate that when administered activities are selected to remain below 200 cGy to the bone marrow,minimal transient effects are noted in white blood
cell and platelet counts (955). However, persistent mild decrements in white blood cell count and/or platelets are seen in some pa-tients who have received multiple RAI therapies. Further, radiation to the bone marrow is impacted by several factors, including renal function. The kidneys are a major means ofiodine excretion from the body, and physiologic radioisotopestudy research in nonthyroidectomized individuals has shown that renal impairment signiﬁcantly reduces RAI ex- cretion (994). [C35] How should patients be counseled about RAI therapy and pregnancy, breastfeeding, and gonadal function? &RECOMMENDATION 88 Women of childbearing age receiving RAI therapy should have a negative screening evaluation for pregnancy prior to RAI administration and avoid pregnancy for 6–12months after receiving RAI. (Strong recommendation, Low-quality evidence) &RECOMMENDATION 89 Radioactive iodine should not be given to nursing women. Depending on the clinical situation, RAI therapy could be deferred until lactating women have stopped breastfeeding orpumping for at least 3
months. A diagnostic123I or low-dose 131I scan should be considered in recently lactating women to detect breast uptake that may warrant deferral of therapy.80 HAUGEN ET AL.
(Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 90 Men receiving cumulative RAI activities ‡400 mCi should be counseled on potential risks of infertility. (Weak recommendation, Low-quality evidence) Women about to receive RAI therapy should ﬁrst undergo pregnancy testing. Gonadal tissue is exposed to radiation fromRAI in the blood, urine, and feces. Temporary amenorrhea/ oligomenorrhea lasting 4–10 months occurs in 20%–27% of menstruating women after131I therapy for thyroid cancer. Al- though the numbers of patients studied are small, long-term rates of infertility, miscarriage, and fetal malformation do not appear to be elevated in women after RAI therapy (995–997).One recent large retrospective cohort study showed that use of RAI was associated with delayed childbearing and decreased birthrate in later years, although it is unclear if this is due toreproductive choice or reproductive health (998). Another largeretrospective study suggested that pregnancy should be post- poned for 1 year after therapy because of an increase in
mis- carriage rate (999), although this was not conﬁrmed in asubsequent study (1000). Ovarian damage from RAI therapy may result in menopause occurring approximately 1 year ear- lier than in the general population, but this result was not as-sociated with cumulative dose administered or the age at which the therapy was given (1001). Radioiodine is also signiﬁcantly concentrated in lactating breast tissue (1002). Therefore, RAIshould not be given to women who are breastfeeding (1003). Adiagnostic 123I or low-dose131I scan can be employed in re- cently lactating women to detect breast uptake that may warrant deferral of therapy (662). Dopaminergic agents might be usefulin decreasing breast exposure in recently lactating women, al- though caution should be exercised given the risk of serious, albeit rare, side effects associated with their routine use tosuppress postpartum lactation (1003,1004). In men, RAI therapy may be associated with a temporary reduction in sperm counts and elevated
serum follicle-stimulating hormone levels (1005,1006). Higher cumulative activities (500–800 mCi) in men are associated with an increased risk of persistent elevation of serum follicle-stimulating hormone levels, but fertility and risks ofmiscarriage or congenital abnormalities in subsequent preg- nancies are not changed with moderate RAI activities ( *200 mCi) (1007,1008). Permanent male infertility is unlikely witha single ablative activity of RAI, but theoretically there could be cumulative damage with multiple treatments. It has been suggested that sperm banking be considered in men who mayreceive cumulative RAI activities ‡400 mCi (1006). Gonadal radiation exposure is reduced with good hydration, frequent micturition to empty the bladder, and avoidance of con-stipation (1009). Some specialists recommend that men wait 3 months (or one full sperm cycle) to avoid the potential for transient chromosomal abnormalities. [C36] How is RAI-refractory DTC classiﬁed? &RECOMMENDATION 91 Radioiodine-refractory structurally evident DTC is clas- siﬁed in patients with appropriate TSH stimulation
and iodine preparation in four basic ways: (i) the malignant/metastatic tissue does not ever concentrate RAI (no uptake outside the thyroid bed at the ﬁrst therapeutic WBS), (ii) the tumor tissue loses the ability to concentrate RAI afterprevious evidence of RAI-avid disease (in the absence ofstable iodine contamination), (iii) RAI is concentrated in some lesions but not in others; and (iv) metastatic disease progresses despite signiﬁcant concentration of RAI. When a patient with DTC is classiﬁed as refractory to RAI, there is no indication for further RAI treatment. (Weak recommendation, Low-quality evidence) The prognosis of patients with DTC is usually favorable, even when metastatic RAI-avid disease is present. For this reason, 131I is considered the gold standard in the treatment of metastatic disease. However, many DTC patients with advanced disease donot respond or become refractory to131I, with some of these patients dying within 3–5 years, but there are also long-term
survivors with very slowly progressive disease. Iodine 131 refractory DTC includes four categories of patients (1010). In the ﬁrst category, the malignant/metastatic tissue does not concentrate131I outside the thyroid bed at the ﬁrst therapeutic WBS. There is no evidence in these patientsthat further treatment with RAI may be of any beneﬁt. Fur- thermore, patients with measurable disease with an absence of131I uptake on subsequent diagnostic WBS may also be considered refractory because even when uptake is seen on posttherapy scan, it will likely have limited beneﬁt. In the second category, the tumor tissue loses the ability to con-centrate131I (in the absence of stable iodine contamination) after previous evidence of uptake. This often occurs in pa- tients with large and multiple metastases and is due to theeradication by131I treatment of differentiated cells able to concentrate RAI but not of poorly differentiated cells that do not concentrate131I and that generally will progress.
In the third category,131I uptake is retained in some lesions but not in others; this pattern is frequent in patients with multiple large metastases as shown by124I studies on PET scan (918) and by comparing results of18FDG-PET scan with131I WBS. In these patients, progression is likely to occur in metastases without uptake (in particular when18FDG uptake is present), and RAI treatment will not be beneﬁcial on the overall out-come of the disease. Some patients may have predominantly RAI-avid disease with only a few lesions that do not con- centrate RAI. While these patients technically meet the def-inition of RAI-refractory disease, they may beneﬁt from acombination of RAI therapy for the majority of the lesions and directed therapy (section [C38]; Recommendation 93) for those few lesions that do not concentrate RAI. In thefourth category, metastatic disease progresses despite sig- niﬁcant uptake of 131I (new lesions, progressive growth of lesions, continual rise
in serum Tg within months of RAItherapy). The deﬁnition of any of these possibilities depends on imaging modalities, including a posttherapy131I WBS combined with other imaging modalities, such as CT scan,MRI, or18FDG PET/CT. The criteria for RAI-refractory disease remain somewhat controversial. Future studies will hopefully help to reﬁne this deﬁnition. Predictive factors for tumor r esponse to RAI treatment are indeed the presence of131I uptake by tumor, and among those patients with RAI uptake, younger age, well-differentiated his- totype, small metastases, and low18FDG uptake. Indeed theseATA THYROID NODULE/DTC GUIDELINES 81
parameters are closely interrelated (823,824,844) and may per- mit predicting the outcome of RAI treatment at the time of the discovery of the metastases. About two-thirds of patients withmetastases de monstrate131I uptake in their metastases, and only half of them will be cured with repeated courses of131It r e a t m e n t . Less clear is the case of patient s with visible RAI uptake in all the known lesions, who are not cur ed despite several treatment courses but whose disease remain s stable and does not progress according to RECIST criteria. It is controversial whether these patients should be considered131Ir e f r a c t o r ya n dw h e t h e rR A I treatment should be abandoned in favor of other treatment mo- dalities. The probability to obtain a cure with further treatments is low and side effects may
increase, including the risk of sec-ondary cancers and leukemias (762,763,844,961). Several pa-rameters should then be taken into consideration for the decision to continue treatment with RAI, including response to previous treatment courses, h i g ho rs i g n i ﬁ c a n t 131I uptake after previous treatment courses, low18FDG uptake in tumor foci, and limited side effects from the RAI therapy. [C37] Which patients with metastatic thyroid cancer can be followed without additional therapy? &RECOMMENDATION 92 (A) Patients with131I-refractory metastatic DTC that is asymptomatic, stable, or minimally progressive who are not likely to develop rapidly progressive, clinically sig- niﬁcant complications and do not have indications for di-rected therapy can be monitored on TSH-suppressive thyroid hormone therapy with serial radiographic imaging every 3–12 months. (Weak recommendation, Low-quality evidence)(B)BRAF or other mutational testing is not routinely rec- ommended for prognostic purposes in patients with RAI-refractory, progressive, locally advanced,
or metastatic DTC. (Weak recommendation, Moderate-quality evidence) Patients with 131I-refractory metastatic DTC often have an indolent clinical course, with no apparent symptoms or ad- verse impact from their disease burden for many years. In the absence of tolerable therapies with signiﬁcant likelihood ofinducing durable complete remission or improving overall survival, treatment should be limited to interventions that prevent morbidity or palliate symptoms. Thus, once131I re- fractory metastatic disease is identiﬁed, attention should be directed toward (i) determining the extent of metastatic dis- ease by staging imaging studies such as CT,18FDG PET/CT, or MRI as described in sections [C9–C13]; (ii) assessingdegree of current or potential symptoms from the disease; (iii) understanding the comorbidities that might inﬂuence the choice of therapies for the metastatic disease; and (iv) de-termining the rate of progression of radiographically evident lesions. Serial assessment of the size and development of metastatic lesions can be enhanced by applying criteriasimilar
to RECIST, as commonly used to assess tumor re- sponse in clinical trials (1011). Representative soft tissue metastatic lesions, typically >1 cm, are identiﬁed as ‘‘tar- gets’’ on cross-sectional imaging, with the longest diameterof each lesion measured. Disease extent can be considered to be stable or minimally progressive if the sum of the longest diameters of the target lesions increases <20% in the absence of new metastatic foci on sequential imaging over 12–15 months of follow-up. No study has identiﬁed an ap- propriate frequency for repeat imaging, but it is reasonable to repeat the staging imaging studies within 3–12 monthsbased on the disease burden and locations of lesions (953,1012). More frequent assessment could be considered once metastatic disease is ide ntiﬁed and/or in response to intercurrent patient symptoms, and less frequent imaging performed once a pattern of stability is identiﬁed. The development of progressive disease, either by RECIST assessment identifying
at least 20% increase in sum oflongest diameters of target lesions, the appearance of signiﬁcant new metastatic lesions, or development of disease-related symptoms should warrant consideration ofappropriate systemic therapies (section [C41]) beyond TSH-suppressive thyroid hormone and/or directed thera- pies (sections [C15] and [C38]). Although serum Tg levelsshould be measured as biomarkers of the disease extent, patients should not be identiﬁed as having progressive disease and requiring more aggressive therapy solely onthe basis of rising levels of Tg; accelerating increases in Tg l e v e l ss h o u l d ,h o w e v e r ,l e a dt oc o n s i d e r a t i o no fm o r e frequent and comprehensive imaging in efforts to identifypreviously occult structural correlates. In each of two recent international, randomized phase III trials of kinase inhibitors for therapy of progressive, RAI- refractory,
metastatic DTC, patients whose tumors containedtheBRAF V600Emutation who were randomized to the pla- cebo treatment arms experienced similar progression-free survival compared with those whose tumors did not harbor aBRAF mutation (1013,1014). Thus, BRAF mutation status does not appear to be of prognostic value once patients reach this degree of advanced disease that would have qualiﬁedthem for these clinical trials, that is, RAI-refractory, locallyadvanced, or metastatic DTC that has progressed by RECIST within 13 or 14 months. [C38] What is the role for directed therapy in advanced thyroid cancer? &RECOMMENDATION 93 (A) Both stereotactic radiation and thermal ablation (RFA and cryoablation) show a high efﬁcacy in treating indi- vidual distant metastases with relatively few side effectsand may be considered as valid alternatives to surgery. (Weak recommendation, Moderate-quality evidence)(B) Stereotactic radiation or thermal ablation should be considered prior to initiation of systemic treatment when the individual distant metastases are symptomatic or at
high risk of local complications. (Strong recommendation, Moderate-quality evidence) Several local treatment modalities other than surgery may be used to treat brain, lung, liver, and bone lesions from thyroid carcinoma. These local treatment modalities shouldbe considered prior to initiation of systemic treatment when the individual distant metastases are symptomatic or at high risk of local complications. They may also be helpful in case82 HAUGEN ET AL.
of progression in a single lesion in patients with otherwise controlled disease during systemic treatment. In these pa- tients, beneﬁts can be achieved in preventing local compli-cations, in improving symptoms such as pain, in delaying theinitiation of systemic treatments, and even in improving survival. These techniques can be a less aggressive alterna- tive to surgery and may be indicated in cases of lung me-tastases associated with insufﬁcient respiratory reserve, poor patient clinical status, or after multiple previous surgical re- sections, local recurrence at the site of previous surgery, orrefusal of additional surgery. In selected patients, the techniques may be an alternative to surgery as ﬁrst-line treatment, and they may induce localtumor control with a similar efﬁcacy to surgical resection. Ofinterest, long-term beneﬁts in terms of disease control have been reported in patients with a single or few metastases and in whom the disease is slowly progressive. Interventional radiology (thermal ablation