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Differentiated thyroid cancer refractory to standard treatment: Systemic therapy

Differentiated thyroid cancer refractory to standard treatment: Systemic therapy
Literature review current through: Jan 2024.
This topic last updated: Feb 14, 2023.

INTRODUCTION — Treatment of most patients with differentiated thyroid cancer (DTC; both papillary and follicular histologies) includes surgery, thyroid hormone therapy, and selective use of radioiodine. When metastatic disease occurs, radioiodine can be curative in a minority of patients, and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy can help to slow the pace of the disease. In addition, external radiotherapy may be useful in some patients. (See "Differentiated thyroid cancer: Overview of management" and "Differentiated thyroid cancer: Radioiodine treatment" and "Differentiated thyroid cancer: External beam radiotherapy".)

However, for those patients with metastatic DTC that progresses despite systemic treatment such as radioiodine and TSH-suppressive thyroid hormone therapy, or focal treatments such as surgery and external beam radiotherapy (EBRT), treatment options have historically been limited. New approaches based upon application of targeted therapies have emerged as effective alternatives for progressive disease.

Systemic targeted therapy for advanced DTC that progresses despite radioiodine and TSH-suppressive thyroid hormone will be reviewed here. Therapies for medullary and anaplastic thyroid cancers are discussed separately. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy" and "Anaplastic thyroid cancer".)

PATIENT SELECTION FOR SYSTEMIC THERAPY — Systemic therapy may be used in patients at significant risk for morbidity or mortality due to progressive metastatic disease in whom benefit of therapy is likely to reasonably outweigh the risks and cost. The rate of disease progression is variable in patients with metastatic differentiated thyroid cancer (DTC), and therefore the pace of disease progression is an important factor in the decision to treat with systemic therapy.

The ideal time to initiate systemic therapy remains unclear. A prospective noninterventional study in patients with progressive, asymptomatic, radioiodine refractory DTC attempted to compare outcomes in patients who were treated with a multikinase inhibitor at study entry with those who continued active surveillance [1]. However, the slow accrual of events in both groups prevented the planned analysis.

Our approach to identifying patients for systemic therapy is as follows:

Patients treated with systemic agents should have a baseline performance status sufficiently functional to tolerate these interventions, such as being ambulatory at least 50 percent of the day (Eastern Cooperative Oncology Group [ECOG] performance status 2 or better). The most commonly used systemic therapies, kinase inhibitors, are associated with adverse effects that may significantly impact quality of life. (See 'Side effects shared by oral kinase inhibitors inhibiting VEGFR' below.)

Patients should be evaluated with comprehensive computed tomography (CT) and/or magnetic resonance imaging (MRI) to establish the extent of disease and disease progression. Prior to therapy or in any patient with suspicious central nervous system symptoms, imaging of the brain should be performed to rule out intracranial metastases that might require other forms of intervention first, such as surgery or radiation.

Patients with asymptomatic metastatic tumors generally less than 1 to 2 cm in diameter and growing in diameter less than 20 percent per year can usually be monitored for disease progression (active surveillance). In this group of patients, known sites of metastatic disease should be imaged by CT or MRI every six months, and potential new sites of disease should be imaged every 12 to 24 months. We continue treatment with TSH suppression (with TSH levels as low as the patient can tolerate, though not necessarily undetectable [2]).

Patients with unresponsive metastatic tumors of at least 1 to 2 cm in diameter and growing by at least 20 percent per year, or patients with symptoms related to multiple metastatic foci that cannot be alleviated with localized treatment such as surgery or external beam radiotherapy (EBRT) are candidates for systemic therapy. Emphasis should be placed on overall tumor burden or individual lesion location, growth trajectory, and potential for morbidity if disease is allowed to progress further.

INITIAL SYSTEMIC THERAPY — The following approach is based upon clinical experience and data from placebo-controlled randomized trials (algorithm 1). Our approach is largely consistent with the American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines, with modifications based upon subsequent research findings [3-5].

General principles

We prefer to administer systemic treatment in the context of a clinical trial. (Active clinical trials can be identified at: ClinicalTrials.gov.) Increasingly, the selection of a specific systemic agent is dictated by the presence of specific gene mutations or signaling pathway abnormalities that are the targets of approved or investigational therapies.

For patients who are unable to participate in clinical trials, first-line treatment options include oral kinase inhibitors that target either angiogenesis or oncogenic signaling pathways. The choice of initial kinase inhibitor depends on the result of somatic mutation testing, if available. (See 'Targetable mutation not identified' below and 'Targetable mutation identified' below.)

For patients whose disease burden, rate of tumor growth, or symptoms necessitate consideration of systemic therapy options, somatic mutation testing can be performed to identify oncogenic kinase abnormalities that might suggest specific treatment options that cannot be administered in the absence of mutational data (eg, gene rearrangements in NTRK, ALK, or RET, or point mutations in BRAF). Given the high cost of such testing and lack of coverage by some insurance providers, this option may not be realistic for some patients, even if the lack of testing limits therapeutic options. Options for reduced cost mutation testing may be available through pharmaceutical companies marketing such targeted drugs.

In most tumors, kinases function as key signaling intermediates that stimulate tumor proliferation, angiogenesis, invasion, metastasis, and avoidance of apoptosis, affecting both the cancer cells as well as the other components of the tumor microenvironment, such as the vascular endothelium. Antiangiogenic multikinase inhibitors (aaMKIs) can improve progression-free survival. However, kinase inhibitors are disease-modifying agents, usually tumoristatic rather than tumoricidal, and only one published study has demonstrated that one of these new agents improved overall survival in a specific prespecified subgroup of patients with thyroid cancer [6].

Conventional cytotoxic agents are rarely used for the treatment of patients with progressive symptomatic differentiated thyroid cancer (DTC) that is unresponsive or not amenable to surgery, radioiodine therapy, or external radiotherapy; complete remission is rare, and long-term responses are uncommon [7,8]. (See 'Therapies infrequently used' below.)

In the studies described below, the definitions of tumor response are based upon the now-standard Response Evaluation Criteria in Solid Tumors (RECIST) (table 1) [9].

Targetable mutation not identified

Multitargeted kinase inhibitor — In the absence of a specific targetable mutation (eg, NTRK, ALK, RET, or BRAF), or if mutation profiling results are not available, we suggest lenvatinib as first choice among oral aaMKIs (algorithm 1). Sorafenib is an alternative option.

As head-to-head comparisons among the various aaMKIs have not been performed and the various trials often have recruited patients with differing eligibility criteria, the selection of which agent to use for initial treatment should prioritize both better study design (such as randomized trials) and a somewhat subjective ranking of drug efficacy and adverse events. Randomized trial evidence supports benefit with lenvatinib [10,11], sorafenib [12], and vandetanib [13], but nonrandomized trials have also indicated efficacy with pazopanib [14], sunitinib [15-17], and other aaMKIs. We prefer lenvatinib as first-line therapy because of the high rate of efficacy and evidence of improved survival in older patients, although it has not been directly compared with other aaMKIs in randomized trials.

Many of the aaMKIs partially inhibit multiple tyrosine kinases (ie, they are multitargeted) at nanomolar concentrations in vitro and often affect multiple signaling pathways. The primary target for all of these effective tyrosine kinase inhibitors is angiogenic signaling in the tumor microenvironment, particularly the vascular endothelial growth factor receptor (VEGFR) family. Although it may take several months before maximum radiographic response is achieved, targeting angiogenesis (and specifically VEGFR signaling pathways) has produced valuable clinical responses and prolonged progression-free survival in randomized trials for metastatic DTC. In phase III trials, median progression-free survival times of 11 to 18 months are reported, with partial responses in up to 63 percent of patients (though complete responses are rare) [11,12].

LenvatinibLenvatinib is an inhibitor of VEGFR, and to a lesser degree, RET and fibroblast growth factor receptor kinases 1 to 4. In 2015, lenvatinib was approved by the US Food and Drug Administration (FDA) for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioiodine treatment [10,18]. The approved starting dose (used in the pivotal phase III trial) is 24 mg orally once daily.

In an international, randomized, double-blind phase III trial, 392 patients with progressive, radioiodine refractory thyroid cancer were randomly assigned in a 2:1 ratio to lenvatinib or placebo [11]. Tumor assessments for initial eligibility as well as serially while on therapy were performed centrally. The median progression-free survival (18.3 versus 3.6 months; hazard ratio [HR] for progression or death 0.21, 99% CI 0.14-0.31) and the response rate (64.8 versus 1.5 percent) were significantly better in the lenvatinib group. A similar response was seen in patients previously treated with another aaMKI, indicating benefit despite previous therapy. Compared with no complete responses in the placebo group, four patients (1.5 percent) in the lenvatinib group experienced durable complete responses. The median overall survival was not reached in either group. A preplanned subgroup analysis demonstrated that patients above the age of 65 years at the time of therapy initiation with lenvatinib had a significantly longer overall survival than those randomized to placebo (HR 0.53, 95% CI 0.31-0.91) [6].

In a randomized trial comparing the efficacy of two different starting doses of lenvatinib, the objective response rate at 24 weeks in patients who started 24 mg daily was 57 percent compared with 40 percent for those who started 18 mg daily (odds ratio 0.50, 95% CI 0.26-0.96), thus not meeting criteria for noninferiority of the two doses [19]. Despite differences in the starting doses, the rates of grade 3 or higher treatment-emergent adverse events were similar across the two arms.

SorafenibSorafenib is an inhibitor of VEGFR 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), common RET/PTC subtypes, c-kit, and less potently, BRAF [20]. In 2013, sorafenib was approved by the FDA for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioiodine treatment [21]. A typical starting dose of 400 mg orally twice daily is being used in selected patients with radiographically progressive metastatic papillary thyroid cancer for whom clinical trials are not available or appropriate; the efficacy of a lower starting dose has not been reported [3,22].

In several small phase II trials, sorafenib had beneficial effects on tumor progression in patients with DTC [23-27]. In a subsequent phase III trial, 417 patients with radioiodine-refractory DTC with locally advanced or metastatic disease that had radiographically progressed within 14 months of entry were randomized to either sorafenib or placebo [12]. Refractory disease was defined as at least one focus of tumor lacking radioiodine uptake, disease that had progressed within one year after radioiodine therapy, or cumulative treatment with at least 600 mCi of iodine 131 (131-I). Median progression-free survival was improved from 5.8 months on placebo to 10.8 with sorafenib (HR 0.59, 95% CI 0.45-0.76). Similar efficacy was seen across a wide variety of predefined subgroups. In a subsequent analysis, it was reported that the presence of a BRAF or RAS mutation was not predictive of response to treatment [28]. Although tumor responses were uncommon, six-month disease control rate was 54 percent. Toxicities led to dose modification in 78 percent of patients and permanent discontinuation of therapy in 19 percent. (See 'Side effects shared by oral kinase inhibitors inhibiting VEGFR' below.)

VandetanibVandetanib is an oral inhibitor that targets VEGFR, RET/PTC, and the epidermal growth factor receptor (EGFR). Vandetanib is available in the United States through a Risk Evaluation and Mitigation Strategy (REMS) program for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer (see "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Vandetanib'). Use outside of the indications defined in the REMS program is discouraged; however, given the strength of the data from a well-designed randomized trial [13], vandetanib may be a treatment option to consider for a patient with radioiodine-refractory, progressive papillary thyroid cancer for whom clinical trials, lenvatinib, and sorafenib are inappropriate. Given the low objective response rate, however, the drug is not likely to yield significant benefit for patients requiring major tumor shrinkage to palliate symptoms.

In the randomized trial, 145 patients with locally advanced or metastatic DTC unresponsive to radioiodine were randomly assigned to vandetanib (300 mg once daily) or placebo [13]. After a median follow-up of approximately 19 months, fewer patients treated with vandetanib had disease progression (52 versus 61 patients in the placebo group [72 versus 84 percent]). Median progression-free survival was 11.1 and 5.9 months in the vandetanib and placebo groups, respectively (HR 0.63, 95% CI 0.54-0.74). There was no difference in objective partial response (8 percent of 72 and 5 percent of 73 patients, respectively) or overall survival (19 and 21 deaths, respectively). In subgroup analysis, efficacy may have been highest in patients with papillary thyroid cancer, and little difference in progression-free survival was suggested in patients with either follicular or poorly differentiated carcinomas. The most common adverse events resulting in discontinuation of vandetanib were prolongation of the QT interval and diarrhea. A larger, randomized, placebo-controlled phase III trial in patients with progressive, radioiodine-refractory DTC is underway.

Contraindications to aaMKI — Relative contraindications to antiangiogenic multikinase inhibitors (aaMKIs) may include major surgery within 28 days, active bleeding, untreated hemorrhagic brain metastases, encasement by tumor of major arteries such as the carotid, or arterial thromboembolic event within the last 6 to 12 months. We also try to minimize use of potent antiangiogenic agents in patients with prior external beam radiotherapy (EBRT) to the neck due to reports of tracheoesophageal fistulas [29].

For patients with contraindications to aaMKIs, a BRAF inhibitor (eg, vemurafenib, dabrafenib) with or without an MEK inhibitor is an alternative. (See 'Mutation-specific kinase inhibitor' below.)

Targetable mutation identified

Mutation-specific kinase inhibitor — If a targetable driver mutation is present (eg, NTRK, ALK, RET, BRAF), we suggest a mutation-specific kinase inhibitor (eg, an FDA-approved selective TRK or RET inhibitor, or use of a BRAF inhibitor) (algorithm 1). Use of a BRAF inhibitor is typically reserved for patients with BRAF V600-mutant papillary thyroid cancer for whom aaMKI therapy might be contraindicated.

BRAF, RET, or TRK inhibitors frequently produce objective responses in DTC, though prolongation of progression-free survival has not yet been demonstrated in randomized trials. Of note, kinases that inhibit signaling along the mitogen-activated protein kinase (MAPK) pathway (eg, the BRAF inhibitors vemurafenib, dabrafenib) may allow re-expression of genes responsible for iodine metabolism in radioiodine-refractory DTC, thus permitting restoration of radioiodine uptake (also called "redifferentiation"). (See 'Assessment for restoration of radioiodine uptake (redifferentiation)' below.)

TRK inhibition – Rearrangements of one of the neurotrophic tropomyosin receptor kinase (NTRK) genes leading to constitutive activation of signaling and tumor proliferation has been reported in a small percentage of patients with DTC [30]. Larotrectinib and entrectinib, highly selective inhibitors of TRK kinases, have been FDA approved for treatment of any solid tumor bearing an NTRK1-3 fusion mutation, including DTC. Of 15 patients with progressive radioiodine-refractory metastatic DTC bearing an NTRK rearrangement treated with larotrectinib across three clinical trials, 87 percent were reported to experience a partial response [31-34]. In an analysis of three phase I or II trials, one of five patients had a response with entrectinib [35]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'NTRK gene fusion-positive tumors'.)

Restoration of radioiodine uptake has been reported with larotrectinib [36]. (See 'Assessment for restoration of radioiodine uptake (redifferentiation)' below.)

RET inhibition – Rearrangements leading to RET/PTC oncogenes are the third most common driver mutations in papillary thyroid cancer, although they may be less commonly associated with advanced, radioiodine-refractory disease. Similar fusion abnormalities exist as well in non-small cell lung cancer along with other malignancies, leading to interest in development of selective RET kinase inhibitors.

Selpercatinib and pralsetinib, oral kinase inhibitors that selectively target RET kinase, are approved by the FDA for the treatment of advanced or metastatic RET fusion-positive thyroid cancer, RET-mutant medullary thyroid cancer, and other types of cancers that have an alteration (mutation or fusion) in the RET gene [37,38]. Of note, high response rates were seen with both selpercatinib and pralsetinib to treat medullary thyroid carcinoma with point mutations, but effectiveness may be less than reported for rearrangements in the RET gene. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

Selpercatinib – In the open-label LIBRETTO-001 trial of selpercatinib in 19 patients with previously treated, radioiodine-refractory, RET fusion-positive, non-medullary thyroid cancer, objective response (complete or partial) was reported in 79 percent [39]. The most common grade 3 or 4 adverse events included hypertension (21 percent), increased alanine aminotransferase (11 percent), increased aspartate aminotransferase (9 percent), hyponatremia (8 percent), and diarrhea (6 percent).

Pralsetinib – In the open-label ARROW trial, in which nine patients with RET-fusion thyroid carcinoma were treated with pralsetinib, the overall response rate was 89 percent, all partial responses [38,40-42]. The most common grade 3 or 4 adverse events included hypertension (21 percent), fatigue (6 percent), diarrhea (5 percent), fever (2.2 percent), and dyspnea (2.2 percent).

BRAF inhibitionVemurafenib and dabrafenib, inhibitors of BRAF kinase, have been studied in patients with BRAF-mutated DTC. Dabrafenib in combination with trametinib (a MEK inhibitor) has received regulatory approval for BRAF-mutated metastatic solid tumors, including papillary thyroid cancer; vemurafenib has not received this broader approval.

These drugs can be considered for those patients with radiographically progressive, radioiodine-refractory BRAF V600-mutant papillary thyroid cancer for whom antiangiogenic therapy might be contraindicated or when a redifferentiation therapy strategy is employed. (See 'Assessment for restoration of radioiodine uptake (redifferentiation)' below.)

Vemurafenib – In a phase II trial in which 51 patients with progressive radioiodine-refractory BRAF V600-mutant papillary thyroid cancer were treated with vemurafenib, the partial response rate was 38.5 percent, and median progression-free survival was 18.2 months in the anti-VEGFR-naïve group [43]. Less benefit was seen in the group previously treated with anti-VEGFR kinase inhibitors (27.3 percent and 8.9 months), but the study was not designed to compare formally the outcomes between the two arms. Common adverse events included rash, fatigue, weight loss, taste alteration, and alopecia; squamous cell carcinomas were identified in 22 percent of patients and noncutaneous squamous cell carcinomas in another 6 percent.

Dabrafenib – In a multicenter, randomized phase II trial comparing dabrafenib (150 mg twice daily) alone or in combination with the MEK inhibitor trametinib (2 mg daily) in 53 patients with BRAF-mutant metastatic papillary thyroid cancer, objective response rates were similar, 50 and 54 percent, respectively [44]. Median progression-free survival and durations of response also did not differ between the two groups, and treatment-related adverse events were similar as well. Thus, the combination did not appear to have an advantage over single therapy with dabrafenib. Notably, the combination of dabrafenib and trametinib has been approved for BRAF-mutated anaplastic thyroid carcinoma, and we have observed durable complete responses in patients with BRAF-mutated poorly differentiated thyroid carcinoma treated with both drugs as well [4]. (See "Anaplastic thyroid cancer", section on 'BRAF V600E mutation identified'.)

Mutations of BRAF are associated with the greatest degree of MAPK activation and functional dedifferentiation. Restoration of radioiodine uptake has been demonstrated in small studies using either of the BRAF inhibitors, dabrafenib or vemurafenib [45]. (See 'Assessment for restoration of radioiodine uptake (redifferentiation)' below.)

PI3K inhibition – Both papillary and follicular carcinomas often develop mutations or upregulation of signaling through phosphoinositide 3-kinase (PI3K) as the disease progresses, leading to the suggestion that targeting this pathway may be of value. A phase II study of everolimus included 25 patients with progressive metastatic DTC who were treated with everolimus 10 mg daily [46]. Although the partial response rate was only 4 percent, median progression-free survival was 43 weeks. A second trial has also preliminarily reported efficacy from monotherapy with everolimus, as has a third with the combination of everolimus and sorafenib; in these trials, particular efficacy was suggested in patients with metastatic Hürthle cell carcinoma [47,48]. Further investigation of the role of targeting this signaling pathway is expected. In patients whose tumors bear PI3K pathway mutations, we may add everolimus to lenvatinib using starting doses approved for renal cell carcinoma (5 mg and 18 mg daily, respectively).

EVALUATING RESPONSE TO TREATMENT

Imaging and assessment of adverse events

While on therapy, we perform CT or MRI of known or suspected sites of disease every two to four months to determine how the disease is responding to therapy (ie, tumor burden).

Patients should also be assessed for potential treatment-related and disease-related complications. It is highly recommended that clinicians using these agents follow a comprehensive and standardized approach to assessment of adverse events during therapy, including careful documentation of the extent of baseline symptoms present prior to initiation of kinase inhibitors [49]. Subsequent management should include consideration of limited drug interruptions and dose modifications, carefully observing for balance of continued anti-tumor efficacy and reduced toxicity [50]. (See 'Side effects shared by oral kinase inhibitors inhibiting VEGFR' below.)

Assessment for restoration of radioiodine uptake (redifferentiation) — In patients treated with mitogen-activated protein kinase (MAPK) pathway inhibitors such as vemurafenib, dabrafenib, and trametinib, we may perform diagnostic radioiodine imaging after one to three months of therapy to determine if sufficient restoration of radioiodine uptake (redifferentiation) has occurred to permit subsequent radioiodine therapy.

In patients who have previously had significant radioiodine dosing, or with extensive pulmonary metastases, diagnostic radioiodine imaging with concurrent dosimetry may allow calculation of radioiodine activity for administration in order to minimize risk of subsequent pulmonary toxicity.

In patients with a negative diagnostic radioiodine scan despite redifferentiation therapy, an empiric activity of 100 to 150 mCi may yet be considered.

Rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS are sequential components leading to activation of MAPK. Activation of MAPK promotes cell division and inhibits the sodium-iodide symporter (which usually facilitates iodine uptake) and thyroid peroxidase (facilitates organification). Mutations of BRAF are associated with the greatest degree of MAPK activation and functional dedifferentiation, followed by RET and NTRK fusions, and least by RAS mutations [51]. Thyroid cancers with these mutations are more likely to be refractory to radioiodine. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer".)

Inhibition of kinases signaling along the MAPK pathway may allow re-expression of genes responsible for iodine metabolism in radioiodine-refractory differentiated thyroid cancer (DTC), thus restoring sufficient radioiodine uptake to permit subsequent radioiodine therapy [52-55]. Restoration of radioiodine uptake has been demonstrated in small studies using either of the BRAF inhibitors, dabrafenib or vemurafenib, as well as inhibitors of MEK [45,56]. As examples:

In a study involving 10 patients with radioiodine-refractory BRAF V600E mutated papillary thyroid cancer, six patients (60 percent) demonstrated new radioiodine uptake after nearly four weeks of therapy with dabrafenib (150 mg orally twice daily) [45]. Following radioiodine treatment with 150 mCi iodine 131 (131-I) in those six patients, two experienced partial response and four remained stable on imaging three months after therapy. Vemurafenib similarly restored radioiodine uptake and sensitivity, with selected tumor biopsies confirming increased thyroid-specific gene expression following effective MAPK pathway inhibition [56].

In an interim analysis of results from another study in which 21 patients were evaluable after treatment with a combination of trametinib and dabrafenib, partial response at six months was 38.1 percent with stable disease in 52.4 percent [57]. There were encouraging increases in radioiodine uptake and decreases in thyroglobulin levels (in the 15 of 21 patients who were antithyroglobulin antibody negative).

Selumetinib is an investigational drug that selectively inhibits MEK 1 and MEK 2 (downstream effectors of MAPK pathway signaling) [58]. In a study of 20 patients with radioiodine-refractory papillary thyroid cancer, 12 patients (60 percent) had new and/or increased radioiodine uptake after treatment with selumetinib (75 mg orally twice daily for four weeks) [55]. In eight patients (40 percent), the absorbed radiation dose in the lesion was sufficient enough to continue selumetinib and receive a therapeutic dose of radioiodine. During six months of follow-up, there were partial responses in five patients and stable disease in three. Selumetinib was most effective in patients with NRAS-mutant thyroid cancers. There is an ongoing trial evaluating the role of selumetinib in augmenting radioiodine responsiveness in metastatic DTC that retains some iodine uptake on diagnostic imaging.

Selumetinib has not been shown to improve the complete remission rate when administered with initial adjuvant radioiodine therapy in patients at high risk for recurrent disease after thyroidectomy [59].

REFRACTORY DISEASE OR KINASE INTOLERANCE — Patients with refractory disease or with intolerance to one kinase inhibitor may benefit from treatment with another. Although cross-resistance has not been reported, likelihood of response is likely somewhat lower, however, with each successive regimen.

For patients who cannot tolerate or who progress on first-line therapy with an antiangiogenic multikinase inhibitor (aaMKI), we discuss investigational agents, further attempts with other aaMKIs (eg, cabozantinib), or (if appropriate) a BRAF inhibitor (eg, vemurafenib or dabrafenib) or TRK or RET inhibitor (eg, larotrectinib or selpercatinib, respectively).

Cabozantinib Cabozantinib is an inhibitor of several tyrosine kinases including VEGFR2, AXL, MET, and RET. In 2021, cabozantinib was approved by the FDA for the treatment of patients with locally recurrent or metastatic DTC that progresses following prior treatment with a VEGFR-targeted kinase inhibitor and that is refractory to radioiodine therapy [60]. Phase 1 and 2 studies have previously shown clinical activity of cabozantinib in patients with radioiodine-refractory DTC, including those previously treated with VEGFR-targeted therapy [61,62].

In an interim analysis (median follow-up 6.2 months) of a double-blind, placebo-controlled, phase 3 trial of cabozantinib in 187 patients with previously treated, radioiodine-refractory differentiated thyroid cancer, cabozantinib improved progression-free survival [63]. In a subsequent report with extended follow-up (median 10.1 months), cabozantinib maintained the improvement in progression free survival (median 11 months versus 1.9 months with placebo [HR 0.22, 96% CI 0.15-0.32]) [64].

For patients who cannot tolerate first-line therapy with a mutation-specific kinase inhibitor, we suggest an aaMKI such as lenvatinib as the next-line option.

Doxorubicin or a taxane are alternatives for patients who are unable to tolerate or who fail several attempts at kinase inhibitor therapy. (See 'Therapies infrequently used' below.)

SIDE EFFECTS SHARED BY ORAL KINASE INHIBITORS INHIBITING VEGFR — Side effects of vascular endothelial growth factor receptor (VEGFR)-targeted antiangiogenic multikinase inhibitors (aaMKIs) may include hypertension, renal toxicity, proteinuria, arthralgia/myalgia, headache, bleeding, myelosuppression, arterial thromboembolism, cardiotoxicity including prolonged QT intervals and risk for arrhythmia, thyroid dysfunction, cutaneous toxicity including hand-foot skin reaction, delayed wound healing, hepatotoxicity, nausea, vomiting, diarrhea, muscle wasting, fistula formation, osteonecrosis of the jaw, and reversible posterior leukoencephalopathy syndrome. TSH may become elevated during treatment, requiring an increase in the dose of thyroid hormone replacement or suppression therapy. Monitoring for and management of these side effects are discussed in detail elsewhere. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

THERAPIES INFREQUENTLY USED

Immunotherapy – The use of agents that accentuate the capacity of a patient's own immune system to attack a malignant tumor has rapidly expanded in the past few years with the introduction of "checkpoint inhibitors." Drugs that block key cell-surface components on tumor cells or T lymphocytes, regulating the interaction between these two cell types, permit the immune system to recognize tumor-specific epitopes or neoantigens presented on the surface and thus allow immune targeting of these abnormal cells. In differentiated thyroid cancer (DTC), one trial evaluated the programmed cell death receptor 1 (PD-1) inhibitor pembrolizumab, 10 mg/kg given intravenously every two weeks for 24 months or until progression or intolerable toxicity [65]. Of 22 patients with progressive metastatic disease and programmed cell death ligand 1 (PD-L1) expression in at least 1 percent of tumor or stroma cells, only two (9.1 percent) experienced a partial response and 54.5 percent had stable disease as their best overall response. The median progression-free survival rate was seven months. Adverse events were typical of those seen in other tumor types, including diarrhea, fatigue, and colitis.

In a preliminary report from a phase II study, adding pembrolizumab to lenvatinib as first-line therapy led to similar rates of partial response and stable disease as lenvatinib alone [66].

Low efficacy was reported from a phase II trial of the CTLA-4 inhibitor, ipilimumab, in combination with the PD-1 inhibitor, nivolumab, in 32 patients, with overall response rate of 9 percent and median progression-free survival 4.9 months [67]. Further clinical trials of checkpoint inhibitors in combination with targeted agents are underway.

Cytotoxic agents – Although conventional cytotoxic agents are occasionally used for the treatment of patients with progressive symptomatic thyroid cancer that is unresponsive or not amenable to surgery, radioiodine therapy, or external radiotherapy, complete remission is rare, and long-term responses are uncommon. In addition, the availability of kinase inhibitors that induce durable responses or stability has changed the standard approach to treating patients with progressive metastatic disease, further limiting the role of cytotoxic agents [7,8]. (See 'Initial systemic therapy' above.)

Doxorubicin is the only cytotoxic agent approved by the US Food and Drug Administration (FDA) for metastatic thyroid cancer. Other single chemotherapeutic agents, including (but not limited to) paclitaxel, bleomycin, cisplatin, carboplatin, methotrexate, melphalan, mitoxantrone, etoposide, and aclarubicin, have not been shown to improve response rates. Similarly, combination therapy with doxorubicin and cisplatin has not been shown to improve the overall response compared with doxorubicin alone, and combination therapy may increase toxicity [68,69].

Thus, we typically reserve conventional cytotoxic agents (eg, doxorubicin) for patients with metastatic refractory DTC who are unable to participate in clinical trials or who either cannot tolerate or fail antiangiogenic multikinase inhibitors (aaMKIs). Cisplatin or other agents may be considered in patients for whom doxorubicin is inappropriate (eg, those with pre-existing impaired cardiac function or myelosuppression). Data regarding combination regimens are even sparser than for single drugs. Such regimens may be appropriate in select patients.

Doxorubicin – In the initial studies with doxorubicin, 19 patients with metastatic papillary or follicular carcinoma were enrolled [8,70]. Partial responses (defined as >50 percent reduction in tumor area on serial radiographs) to doxorubicin were seen in seven patients (37 percent), and stable disease was reported in another six. Pulmonary metastases appeared to be more likely to respond than bone metastases. By 1974, doxorubicin was considered the "drug of choice" for treating progressive, metastatic thyroid cancer [71]. Other studies of doxorubicin monotherapy have utilized varying definitions of response, but with similar results (30 to 40 percent partial response) [68].

In a subsequent report of patients with documented progressive disease prior to chemotherapy, partial response (using World Health Organization [WHO] criteria) after six months of doxorubicin treatment was seen in only 5 percent of patients, and stable disease between 1 and 22 months of duration was described in another 42 percent [72]. Response was significantly higher in those patients treated with 60 mg/m2 every three weeks, compared with 15 mg/m2 weekly. Overall, best responses occurred in patients with pulmonary metastases and high performance status.

The recommended dose of doxorubicin for monotherapy is 60 to 75 mg/m2 every three weeks, administered as a continuous intravenous infusion for 48 to 72 hours to minimize the risk of cardiac toxicity. Cumulative doses of up to 600 mg/m2 can be administered in responsive patients. Common adverse events can include granulocytopenia with accompanying infections, nausea, vomiting, and alopecia.

Taxanes – The use of taxanes in DTC is primarily based upon suggestion of efficacy in anaplastic carcinoma [73], rather than specific clinical trials. One report described three patients with metastatic DTC, all of whom had progressed despite radioiodine therapy [74]. Biweekly treatment with docetaxel led to disease stabilization in all three, lasting 14 to 18 months, but no objective responses were described.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)

SUMMARY AND RECOMMENDATIONS

Approach to identifying patients for systemic therapy

Patients should be evaluated with comprehensive CT and/or MRI to establish the extent of disease and disease progression. Prior to therapy or in any patient with suspicious symptoms, imaging of the brain should be performed to rule out intracranial metastases that might require other forms of intervention first, such as surgery or radiation. (See 'Patient selection for systemic therapy' above.)

Patients with asymptomatic metastatic tumors generally less than 1 to 2 cm in diameter and growing in diameter less than 20 percent per year can usually be monitored for disease progression (active surveillance). Known sites of metastatic disease should be imaged by CT or MRI every six months, and potential new sites of disease should be imaged every 12 to 24 months. (See 'Patient selection for systemic therapy' above.)

Patients with metastatic, unresponsive tumors at least 1 to 2 cm in diameter and growing by at least 20 percent per year, or patients with symptoms related to multiple metastatic foci that cannot be alleviated with surgery or EBRT are candidates for systemic therapy (algorithm 1). (See 'Patient selection for systemic therapy' above.)

General principles of initial systemic therapy

We prefer to administer systemic treatment in the context of a clinical trial. (Active clinical trials can be identified at: ClinicalTrials.gov.) Increasingly, these options are dictated by the presence of specific gene mutations or signaling pathway abnormalities that are the targets of approved or investigational therapies. (See 'General principles' above.)

For patients, who are unable to participate in clinical trials, the choice of initial kinase inhibitor depends on the result of somatic mutation testing, if available. (See 'General principles' above.)

For patients whose disease burden, rate of tumor growth, or symptoms necessitate consideration of systemic therapy options, somatic mutation testing can be performed to identify oncogenic kinase abnormalities that might suggest specific treatment options that cannot be administered in the absence of mutational data (eg, gene rearrangements in NTRK, ALK, or RET, or point mutations in BRAF). Given the high cost of such testing and lack of coverage by many insurance providers, this option may not be realistic for many patients even if the lack of testing limits therapeutic options. (See 'Initial systemic therapy' above.)

Selection of initial systemic therapy

In the absence of a mutation, or if results are not available, we suggest lenvatinib rather than another antiangiogenic multikinase inhibitor (aaMKI) (Grade 2B). Among the other aaMKIs, sorafenib is our next preferred option. (See 'Targetable mutation not identified' above.)

If tumor mutation results are available, we suggest a mutation-specific kinase inhibitor (eg, a RET, TRK, or BRAF inhibitor) if one of those mutations has been documented (Grade 2C). BRAF inhibitors can be considered for those patients with radiographically progressive, radioiodine-refractory BRAF V600-mutant papillary thyroid cancer for whom antiangiogenic therapy might be contraindicated or if a redifferentiation approach is entertained. (See 'Targetable mutation identified' above.)

Evaluating response to treatment

Patients require imaging (CT or MRI) of known or suspected sites of disease every two to four months to determine response to therapy. (See 'Imaging and assessment of adverse events' above.)

Patients should also be assessed for potential treatment- and disease-related complications. (See 'Imaging and assessment of adverse events' above.)

Patients being treated with a BRAF or other mitogen-activated protein kinase (MAPK)-pathway inhibitor may undergo diagnostic radioiodine imaging to determine if sufficient restoration of radioiodine uptake has occurred to permit subsequent radioiodine therapy. (See 'Assessment for restoration of radioiodine uptake (redifferentiation)' above.)

Refractory disease

For patients who cannot tolerate or in whom initial therapy with an aaMKI fails, we discuss investigational agents, further attempts with other aaMKIs (eg, cabozantinib), or, if not done previously, somatic mutation testing to suggest mutation-specific treatment options, eg, a BRAF inhibitor (eg, vemurafenib or dabrafenib), a RET inhibitor (selpercatinib), or TRK inhibitor (eg, larotrectinib or entrectinib). (See 'Refractory disease or kinase intolerance' above.)

For patients who cannot tolerate or in whom initial therapy with a mutation-specific kinase inhibitor fails, an aaMKI such as lenvatinib is an alternative. (See 'Targetable mutation identified' above and 'Refractory disease or kinase intolerance' above.)

Doxorubicin is an alternative for patients who are unable to tolerate or who fail several attempts at kinase inhibitor therapy. (See 'Refractory disease or kinase intolerance' above and 'Therapies infrequently used' above.)

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References

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