Radioiodine Refractory Differentiated Thyroid Cancer: Time to Update the Classifications

Abstract

Background:

The management of aggressive and progressing metastatic differentiated thyroid cancer (DTC) is very difficult, and the determination as to when such patients are refractory to ¹³¹I therapy (e.g., radioiodine refractory) is problematic and controversial.

Objective:

The objective of this review is to discuss (i) the present major classifications of radioiodine refractory disease in DTC, (ii) factors that should be considered before designating a patient's DTC as radioiodine refractory, (iii) potential approaches and caveats to help manage and minimize a patient's exclusion from an ¹³¹I therapy that may have potential benefit in patients with aggressive and progressing metastatic DTC, (iv) next steps for revision of the classifications of radioiodine refractory DTC, and (v) areas for future research.

Summary:

To date, the classifications of radioiodine refractory DTC, although very useful, are not sacrosanct especially in the context of individualized patient management, and merely because a patient meets one or more of the various classifications, one should not consider by definition, fiat, or de facto that that a patient's DTC is radioiodine refractory. Rather, each patient should be individually managed with a good understanding of the limitations of the various classifications and potential approaches to help manage that patient. With awareness of the suggestions and caveats discussed herein and with assessment of the many other factors that affect the patient's specific clinical situation, the managing physician can deliver appropriate individualized patient care. A multi-organizational committee should be established as a standing committee to supervise and assist in the update of the classifications of radioiodine refractory DTC, including discussions of their limitations.

Conclusion:

Classifications to help determine radioiodine refractory disease will continue to evolve as (i) more studies are published, (ii) managing physicians better understand the limitations and confounding factors of present classifications, and (iii) new agents either increase or reestablish ¹³¹I uptake.

Introduction

Iodine 131 (¹³¹I) is one of the most important treatment options for patients with distant metastatic differentiated thyroid cancer (DTC), and when a patient no longer responds to ¹³¹I treatment (i.e., radioiodine refractory), additional therapeutic options are available including tyrosine kinase inhibitors. Although most physicians will agree that a patient who is radioiodine refractory should not receive any further ¹³¹I treatment, the actual classification of a patient as radioiodine refractory is problematic and controversial. In order to determine when a patient will no longer respond to ¹³¹I, multiple classifications have been described to categorize a patient as radioiodine refractory to spare the patient from the possibly untoward effects of an ¹³¹I treatment with little to no benefit. However, the classifications of radioiodine refractory DTC need to be updated. This is important because patients who have aggressive and progressing metastatic DTC have access to a diminishing set of therapeutic options, and I would submit that no treating physician has the intent of inappropriately eliminating a treatment option that has the possibility of achieving a reasonable period of progression-free survival with acceptable side effects. The objective of this article is to review the following: (i) the development of the major classifications of radioiodine refractory DTC, (ii) multiple present classifications of radioiodine refractory DTC, (iii) the supporting sources and literature of those classifications, and iv) the limitations of those classifications. This review closes proposing next steps for updating the classifications of radioiodine refractory DTC, potential approaches and caveats to help manage and minimize a patient from being excluded from an ¹³¹I therapy that may have potential benefit, and future areas for research.

The development of classifications of radioiodine refractory DTC

First, I respectfully acknowledge and compliment the many individuals from many institutions and committees for their pioneering time and energy in the initial development of classifications to help better determine which patients with DTC are and are not radioiodine refractory (1,2).

One of the initial efforts to classify radioiodine refractory disease was by an international panel of experts in September 2010 during the 14th International Thyroid Congress in Paris, France (1). Attendees were members of at least one of the following organizations: the American Thyroid Association (ATA), the European Thyroid Association, Latin American Thyroid Society, and the Asia Oceania Thyroid Association. Funding was provided by Bayer HealthCare Pharmaceuticals, and the authors affirmed that the content was not influenced by the sponsor. The panel classified radioiodine refractory DTC (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/thy) and stated that the situation became more problematic when there were mixed responses to ¹³¹I. A subsequent international panel of experts gathered in September 2012 in Pisa, Italy with their classification published in 2014 (Supplementary Table S2) (2). In addition, they proposed the following algorithm: “Once one or more metastatic lesions fail to take up radioactive iodine and continue to grow, these patients are considered refractory and radioactive iodine treatment is abandoned. For such patients, alternative systemic therapy is considered when both the tumor burden is substantial and tumor progression is documented” (2). The above panel in Pisa was conducted by SciStrategy Communications and supported by Bayer HealthCare Pharmaceuticals. The two classifications from the two panels have frequently been referenced by other articles discussed below, and these panels represent primary initial sources for classifications of radioiodine refractory DTC.

Tuttle et al. (3) in 2014 proposed definitions of radioiodine refractory DTC (Supplementary Table S3). The authors advise that “while not definitively classifying a patient as being completely refractory to RAI, the … clinical factors [Supplementary Table S4] make it much less likely that RAI therapy will achieve a clinically significant therapeutic response.”

Sacks et al. (4) classified radioiodine refractory DTC (Supplementary Table S5). Of note, the lack of radioiodine avidity after even a diagnostic radioiodine scan in one or more lesions was considered radioiodine refractory disease. Sacks et al. further stated, “Generally speaking, we recommend that the definition of RAI–refractory DTC be based on clinical evidence or on imaging data showing at least one lesion that does not take up RAI and thus encompasses both truly refractory disease as well as resistant disease” (4).

In early 2016, the ATA published their 2015 guidelines classifying radioiodine refractory disease in Recommendation 91 (Supplementary Table S6) (5).

The classifications for radioiodine refractory in the prescribing information for sorafenib (Nexavar^®) (6) and lenvatinib (Lenvima^®) (7) are also available in Supplementary Tables S7 and S8, respectively.

Distilled classifications

The distilled classifications are noted in Table 1.

Table 1.

Summary of Various Radioiodine Refractory Proposed Classifications

1.	Malignant/metastatic tissue does not concentrate radioiodine on a diagnostic radioiodine scan.
2.	Malignant tissue does not concentrate radioiodine on a post-¹³¹I therapy scan.
3.	The tumor tissue loses the ability to concentrate radioiodine after previous evidence of radioiodine-avid disease.
4.	Radioiodine is concentrated in some lesions but not in others.
5.	Metastatic disease progresses despite significant concentration of radioiodine.
6.	>600 mCi of cumulated ¹³¹I therapy.

Literature support for classifications

The literature supporting the cited classifications are limited to a few citations (1,2,8). Although not all citations will be discussed herein, key references in the ATA guidelines comprise Schlumberger et al. (2), which is the report of the 2012 panel, and Brose et al. (1), the report of the 2010 panel. Both are frequently cited in other articles. Vaisman et al. (9.), who were also referenced, provide some citations in support of the classifications, but the support offered by these citations is limited. Of note, however, Vaisman et al. (9) discuss more extensively than the ATA some of the limitations to be considered when classifying a patient's DTC as radioiodine refractory. Durante et al. (8) propose that patients should be treated until the disappearance of any uptake or until a cumulative ¹³¹I activity of 22 GBq (600 mCi) had been administered. The single administered prescribed activity was typically 3.7 GBq (100 mCi). However, Durante et al. (8) report that 4% of patients achieved negative diagnostic ¹³¹I scans with a cumulative activity higher than 22.2 GBq (600 mCi). Although this finding has been taken to suggest that a patient who has received over 22.2 GBq (> 600 mCi) of ¹³¹I most likely is radioiodine refractory DTC, I would draw from the finding that this classification is not sacrosanct and that a better classification would be whether there is an adequate and durable response, which I discuss later. As with many of the articles involving controversial areas of the management of DTC, there are no good prospective studies, and each study has its own limitations. As an example, the retrospective study by Durante et al. (8) used dual probe rectilinear scanners for imaging from 1971 until 1994. This is understandable, but this inferior camera technology is still a limitation Sabra et al. (10) state that despite radioiodine-avid disease, ¹³¹I therapy is ineffective in achieving a cure in most patients. Sabra et al. (11) have also been referenced regarding patients with negative diagnostic scans and positive-post-therapy scans that would most likely be radioiodine refractory. However, 44% (12/27) of patients with DTC, negative “properly –conducted” diagnostic scans, and positive post-therapy scans had stable cross-sectional imaging after ¹³¹I therapy. Whether this is due to the therapeutic effect of the ¹³¹I therapy or the patient's natural course of their disease is not known, but this result would argue against the statement by the ATA that “patients with measurable disease with an absence of ¹³¹I uptake on subsequent diagnostic whole body scan (WBS) may also be considered refractory because even when uptake is seen on post-therapy scan, it will likely have limited benefit.” The remaining 56% of patients studied by Sabra et al. (11) demonstrated structural disease progression with empiric activities, and the authors concluded, “… in this small subset of patients with persistent progressive disease despite a positive-post-therapy RAI scan argues that treatments other than repeated empiric ¹³¹I dosing be strongly considered.” I have emphasized empiric and submit that this was not necessarily an argument that the patients were radioiodine refractory, but rather another possibility is insufficient empiric ¹³¹I activity. Half of the patients received an ¹³¹I activity of ≤5.55 GBq (150 mCi).

Limitations of the cited classifications

Before discussing the limitations of the classifications, I would like to emphasize that I am in full agreement that any patient who meets one or more of the above classifications has a significantly higher likelihood of being radioiodine refractory than a patient who does not meet one of these classifications. I also agree with the statement that when a patient is truly radioiodine refractory, then that patient should not receive any further ¹³¹I. However, the issue is when is the patient truly radioiodine refractory, and I do not believe that the current classifications are necessarily sufficient evidence for establishing radioiodine refractory disease. In addition, and most importantly, I believe that authors of recent articles discussing the various proposed classifications of radioiodine refractory DTC are not necessarily discussing in sufficient detail the factors and limitations of the classifications that have been previously considered (1,3); in some articles, in fact, discussion of the factors and limitations have been completely eliminated (12 –17). This in turn—intended or unintended—tends to reinforce the notion that these classifications are somehow cast in stone. Thus, I view with concern the gradual abandonment of limiting factors as a vital part of the context within which we discuss the classifications of radioiodine refractory DTC. The mere fact that those authors choose to ignore these factors in their work does not convey the classifications are based on evidence. Creditably, some authors, for example Tuttle et al. (3) and Cabanillas et al. (18), continue to discuss at least some of the limitations. Accordingly, the discussion of these factors and limitations of the classifications of radioiodine refractory disease is one of the main objectives of this article.

Although physicians in academic settings and at large institutions may routinely treat patients with aggressive and progressing metastatic DTC, many patients are managed by physicians who only treat several such patients a year, if that, and it is difficult for these physicians not only to stay up to date with the various guidelines, but also to stay up to date regarding the limitations of the classifications of radioiodine refractory disease. Without detailed discussion of the limitations, the classifications—again, intended or unintended—may be accepted at face validity. In this section, therefore, I discuss selected classifications that appear in one form or another in the various articles, guidelines, and/or prescribing information. I further discuss why these classifications are not infallible and why, therefore, they should not be used in such a manner as to confer certainty that the patient's DTC is radioiodine refractory. Finally, although it is inevitable and appropriate that research studies produce and require strict classifications, such classifications are again not sacrosanct. Thus, with an absence of a clear understanding of their limiting conditions, such classifications are only conditionally appropriate for the management of individualize care.

Classification 1: Malignant/Metastatic Tissue Does Not Concentrate Radioiodine on a Diagnostic Radioiodine Scan

Although a negative diagnostic radioiodine scan definitely increases the likelihood that the patient's metastases are radioiodine refractory, this classification is problematic for many reasons. Wells et al. (19) reviewed 11 articles and reported her institutional experience. She showed that in patients with a negative diagnostic radioiodine scan, the post-¹³¹I therapy scan may be positive in as many as 25% to 80% of patients (see Table 2) (20 –30). As already discussed above, I believe that the 2015 ATA Guidelines (5) discount this finding without merit by stating that “patients with measurable disease with an absence of ¹³¹I uptake on subsequent diagnostic [whole body scans] may also be considered refractory because even when uptake is seen on post-therapy scan, it will likely have limited benefit.” The problem is that the authors do not amplify or even discuss the many factors that affect a diagnostic radioiodine scan; they simply leave the inference that a negative diagnostic scan despite the presence of a positive post-¹³¹I therapy scan is essentially prima facie evidence for radioiodine refractory disease. This, however, is not the case. Sanctioning the classification of a patient with measurable disease and negative diagnostic scan even with a positive post-therapy scan as radioiodine refractory disease may inappropriately eliminate a potential useful treatment in a patient who is typically running out of options. In the wide spectrum of patients who may have negative radioiodine scans and positive thyroglobulins, I am again speaking of patients with aggressive and progressing metastatic DTC. In fact, the statement of “even in the presence of a [positive] post-therapy scans … ” argues that the patient with a negative diagnostic radioiodine scan may in fact be radioiodine responsive. In short, there are factors that may affect whether the radioiodine diagnostic scan succeeds in detecting radioiodine-avid metastatic disease; these factors, therefore, deserve to be addressed but rarely are.

Table 2.

Positive Post-Therapy Radioiodine Scans After A Negative Pre-Therapy Diagnostic Scan ^*

Author	Tg+/Dx WBS negative and subsequent post-Tx WBS	Patients with positive post-Tx WBS	Percent positive post-Tx WBS	Dx dose/Tx dose
deKeizer (20)	16	11	69%	370 MBq/7.4 GBq (10 mCi/200 mCi)
Fatourechi (21)	24	6	25%	111 MBg/7.4–11.1 GBq (3 mCi/199–300 mCi)
Kabasakal (22)	24	15	63%	185 MBq/5.6–11.1 GBq (5 mCi/150–300 mCi)
Koh (23)	28	12	43%	148 MBq/5.6 GBq (4 mCi/150 mCi)
Mazzaferri (24)	10	8	80%	111–185 MBq/1.1–25.9 GBq (3–5 mCi/30–700 mCi)
Pachucki (25)	11	7	64%	270 MBq /6.73 ± 0.96 GBq (7.3 mCi/182 mCi)
Pacini, 1987 (26)	17	16	94%	185 MBq/2.8–5.2 GBq (5.0 mCi/75–140 mCi)
Pineda (27)	17	16	94%	185 MBq/3.7–1.1 GBq (5 mCi/100–300 mCi) (3 pts received 55 MBq [1.5 mCi])
Ronga (28)	11	7	64%	74–148 MBq/1.5–5.6 GBq (2–4 mCi/40–150 mCi)
Saghari (29)	26	14	54%	185MBq/3.7–7.4 GBq (5 mCi/100–200 mCi)
van Tol (30)	56	28	50%	74 MBq, repeated with 370MBq if neg /5.6 GBq (2 mCi/10 mCi if neg/150 mCi)
Wells (19)	47	30	64%	74 MBq//10.9 ± 3.7 GBq (2 mCi//295 ± 101 mCi)

Table adapted from reference (19).

Dx, diagnosis; Tx, treatment; WBS, whole body scan.

The factors that can affect whether a diagnostic radioiodine scan will detect metastatic disease include categories of preparation, prescribed activity, and imaging technique.

First, preparation is paramount and, as already noted in the 2015 ATA guidelines (5), excessive intake of recent stable iodine (¹²⁷I) (e.g., contrast, amiodarone, kelp, etc.) may result in a negative diagnostic radioiodine scan by blocking the uptake of the radioiodine in the metastases. However, I submit that other than a history from the patient of no recent iodine load, some facilities do not confirm that there has been no recent excessive iodine load with either a spot urine iodine measurement, spot urine iodine/creatinine ratio, or a 24-hour urine iodine collection. Although a recent article by Vassaux et al. (31) presents data that may indicate that the measurements of urine iodine levels may not be accurate, until this is confirmed, I believe this is reasonable to measure urinary iodine concentrations. Likewise, Vaisman et al. (9) note that it is also important to assure adequate elevation of the patient's thyrotropin (TSH) after thyroid hormone withdrawal. A physician could inappropriately classify a patient's DTC with a negative diagnostic radioiodine scan as radioiodine refractory if the TSH is not appropriately elevated. One might just assume an assurance that the patient has not had an excessive intake of stable iodine and that the TSH is elevated sufficiently, but this is not necessarily the case. Based on personal experience, I have observed that a large number of practices do not check urine for excessive iodine load nor TSH levels after thyroid hormone withdrawal.

Second, regarding the prescribed activity of radioiodine, not all radioiodine diagnostic scans are created equal. Radioiodine scans may be performed with 7.4–185 MBq (0.2 to 5 mCi) of ¹²³I or even higher activities of ¹³¹I, which can make a significant difference (32). Specifically, the higher the prescribed activity with all other parameters constant, the higher the detection rates of radioiodine-avid metastases, thereby reducing the likelihood that that patient is falsely classified as non-radioiodine avid, and hence, radioiodine refractory. With the hope for future approval of ¹²⁴I, the literature already has demonstrated the superiority of this positron-emitting isotope of iodine and the use of positron emission cameras to deliver images that are superior for the detection of radioiodine-avid metastatic disease relative to planar and single photon emission computed tomography (SPECT)-CT single photon isotopes (e.g., ¹²³I and ¹³¹I) (33). However, demonstrating that a metastatic lesion is radioiodine-avid on an ¹²⁴I scan is not in and of itself indicative that it will be responsive to an ¹³¹I therapy.

Third, in regard to techniques, this classification assumes that all imaging procedures for radioiodine imaging are the same. They are not. One should not automatically assume that a patient is radioiodine refractory because malignant metastatic tissue, either measurable or non-measurable, does not concentrate radioiodine. A list of several techniques that enhance the detection of radioiodine-avid lesions is shown in Table 3, and a full discussion of these techniques with examples as well as a discussion of how these techniques improve detection are available elsewhere and are not within the scope of this review (34). But imaging technique matters!

Table 3.

Radioiodine Imaging Techniques to Enhance Detection of Locoregional and/or Metastases of Differentiated Thyroid Cancer ^*

• Spot parallel hole collimator image

• Spot pinhole collimator image

• Longer acquisition time

• Earlier or delayed initiation of images

• Alter contrast and brightness of display

• Additional imaging driven by patient-specific history

• Adequate thyrotropin stimulation

• Confirming absence of excessive iodine administration

• Single photon emission computed tomography–computed tomography

Reference (35).

In summary, a negative diagnostic radioiodine scan is not a sufficient finding to confirm a classification of radioiodine refractory disease for either measurable or non-measurable disease. Although all of us believe we deliver quality radioiodine scanning, we may not do this all of the time in every instance. However, even if a facility is delivering quality radioiodine scanning and preparation and imaging technique are excellent, negative diagnostic radioiodine scans cannot be taken as difinitive for the classification of radioiodine refractory disease.

Classification 2: Malignant Tissue Does Not Concentrate Radioiodine on a Post-¹³¹I Therapy Scan

When malignant tissue is not visualized on a post-¹³¹I therapy scan, the patient's malignant tissue is indeed most likely radioiodine refractory, and, for many years, this classification has been one of the best findings to correctly characterize the patient's malignant tissue as non-radioiodine-avid, hence, radioiodine refractory. However, this is not necessarily reliable in all instances, and the managing physician should be aware of the limitations. As discussed earlier, assuring the quality of the imaging technique is very important to maximizing the sensitivity of a radioiodine diagnostic scan as well as the post-¹³¹I therapy scan, and, for the post-¹³¹I therapy scan, one of the most critical issues is the time of imaging the patient after the administration of the therapeutic ¹³¹I (see Table 4). Specifically, Salvatori et al. (35), Hung et al. (36), Lee et al. (37), Chong et al. (38), and Kodani et al. (39) have reported on the detection of metastases on post-¹³¹I therapy scans based on the time of the scanning from administration of the therapeutic activity, and the data strongly support that the timing can make a difference in detection of radioiodine-avid metastases.

Table 4.

A Post- ¹³¹ I Therapy Scan Performed on a Single Day is Not Necessarily Sacrosanct

Reference	Total number	Positive only on early scan	Positive only on late scan
Salvatori (35)	134 patients	7.5% (10/134) on day 3	12% (16/134) on day 7
Hung (36)	122 lesions	28% (18/63) of lymph nodes, 17% (7/41) of lung metastases, and 16% (3/18) of bone metastases 5% of remnant tissues On day 3–6	Day 10–11 scan
Lee (37)	81 patients		5% (4/81) of patients had 5 additional lesions
Chong (38)	52 patients		22% (10/45) lung metastasis and 33% (5/15) bone metastasis on day 7
Kodani (39)	24 patients		29% (2/7) lung metastasis and 20% (1/5) bone metastasis on the day 7–9 scan

Salvatori et al. (35) reported that if the patient was scanned at an earlier or later time after the administration of an ¹³¹I therapy, one may falsely conclude that a metastasis is radioiodine non-avid when in fact it is radioiodine avid. Salvatori et al. (35) reported on 134 patients evaluated with two sequential whole-body scans performed 3 days and 7 days after ¹³¹I therapy. Late scans provided more information compared to early scans in 12% (16/134) of patients, and early scans visualized more information than late scans in 7.5% (10/134) of patients. Again, the fact that the post-¹³¹I therapy scan has radioiodine uptake is not indicative that the patient will respond to ¹³¹I therapy. However, a negative post-¹³¹I therapy scan does not necessarily mean that the patient is non-radioiodine-avid and could not benefit from a (partial) response.

In regard to similar studies, Hung et al. (36) evaluated 239 patients and three sequential scans were performed on days 3 or 4, days 5 or 6, and days 10 or 11 after ¹³¹I therapy. Of 122 lesions observed, 28% (18/63) of lymph nodes, 17% (7/41) of lung metastases, and 16% (3/18) of bone metastases were missed on the late images on 10–11 day scans, and 5% of remnant tissues were missed on the late images on the 10–11 day scan. They concluded, “[E]arlier imaging is necessary and important for detection of metastatic lesions in patients with DTC.” Lee et al. (37) evaluated 81 patients with two sequential whole-body scans 3 days and 10 days after ¹³¹I therapy, of which 5% (4/81) of patients had five additional lesions identified on the delayed scan. The five lesions were located in the lung (2), cervical lymph nodes (2), and the thyroid bed (1). Of 8 patients with increased thyroglobulin (T)g levels >10 ng/mL with negative early scans, the delayed scan identified three patients with additional lesions. Chong et al. (38) evaluated 52 patients with lung and bone metastases with early (3 days) and delayed (seven days) scans. For lung and bone metastases, 22% (10/45) and 33% (5/15) were not observed on the early scans, but were detected on delayed scanning. Kodani et al. (39) evaluated 24 patients with DTC who had early (day 3) and delayed (7 to 9 days) scans performed and demonstrated that for lung metastases, 29% (2/7) were only seen on the delayed scan, and for bone metastasis, 20% (1/5) were only seen on the delayed scan.

Thus, even if a lesion is not visualized on a post-¹³¹I therapy scan that does not mean that the patient is radioiodine refractory. In a later section, I propose potential approaches to manage these patients.

In summary, radioiodine imaging technique is also important for post-¹³¹I therapy scans, and for this scan, the interval of the scanning after the ¹³¹I therapy can fail to reveal as many as 12% of patients that have radioiodine uptake. When there is radioiodine uptake, there is the possibility of a response to an ¹³¹I therapy when an appropriate amount of therapeutic ¹³¹I activity is administered, and although the likelihood of a reasonable therapeutic response is again definitely and significantly reduced, these patients with aggressive and progressing metastatic DTC should have this potential treatment option explored. Since a patient with a negative radioiodine diagnostic scan and either a positive or negative post-¹³¹I therapy scan has obviously already been treated with a “blind” ¹³¹I therapy, the key metric becomes progression, which I consider later. However, for those patients with negative diagnostic radioiodine scans, which many authors consider a conclusive classification of radioiodine refractory disease, consideration of a “blind” ¹³¹I therapy is an option (discussed later). In short, a negative post-¹³¹I therapy scan is not corroborative evidence of either non-radioiodine-avid disease or radioiodine refractory disease. Further research is warranted.

Classification 3: The Tumor Tissue Loses the Ability to Concentrate Radioiodine After Previous Evidence of Radioiodine-Avid Disease

The problem with this classification is that the discussions typically and ambiguously do not assert whether they are speaking about diagnostic radioiodine scanning or post-¹³¹I therapy scanning. and I submit that for many authors, it does not matter whether or not it is diagnostic or post⁻¹³¹I therapy. The limitations of both diagnostic radioiodine scanning and post-¹³¹I scanning have been discussed earlier in classifications 1 and 2 respectively, and as this classification as written should not be a classification, and if it is, it should have a detail discussion of the limitations.

Classification 4: Radioiodine Is Concentrated in Some Lesions But Not in Others

By this classification, if a patient has four bone lesions, and three bone lesions have radioiodine uptake but one lesion does not, then some physicians classify this patient's DTC as radioiodine refractory and ¹³¹I is not considered an option. However, some or many lesions may still benefit from ¹³¹I therapy. For example, why couldn't the physician potentially treat the nonfunctioning bone metastases with targeted treatment options (e.g., surgery, radiofrequency ablation, cryotherapy, embolization, external radiation therapy) and then treat the other three bone metastases with ¹³¹I? After members of the ATA and the reviewers commented on the draft of the 2015 ATA guidelines, the authors of the 2015 ATA guidelines subsequently discussed this context within the text. However, the guidelines still preface, “While these patients technically meet the definition of RAI refractory disease, they may benefit from a combination of RAI therapy for the majority of the lesions and direct therapy for those few lesions that do not concentrate RAI” (5). Rather than trying to technically defend the definition of radioiodine refractory as correct, which is not appropriate for some of the lesions, I propose that one should simply identify the limitation of that classification. In addition, I submit that the use of “classification,” “category,” or “criteria” is preferably over the term “definition.” To quote Jay Heinrichs' definition of the term definition, it is “[w]ords used to turn opinion into truth” (40).

Classification 5: Metastatic Disease Progresses Despite Significant Concentration of Radioiodine

This is one of the most useful—perhaps the most useful—of all classifications. However, simply stating this as a “definition” or even as a “classification” of radioiodine refractory disease is not sufficient. With this classification at least six important factors of progression must be considered and should always be discussed. But they frequently are not discussed. Also, in full disclosure, these factors are certainly not original or novel in this review. The factors are: What therapeutic prescribed activity ¹³¹I was administered? What are the metrics used to determine response? What are the criteria of those metrics to determine response, stabilization, or progression? What was the duration of the response? What were the adverse effects, and what was the benefit-to-side-effect ratio? Unfortunately, when this classification appears as written above, the implication—again intended or unintended—may be any progression at any time with any therapeutic activity of ¹³¹I equals radioiodine refractory disease. When this classification is then promulgated in subsequent articles without the accompaniment of the necessary details, physicians can—and do—take the “definition” to be definitive and sacrosanct. As discussed earlier, while physicians in academic settings may be routinely treating these patients and know these questions, physicians who may treat only of few such patients a year may not be aware of the limitations of the classifications and assume that any progression at any time with any therapeutic activity of ¹³¹I equals radioiodine refractory disease. Neither in publication nor in training should this classification be disseminated without discussion of the aforementioned six factors.

The first factor is the amount of prescribed activity of ¹³¹I administered for the therapy, which may be important. Was the amount of prescribed activity of ¹³¹I administered as an empiric prescribed activity of 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi), or a dosimetrically guided prescribed activity that could be much higher? Although controversy remains regarding the effectiveness of empiric prescribed activity versus dosimetrically-guided activity(44–45), which is beyond the scope of this article, one of the core fundamentals of radiation therapy is that the physician must deliver enough radiation absorbed dose to achieve the objectives of cure, stabilization, or palliation. If the physician lowers the prescribed activity, it is intuitive that the lower activity will deliver lower radiation absorb dose to the metastasis, which in turn increases the likelihood that the radiation absorb dose delivered will not reach the necessary absorbed dose threshold to achieve the desired objective. This is fundamental radiation therapy planning. Thus, if patients have aggressive and progressing metastatic DTC after ¹³¹I therapies of perhaps 3.7 GBq (100 mCi) prescribed activity of ¹³¹I for each administration every three or six months, then that may not be indicative of radioiodine resistant disease, but rather that may be the result of a radioiodine resistant physician.

The second and third factors are the metrics for response and the change of those metrics to determine response, stabilization, or progression. Some of the articles address the metrics (4,5), but most of the articles do not. In addition, the metrics need to be better categorized. Although RECIST (Response Evaluation Criteria in Solid Tumors) or PERCIST (Positron Emission Tomography Response Criteria in Solid Tumors) are excellent metrics for patients in research studies in which standardization is necessary and relevant for individual patients, these metrics may not necessarily be appropriate for all patients. I submit that more detailed guidelines regarding the metrics and the change of those metrics may be warranted for inclusion in guidelines with the emphasis that the metric and the change of metrics should be individualized for each patient.

The fourth factor is the duration of response. If the patient's disease progresses 14 months after an ¹³¹I therapy, is this a signal of radioiodine refractory disease? Rather, I would submit that the physician should consider another therapeutic administration of ¹³¹I. If progression-free survival with lenvatinib of 14 months may be considered a good response, then why wouldn't progression-free survival of 14 months after a single administration of ¹³¹I not be considered a good response and warrant consideration of another therapy with ¹³¹I? The problem becomes what duration or response after a therapy of ¹³¹I warrants consideration of another therapy of ¹³¹I and what duration of response warrants classifying the patient's disease as radioiodine refractory? There are no good guidelines or data at this time, but I would agree with some of the suggestions in the literature (3). I would submit that a durable response of ≥12 months warrants consideration of another ¹³¹I therapy, ≥6 to <12 months warrants individualization, and <6 months warrants classification as radioiodine refractory. However, these should not be definitions of progression or absolute thresholds; rather, each patient should be evaluated individually.

The next factor is side effects. The risk of adverse effects and the tolerance for side effects must be weighed relative to the potential benefits. To simply argue that the patient should not have another ¹³¹I therapy because the patient has xerostomia and that it may worsen after another therapy with ¹³¹I may not be reason enough to eliminate an ¹³¹I therapy that may have the potential benefit of obtaining another 12 months or more of progression-free survival. To worry about leukemia in a patient with aggressive and progressing metastatic disease may again not be as important as obtaining 12 months of progression-free survival. Additionally, aggressive management of patients to reduce untoward effects of ¹³¹I therapy is important and should be started with the first ¹³¹I treatment—not later. However, this subject is beyond the scope of this review.

The final factor discussed herein, is the patient's personal desires such as how much risk of side effects for potential benefit the patient is willing to accept.

In summary, weighing the amount of ¹³¹I activity the physician will administer, the response to the previous treatment, the duration of that response, the side effects, the benefit-to-side-effect assessment, and the patient's desires will help determine whether or not radioiodine is no longer an option. Simple “progression” should not be a criterion for categorizing metastatic disease as radioiodine refractory disease.

Classification 6: ≥600 mCi of Cumulated ¹³¹I Therapy

For this classification, there is no prospective and only limited retrospective studies available to confirm this threshold. One of the original sources using this classification was Durante et al. (8), who observed that 4% (5/127) of patients did not achieve negative diagnostic radioiodine scans with a cumulative activity of ¹³¹I higher than 22.2 GBq (>600 mCi). Huang et al. (41) observed that 79% of patients resolved ¹³¹I-avid disease and 88% of patients achieved disease-free remission before exceeding a cumulative activity of >22.2 GBq (>600 mCi) of ¹³¹I. Huang et al. (41) recommended that “repeated ¹³¹I therapy >600 mCi is not advised unless there is a high probability that it would benefit the patient.” Although this a reasonable recommendation and what is considered a “high” probability of benefit is not discussed, several problems arise from these articles. First, in a subsequent publication (4), the condition of “unless there is a likelihood of benefit” disappears from the classifications. Second, in the study by Durante et al., 4% of patients did apparently have a “response” with cumulative activities of 22 GBq (>600 mCi), and in the study by Huang et al., 12% of patients had a response. Rather than reaching a cumulative activity threshold of ¹³¹I activity, the response to the previous ¹³¹I therapy is more important. If the response to the previous cumulative ¹³¹I activity of 11.1 GBq (300 mCi) is “unacceptable,” then I submit that the patient is radioiodine refractory and has reached his/her maximum cumulative activity before reaching a cumulative activity of 22.2 GBq (>600 mCi). If the patient's response to the previous cumulative ¹³¹I activity of 37 GBq (1 curie) is acceptable, then I submit that the patient is not radioiodine refractory and has not reached his/her maximum cumulative activity. Of course, other factors such as benefits versus side effects must be considered, and in a dire situation, the patient may accept more side effects to obtain whatever benefit they can. Although I agree that the likelihood of an acceptable outcome from additional ¹³¹I therapy definitely decreases as the cumulative activity increases, a set threshold should not be a classification.

What Are the Next Steps for Classification of Radioiodine Refractory DTC?

First, I propose the formation of a standing committee of those specialty societies involved with the management of radioiodine refractory DTC with the objective of updating the classifications of radioiodine refractory disease. In addition to the permanent membership of the ATA and European Thyroid Association, this standing committee should include permanent members from the Society of Nuclear Medicine and Molecular Imaging and European Association of Nuclear Medicine. Second, I propose that the committee conduct further discussions to consider the participation of other permanent organizations such as oncology societies (e.g., American Society of Clinical Oncology) and representatives from patient support groups (e.g., Thyroid Cancer Survivors Association, Inc., ThyCa, or Light of Life Foundation, among others). Third, the updating of the classifications of radioiodine refractory DTC should be accompanied by a detailed discussion of the limitations of each classification. Fourth, the committee should commission an independent group to conduct a systemic review of relevant evidence regarding radioiodine refractory DTC. Fifth, the committee should publish the updated classifications and the limitations for each classification in the journals of the societies that sit on the conjoint committee. Sixth, the committee should continue to meet as a committee biennially or more frequently on an as-needed basis (e.g., when the Food and Drug Administration approves a MEK inhibitors such as selumetinib, dabrafenib, or trametinib or ¹²⁴I for imaging, lesion dosimetry, normal organ dosimetry, or all three).

Proceeding in the interim

As physicians practicing medicine following the Hippocratic Oath, it is our responsibility to “treat the ill to the best of [our] ability,” and with that in mind, I propose several thoughts and approaches.

First, although patients with aggressive and progressing metastatic DTC are facing diminishing treatment options and have a decreased likelihood of a good and durable response to ¹³¹I, the option of ¹³¹I therapy should not be dismissed from the therapeutic armamentarium solely because the patient meet one or more of the promulgated classifications for radioiodine refractory DTC. Rather, in deciding whether a patient is radioiodine refractory, the treating physician or team should assess multiple factors and limitations of the classifications and individualize the patient's care.

However, until further data are available, and based on our earlier discussions herein, I submit further consideration of the following caveats, suggestions, quality control measures, and management options.

Consider referring the patient to a facility that routinely handles patients with aggressive and progressing metastatic DTC.

Do not necessarily consider a DTC patient to be radioiodine refractory just because the patient's diagnostic radioiodine scan is negative (see number 4 below)

Do not necessarily consider a patient's DTC as radioiodine responsive just because the patient's radioiodine diagnostic or post-¹³¹I therapy scan is positive (see number 4 below).

Assess the quality of the radioiodine diagnostic scans and post-¹³¹I therapy scans. Not all scans are created equal. Assess the following factors that may affect the quality of the radioiodine scans that one's patients are receiving, which in turn can significantly affect the ability to visualize radioiodine uptake in metastases on radioiodine scans (32,34):

Obtain history of any excessive iodine intake.

Measure spot urine iodine level, spot urine iodine/creatinine ratios, or 24-hour urine iodine collections.

Evaluate adequate elevation of TSH levels in patients prepared by withdrawing thyroid hormone and rhTSH.

Assure that the time of administration of radioiodine and imaging after injections of recombinant human thyroid stimulating hormone is appropriate.

Assure appropriate time of diagnostic imaging after administration of radioiodine to maximize sensitivity of the imaging procedure.

Assure the time of administration of radioiodine and ¹³¹I therapy after injections of recombinant human thyroid stimulating hormone is appropriate.

Know the amount of prescribed activity of radioiodine administered for the diagnostic scan.

Assure appropriate technique for radioiodine imaging (e.g., duration of imaging acquisition, time of imaging acquisition, delayed imaging, and type of imaging), not just whole-body imaging, but including spot images, pin-hole images, SPECT-CT, or all of the above (see Table 3).

Perform post-¹³¹I therapy radioiodine scan at an appropriate time after administration of the therapeutic activity of ¹³¹I. As discussed above, avoid performing radioiodine post-therapy scan as late as 10 days after ¹³¹I therapy. Recommend performing scans earlier such as at three to four days after ¹³¹I therapy, and, if one does perform scans at three to four days and if that scan is negative, consider a repeat scan in selected patients at six to seven days.

In the presence of one or more lesions that are non-radioiodine avid on either a radioiodine diagnostic scan or a post-¹³¹I therapy scan, do not consider this incontrovertible evidence of radioiodine refractory DTC. Consider local treatment (e.g., surgery, radiation therapy, radiofrequency ablation, cryotherapy, embolization, etc.) of the lesion(s) that are nonradioiodine avid and ¹³¹I therapy for the other radioiodine avid lesions.

Assess the structural response (e.g., complete remission, partial response, stable disease, progression, etc.). But the response criteria should not necessarily be by RECIST criteria. Again, when one is managing an individual patient, this is not a research study that requires strict adherence to a specific criterion such as RECIST; rather, one should individualize what is and is not going to be considered as an acceptable response based on the patient's clinical situation and desires.

Assess the change of thyroglobulin levels (e.g., the amount of decrease, stabilization, or increase Tg level, and, if increasing, the rate of rise of the Tg level.). Although a frequently quoted cliché is, “No one has died from an elevated Tg level,” the absolute Tg level and rate of increasing Tg level has prognostic value. Further research is warranted.

Assess the duration of response (e.g., <6 months, ≥6–12 months, ≥12 months). Further research is warranted.

Assess the amount of prescribed activity of ¹³¹I administered for all therapies with especial attention to the amount of activity for the last therapy. The amount of prescribed activity of ¹³¹I therapy that a facility can or will administer can be empiric and as low as 75 mCi to 200 mCi or dosimetrically guided activity. Although there remains controversy regarding empiric and dosimetrically-guided prescribed activity of ¹³¹I (42 –46), the amount of prescribed activity is important. As discussed earlier, the amount of radioiodine activity administered is one of the major factors in the amount of radiation absorbed dose that is delivered to the metastases.

The frequency and severity of side effects from the previously administered ¹³¹I therapies are important as are the patient's desires regarding real or perceived potential benefit relative to real or perceived potential risk. This does not just include salivary side effects but evaluation of other organs, where appropriate, such as the response of the complete blood count and pulmonary function tests to the previous therapy.

Because a patient has been administered a cumulative activity of ¹³¹I exceeding a predetermined threshold, one should not consider that patient as radioiodine refractory. As already discussed, such a determination depends on multiple factors, such as the prescribed activity of individual ¹³¹I therapies, frequency of therapies and most importantly, response to the previous ¹³¹I therapy.

Consider a “blind” ¹³¹I therapy with either an empiric or dosimetrically-guided prescribed activity of ¹³¹I.

If a “blind” treatment such as in #12 above is not considered as an option, consider a novel approach of a “exploratory” scan with 30 mCi (47). The scan is performed approximately 24 hours after the administration of 30 mCi, and if the scan is positive for radioiodine avid metastases, then the balance of the plan therapeutic prescribed activity is immediately administered. If the scan is negative, no further ¹³¹I is administered.

Ultimately, the management of patients does not consist in strict adherence to six less-than-definitive classifications; it is individualized care of each patient that matters. Although the above approaches have not been confirmed to alter outcomes and although the likelihood of altering the outcome remains reduced, I believe that they can potentially alter outcomes in some patients. Until further data are available and before I eliminate a potential therapeutic option, I believe these suggestions are reasonable to consider in assessing and managing selected patients with aggressive and progression DTC.

Future research

Future research is warranted in almost all of the areas discussed above as well as the impact of MEK inhibitors on redifferentiation (48,49), ¹²⁴I lesion detection, and ¹²⁴I dosimetry of lesions, whole body, and organs. Also, further research is encouraged by committees such as the Committee on Medical Internal Radiation Dose to help assess whether small metastases that may not be large enough to be seen on radioiodine diagnostic or post-¹³¹I therapy scans can receive a therapeutic absorbed dose with the administration of an acceptable amount of prescribed ¹³¹I activity.

Summary

Patients who have aggressive and progressing metastatic DTC that is suspected to be radioiodine refractory represent very difficult management situation. Too few therapies are applicable to these patients' circumstances to warrant elimination of therapies that are potentially beneficial. Thus, we should not want to eliminate a potentially beneficial ¹³¹I therapy prior to initiation of therapy with a tyrosine kinase inhibitor. Yet this can occur as the result of an absolute reliance on the current classifications of radioiodine refractory DTC. Notwithstanding the utility of such classifications, they are not inviolable. Thus, because a patient meets one or more of the various classifications, a physician, who may reasonably assign a high probability that a given patient is radioiodine refractory, may not safely take such classifications an uninfringeable truth. The classifications may be appropriate for standardization for research studies, but for patients who are not in a research study, each should be individually managed with a good understanding of the limitations of the various classifications and potential approaches to help manage those limitations. With awareness of additional approaches, caveats, and suggestions as discussed above and with the assessment of the many other factors that affect the patient's specific clinical situation—not the least of which are the patient's desires and the balance of risks and benefits—reasonable individualized patient care can be delivered. A multiorganizational committee should be established to update the classifications of radioiodine refractory DTC, and the publication of those refinements should include a meticulous discussion of the limitations of each classification. In addition, this committee should be a standing committee that meets regularly based on needs. With the development and, hopefully, approved by the U.S. Food and Drug Administration of MEK inhibitors or other agents that may reestablish radioiodine uptake in DTC and the approval and validation of lesional dosimetry with ¹²⁴I, additional updating of the classification of radioiodine refractory will be necessary. As holds true for personalized approaches to patient care in general, the patient's care should be individualized when managing patients with aggressive and progressing metastatic DTC.

Footnotes

Acknowledgments

I thank Sheila Beaman, our nuclear medicine research assistant, for her library and technical support, and Dr. Di Wu for her editorial assistance. I also thank our grateful patients who help underwrite my research and educational efforts.

Author Disclosure Statement

Douglas Van Nostrand is a speaker and consultant to Jubilant Draximage. No other competing financial interests exist.

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Radioiodine Refractory Differentiated Thyroid Cancer: Time to Update the Classifications

Abstract

Background:

Objective:

Summary:

Conclusion:

Introduction

The development of classifications of radioiodine refractory DTC

Distilled classifications

Literature support for classifications

Limitations of the cited classifications

Classification 1: Malignant/Metastatic Tissue Does Not Concentrate Radioiodine on a Diagnostic Radioiodine Scan

Classification 2: Malignant Tissue Does Not Concentrate Radioiodine on a Post-131I Therapy Scan

Classification 3: The Tumor Tissue Loses the Ability to Concentrate Radioiodine After Previous Evidence of Radioiodine-Avid Disease

Classification 4: Radioiodine Is Concentrated in Some Lesions But Not in Others

Classification 5: Metastatic Disease Progresses Despite Significant Concentration of Radioiodine

Classification 6: ≥600 mCi of Cumulated 131I Therapy

What Are the Next Steps for Classification of Radioiodine Refractory DTC?

Proceeding in the interim

Future research

Summary

Footnotes

Acknowledgments

Author Disclosure Statement

References

Classification 2: Malignant Tissue Does Not Concentrate Radioiodine on a Post-¹³¹I Therapy Scan

Classification 6: ≥600 mCi of Cumulated ¹³¹I Therapy