Redifferentiation of Differentiated Thyroid Cancer: Clinical Insights from a Narrative Review of Literature

Abstract

Background:

Patients who have metastatic differentiated thyroid cancer (mDTC) frequently have negative diagnostic and/or post-therapy radioiodine scans. As a result, ¹³¹I therapy is frequently no longer considered a therapeutic option for these patients. However, with the knowledge of genomic alterations of patients with mDTC, the use of selected agents in specific patient groups may be used with the intention to re-establish ¹³¹I uptake (i.e., redifferentiation) and additional ¹³¹I therapy. The objectives of this narrative review are to present definitions of related terminology, a brief overview of the molecular mechanisms of redifferentiating agents, and a narrative review of the literature for redifferentiation in patients who have radioiodine refractory mDTC.

Summary:

We searched multiple electronic databases and reviewed the relevant English-language literature reported after 2010. Fourteen articles were included in this narrative review.

Conclusions:

Preliminary data suggest that select agents may offer potential for re-establishing ¹³¹I uptake in selected patients with radioiodine refractory mDTC (e.g., negative diagnostic and/or post-therapy radioiodine scans). These agents may also enhance uptake (e.g., uptake enhancement) in patients who have ¹³¹I uptake in mDTC on a diagnostic and/or post-therapy radioiodine scan. As a result, this may facilitate higher absorbed dose delivered (Gy (rad]) per ¹³¹I activity administered [GBq (mCi)]. This in turn may increase the likelihood of a better therapeutic effect for the planned administered ¹³¹I activity or a reduction in the originally planned administered ¹³¹I activity, while achieving the same intended therapeutic effect with potentially less untoward effects. Further studies are warranted to confirm these preliminary observations and to confirm acceptable subsequent ¹³¹I therapy responses after redifferentiation and/or uptake enhancement.

Introduction

Multiple authors have reported on re-establishment (i.e., redifferentiation) of radioiodine uptake in patients who have differentiated thyroid cancer (DTC), have known or suspected metastatic disease, and are considered radioiodine refractory by the patient's management team.^{1

–14} Figure 1 demonstrates an example. Redifferentiation is an exciting and potentially valuable management option for increasing the utility of ¹³¹I therapy in patients with progressive metastatic DTC that are classified as radioiodine refractory disease (e.g., negative diagnostic and/or post-therapy radioiodine scans).

FIG. 1.

The image on the left is a diagnostic PET scan performed after the administration of ¹²⁴I and demonstrates no evidence of radioiodine avid metastatic DTC. Physiological activity such as in the blood pool, salivary glands, and GI track is present. The PET image on the right was performed in the same patient with ¹²⁴I after pretreatment with selumetinib and demonstrates multiple areas of marked ¹²⁴I uptake in metastases in the chest and neck. This is an excellent example of redifferentiation. ¹ (Reproduced with permission from the author and the New England Journal of Medicine]. PET, positron emission tomography.

This article presents definitions of related terminology and a narrative review of the literature updating the previous reviews of Buffet et al.,¹⁵ Fugazzola et al.,¹⁶ Lamartina et al.,¹⁷ and Van Nostrand¹⁸ regarding redifferentiation of the aforementioned patients. This review includes discussions of (1) the various genomic alterations; (2) a brief overview of their molecular mechanisms; (3) redifferentiating agents; (4) dose, frequency, and duration of administration of each redifferentiating agent; (5) results and safety of redifferentiation; and (6) reported efficacy of subsequent ¹³¹I therapies. Following these topics, we discuss selection of patients, reimbursement issues, and future studies.

Terminology

To communicate effectively and efficiently, it is essential to consistently use the same terminology, each with a consistent meaning. Terminology is important to consider for types of ¹³¹I therapy, the classifications of radioiodine refractory DTC, and the categories of redifferentiation.

Cooper et al. in the 2009 American Thyroid Association Guidelines¹⁹ and Van Nostrand²⁰ proposed terminology for ¹³¹I therapies with further confirmation by the Martinique Working Group in 2019.²¹ This included the definition of ¹³¹ I therapy and the definitions and objectives of remnant ablation, adjuvant treatment, and treatment of known metastatic disease of DTC. Specifically, ¹³¹ I therapy refers generically to all types of therapeutic administrations of ¹³¹I for DTC. Remnant ablation has the objective “... to destroy postoperatively residual presumably benign thyroid tissue to facilitate initial staging and follow-up studies (such as serum thyroglobulin [Tg] and radioactive iodine imaging).”

Adjuvant treatment has the objective “... to destroy subclinical tumor deposits that may or may not be present after surgical resection of all known primary tumor tissue and metastatic foci. The goals of adjuvant treatment are to improve disease specific survival, decrease recurrence rates, as well as to improve progression-free survival.” Treatment is to destroy “... known biochemical or structural disease and refers to the goal of destroying persistent or recurrent DTC foci with ¹³¹I in order to improve progression-free, disease specific, and overall survival.”²¹ It is in the latter category of ¹³¹I therapy that the terminology for radioiodine refractory disease becomes important.

In regard to radioiodine refractory differentiated thyroid cancer, Brose et al.,²² Schlumberger et al., ²³ Tuttle and Sabra,²⁴ and Sacks and Braunstein²⁵ previously proposed and refined definitions of radioiodine refractory DTC Subsequently, Van Nostrand,²⁶ Giovanella and Van Nostrand,²⁷ and Jin et al.²⁸ discussed the limitations of these definitions, and Van Nostrand²⁶ has proposed that any classification systems should incorporate an understanding of the inherent limitations and enable qualitative estimates of the likelihood (high, intermediate, or low) that a patient's DTC is truly radioiodine refractory.

However, with the arrival of the ability to re-establish ¹³¹I uptake in selected patients who have DTC, the classification of a patient as radioiodine refractory has become even more problematic. No longer can the term radioiodine refractory connote that a patient will NEVER respond to an ¹³¹I therapy. As a result, Gulec has proposed the term radioiodine indifferent, and we propose other terms such as radioiodine indeterminate or radioiodine undetermined (S. Gulec, pers. comm.). Presently, a committee is addressing the variable classifications of radioiodine refractory DTC and will be addressing the terminology for radioiodine refractory and redifferentiation.

This committee is the International Committee on the Classifications of Radioiodine Refractory Differentiated Thyroid Cancer established by the Martinique Working Group. The membership includes representatives appointed by various societies as well as additional selected individual members as noted in Supplementary Table S1. This committee includes nuclear medicine physicians, endocrinologists, oncologist, radiation oncologist, and a patient representative. Ultimately, the final terminology should clearly denote that the many factors and approaches that the patient's management team should consider before categorizing a patient as radioiodine refractory.

In regard to the term, redifferentiation, we submit that there are two categories of patients who may be considered for redifferentiation: (1) patients with negative diagnostic and/or post-therapy radioiodine scans, and (2) patients with visible uptake on a diagnostic and/or post-therapy radioiodine scans—although in the latter category, not all lesions potentially having uptake. Despite these two categories, we submit that the term, redifferentiation, typically has the connotation for the first category of patients.

As discussed later in this review, Rothenberg et al.³ have shown clearly that a patient who has a positive diagnostic and/or post-therapy radioiodine scan can have visible uptake that is even greater with redifferentiation. Although this is redifferentiation, we believe we need a different term for this second category, and we propose the term, uptake enhancement. This will encourage us to start considering uptake enhancement as an additional management option in patients who already have visible uptake, heretofore not typically considered for redifferentiation.

Molecular Mechanism

Multiple authors, such as Landa et al.²⁹ and Aashiq et al.,³⁰ have previously discussed the molecular basis of redifferentiating agents. Although not the objective of this review, the genetic alterations of the MAPK (mitogen-activated protein kinase) pathway diminish the signaling of the sodium iodide symporter, which results in reduced radioiodine uptake. These genetic alterations may be potentially inhibited by drugs such as by dabrafenib and vemurafenib targeting BRAF^V600E and trametinib targeting MEK, thereby potentially re-establishing radioiodine uptake.^29,30

Literature Search

The MedStar Health clinical medical librarian (L.H.) searched Medline, Embase, and Cochrane database for articles related to redifferentiation radioiodine refractory differentiated thyroid cancer, with the details of the search terms described in Supplementary Table S2. In keeping with a narrative review, one author (D.V.N.) screened the identified relevant articles and selected the studies (including case reports, retrospective studies, and prospective studies that reported clinical attempts to redifferentiate radioiodine refractory DTC). No preclinical studies were included. Institutional Review Board review was not needed for a literature review.

Results of Narrative Literature Review

Fourteen articles reported on redifferentiation for eight genetic alterations, including on the utilization of seven different agents, alone or in combination. Table 1 notes the number of patients screened and evaluated followed by the generic alterations and results of redifferentiation. This includes three prospective clinical trials, one pilot clinical trial, four retrospective studies, and six articles reporting on only one or two cases. The largest studies included 20, 21, and 24 patients, respectively. In studies of eight or more patients, the rates of successful redifferentiation rate varied from 33% to 95%. However, the procedures and redifferentiation agents varied significantly (Table 2). Table 3 notes the number of patients whose tumors redifferentiated and were treated with ¹³¹I, followed by their therapeutic safety outcomes. The combined articles reported treatment of 101 patients after redifferentiation, and studies that treated at least 6 patients with ¹³¹I reported response rates from 33% to 100% (e.g., stable and partial response) (Table 3).

Table 1.

Study and Patient Characteristics

Author	Genetic profile	Patients screened	Patients evaluated	Criteria for radioiodine refractory	Agent(s)	Increase of radioiodine uptake
Ho et al.¹	BRAF^V600E , NRAS, wild type, NTRK, RET/PTC	24	20	Index metastasis not radioiodine-avid on diagnostic RAI scan RAI-avid metastatic lesion that remained stable in size or progressed despite radioiodine treatment 6 months or more before enrollment ¹⁸FDG avid lesions	Selumetinib	12/20 4/9 BRAF^V600E 5/5 NRAS 2/3 RET/PTC 1/3 wild type
Rothenberg et al.^2,3	BRAF^V600E	10	10	Non-avid RAI scan within 14 months	Dabrafenib	6/10
Huillard et al.⁴	BRAF^V600E tall cell variant of PTC	1	1	Non-RAI avid pulmonary metastases on post-¹³¹I therapy scan	Vemurafenib	1/1
Jaber et al.⁵	9 BRAF^V600E 2 NRAS 1 KRAS 1 wild type (11 DTC and 2 PDTC)	13	13	No RAI uptake at known sites of metastases Progressive disease despite previous ¹³¹I tx Progressive disease within 1 year of ¹³¹I tx	Selective trametinib, dabrafenib, and/or vemurafenib	8/13
Dunn et al.⁶	10 BRAF^V600E	12	10	Metastasis not radioiodine-avid on diagnostic RAI scan ≤2 years of enrollment RAI-avid metastatic lesion that remained stable in size or progressed despite radioiodine treatment 6 months or more before enrollment ¹⁸FDG avid lesions with max SUV ≥5	Vemurafenib	4/12
Iravani et al.⁷	3 NRAS (2 FTC and 1 PDTC) 3 BRAF^V600E (3 PTC)	6	6	All patients either never had RAI-avid metastases or had imaging and biochemical progression despite ¹³¹I tx in past 12 months.	Dabrafenib, trametinib, vemurafenib, and/or cobimetinib	1/3 RAS and 3/3 BRAF^V600E had increased ¹²⁴I uptake.
Leboulleux et al.⁸	BRAF K601E (PDTC)	1	1	Contraindication for tx with antiangiogenic drugs	Dabrafenib and trametinib	1/1
Grousin et al.⁹	EML4-NRTK3	1	1	After ¹³¹I txs after 12 years (total cumulative activity of 1405 mCi), pt had relapse and no uptake on RAI scan	Larotrectinib	1/1
Leboulleux et al.¹⁰	BRAF^V600E	24	21	RAIR metastatic DTC with RECIST progression within 18 months before enrollment and no lesion >3 cm (1 pt had uptake on pre-dabrafenib and trametinib tx)	Dabrafenib and trametinib	11/17 had increased uptake on a diagnostic scan after 4 weeks of dabrafenib and trametinib. 20/21 had uptake on a post-¹³¹I therapy scan
Lee et al.¹¹	TPR-NTRK1 or CCDC6-RET	2 pediatric patients	2	Negative metastases on post-¹³¹I scan with progressive refractory lung metastases	Larotrectinib and selpercaptinib	2/2
Grousin et al.¹²	NCOA4-RET	1	1	RAI scan before selpercaptinib was negative.	Selpercaptinib	1/1 Tx 2 weeks later
Bogsbud et al.¹³	BRAF^V600E	1	Treated twice	Negative pre-dabrafenib RAI scan	Dabrafenib	Increased after both first and second treatment
Leboulleux et al. 2021¹⁴	RAS	11	10	Not defined but 30% of patients had RAI uptake on a pre-trametinib RAI scan	Trametinib	Three (30%) patients had abnormal RAI on baseline scan, four (40%) after trametinib, and six (60%) on post-¹³¹I therapy scan.

DTC, differentiated thyroid cancer; FDG, fluoro-deoxyglucose; PDTC, poorly differentiated thyroid cancer; RAI, radioactive iodine; SUV, standard uptake value.

Table 2.

Examples of Redifferentiation Procedures

Ho et al.¹	Selumetinib 75 mg po bid × 4 weeks. If ¹²⁴I PET scan was positive, then selumetinib continued to perform dosimetry and subsequently discontinued 2 days after ¹³¹I therapy.
Rothenberg et al.²	Dabrafenib 150 mg po qd for 25 days before ¹³¹I scan. If positive, dabrafenib was continued to day 37, tx with 150 mCi of ¹³¹I, and dabrafenib was continued for five more days.
Dunn et al.⁶	Vemurafenib 960 mg po bid for approximately 4 weeks. If ¹²⁴I PET scan had radioiodine uptake and at least one “index tumor” (≥5 mm) met the lesional dosimetry criteria [≥2000 cGy) with ≤300 mCi of ¹³¹I, that patient was considered as a responder and then patient continued on vemurafenib and treated with ¹³¹I activity determined by dosimetry. Vemurafenib was discontinued 2 days after ¹³¹I therapy.
Iravani et al.⁷	For NRAS: trametinib 2 mg po qd × 4 weeks
Iravani et al.⁷	For BRAF^V600E : combination of dabrafenib 150 mg po qd and trametinib 2 mg po qd × 4 weeks (or vemurafenib 960 mg po bid × 4 weeks and cobimetinib 60 mg po qd × 4 weeks). Calculation of the therapy activity of ¹³¹I is complicated and beyond the scope of this review.
Groussin et al.⁹	Larotrectinib 100 mg po bid (duration not listed)
Leboulleux et al.¹⁰	Dabrafenib 150 mg po bid and trametinib 2 mg po qd for 42 days. On day 28, a radioiodine scan was performed. After 35 days, a therapy of ¹³¹I was administered.
Groussin et al.¹²	Selpercaptinib 160 mg po bid for × 3 weeks

PET, positron emission tomography.

Table 3.

Factors for Consideration in Future Redifferentiation Studies

Patient selection

Criteria to consider patients for redifferentiation

Criteria to consider patients for uptake enhancement

Agents for redifferentiation and/or uptake enhancement

What redifferentiation agent(s) for which genomic alteration?

What protocol for each redifferentiation agent?

Evaluation of combination of agents

Criteria for performing ¹³¹I therapies after redifferentiation and/or uptake enhancement

Lesional dosimetry for therapeutic effect for ¹³¹I therapy

Whole body dosimetry to help minimize bone marrow and/or pulmonary side effects

Simplified whole body dosimetry

Salivary dosimetry to minimize salivary side effects and value of preventive treatments for such

Criteria for assessing outcomes of ¹³¹I therapies after redifferentiation and/or uptake enhancement

Assessment of outcomes of ¹³¹I therapies after redifferentiation and/or uptake enhancement

Assessment of side effects of ¹³¹I therapy after redifferentiation and/or uptake enhancement

Comparison of redifferentiation vs. tyrosine kinase inhibitors

Criteria of therapeutic outcomes for consideration of repeat redifferentiation and¹³¹I retreatment

Evaluation of redifferentiation in patients with undifferentiation or anaplastic thyroid cancer

Cost analysis

¹²⁴I FDA approval

FDA, Food and Drug Administration.

Bogsrud et al.¹³ has presented a meeting abstract on one case in which the authors attempted redifferentiation twice and treated the patient with ¹³¹I twice. Four months after 6 weeks of treatment with dabrafenib followed by an ¹³¹I treatment, the patient had a response (e.g., Tg doubling time increased from 6 to 56 months and the added targeted tumor volume of the three lesions was reduced by 35%). However, after about 10 months, the target tumor lesions progressed, redifferentiation was repeated as was an ³¹I therapy with the resultant Tg doubling time at 5 months increased from 8 to 52 months and the volume of the three lung lesions reduced 33%.

The patient subsequently had intercurrent heart failure and died. This case report demonstrates that a patient may undergo a second attempt with redifferentiation with a response. Huillard et al.⁴ also redifferentiated and treated a patient with ¹³¹I twice with partial responses. However, the first treatment was after 7 months of continuous administration of vemurafenib and the second was after 3 months of continuous administration of dabrafenib. As a result, one is unable to determine whether the partial responses were due to redifferentiation, vemurafenib, dabrafenib, or a combination thereof.

Opinion on Clinical Practice Considerations

Overview

The literature on redifferentiation of patients with known or highly suspected metastatic DTC is subject to many limitations, as noted in Table 4. However, these initial reports suggest the potential promise of redifferentiation in selected patients with progressive metastatic radioiodine refractory DTC.

Table 4.

Limitations in the Evidence on Redifferentiation of Differentiated Thyroid Cancer

Small No. of

Studies

Patients

Limitations in variables

Protocols for redifferentiation

Little or no information regarding technique of radioiodine scans

Isotopes used (e.g., ¹²³I, ¹²⁴I, and ¹³¹I)

Criteria for definition of radioiodine refractory DTC

Criteria of the RAI uptake resulting from redifferentiation to perform ¹³¹I treatment

Methods (e.g., empiric vs. dosimetry) to determine ¹³¹I activities that were used for ¹³¹I therapies after redifferentiation

Follow-up

Metrics for assessing outcomes

Selection of patients for consideration of redifferentiation

As noted earlier, the published literature is limited, and more studies are clearly warranted to further develop the indications for redifferentiation, possible subsequent ¹³¹I therapies, and subsequent ¹³¹I therapeutic responses. However, for facilities within the United States, we submit that presently there are at least four management approaches that one may consider for redifferentiation in patients with progressive metastatic differentiated thyroid cancer with or without negative diagnostic and/or post-therapy radioiodine scans.

Prospective study

Ideally, redifferentiation interventions should be offered in prospective studies. This not only encourages performance of prospective studies but also encourages patients to enter prospective studies resulting in acquiring faster and higher quality scientific data. However, at the time of this article submission, there are limited number of sites prospectively evaluating redifferentiation. As of October 2022, there were only several sites listed on clinical trials.gov. All of these were either not within the United States, not recruiting, and/or recruiting status was unknown. One site was active at Leiden University Medical Center in the Netherlands.³¹ As a result, many patients who have progressive metastatic disease classified as radioiodine refractory, with or without negative diagnostic and/or post-therapy radioiodine scans, may not have access to these agents through clinical trials.

“Right-To-Try” law in the United States

Even if one argues that redifferentiation should ideally be offered in a research trial, a relatively new “Right-To-Try” law in the United States may enable patients to use agents that the Food and Drug Administration (FDA) have not approved and are only available in a research trial. Brown et al. discussed the details of this law³²; however, and as noted by Van Nostrand,³³ this option may be difficult to implement.

Clinical use of an agent approved by the FDA for an unapproved FDA indication

In the United States, an agent approved by the FDA may be used for an unapproved FDA indication. Furthermore, most of these agents reported in this review are approved by the FDA for one or more indications—but none are approved for redifferentiation of progressive metastatic differentiated thyroid cancer. However, patients who have progressive metastatic DTC may be running out of therapeutic options, and may not have access to a prospective study on redifferentiation for that patient's specific genomic alteration.

As a result, we believe that redifferentiation may be considered as a clinical management option, offered to select patients with appropriate explanation. In consideration of this management option, the management team should consider many factors (Table 5), including the patient's preferences and values. Although Table 5 suggests that the patient should have one of the known genomic alterations noted in Table 1, there is a potential argument to consider redifferentiation when the patient has papillary thyroid cancer and the patient's genomic profile is not known because as many as 50% of such patients may have a BRAF^V600E genetic alteration.³⁴

Table 5.

Factors to Consider in Redifferentiation and Possible Subsequent ¹³¹I Therapy of Differentiated Thyroid Cancer

Patient has known (i.e., biopsy confirmation) or has a high suspicion for metastatic DTC (e.g., imaging such as CT strongly indicative of metastasis).

What is the probability that the patient's DTC is truly radioiodine refractory to ¹³¹I?

The intent to enhance radioiodine uptake even though radioiodine uptake is present (e.g., uptake enhancement).
(Discussed further in the section entitled “Terminology”)

Patient has one of the known genotypes in Table 1.

The intended agent(s) is available for use.

The facility is capable of administering the desired agent.

No contraindications to the planned agent and/or ¹³¹I therapy

Patient preferences

Drug reimbursement issues
(Discussed further in the section entitled “Reimbursement”)

Patients with radioiodine avid DTC

An additional category of patients to consider redifferentiation is patients who already have demonstrated the presence of radioiodine avid DTC with the objective of uptake enhancement. For any therapy, the objective is to maximize therapeutic outcome while minimizing side effects. For ¹³¹I therapy, one principal factor is maximizing absorbed dose delivered (Gy [rad]) per activity administered of ¹³¹I (MBq [mCi]). As demonstrated by Rothenberg et al.,³ all of his six patients had radioiodine avid disease that had significant uptake enhancement with the administration of dabrafenib. Hence, Rothenberg et al.^2,3 have clearly demonstrated that update enhancement is achievable in select patients, thereby theoretically increasing the absorbed dose delivered per administered activity of ¹³¹I.

However, we are not proposing this as a standard clinical practice. Rather, we propose further study, and a key factor to facilitate this potential therapeutic enhancement will be dosimetry, which must include at a minimum whole-body dosimetry and—preferably—lesional and salivary gland dosimetry. One of the values of lesional dosimetry is that although one may increase the Gys (rad) delivered to the metastases per administered activity, the administered activity may still not deliver enough absorbed dose to the tumor that equals or exceeds a predetermined amount of Gys (rad) required for a potentially successful outcome. Update enhancement is an additional exciting and potentially important management option.

Reimbursement

In our practice (in the United States), we experience minimal difficulties in the pursuit of cost reimbursement for the various agents that may be used for redifferentiation. However, this is more difficult for patients with radioiodine avid disease, and we believe that this will require studies demonstrating improved outcomes. Nevertheless, for patients with negative diagnostic and/or ¹³¹I post-therapy scans in whom we are pursuing redifferentiation, our initial approach is to have a discussion between our oncologist (I.V.) and the third party payer representative.

In brief, our justification for reimbursement of the FDA-approved agent(s) for a non-FDA-approved indication includes (1) a presentation of the patient's clinical situation of progressive multiple distant metastases, (2) an emphasis that the patient is running out of therapeutic options, (3) our consideration–but potential postponement–of using a tyrosine kinase inhibitor (TKI) (i.e., sorafenib or lenvatinib), (4) a summary of the planned use, rational, and evidence to date of the redifferentiation agent(s) that may be followed by an ¹³¹I therapy, (5) the cost for the administration of the agent(s) would be similar to the cost for the administration of a TKI for the same period of time (e.g., ½ to two times), and (6) if redifferentiation and ¹³¹I therapy are successful, the expense for the redifferentiating agent(s) would only be for ∼6 weeks rather than the continuous expense for the continued use of a TKI for many months.

In case of denial by the third-party payer in the United States, we have experienced excellent success in obtaining short-term access to the redifferentiating agent(s) for compassionate use at no cost to the patient, and none of the authors herein receive or have received any financial remuneration in any form from the pharmaceutical companies for this purpose.

Conclusion

Redifferentiation and uptake enhancement are extremely exciting, promising therapeutic strategies, with the former potentially available clinically in the management of selected patients who have progressive metastatic DTC. Of course, future studies are needed to confirm these preliminary observations and to confirm acceptable subsequent ¹³¹I therapeutic responses after redifferentiation and/or uptake enhancements. In addition, new advances create new questions and issues that we need to address to ensure optimal patient treatment (Supplementary Table S3).

Footnotes

Authors' Contributions

Conceptualization (lead), writing—original draft (lead), formal analysis (lead), and writing—review and editing (equal) by D.V.N. Conceptualization (supporting) and writing—review and editing (equal) by I.V. and K.D.B. Writing—review and editing (equal) by K.K. Methodology (lead for literature search) and writing—review and editing (equal) by L.H.

Financial Disclosures

None of the authors receive or have received any financial remuneration or incentives in any form for obtaining agents for redifferentiation for compassionate use.

Author Disclosure Statement

D.V.N. is consultant to and speaker for Jubilant Radiopharma. The other authors have no disclosures.

Funding Information

No competing financial interests exist.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

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