A Joint Statement from the American Thyroid Association,the European Association of Nuclear Medicine,the European Thyroid Association,the Society of Nuclear Medicine and Molecular Imaging on Current Diagnostic and Theranostic Approaches in the Management of Thyroid Cancer

Abstract

Background:

The American Thyroid Association (ATA), the European Association of Nuclear Medicine, the European Thyroid Association, and the Society of Nuclear Medicine and Molecular Imaging have established an intersocietal working group to address the current controversies and evolving concepts in thyroid cancer management and therapy. The working group annually identifies topics that may significantly impact clinical practice and publishes expert opinion articles reflecting intersocietal collaboration, consensus, and suggestions for further research to address these important management issues.

Summary:

In 2019, the intersocietal working group identified the following topics for review and interdisciplinary discussion: (i) perioperative risk stratification, (ii) the role of diagnostic radioactive iodine (RAI) imaging in initial staging, and (iii) indicators of response to RAI therapy.

Conclusions:

The intersocietal working group agreed that (i) initial patient management decisions should be guided by perioperative risk stratification that should include the eighth edition American Joint Committee on Cancer staging system to predict disease specific mortality, the modified 2009 ATA risk stratification system to estimate structural disease recurrence, with judicious incorporation of molecular theranostics to further refine management recommendations; (ii) diagnostic RAI scanning in ATA intermediate risk patients should be utilized selectively rather than being considered mandatory or not necessary for all patients in this category; and (iii) a consistent semiquantitative reporting system should be used for response evaluations after RAI therapy until a reproducible and clinically practical quantitative system is validated.

Introduction

Controversies over the extent of surgical treatment and the appropriate use of radioactive iodine (RAI) span seven decades. Guidelines have been generated at an encyclopedic scale using largely retrospective data. The state of the affair stands at an equipoise. The reasons for the equipoise are manifold, and only to be unfolded as the oncobiology of thyroid cancer is better understood. The American Thyroid Association (ATA), the European Association of Nuclear Medicine, the European Thyroid Association, and the Society of Nuclear Medicine and Molecular Imaging have established an intersocietal working group to address the current controversies and evolving concepts in thyroid cancer, and to publish expert opinion articles reflecting the intersocietal collaboration and consensus (1 –3). The article is organized to provide a clinical and technical background related to the topic of interest followed by a discussion of current approaches, future directions, and the working group consensus statements.

Methodology

The topics discussed in this article were identified at the 2019 intersocietal working group meeting as important areas of controversy that could benefit from interdisciplinary review and discussion. Each of the three major topic areas was initially reviewed by two coauthors (an endocrinologist and nuclear medicine specialist) who provided verbal and written presentations to the entire working group. After group interactions through virtual audio–visual meetings, emails, and editing of the written summaries, the two coauthors for each topic area prepared written summaries and conclusions that reflected the group discussions for inclusion in the final article. The first and last authors integrated those written work products into a final version of the article that was then reedited by the six primary writing coauthors and finally re-reviewed by each member of the intersocietal working group and endorsed by the four societies. Institutional review board approval was not required as no patient-specific data was included.

Review: Perioperative Risk Stratification

Traditional risk stratification integrates prognostic clinicopathological information obtained from preoperative evaluations, intraoperative findings, and early postoperative testing into staging systems and risk categories with the aim to predict disease-specific mortality and risk of disease recurrence (4,5). Consistent with American Joint Committee on Cancer (AJCC) eighth edition staging rules, all preoperative, intraoperative, and postoperative data obtained in the first 4 months after initial surgical treatment should be included in the perioperative risk stratification. The extent of surgery and need for RAI treatment are based on risk categories defined. While dynamic risk stratification is integral to ongoing follow-up management and treatment recommendations, this article focuses on risk stratification in the immediate perioperative period that guides initial recommendations.

Current standards: risk stratification with comprehensive perioperative clinicopathological data

The 2015 ATA thyroid cancer guidelines recommend that the 2009 ATA initial risk stratification system be used to predict the likelihood of identifying structural disease during follow-up. Several additional prognostic factors were also proposed to “further refine risk stratification” [the Modified 2009 ATA initial risk stratification system (6,7)]. Though it was thought that consideration of these additional secondary (modifying) factors may improve risk stratification, the guidelines acknowledged that “the incremental benefit of adding these specific prognostic variables to the 2009 initial risk stratification system has not been established (7). Likewise, the eighth edition of the AJCC staging system notes that a wide variety of secondary clinical features may be useful in clinical decision making without integrating those secondary factors into the prognostic stage group definitions (4). Experts promoting this very individualized risk-stratified approach to patient management often work within the context of experienced multidisciplinary teams and, therefore, have accurate, detailed, and comprehensive information to utilize in risk assessment (8).

Clinical considerations: risk stratification in the absence of complete, accurate, and detailed risk factor descriptions

We reviewed the eighth edition of the AJCC staging system and the current ATA risk of structural disease recurrence staging systems to identify a minimum data set (primary risk factors) that are needed to accurately assign patients to a specific AJCC prognostic stage (I, II, III, or IV) and ATA risk category (low, intermediate, or high) (Table 1). We then examined how a complete knowledge of the wide variety of additional modifying risk factors (secondary risk factors) would impact individual risk stratification and clinical decision making.

Table 1.

Risk Stratification

	AJCC eighth edition	ATA 2015	Theranostic
Primary risk factors
Basic histology (DTC vs. anaplastic vs. MTC)	√	√	√
Age at diagnosis <55 vs. ≥55 years	√
Primary tumor size <4 cm vs. ≥4 cm	√
Presence or absence of lymph node metastasis	√	√
Presence or absence of gross extrathyroidal extension	√	√
Specific structures grossly invaded by tumor	√
Incomplete tumor resection (gross residual disease)^a		√
Presence or absence of distant metastasis	√	√
Postoperative thyroglobulin suggestive of distant metastasis^a		√
RAI uptake outside thyroid bed, if performed		√	√
Secondary modifying risk factors
Specific age at diagnosis	√
Number of metastatic lymph nodes	√	√
Size of metastatic lymph nodes	√	√
Location of metastatic lymph nodes (N1a vs. N1b)	√
Size of metastatic foci within metastatic lymph nodes	√
Presence or absence of extranodal extension	√	√
Incomplete tumor resection (gross residual disease)^a	√
Subtypes of DTC	√	√
High mitotic index	√
Presence of perineural invasion	√
Presence or absence of tumor capsule invasion	√	√
Presence or absence of microscopic vascular invasion	√	√
Extent of microscopic capsular and/or vascular invasion		√
Unifocal vs. multifocal tumor foci	√	√
Postoperative serum thyroglobulin^a	√
RAI uptake outside thyroid bed, if performed^a		√	√
ATA risk category (low, intermediate, or high)	√
Mutational status and molecular profile of the tumor		√	√

Considered both primary and secondary risk factors.

AJCC, American Joint Committee on Cancer; ATA, American Thyroid Association; DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; RAI, radioactive iodine.

Primary risk factors

Only a small set of primary risk factors drive the eighth edition AJCC staging system and ATA initial risk stratification. This basic information is readily available to clinicians with access to standard histology and operative reports. The ATA risk stratification system also includes an evaluation of the postoperative serum thyroglobulin (Tg) as a very early response to therapy variable that is not incorporated as a staging criterion in the AJCC staging system. None of these primary risk factors requires detailed histological tumor descriptions or functional/structural imaging procedures that are not routinely available. Thus, this basic minimum data set of primary risk factors should be available to patients and clinicians across a wide variety of practice settings. As a result, appropriate AJCC and ATA 2009 structural risk assessment staging should be possible for most thyroid cancer patients.

Secondary modifying risk factors

The eighth edition does note that a wide variety of clinicopathological features could be considered as additional factors recommended for consideration as part of clinical care. These include the location of involved lymph nodes (central vs. lateral neck), number of involved lymph nodes, number of lymph nodes sampled, size of largest involved lymph node, size of metastatic foci within involved lymph nodes, extranodal extension, vascular invasion, postoperative serum Tg, completeness of resection, and histological subtypes. In addition, alternative ways to assess the impact of age at diagnosis on survival can also provide further refinement of AJCC eighth edition risk estimates (9 –11) (Table 1). While clinically relevant, none of these additional clinical factors are used to modify the prognostic stage groups (I, II, III, or IV) assigned based on the basic risk factors. Similarly, a wide variety of clinicopathological features can be used as secondary modifying risk factors to further individualize ATA risk estimates.

From a practical clinical perspective, most patients will be assigned the same ATA risk when evaluated using either the 2009 ATA initial risk stratification system or the modified 2009 ATA initial risk stratification. All patients classified as high risk or low risk by the 2009 risk stratification system continue to be in the same risk category assigned by the modified 2009 risk system. However, some patients classified as intermediate risk by the 2009 risk system will be moved to the modified 2009 high-risk category (follicular thyroid cancer with extensive vascular invasion, or largest metastatic lymph node ≥3 cm) or to the modified 2009 low-risk category (≤5 metastatic lymph nodes, all <0.2 cm; encapsulated follicular variant of papillary thyroid cancer, and well-differentiated follicular thyroid cancer with <4 foci of vascular invasion). Thus, while secondary risk factors can be used clinically to modify AJCC eighth edition, and ATA initial risk stratification risk estimates, these modifications in risk are relatively minor, do not change the AJCC prognostic stage, and infrequently change the ATA risk category assignment.

Future directions: risk stratification with integration of molecular theranostics

The current risk adapted approach to thyroid cancer management aligns the intensity of therapeutic interventions, including surgical treatment, subsequent RAI therapy, and thyrotropin (TSH) suppressive therapy, with clinical outcome risks. This typically results in more aggressive interventions for high-risk patients and less aggressive therapies for low-risk patients. Unfortunately, there is no guarantee that more aggressive therapies will necessarily improve clinical outcomes in high-risk patients or conversely that more minimalistic therapies would necessarily be effective for low-risk patients.

Molecular theranostics refers to selection of appropriate therapeutic interventions based on patient- and tumor-specific data regarding genomic alterations and their functional proteomic expressions, which are the prime determinants of RAI oncophysiology. It has the potential to devise patient-specific interventions including surgical treatment and RAI therapy. Molecular theranostics comprises molecular cytology, molecular pathology, and molecular imaging.

“Differentiated” thyroid cancers are biologically and functionally heterogeneous. Pathways of papillary thyroid cancer oncophysiology, and their impact on iodine metabolism, correlations between morphology and driver genetic mutations as well as functional thyroid differentiation were systematically first described in the Cancer Genome Atlas project (12). Papillary thyroid cancer encompasses several tumor types that have mutually exclusive mutations of genes encoding effectors that signal through the mitogen-activated protein kinase (MAPK) pathway. BRAF ^V600E accounts for 60% of these mutations, followed by RAS (15%) and chromosomal rearrangements that lead to illegitimate expression of the kinase domains of BRAF or of receptor tyrosine kinases, such as RET, NTRK, and ALK (12%). The remaining 13% mostly have no known driver mutations or a discrete genomic aberration.

The different mutations are associated with different morphological variants, gene expression, signaling, and clinical characteristics (13). Expression of the mutated BRAF ^V600E oncoprotein has variable degree of suppressive effect on the expression of genes required for iodine uptake, organification, and retention resulting in variable theranostic power for RAI scanning and responsiveness to RAI therapy. A descriptive term characterizing this metabolic compromise is “Radioactive iodine indifference.” RAS-driven carcinomas have less aberrations in the MAPK output, thus, preserve their RAI avidity to a better degree.

The cancer genome atlas project produced a single metric, referred as the thyroid differentiation score (TDS). The TDS is a composite quantitative measure of functional differentiation of individual cancers. Certain types of genomic alterations have more pronounced derangements in RAI metabolism resulting in variable levels of TDS. Preclinical and clinical data correlating molecular profiles and TDS are strongly compelling and are increasingly being considered as important factors in clinical decision making.

The phenotypic expression of these altered molecular profiles translates into functional characteristics with theranostic importance. Theranostic risk stratification begins before surgical treatment, with molecular profiling of a suspicious nodule by fine needle aspiration. Tumor biology information encrypted in the molecular profile can be combined with clinical features to help determine the extent of initial surgical treatment (lobectomy vs. total thyroidectomy), and indications for RAI treatment.

Summary and Conclusions: Perioperative Risk Stratification

The traditional risk stratification models provide highly predictive and prognostic information, but lack theranostic value. Traditional risk stratification systems can be further refined by incorporation of patient- and tumor-specific molecular profiles that have theranostic power, to optimize patient-specific (individualized) treatment decisions.

We are in agreement that initial staging to utilize the eighth edition AJCC system to predict disease-specific mortality, and the modified 2009 ATA risk stratification system to estimate structural disease recurrence should be implemented. We also are in agreement for judicious incorporation of molecular theranostics in the primary framework to guide initial patient management decisions in differentiated thyroid cancer (DTC).

Review: The Role of Diagnostic RAI Imaging in Initial Staging

Optimal patient selection for RAI treatment requires consideration and evaluation of multiple factors beyond postoperative disease status and risk stratification (14). When defining the role for a given diagnostic test for staging of patients with thyroid cancer, it is important to weigh the sensitivity and specificity of the test as well as its contribution to “actionable information” that alters management decisions outside of information already available (5). The diagnostic test should provide information that can be integrated with the preoperative clinical data and surgical pathology, and second, it should have impact on patient management, with the anticipation that such changes in intervention would improve outcomes such as disease-free and overall survival. Diagnostic RAI whole body scans (WBS) are performed with the intent of identifying and localizing regional and distant metastatic disease. The findings on diagnostic radioiodine scans may guide the decision how to proceed with RAI treatment or what ¹³¹I activity to prescribe for an individual patient based on the institutional protocols/algorithms.

Current standards: clinical and technical considerations in RAI imaging

In addition to the tumor's biological attitude toward RAI, the sensitivity for detecting metastatic lesions by RAI imaging is dependent on the (i) specific isotope of RAI, (ii) imaging technique, and (iii) administered activity. The most common choice for clinical RAI imaging and dosimetry is the radioisotope ¹³¹I, a beta particle and gamma photon emitter. The physical properties of ¹³¹I are not optimal for highest quality imaging. The other factor contributing to less than optimal image quality is the relatively low administered activities in the range of 1–5 mCi (37–185 MBq), which are used in an effort to avoid “stunning” when used before RAI treatment.

¹²³I is predominantly a gamma emitter with better physical qualities for standard gamma camera imaging. In addition, higher administered activities can be used compared with ¹³¹I with less concern for stunning. The 13-hour half-life of ¹²³I limits its utility for dosimetry protocols. Also, it is more expensive and is not as readily available as ¹³¹I. Diagnostic ¹³¹I scans performed with 1–5 mCi (37–185 MBq) administered activities, particularly when used in a pre-RAI treatment setting, may have limited diagnostic and theranostic yield. Subtle or nonvisualized foci of RAI avid disease on low-activity diagnostic ¹³¹I scans may more readily be disclosed on post-treatment scans with therapeutic administered activities. Single photon emission computer tomography (SPECT)/computed tomography (CT) technique offers much improved spatial resolution and clearly improves anatomic localization accuracy; however, it does not offer better sensitivity than planar imaging. The technical advantages and improved image characteristics of SPECT/CT are well documented (14 –16).

The RAI image interpretation in the neck has a unique challenge in the first postsurgical imaging setting. This is a very important but not well-recognized clinical problem, which has the potential to influence the accurate staging of the neck in a post-thyroidectomy patient. The differentiation of some isolated thyroid remnants and nodal metastases is more problematic than usually appreciated. Utilization of SPECT/CT (¹³¹I) or positron emission tomography (PET)/CT (¹²⁴I) has improved the image clarity in terms of spatial resolution, but does not completely resolve this dilemma (14 –17). After total thyroidectomy, SPECT/CT (¹³¹I) imaging usually identifies small foci of normal residual thyroid tissue around structures such as Berry's ligament and Zuckerkandl tubercle retained to avoid injury to the recurrent laryngeal nerve and at the superior poles of the gland to protect the superior laryngeal nerve (18,19). These remnants are identified as an “off-midline focal activity” on high-resolution RAI SPECT/CT or PET/CT imaging and may be reported as nodal disease leading to erroneous upstaging to N1 from an actual N0 status. The pyramidal lobe remnant may appear as “midline focal activity.”

Clinical considerations: role of diagnostic RAI imaging as part of initial staging for ATA intermediate risk patients

Patients in the intermediate-risk category, as defined in ATA guidelines, carry recurrence rates between 5% and 30% (7). Detection of RAI-avid occult metastases is very important for improved risk stratification and potential long-term management planning. Two general strategies exist in RAI imaging in the initial post-total thyroidectomy setting: (i) pre-RAI treatment imaging and (ii) post-RAI treatment imaging. The rationales for these approaches are different. The main argument is whether pretreatment imaging could have a meaningful and clinically relevant impact on the decision for and the choice of the administered activity of ¹³¹I used for RAI treatment.

Pre-RAI treatment imaging has potential benefits in a theranostic context. Conversion to an M1 status from an M0 is arguably the most important utility. The theranostic power of pretreatment RAI imaging, however, is hampered by biological, technical, and practical constraints. The most challenging issue is N0 to N1 conversion by means of low-activity imaging since distinction between small foci of residual normal thyroid tissue and true nodal metastases could be difficult. In addition, N0 to N1 conversion may not necessarily change the risk category from intermediate risk to high risk in many cases (8). Diagnostic ¹³¹I scanning with low activity (planar studies with or without SPECT/CT imaging) may not detect metastases in normal-size cervical lymph nodes as most papillary carcinomas show depression in RAI avidity.

By virtue of their molecular pathogenesis, the detection yield is potentially better with distant metastases, including micronodular pulmonary metastases that are too small to be detected on routine chest X-ray and may remain undetected on CT as well. The clinical utility of pre-RAI imaging is mostly investigated in mixed (intermediate- and high-risk categories) patient populations and largely dependent on institutional practices and algorithms used for RAI treatment.

There are publications that strongly advocate routine use of pretreatment scans to improve detection of metastatic sites and management decisions. Two different analyses in a mixed cohort of 320 (low, intermediate, and high risk) patients reported a change in clinical strategy using 1 mCi ¹³¹I SPECT/CT imaging. This was determined by the study institution's treatment criteria (remnant ablation, 30 mCi (1.1 GBq); nodal disease, 100–150 mCi (3.7–5.6 GBq); distant metastasis, 200–300 mCi (7.4–11.1 GBq) (14,20). The studies confirmed the superior spatial resolution of SPECT/CT. A commonly cited study, advocating pretreatment imaging, pointed out physiological information obtained by pretreatment imaging that could be helpful in the clinical evaluation of patients (21). Another study in support of pretreatment RAI imaging reported clinical benefits of ¹²³I planar imaging within the framework of the institutional RAI treatment protocol (22).

Better spatial resolution of pretreatment SPECT/CT imaging with a potential impact on institutional treatment planning or clinical decision making was also reported in other reports (23 –25). A consistent finding in most studies is an overall rate of ∼6% for detection of extracervical metastatic disease. Additional information obtained with pretreatment RAI imaging has the potential to influence management decisions; however, this is dependent on the institutional criteria set for adjusting the administered activity. Pretreatment RAI imaging can be used to establish a baseline for subsequent diagnostic imaging. To serve this particular purpose, the diagnostic imaging studies should be performed using the same protocol. Logistical considerations related to recombinant human TSH (rhTSH) and/or the implications of a withdrawal protocol are also factors that can influence the routine utilization of pretreatment RAI imaging.

Post-RAI treatment imaging has a higher yield for detection of occult lesions for “RAI-avid disease” on a by-lesion basis (26 –32) and should always be obtained. Identification of previously unknown distant metastases was demonstrated in ∼2% of low- and intermediate-risk DTCs (33). Post-treatment imaging is not theranostic as it is obtained after the RAI treatment is given, but is nevertheless highly informative. Post-treatment scans should always be obtained for staging of RAI-avid disease and identification of tumors that are not RAI avid.

Future directions: improving the theranostic power of RAI imaging

Ideally, a dynamic-theranostic model of risk stratification includes RAI imaging before RAI therapy for optimal treatment planning. Clinical expectations from RAI imaging may not be met in all patients since the avidity for RAI varies based on histology, tumor genotype, and molecular profile. This becomes particularly important for adjuvant treatment decisions in patients in the intermediate-risk category. Therapeutic strategies and endpoints also need to be clarified to establish the pretreatment imaging as a “value-added” step. The theranostic power of RAI imaging, compromised by aberrant MAPK output along with other pathways and epigenetic events, may be improved with MAPK modulators, similar to TSH stimulation. Currently the clinical data are limited but very compelling, backed by physiological considerations (34 –38).

From a technical perspective, ¹²⁴I PET/CT imaging may offer clinical advantages. ¹²⁴I is a PET radioisotope with a 4.2-day half-life. It offers superior imaging characteristics with enhanced spatial resolution and image sensitivity due to the coincidence detection principle of PET imaging. ¹²⁴I also has a favorable half-life that permits the evaluation of in vivo iodine kinetics. A uniform clinical protocol for ¹²⁴I PET/CT imaging, image analysis, and quantification is yet to be established. Despite its technical advantages, and supporting data (17,39,40,42 –46), ¹²⁴I PET/CT use is still restricted to clinical trial settings.

Summary and Conclusions: The Role of Diagnostic RAI Imaging in Initial Staging

Neck ultrasonography (US) and serum Tg determinations have well-established roles in perioperative evaluation. Diagnostic RAI imaging in a pre-RAI treatment setting may yield information relevant to clinical decision making only in selected patients in the intermediate-risk category. Limitations of low-activity imaging should be recognized. Institutional management algorithms play a significant role in determining the role for pretreatment imaging as a “value-added” step (Table 2). Post-treatment scans should always be obtained for staging of RAI-avid disease and identification of tumors that are not RAI avid.

Table 2.

Pre-Tx Radioactive Iodine Imaging In Intermediate Risk Category

	Technical considerations	Biological considerations
Sensitivity^a	• RAI activity dependent• Higher activities are a concern for “stunning”	• Tumor biology dependent• Poor RAI avidity is not uncommon^b • Higher yield with RAS-like tumors
Specificity^c	• Equal with all RAI isotopes [¹³¹I = ¹²³I = ¹²⁴I]	• Challenging for identification accuracy in cervical nodal disease^d
Spatial resolution^e	• PET/CT>SPECT/CT>PLANAR	• Same as sensitivity and specificity

	Clinical considerations
Potential clinical benefit	• Upstaging from N0 to N1 and/or from M0 to M1^f • The utility of the diagnostic RAI scan is firmly dependent on institutional treatment algorithms and strategies

Ability to identify RAI-avid foci.

“Differentiated” thyroid cancers, particularly papillary type, most particularly those with BRAF mutations, express variable degrees of RAI avidity.

Ability to distinguish cancer vs. tissues of physiological or nonmalignant tissue.

Thyroid normal presumably, volume small very surgical remnants may be misinterpreted for nodal metastases, leading to false upstaging.

Ability to discriminate areas of uptake as separate foci.

N0 to N1 upstaging may not necessarily change the risk category, and thus may not translate into change in treatment strategy.

CT, computed tomography; PET, positron emission tomography; SPECT, single photon emission computer tomography.

Distinction between cervical nodal metastases and focal remnants remains problematic in the interpretation of both pretreatment and post-treatment images. As it stands, the utility of the diagnostic RAI scan is firmly dependent on institutional treatment algorithms and strategies. In the molecular theranostics paradigm, the role for diagnostic RAI molecular imaging has to be redefined.

We support a selective use approach to diagnostic RAI scanning in ATA intermediate-risk patients rather than routine use or denial for all patients in this category.

Review: The Indicators of Response to RAI Therapy in the Setting of Structurally Identifiable DTC

It is obvious that in any disorder, the response to interventions should be categorized in a standardized manner. This is essential for clinical research on the efficacy of treatment modalities or protocols and consequently for the generation of guidelines. At the individual patient level, response categories help to assess treatment success, or the lack thereof, and the need for continuation or changing the therapeutic approach. In many solid tumors, well-defined therapy response categories have been established using the response evaluation criteria in solid tumors (RECIST) based on anatomic imaging (47 –49). For PET imaging, functional tumor volume and PET response criteria for solid tumors (PET response criteria in solid tumors [PERCIST]) have been developed and applied to a number of solid tumors (50,51).

The immune-related response criteria were specifically developed for response evaluations for immuno-oncology drugs (immune checkpoint inhibitors) to address the problem of pseudoprogression (52). RECIST 1.1 has been used for response evaluation after TKI treatments (48), and to a lesser degree after RAI treatment (54). These evaluation criteria are designed for clinical studies but can be applied to clinical practice. US imaging is the standard anatomic imaging modality for cervical nodal disease for thyroid cancer. Multiplanar dimensions and volume calculations can be reliably and reproducibly produced. Currently, the RECIST system, based on measurement of index lesion sizes on cross-sectional imaging, is the most commonly accepted standard for treatment evaluation for solid cancers within the context of clinical trials (48,54 –56).

Current standards: objective response measures to RAI treatment of structural disease

The term “structural disease” refers to persistent/recurrent/metastatic disease with lesions visible by imaging, whereas “biochemical disease” refers to occult disease without any identifiable lesions by clinical imaging. Structural disease may declare itself in a synchronous or metachronous manner. The definition and detection of these two presentations are different, as well as their response to treatment evaluations. Synchronous disease is defined as extrathyroidal disease present at the time of initial presentation. This could be locally advanced cervical disease and/or extracervical distant metastatic disease, either one of which could be clinically evident before the initial surgical treatment or could be disclosed intraoperatively or postoperatively by RAI imaging. Metachronous disease indicates a progression to a recurrent/metastatic state with lesions visible by clinical imaging after a period of latency.

The response to initial therapy has been categorized in most guidelines, using the ATA definitions: “excellent response (no evidence of disease),” “biochemical incomplete response,” “indeterminate response,” and “structurally incomplete response.” Currently, no uniform response criterion for RAI therapy in structural disease has been established. Treatment decisions regarding continuation or discontinuation of RAI therapy in individual patients are based on subjective criteria and hardly comparable between institutions. As a consequence, it is difficult to uniformly define response or resistance to RAI treatment.

Definition of response to RAI therapy in structural disease

Response to therapy is expressed in terms of clinical outcomes or objective responses. The objective response criteria/measures are anatomic volume, functional volume, and Tg. The translation of objective responses into clinical outcomes (survival, disease-free survival) is determined by oncopathophysiology of disease progression. These involve complex molecular profiles/patterns of local invasion and metastases as well as tumor–host interactions. Response to treatment evaluation after the first postsurgical RAI treatment (primary RAI treatment) and other (secondary) RAI treatments performed for persistent/recurrent/metastatic disease has some differences. In the initial RAI treatment setting, the target structural lesions may include malignant tissue and the non-neoplastic remnant tissue, whereas in a secondary setting, the target is the malignant tissue.

The current reporting system, as suggested by ATA guidelines, proposes the terms “excellent response,” “indeterminate response,” “biochemically incomplete response,” and “structurally incomplete therapy response” as definitions of response. These definitions, for establishing the baseline after the initial RAI treatment, are very helpful. Response to treatment evaluation after secondary treatments ideally should include quantitative/semiquantitative measures and Tg level. Tg, as a sensitive and specific biomarker (in a setting of complete remnant ablation), has a strong role. However, the considerations that apply to functional imaging are valid for Tg as well (tumor regression vs. change in functional differentiation status).

Functional imaging for DTC

Routine RAI imaging in current clinical use includes whole body planar and regional SPECT techniques. No standard quantitative expressions of response is in routine use with RAI imaging. Visually appraised reduction in the tumor uptake in the post-treatment follow-up is frequently used as a response criterion. A potential caveat in the interpretation of a decreased RAI uptake in follow-up is the possibility of functional tumor dedifferentiation in the course of the disease. This possibility should be evaluated by the utilization of fluorodeoxyglucose (FDG) PET/CT imaging, which reflects the glycolytic activity of the tumors.

Thyroid cancers of aggressive clinical behavior have high glycolytic activity. This has a clear prognostic importance as originally demonstrated in a 2000 study published by the Memorial Sloan Kettering Cancer Center (MSKCC) group (57) and has been updated in a 2019 study incorporating additional molecular data (58). The FDG–RAI relationship is not a simple “flip-flop” phenomenon. Linked to the root driver oncogenic events, but most intimately associated with downstream translational and post-translational events, these two phenotypic expressions have a distinct presence in individual tumors. The enhanced glycolytic activity, clinically demonstrated by FDG-PET imaging, is associated with poor clinical outcomes. Integration of RAI and FDG PET imaging results for individual patients can provide valuable insights into the theranostic risk stratification model.

In pursuit of a standardized system, similar to RECIST, PERCIST, based on measurement of standard uptake value (SUV) corrected for lean body mass (SUL), has been developed for treatment evaluation for solid cancers. PERCIST 1.0 was published in 2009 and was successfully applied for systematic and structured assessment of response to therapy with FDG-PET/CT in patients with cancer. PERCIST categories with clinical use guidelines have been clearly defined (50,51).

Thyroglobulin

In clinical practice, RAI imaging during follow-up is performed along with concurrent serum Tg and anti-Tg antibody (TgAb) measurements. Tg level is part of the panel including TSH/Tg/TgAb, as the TSH affects Tg levels, and the presence of antibodies determines whether serum Tg can be measured reliably by an immunometric test. The diagnostic value of Tg is improved with the use of TSH stimulation (induced by withdrawal or rhTSH) (59). In the context of early detection of recurrent/metastatic disease, the role for a high-sensitivity assay (60) and Tg doubling time (61) have been shown to be clinically valuable. For evaluation of response to RAI treatment, the change in the levels of Tg pretreatment to post-treatment is reflective of tumor volume change. The Tg level is also dependent on functional tumor differentiation. From a technical perspective, it cannot be used as a reliable quantitative indicator in the presence of TgAb. In disease-free patients, high TgAb levels usually decline over time. A rising trend in TgAb, or a conversion to a positive state from a negative state (de-novo TgAb appearance) in contrast, may be suggestive of persistent disease (62).

Future directions: integration of quantitative measures in anatomic and functional imaging

To develop a clinically valid and reproducible response criterion for response evaluation, the complex nature of functional differentiation of thyroid cancer needs to be appreciated. Validation and standardization of quantitative response measures of anatomic and functional imaging modalities, and their integration into clinical thyroid cancer imaging are needed. Functional imaging is particularly important in “DTC.” Quantitative functional imaging is more robust in PET imaging than in SPECT. The basic quantitative measure for PET imaging is “functional volume” (FV). The FV is defined as the size of a lesion that has a SUV of a predetermined threshold value. The FV usually is different from the anatomic volume measured by CT. Functional volume calculations are applicable to both FDG and ¹²⁴I imaging.

Summary and Conclusions: The Indicators of Response to RAI Therapy in the Setting of Structurally Identifiable DTC

There is an obvious need for a uniform classification system to describe response to RAI therapy in structural disease (Table 3). The components of such a system should include anatomic as well as functional imaging criteria. The concepts, imaging categories, and the resulting management changes from TKI studies can be transferred to the RAI treatment setting(s) adopting RECIST 1.1 criteria. However, in clinical practice, this may be extremely challenging. RECIST criteria are not used in routine clinical practice at present. Post-RAI treatment changes noted in functional imaging such as RAI-SPECT-CT, ¹²⁴I-PET-CT, and FDG-PET (PERCIST) are more complex (tumor regression vs. a change in functional differentiation status).

Table 3.

Response Evaluation

Modality	Quantitative	Semiquantitative qualitative	Site specificity	Limitations
Ultrasonography	Volume calculation	Bidimensional measurements	Cervical disease only	Cervical disease only
CT	Anatomic volume RECIST	Bidimensional measurements	All	Underpowered for micronodular lung disease
RAI scan
Planar (¹³¹I)	Geometric mean^a	Strong/faint/no uptake	All	Differentiation dependent^c Challenging specificity in cervical disease^d
SPECT(CT) (¹³¹I)	Functional volume^b	Strong/faint/no uptake
PET/CT (¹²⁴I)	Functional volume^b	SUV
FDG-PET/CT	Functional volume^e	SUV	All	Differentiation dependent
Thyroglobulin	Numeric	Numeric	None	Differentiation dependent

The square root of multiplication of counts/activity measured in anterior and posterior views on a planar image.

Volume of the RAI-avid tissue measured on functional imaging (SPECT/CT or PET/CT).

“Differentiated” thyroid cancers, particularly papillary type, most particularly those with BRAF mutations, express variable degrees of RAI avidity.

Surgical remnants may be misinterpreted for nodal metastases.

Volume of the FDG-avid tissue measured on FDG-PET/CT.

FDG, fluorodeoxyglucose; RECIST, response evaluation criteria in solid tumors; SUV, standard uptake value.

We agree that a consistent semiquantitative reporting system should be used for response evaluation after RAI therapy, until a reproducible and clinically practical quantitative system is validated.

Final Summary and Conclusions

Risk stratification remains paramount in surgical, nuclear, and molecular treatment planning. The existing risk stratification models provide highly accurate predictive and prognostic information, but lack theranostic value. Traditional risk stratification systems can be refined, by incorporation of patient- and tumor-specific molecular markers that have theranostic power, to optimize patient-specific (individualized) treatment decisions. RAI imaging is an indispensable component of dynamic and theranostic risk stratification. Post-treatment scans should always be obtained for staging of RAI-avid disease and identification of tumors that are not RAI avid. The “value-added” role for pretreatment diagnostic RAI molecular imaging has to be clarified and redefined. There is an obvious need for a uniform classification system to describe response to RAI therapy in structural disease. The components of such a system should include anatomic as well as functional imaging criteria.

Ethical Committee Approval

Approval for this study was not required as no patient-specific data were included.

Footnotes

Acknowledgments

The article was written by Seza Gulec, Michael Tuttle, Anca Avram, Victor Bernet, Markus Luster, and Johannes Smit with review, editing, and additional input from the coauthors. Laszlo Hegedüs moderated the intersocietal group discussions and facilitated the collaboration between the coauthors. The coauthors of the article are the delegates of the respective societies invited to the Martinique 2020 intersocietal meeting. Coauthorship sequence following the lead author is based on alphabetical order. The intersocietal working group is grateful to Drs. Ciprian Draganescu and Patrick Bourguet for organizing the Martinique Conferences.

Authors' Contribution

S.A.G., A.M.A., V.J.B., M.L., J.W.A.S., and R.M.T. were involved in conception, writing, review, and critical editing. S.A., P.B., C.D., R.E., and F.G. carried out conception and review. L.G., B.G., L.H., J.J., R.T.K., and W.J.G.O. carried out conception, review, and critical editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Tuttle

, Ahuja

, Avram

, et al. 2019. Controversies, consensus, and collaboration in the use of I-131 therapy in differentiated thyroid cancer: a joint statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid, 29:461–470.

Verburg

, Ahuja

, Avram

, et al. 2020. Brief progress report from the inter-societal working group on differentiated thyroid cancer. Eur J Nucl Med Mol Imaging, 47:1345–1347.

Ahuja

, Avram

, Dillehay

, et al. 2019. The martinique principles. J Nucl Med, 60:1334–1335.

Tuttle

, Haugen

, Perrier

. 2017. Updated American Joint Committee on Cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why?. Thyroid, 27:751–756.

Tuttle

, Alzahrani

. 2019. Risk stratification in differentiated thyroid cancer: from detection to final follow-up. J Clin Endocrinol Metab, 104:4087–4100.

Cooper

, Doherty

, Haugen

, et al. 2009. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.

Haugen

, Alexander

, Bible

, et al. 2016. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26:1–133.

Carty

, Doherty

, Inabnet

3rd , et al., Surgical Affairs Committee of the American Thyroid Association 2012. American Thyroid Association statement on the essential elements of interdisciplinary communication of perioperative information for patients undergoing thyroid cancer surgery. Thyroid, 22:395–399.

Adam

, Thomas

, Hyslop

, et al. 2016. Exploring the relationship between patient age and cancer-specific survival in papillary thyroid cancer: rethinking current staging systems. J Clin Oncol, 34:4415–4420.

10.

Ganly

, Nixon

, Wang

, et al. 2015. Survival from differentiated thyroid cancer: what has age got to do with it?. Thyroid, 25:1106–1114.

11.

Ghaznavi

, Ganly

, Shaha

, et al. 2018. Using the American Thyroid Association risk-stratification system to refine and individualize the American Joint Committee on Cancer eighth edition disease-specific survival estimates in differentiated thyroid cancer. Thyroid, 28:1293–1300.

12.

Cancer Genome Atlas Research Network. 2014. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 159:676–690.

13.

Fagin

, Wells

Jr . 2016. Biologic and clinical perspectives on thyroid cancer. N Engl J Med, 375:1054–1067.

14.

Avram

, Esfandiari

, Wong

. 2015. Preablation I-131 scans with SPECT/CT contribute to thyroid cancer risk stratification and I-131 therapy planning. J Clin Endocrinol Metab, 100:1895–1902.

15.

Grewal

, Tuttle

, Fox

, et al. 2010. The effect of posttherapy I-131 SPECT/CT on risk classification and management of patients with differentiated thyroid cancer. J Nucl Med, 51:1361–1367.

16.

Ciappuccini

, Heutte

, Trzepla

, et al. 2011. Postablation I-131 scintigraphy with neck and thorax SPECT-CT and stimulated serum thyroglobulin level predict the outcome of patients with differentiated thyroid cancer. Eur J Endocrinol, 164:961–969.

17.

Gulec

, Kuker

, Goryawala

, et al. 2016. I-124 PET/CT in patients with differentiated thyroid cancer: clinical and quantitative image analysis. Thyroid, 26:441–448.

18.

Zeuren

, Biagini

, Grewal

, et al. 2015. RAI thyroid bed uptake after total thyroidectomy: a novel SPECT-CT anatomic classification system. Laryngoscope, 125:2417–2424.

19.

Gulec

, Kuker

. 2017. Radioactive iodine remnant ablation: The beta-knife completion thyroidectomy. Mol Imaging Radionucl Ther, 26(suppl 1):16–23.

20.

Avram

, Fig

, Frey

, et al. 2013. Preablation I-131 scans with SPECT/CT in postoperative thyroid cancer patients: what is the impact on staging?. J Clin Endocrinol Metab, 98:1163–1171.

21.

Van Nostrand

, Aiken

, Atkins

, et al. 2009. The utility of radioiodine scans prior to I-131 ablation in patients with well-differentiated thyroid cancer. Thyroid, 19:849–855.

22.

Chen

, Yasrebi

, Samii

, et al. 2012. The utility of I-123 pretherapy scan in I-131 radioiodine therapy for thyroid cancer. Thyroid, 22:304–309.

23.

Spanu

, Solinas

, Chessa

, et al. 2009. I-131 SPECT/CT in the follow-up of differentiated thyroid carcinoma: incremental value versus planar imaging. J Nucl Med, 50:184–190.

24.

Song

, Mosci

, Akatsu

, Basina

, et al. 2018. Diagnostic 123I whole body scan prior to ablation of thyroid remnant in patients with papillary thyroid cancer: implications for clinical management. Clin Nucl Med, 43:705–709.

25.

Avram

, Rosculet

, Esfandiari

, et al. 2019. Differentiated thyroid cancer outcomes after surgery and activity-adjusted I-131 theragnostics. Clin Nucl Med, 44:11–20.

26.

Fatourechi

, Hay

, Mullan

, et al. 2000. Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer?. Thyroid, 10:573–577.

27.

Sherman

, Tielens

, Sostre

, et al. 1994. Clinical utility of posttreatment radioiodine scans in the management of patients with thyroid carcinoma. J Clin Endocrinol Metab, 78:629–634.

28.

Urhan

, Dadparvar

, Mavi

, et al. 2007. I-123 as a diagnostic imaging agent in differentiated thyroid carcinoma: a comparison with I-131 post-treatment scanning and serum thyroglobulin measurement. Eur J Nucl Med Mol Imaging, 34:1012–1017.

29.

Donahue

, Shah

, Lee

, et al. 2008. Initial staging of differentiated thyroid carcinoma: continued utility of posttherapy I-131 whole-body scintigraphy. Radiology, 246:887–894.

30.

Iwano

, Kato

, Nihashi

, et al. 2009. Comparisons of I-123 diagnostic and I-131 posttreatment scans for detecting residual thyroid tissue and metastases of differentiated thyroid cancer. Ann Nucl Med, 23:777–782.

31.

Bravo

, Goudarzi

, Rana

, et al. 2013. Clinical significance of discordant findings between pre-therapy (123)I and post-therapy I-131 whole body scan in patients with thyroid cancer. Int J Clin Exp Med, 6:320–333.

32.

Pacini

, Schlumberger

, Dralle

, et al. 2006. European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 154:787–803.

33.

Agate

, Bianchi

, Brozzi

, et al. 2019. Less than 2% of the low- and intermediate-risk differentiated thyroid cancers show distant metastases at post-ablation whole-body scan. Eur Thyroid J, 8:90–95.

34.

, Grewal

, Leboeuf

, et al. 2013. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 368:623–632.

35.

Rothenberg

, McFadden

, Palmer

, et al. 2015. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res, 21:1028–1035.

36.

Dunn

, Sherman

, Baxi

, et al. 2019. Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers. J Clin Endocrinol Metab, 104:1417–1428.

37.

Leboulleux

, Dupuy

, Lacroix

, et al. 2019. Redifferentiation of a BRAF K601E-mutated poorly differentiated thyroid cancer patient with dabrafenib and trametinib treatment. Thyroid, 29:735–742.

38.

Buffet

, Wassermann

, Hecht

, et al. 2020. Redifferentiation of radioiodine-refractory thyroid cancers. Endocr Relat Cancer, 27:113–132.

39.

Jentzen

, Freudenberg

, Eising

, et al. 2008. Optimized I-124 PET dosimetry protocol for radioiodine therapy of differentiated thyroid cancer. J Nucl Med, 49:1017–1023.

40.

Van Nostrand

, Moreau

, Bandaru

, et al. 2010. I-124 positron emission tomography versus I-131 planar imaging in the identification of residual thyroid tissue and/or metastasis in patients who have well-differentiated thyroid cancer. Thyroid, 20:879–883.

41.

[Deleted].

42.

Plyku

, Hobbs

, Huang

, et al. 2017. Recombinant human thyroid-stimulating hormone versus thyroid hormone withdrawal in I-124 PET/CT-based dosimetry for I-131 therapy of metastatic differentiated thyroid cancer. J Nucl Med, 58:1146–1154.

43.

Kuker

, Sztejnberg

, Gulec

. 2017. I-124 imaging and dosimetry. Mol Imaging Radionucl Ther, 26(Suppl 1):66–73.

44.

, Ylli

, Heimlich

, Burman

, et al. 2019. I-124 positron emission tomography/computed tomography versus conventional radioiodine imaging in differentiated thyroid cancer: a review. Thyroid, 29:1523–1535.

45.

Weber

, Binse

, Nagarajah

, et al. 2019. The role of I-124 PET/CT lesion dosimetry in differentiated thyroid cancer. Q J Nucl Med Mol Imaging, 63:235–252.

46.

Freudenberg

, Antoch

, Jentzen

, et al. 2004. Value of I-124 PET/CT in staging of patients with differentiated thyroid cancer. Eur Radiol, 14:2092–2098.

47.

World Health Organization 1979 WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization Offset Publication No. 48, Geneva, Switzerland.

48.

Therasse

, Arbuck

, Eisenhauer

, et al. 2000. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 92:205–216.

49.

Eisenhauer

, Therasse

, Bogaerts

, et al. 2009. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45:228–247.

50.

Wahl

, Jacene

, Kasamon

, et al. 2009. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med, 50 Suppl 1:122S–150S.

51.

O JH, Lodge

, Wahl

. 2016. Practical PERCIST: a simplified guide to PET response criteria in solid tumors 1.0. Radiology, 280:576–584.

52.

Wolchok

, Hoos

, O'Day

, et al. 2009. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res, 15:7412–7420.

53.

[Deleted].

54.

, Shin

, Kim

, et al. 2019. Extended real-world observation of patients treated with sorafenib for radioactive iodine-refractory differentiated thyroid carcinoma and impact of lenvatinib salvage treatment: a Korean Multicenter Study. Thyroid, 29:1804–1810.

55.

Lee

, Kim

, et al. 2019. Lesion-based evaluation predicts treatment response to lenvatinib for radioactive iodine-refractory differentiated thyroid cancer: a Korean Multicenter Retrospective Study. Thyroid, 29:1811–1819.

56.

Klubo-Gwiezdzinska

, Burman

, Van Nostrand

, et al. 2012. Radioiodine treatment of metastatic thyroid cancer: relative efficacy and side effect profile of preparation by thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid, 22:310–317.

57.

Wang

, Larson

, Fazzari

, et al. 2000. Prognostic value of [18F] fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab, 85:1107–1113.

58.

Suh

, Choi

, Paeng

, et al. 2019. Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer. BMC Cancer, 19:1260.

59.

Giovanella

, Duntas

. 2019. Management of endocrine disease: the role of rhTSH in the management of differentiated thyroid cancer: pros and cons. Eur J Endocrinol, 181:R133–R145.

60.

Giovanella

, Feldt-Rasmussen

, Verburg

, et al. 2015. Thyroglobulin measurement by highly sensitive assays: focus on laboratory challenges. Clin Chem Lab Med, 53:1301–1314.

61.

Verburg

, Mäder

, Grelle

, et al. 2017. Only a rapid complete biochemical remission after I-131 therapy is associated with an unimpaired life expectancy in differentiated thyroid cancer. Horm Metab Res, 49:860–868.

62.

Verburg

, Luster

, Cupini

, et al. 2013. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid, 23:1211–1225.