Medullary thyroid cancer: Systemic therapy and immunotherapy

INTRODUCTION — Medullary thyroid cancers (MTCs) are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine, in contrast with the normal thyroid follicular cells and many of the differentiated cancers that derive from them. MTCs occur both as sporadic tumors and as inherited components of multiple endocrine neoplasia (MEN) type 2. They can secrete calcitonin and carcinoembryonic antigen (CEA), both of which can serve as tumor markers, along with other humoral substances that may contribute to paraneoplastic syndromes.

The primary treatment for MTC is extensive and meticulous surgical resection. There is a limited role for external beam radiotherapy (EBRT). Unlike differentiated thyroid cancers, the neuroendocrine-derived MTC is not responsive to either radioiodine or thyroid-stimulating hormone (TSH) suppression. Therefore, these options are not appropriate for treatment of progressive metastatic MTC.

For patients with progressive or symptomatic metastatic disease who cannot be treated by surgery, radiotherapy, or other focal ablative interventions, targeted systemic therapies are effective interventions. Additional investigational options are emerging. Alternatively, treatment with either cytotoxic chemotherapy or biologic response modifiers may provide some benefit for occasional patients who fail or are ineligible for targeted therapies.

Current and experimental systemic therapy for advanced medullary thyroid carcinomas will be reviewed here. The diagnosis and surgical treatment of medullary thyroid cancer as well as systemic therapies for differentiated and anaplastic thyroid carcinomas are discussed separately.

●(See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

●(See "Medullary thyroid cancer: Surgical treatment and prognosis".)

●(See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy".)

●(See "Anaplastic thyroid cancer".)

PATIENT SELECTION FOR SYSTEMIC THERAPY — For patients with progressive or symptomatic metastatic disease who cannot be treated by surgery, radiotherapy, or other focal interventions, targeted systemic therapies are effective interventions. These therapies have significant toxicities and, therefore, it is important to limit the use of systemic treatments to patients with adequate baseline performance status and with significant risk for morbidity or mortality due to progressive metastatic disease.

●Performance status – Patients should have a baseline performance status sufficiently functional to tolerate systemic therapy. The Eastern Cooperative Oncology Group [ECOG] scale is a commonly used metric to measure performance status (table 1). Patients with a performance status of 2 or better usually tolerate therapy better than those with a worse score.

●Progressive metastatic disease – Patients with metastatic disease are monitored for progression with serum calcitonin and carcinoembryonic antigen (CEA) levels measured every three to six months as well as computed tomography (CT) and/or magnetic resonance imaging (MRI) of the neck, chest, and abdomen to monitor growth of disease. The frequency of repeating imaging studies is dependent on the magnitude and rate of rise of the calcitonin and CEA values. Radionuclide bone imaging can be helpful in selected cases when cross-sectional imaging fails to identify the source of the persistent hypercalcitoninemia. Fluorine-18-fludeoxyglucose-positron emission tomography (FDG-PET) and gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (Ga-68-DOTATATE-PET) can both be used when biochemical and anatomic progression do not correlate, to detect small soft tissue lesions, bone lesions, or lesions outside the field of view of cross-sectional scans; some studies favor GA-DOTATATE over FDG-PET [1,2]. However, these advanced imaging modalities may not be uniformly available. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Subsequent management'.)

Patients with adequate performance status and any of the following are candidates for systemic therapy:

•Symptoms related to multiple metastatic foci that cannot be addressed with local intervention (surgery, external beam radiotherapy [EBRT], or focal ablative procedures).

•Metastatic tumors ≥1 to 2 cm in diameter, growing by ≥20 percent per year. Emphasis should be placed on overall tumor burden or individual lesion location, growth trajectory, and potential for symptomatic morbidity if disease is allowed to progress further.

•Calcitonin doubling times ≤2 years (particularly those with calcitonin doubling times <6 months).

Patients without any of these features can usually be monitored, treating symptoms like diarrhea with symptomatic support. Known sites of metastatic disease should be imaged by CT or MRI every 6 to 12 months, and screening for potential new sites of disease should be performed every 12 to 24 months. Scanning frequency within the range suggested can be guided by CEA and calcitonin serial measurements measured every three to six months. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Serum calcitonin and CEA measurement'.)

CHOICE OF INITIAL THERAPY — Increasingly, therapeutic selections are dictated by the presence of specific gene mutations or signaling pathway abnormalities that are the targets of approved or investigational therapies. Patients with progressive metastatic disease that warrants systemic therapy should have molecular characterization of the primary tumor (or metastatic foci) to identify tumors that harbor a somatic RET pathogenic variant (which would suggest treatment with a specific RET inhibitor) (algorithm 1). Targeted therapies can potentially provide long-term disease stabilization and delay progression in selected patients; however, no study has yet reported improved survival.

Consistent with several consensus guidelines statements, molecular testing should be performed in an appropriately accredited laboratory using clinically validated procedures [3]. Although RET mutation testing may be performed on most surgically obtained specimens, or even on specimens that derive from fine-needle aspiration (FNA), testing should be attempted on the most recently obtained tissue to optimize likelihood of adequate deoxyribonucleic acid (DNA) retrieval. In the absence of available tumor-derived tissue, DNA extracted from a blood specimen (ie, a "liquid biopsy") can occasionally identify a tumor-derived RET mutation. Multiple commercial laboratories now perform such molecular testing routinely, with instructions for specimen collection and third-party payer authorization available on their individual websites; individual pharmaceutical companies that market RET-selective inhibitors may also sponsor reduced-cost testing programs.

The following treatment strategy is based upon data from randomized trials, open-label studies, and clinical experience. Our approach is largely consistent with the American Thyroid Association (ATA) guidelines [4].

RET mutation identified: Selective RET kinase inhibitor — Pathogenic variants in RET are detected in most medullary thyroid cancers (MTCs). For patients whose tumors bear somatic or germline RET mutations, we recommend a selective RET kinase inhibitor (selpercatinib) rather than an antiangiogenic multikinase inhibitor (aaMKI), based on improved outcomes in open-label, randomized and nonrandomized trials, as well as relatively lower levels of adverse effects compared with aaMKIs (algorithm 1) [4-7]. (See 'Vandetanib' below and 'Cabozantinib' below.)

The nature of the underlying RET mutation may influence the outcome. Selpercatinib appears to have excellent inhibitory potential against the "gatekeeper" mutation in RET codon 804, in contrast with vandetanib or cabozantinib. However, mutations in codon 810 may yield resistance to selpercatinib, and such mutations have been reported to emerge in patients on therapy with RET-selective inhibitors [8].

Selpercatinib — Selpercatinib is a US Food and Drug Administration (FDA)-approved oral kinase inhibitor used to treat advanced or metastatic MTC and other types of thyroid cancers that have an alteration (mutation or fusion) in the RET gene [9].

●Efficacy – Selpercatinib reduces risk of disease progression when compared with cabozantinib or vandetanib. It is also effective in patients previously treated with cabozantinib and/or vandetanib. As examples:

•In the open-label, randomized trial (LIBRETTO-531) comparing selpercatinib with either cabozantinib or vandetanib in 291 patients with progressive, locally advanced or metastatic RET-mutant MTC who had not previously received treatment with a kinase inhibitor, median progression-free survival was not reached in the selpercatinib group and was 16.8 months in the active comparator group (HR for disease progression or death 0.28, 95% CI 0.16-0.48) [7]. The 12-month progression-free survival was better with selpercatinib (86.8 versus 65.7 percent with cabozantinib or vandetanib). Complete response occurred in 11.9 and 4 percent, respectively, and partial response in 57.5 and 34.7 percent, respectively.

There were fewer adverse events of grade 3 or higher in the selpercatinib group (52.8 versus 76.3 percent), and fewer patients discontinued treatment due to adverse events (4.7 versus 26.8 percent). Treatment failure-free survival, a composite endpoint that captures improved efficacy and reduced toxicity, at 12 months was 86.2 percent (95% CI 79.1-91.0) in the selpercatinib group and 62.1 percent (95% CI 48.9-72.8) in the control group. With a small number of mortality events recorded, overall survival appeared to favor the selpercatinib group as well.

•In the open-label LIBRETTO-001 study of selpercatinib in 143 patients with advanced RET-mutant MTC, previously treated or not treated with cabozantinib and/or vandetanib, the overall response rate (ORR) was 69 and 73 percent, respectively [10]. Complete response was reported in 9 percent of patients previously treated with an aaMKI and 11 percent in those who were treatment naive; partial response was 60 and 61 percent, respectively. Although median progression-free survivals have still not been reached, 12-month rates were 82 and 92 percent, respectively. For patients with disease-related symptoms such as diarrhea or ectopic Cushing syndrome, selpercatinib can lead to rapid palliation [11].

•Due to the rapid tumor shrinkage seen with selpercatinib [12], another trial is evaluating selpercatinib before thyroidectomy (ie, neoadjuvant therapy) in patients with locally advanced primary tumor or nodal metastases. (See "Medullary thyroid cancer: Surgical treatment and prognosis", section on 'Locally advanced or metastatic MTC'.)

●Dosing and monitoring – For patients ≥50 kg, the initial dose is 160 mg twice daily (with or without food), whereas for patients <50 kg, it is 120 mg twice daily. It is important to avoid concomitant use of gastric acid-reducing medications, which can reduce plasma concentrations of selpercatinib. If not possible and the patient is taking a proton pump inhibitor, selpercatinib should be taken with food. If patients are taking a locally acting antacid or an H2 receptor antagonist, selpercatinib should be taken two hours before the acid-reducing medication, or 2 or 10 hours after the locally acting antacid or H2 receptor antagonist, respectively. Dose reductions for adverse reactions may be necessary (eg, reduce both the morning and evening dose by 40 mg).

Liver biochemical tests should be measured prior to initiating selpercatinib and every two weeks after initiation. If liver tests remain stable after the first three months, monitor monthly thereafter. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Selpercatinib'.)

Assess QT interval, electrolytes, and TSH prior to initiation and periodically thereafter. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Selpercatinib'.)

●Adverse effects – The most common grade 3 or 4 adverse events included hypertension (21 to 42 percent), increased alanine aminotransferase (11 to 26 percent), increased aspartate aminotransferase (9 to 24 percent), hyponatremia (8 percent), and diarrhea (6 to 26 percent). Common side effects occurring in ≥20 percent of patients included dry mouth (32 percent), diarrhea, constipation, nausea, abdominal pain, rash, hypertension, headache, fatigue, and edema [7,10]. Severe adverse effects included hypertension (18 percent) and QT prolongation (4 percent). Hypersensitivity reactions occurred in approximately 4 to 5 percent of patients. Increased levothyroxine dose requirements were observed in 13 percent of patients. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Selpercatinib'.)

Pralsetinib — Pralsetinib is an FDA-approved oral kinase inhibitor used to treat advanced or metastatic RET fusion-positive thyroid cancers. In July 2023, the manufacturer voluntarily withdrew the preliminary FDA-approved indication for RET-mutant MTC due to an inability to complete the trial needed to fulfill postmarketing requirements. The decision to withdraw the indication was not due to any new safety or efficacy data [13].

●Efficacy – In the open-label ARROW trial, 122 patients with RET-mutant MTC were treated with pralsetinib [14]. The overall response rate was 60 percent in patients who had previously been treated with cabozantinib and/or vandetanib and 71 percent in patients who were treatment naïve. In the 55 patients previously treated with cabozantinib and/or vandetanib, the partial and complete response rates were 58 and 1.8 percent, respectively [15,16].

●Dosing and monitoring – In adults, initial dose is 400 mg once daily, on an empty stomach. Dose adjustments may be necessary for adverse reactions or potential drug interactions. Liver biochemical tests should be measured prior to initiating pralsetinib and every two weeks after initiation. If liver tests remain stable after the first three months, monitor monthly thereafter. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Pralsetinib'.)

●Adverse effects – The most common grade 3 or 4 adverse events included hypertension (17 percent), fatigue (6 percent), diarrhea (5 percent), fever (2.2 percent), and dyspnea (2.2 percent). Elevations in aminotransferases are common.

RET mutation not identified — If a RET mutation is not identified, we prefer to administer systemic treatment as part of a clinical trial where available.

Targetable mutation other than RET identified — Usually in the absence of a RET mutation, other oncogenic mutations (eg, mutations in the RAS gene or activating rearrangements of the ALK gene) can be observed with extended genomic testing. In these instances, available targeted drug therapy can be used. If not available, participation in a clinical trial of more selective kinase inhibitors targeting the rare mutated gene may be considered [17,18]. If a clinical trial is not feasible, patients are generally treated with an oral aaMKI.

Targetable mutation not identified (or mutation analysis not available): aaMKI — For patients without a RET or other targetable mutation, who are unwilling or unable to participate in clinical trials, we suggest either vandetanib or cabozantinib as the initial choice of oral aaMKI (algorithm 1). Sorafenib, sunitinib, or lenvatinib are reasonable options for patients who fail either or both cabozantinib and vandetanib.

As in other tumors, constitutively activated tyrosine kinases stimulate tumor proliferation, angiogenesis, invasion, and metastasis. Small molecule inhibitors of select tyrosine kinases have been studied in advanced MTC, given the oncogenic role of inherited and somatic mutations in the tyrosine kinase RET, as well as the contributory roles of tyrosine kinases in growth factor receptors such as the vascular endothelial growth factor receptor (VEGFR) [19,20]. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Overview of angiogenesis inhibitors", section on 'Small molecule tyrosine kinase inhibitors'.)

In randomized trials of aaMKIs with nonselective RET inhibitory activity (eg, vandetanib, cabozantinib), partial responses are reported in approximately 20 to 60 percent of patients [5,21]. Although complete responses are rare, kinase inhibitors can potentially provide long-term disease stabilization. However, data on the ability of any of these agents to improve survival are limited. aaMKIs potently inhibit multiple kinases and often affect multiple signaling pathways. The inhibitory activity against VEGFR contributes to toxicities.

In the studies described below, the definitions of tumor response are based upon the now-standard Response Evaluation Criteria in Solid Tumors (RECIST), version 1 [22].

Vandetanib — Vandetanib is an oral inhibitor that targets VEGFR, RET, and the epidermal growth factor receptor (EGFR) [23]. It is available in the United States through a Risk Evaluation Mitigation Strategy (REMS) program and in Europe, where it is monitored by the Commission on Human Medicines and the Medicines and Healthcare products Regulatory Agency [24-27]. It is approved for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease. In the United States, distribution is restricted to prescribers and pharmacies participating in the REMS program. In Europe, the European Medicines Agency has only provided approval of vandetanib for treatment of patients with a confirmed RET mutation [28].

●Efficacy – In a phase II trial limited to patients with metastatic or unresectable hereditary MTC (either familial MTC or multiple endocrine neoplasia type 2A [MEN2A]), vandetanib (300 mg daily) was administered to 30 patients [29]. Confirmed partial response was observed in six (20 percent) patients, and another 16 (53 percent) patients had stable disease lasting at least 24 weeks. The most common adverse events that occurred in more than one-half of patients were diarrhea, rash, fatigue, and nausea.

An international, randomized phase III trial of vandetanib (300 mg daily) was performed in over 300 patients with unresectable locally advanced or metastatic sporadic or hereditary MTC. After a median follow-up of 24 months, vandetanib prolonged progression-free survival compared with placebo (hazard ratio [HR] 0.46, 95% CI 0.31-0.69) [24,30]. The median progression-free survival had not yet been reached for the vandetanib group but was predicted to be 30.5 months compared with 19.3 months in the placebo group. The objective response rate was significantly higher in the vandetanib group (45 versus 13 percent). No difference was observed in overall survival between the two treatment arms despite the improvement in progression-free survival, although the final survival analysis will be performed when sufficient number of deaths have occurred.

In a post hoc analysis, patients with both progressive and stable disease were eligible for enrollment, and outcomes were similar in the two groups [31]. However, patients with carcinoembryonic antigen (CEA) doubling times greater than 24 months were unlikely to benefit from treatment. The presence of a somatic RET M918T mutation predicted an improved progression-free survival [30]. In a subsequent reanalysis of RET genotyping from the randomized phase III trial, combined with an additional cohort of 50 patients, efficacy of vandetanib in patients lacking a confirmed somatic RET mutation was markedly limited compared with RET-positive patients [32].

●Dosing and administration – The recommended starting daily dose is 300 mg orally. For patients with moderate kidney impairment (creatinine clearance 30 to 50 mL/min), the starting dose should be reduced to 200 mg daily. Use is not recommended with creatinine clearance <30 mL/minute. As part of the REMS program requirements, electrocardiograms (ECGs) and serum potassium, calcium, magnesium, and TSH should be obtained at 2 to 4 weeks and 8 to 12 weeks after starting treatment, and every 3 months thereafter. Patients with diarrhea may require more frequent monitoring.

A randomized trial evaluated the relative efficacy and tolerability of starting with the lower 150 mg daily dose compared with the approved 300 mg dose in 81 patients with progressive MTC [33]. The objective response rate was 29 percent (95% CI 17.6-44.5 percent) in patients who started at 300 mg daily compared with 20 percent (95% CI 10.5-34.8 percent) in those who started at only 150 mg daily. Side effects were typical of those previously reported with the drug, though more commonly seen at the higher starting dose.

Cabozantinib — Cabozantinib is an oral, small molecule kinase inhibitor that targets VEGFRs 1 and 2, c-MET, and RET [34]. The inhibitory activity against c-MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC. Cabozantinib is approved by the FDA for the treatment of progressive, metastatic MTC [35].

●Efficacy – In a phase I, dose-escalation study, 10 of 35 MTC patients (29 percent) achieved a confirmed partial response [36]. Stable disease of at least six months duration was observed in 15 of 37 patients with MTC. The overall rate of partial responses and six-month, progression-free survival was 68 percent. Responses were seen in patients regardless of the RET mutation status of their tumors, indicating that the drug is active in patients without RET activating mutations.

In a randomized trial, 330 patients with progressive, metastatic or unresectable locally advanced MTC were randomly assigned to receive either cabozantinib (140 mg) or placebo once daily [35,37,38]. A significant prolongation in progression-free survival was observed for cabozantinib treatment compared with placebo (11.2 versus 4.0 months; HR 0.28, 95% CI 0.19-0.40). Partial responses were observed in 27 versus 0 percent. Median overall survival was nonsignificantly improved by 5.5 months with cabozantinib therapy (26.6 versus 21.1 months; HR 0.85, 95% CI 0.64-1.12) [39].

In a subsequent analysis, progression-free survival was markedly improved in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 versus 17 weeks; HR 0.15, 95% CI 0.08-0.28), or whose tumors contained RAS mutations (47 versus 8 weeks; HR 0.15, 95% CI 0.02-1.10) [40]. Although no improvement in progression-free survival was observed in patients whose tumors lacked either a RET or RAS mutation, the partial response in that cohort was 21 percent, indicating that there was still some degree of activity of the drug regardless of known mutation status. In a post hoc analysis, overall survival was significantly improved in patients with RET M918T mutations (44.3 months with cabozantinib versus 18.9 months with placebo; HR 0.60, 95% CI 0.38-0.94) [41].

●Dosing and administration – The recommended starting dose of cabozantinib is 140 mg daily, with dose reductions to adjust for tolerability.

Lower starting doses, such as 60 mg used for other malignancies, are also well tolerated but may be less effective. In a preliminary report from the phase IV EXAMINER trial comparing two different cabozantinib formulations (60 mg tablet versus 140 mg capsule) in patients with progressive metastatic MTC, both dose regimens showed activity in advanced MTC. However, the 60 mg tablet did not meet prespecified noninferiority criteria for progression-free survival versus the 140 mg capsule. The safety profile was consistent with that observed previously with single-agent cabozantinib [42].

Although not mandated in its approval, safety monitoring during therapy should include periodic assessment (eg, monthly at initiation) of electrolytes, calcium, and TSH.

Side effects and their management — Side effects that are common to all the VEGF-targeted aaMKIs include hypertension, renal toxicity, bleeding, myelosuppression, arterial thromboembolism, cardiotoxicity, cutaneous toxicity including hand-foot skin reaction, delayed wound healing, hepatotoxicity, and muscle wasting. These side effects and their management are discussed in detail elsewhere. For patients with post-thyroidectomy hypothyroidism or reduced parathyroid function, aaMKIs can also lead to increased dose requirements for thyroid hormone and vitamin D derivatives. (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".)

Contraindications to or intolerance of aaMKIs — 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 [43].

For patients with contraindications to or intolerance of aaMKIs, cytotoxic chemotherapy or investigational therapies are alternatives (algorithm 1). (See 'Traditional cytotoxic agents' below and 'Investigational therapy' below.)

EVALUATE RESPONSE TO THERAPY — Patients with metastatic disease are monitored for progression with serum calcitonin and carcinoembryonic antigen (CEA) levels measured every three to six months as well as CT and/or MRI of the neck, chest, and abdomen to monitor growth of disease. The frequency of repeating imaging studies is dependent on clinical factors (eg, magnitude and rate of rise of the calcitonin and CEA values, location of lesions, overall burden of disease). (See 'Patient selection for systemic therapy' above.)

Stable disease — For patients with stable disease, continue same therapy with continued monitoring.

Disease progression — For patients who progress on a preferred kinase inhibitor, a trial of other kinase inhibitors is warranted. A biopsy can be performed on a progressing or resistant lesion with genomic testing to identify potential mechanism of resistance (algorithm 1).

●RET mutation present – Selection of another first-generation selective RET inhibitor or an investigational second-generation agent should be based upon updated mutational profile.

●RET mutation absent – If disease progresses while on preferred aaMKIs (vandetanib, cabozantinib), a trial of a different antiangiogenic multikinase inhibitor (aaMKI; eg, sorafenib, sunitinib, lenvatinib) is warranted. (See 'Other aaMKIs' below.)

●Patients treated with multiple kinase inhibitors – For patients who are unable to tolerate or who fail several attempts at kinase inhibitor therapy, cytotoxic chemotherapy is an alternative. Among the cytotoxic agents, dacarbazine-based regimens, such as cyclophosphamide-vincristine-dacarbazine, may be preferable. (See 'Traditional cytotoxic agents' below.)

Other aaMKIs — Sorafenib, sunitinib, and lenvatinib may be used in highly selected patients with advanced medullary thyroid cancer (MTC) who are unable to participate in clinical trials and who progress on preferred therapies. These aaMKIs are generally considered second- or third-line therapy.

●Lenvatinib – Lenvatinib is an orally administered aaMKI that targets vascular endothelial growth factor receptor (VEGFRs), RET, and fibroblast growth factor receptors (FGFRs) 1 to 4. In a phase II trial, 59 patients with surgically unresectable, progressive MTC were treated with lenvatinib, starting at 24 mg daily [44]. The best overall response rate was 35 percent (95% CI 24-49 percent), all partial responses. Another 44 percent had stable disease. Identical response rates were observed in the cohorts previously treated and never treated with prior VEGFR-targeted therapies. Median progression-free survival and overall survival were 9.0 months (95% CI 7.0-not estimable) and 16.6 months (95% CI 14.0-not estimable), respectively. Typical side effects were observed, including diarrhea, hypertension, and decreased appetite. (See 'Side effects and their management' above.)

Lenvatinib is approved in the United States to treat progressive, metastatic, radioiodine-refractory differentiated thyroid cancer. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Targetable mutation not identified'.)

●Sorafenib – Sorafenib is an oral, small molecule aaMKI that targets VEGFR 2 and 3 and most mutant forms of RET [45]. In a pilot study, five patients with metastatic MTC were treated with sorafenib, starting at 400 mg twice daily [46]. After six months of treatment, responses were described in two (including one complete response) and symptomatic improvement was seen in all, but most patients required a dose reduction due to side effects.

In addition, preliminary results from a larger (n = 16), open-label, phase II study of sorafenib in patients with metastatic MTC showed a partial response in one patient with sporadic MTC and a median progression-free survival of nearly 18 months [47]. Partial response (n = 3) or durable stable disease (n = 3) was also reported in six of eight MTC patients participating in a phase I study of combination sorafenib and tipifarnib [48].

Sorafenib is approved in the United States for treatment of unresectable hepatocellular cancer, advanced renal cell cancer, and progressive, radioiodine-refractory differentiated thyroid cancer. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Targetable mutation not identified'.)

●Sunitinib – Sunitinib is an oral, small molecule aaMKI that targets all three VEGFRs and RET [49]. Limited results in patients with MTC include the following:

•A prolonged partial response was described in one patient with MTC treated with sunitinib, 50 mg daily for 28 days followed by 14 days of no treatment per cycle [50].

•In an open-label, phase II trial in patients with progressive refractory thyroid cancer (n = 7 with MTC) with a median follow-up of 15.5 months, three MTC patients had a complete or partial response, and disease stabilization occurred in two [51].

•Interim analysis from a second open-label, phase II trial reported partial responses or stable disease for greater than 12 weeks in three of eight MTC patients [52].

Sunitinib is approved in the United States for treatment of advanced renal cell cancer and for refractory gastrointestinal stromal tumors.

Traditional cytotoxic agents — We reserve cytotoxic agents for patients who cannot tolerate or progress while taking selective RET kinase inhibitors and aaMKIs and who are unable to participate in clinical trials. In patients with progressive metastatic MTC, treatment with traditional cytotoxic agents provides limited benefit. Partial responses are reported in approximately 10 to 20 percent of patients, but long-term responses are uncommon. The availability of kinase inhibitors that can stabilize progressive metastatic disease has changed the standard approach to treating these patients, limiting the role of cytotoxic agents.

Most regimens for patients with MTC combine dacarbazine with other agents, including vincristine, fluorouracil, cyclophosphamide, streptozocin, or doxorubicin, without significant advantage of one combination compared with another [53]. In one widely cited report, the combination of cyclophosphamide (750 mg/m²), vincristine (1.4 mg/m²), and dacarbazine (600 mg/m² daily for two days in each cycle) every three weeks was administered to seven patients with metastatic MTC [54]. Two patients experienced >50 percent shrinkage in tumor dimensions lasting more than one year, and two others had stable disease.

A more complex regimen (repeating cycles of doxorubicin 60 mg/m² on day one, and streptozocin 500 mg/m² daily for five consecutive days, followed four weeks later with fluorouracil 400 mg/m² and dacarbazine 200 mg/m² daily for five consecutive days) was given to 20 patients with progressing distant metastases [55]. Three patients (15 percent) had partial responses lasting more than 18 months, and 10 (50 percent) were stable for at least eight months. Toxicities of dacarbazine include neutropenia, thrombocytopenia, nausea, vomiting, and hepatotoxicity.

Doxorubicin (60 to 75 mg/m² every three weeks, or 15 mg/m² weekly) is approved by the US Food and Drug Administration (FDA) for the treatment of all histologies of metastatic thyroid carcinoma including MTC, but fewer than 30 percent of patients have an objective response, none are complete, and the duration is generally short [56,57].

Doxorubicin is administered as a continuous intravenous infusion for 48 to 72 hours to minimize the risk of cardiac toxicity. Common adverse events can include granulocytopenia with accompanying infections, nausea, vomiting, and alopecia.

INVESTIGATIONAL THERAPY

Immunotherapy — Immunotherapy of thyroid cancer holds some promise but has had little clinical application. One approach is to induce host immunity to the tumor by administering tumor-derived vaccines or inoculations of tumor-cell transfectants expressing specific cytokines. Another is to administer monoclonal antibodies coupled to radioisotopes to deliver radiotherapy. These therapies have been tried more often for patients with medullary thyroid cancer (MTC) than for other types of thyroid cancer. However, they remain investigational. (See "Principles of cancer immunotherapy".)

Tumor vaccines — A novel approach to targeted immunotherapy is the use of tumor vaccines. Dendritic cells, which are derived from bone marrow antigen-presenting cells, are capable of presenting tumor-associated antigens, thereby generating cytotoxic T-cells targeting tumor cells.

In preliminary studies in patients with metastatic MTC, treatment with stimulated dendritic cells was promising, as illustrated by the following:

●In one study, dendritic cells were obtained from each of seven patients and stimulated in the presence of both calcitonin and carcinoembryonic antigen (CEA) [58]. Following periodic intracutaneous injections of the stimulated dendritic cells, one patient experienced a partial response, including complete regression of hepatic metastases, which was associated with a 70 percent reduction in serum tumor markers. Two other patients had mixed responses.

●In another study, dendritic cells were stimulated using lysates of each individual patient's surgically resected primary tumor [59]. Three of 10 patients had partial responses, including one with complete resolution of radiographic evidence of disease.

Toxicities in both trials were minor, including low-grade fever and asymptomatic transient autoantibody development. Further small studies are underway, refining the procedures to enhance the potency of the dendritic cell vaccines [60,61].

Radioimmunotherapy — The expression of CEA on MTC cells led to the exploitation of radiolabeled anti-CEA monoclonal antibodies for radioimmunotherapy. In the initial trials, antitumor effects were noted using anti-CEA/anti-diethylenetriamine pentaacetic acid (DTPA)-indium recombinant bispecific antibody (BsMAb), followed four days later by a 131I-labeled indium hapten [62]. In a subsequent nonrandomized trial in patients with progressive metastatic MTC (defined as a calcitonin doubling time less than two years), median overall survival after administration of this therapy was 110 months [63]. This compared favorably with a contemporaneous untreated cohort's median survival of only 60 months.

Significant toxicities included grade 4 neutropenia and thrombocytopenia, lasting up to three weeks, and one patient (who had received previous radiotherapies) developed myelodysplasia.

Radiolabeled octreotide — In a phase II trial in 31 patients with progressive metastatic MTC, treatment with radiolabeled octreotide, (90)Yttrium-1,4,7,10-tetra-azacyclododecane N,N',N'',N'''-tetraacetic acid [(90)Y-DOTA]-Tyr(3)-octreotide (TOC) resulted in decreases in calcitonin levels in nine patients (29 percent) [64,65]. Responders had a significantly longer median survival (109 months from time of diagnosis compared with 80 months in nonresponders). Hematologic and renal toxicities occurred in four and seven patients, respectively.

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: Medullary thyroid cancer".)

SUMMARY AND RECOMMENDATIONS

●Medullary thyroid cancer – Medullary thyroid cancers (MTCs) are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine. The primary treatment for MTC is extensive and meticulous surgical resection. There is a limited role for external beam radiotherapy (EBRT). (See "Medullary thyroid cancer: Surgical treatment and prognosis".)

●Patient selection for systemic therapy – Systemic "targeted therapies" have significant toxicities. Therefore, it is important to limit the use of systemic treatments to patients with adequate baseline performance status (eg, Eastern Cooperative Oncology Group (ECOG) performance status ≤2; (table 1)) and with significant risk for morbidity or mortality due to progressive metastatic disease, including any of the following:

•Symptoms related to multiple metastatic foci that cannot be addressed with local intervention (surgery, EBRT, or focal ablative procedures).

•Metastatic tumors ≥1 to 2 cm in diameter, growing by ≥20 percent per year. Emphasis should be placed on overall tumor burden or individual lesion location, growth trajectory, and potential for symptomatic morbidity if disease is allowed to progress further.

•Calcitonin doubling times ≤2 years (particularly those with calcitonin doubling times <6 months).

Patients without any of these features can usually be monitored for disease progression, treating symptoms like diarrhea with symptomatic support. (See 'Patient selection for systemic therapy' above.)

●Choice of therapy – Patients with progressive metastatic disease that warrants systemic therapy should have molecular characterization of the primary tumor (or metastatic foci) to identify tumors that harbor a somatic RET pathogenic variant (which would suggest treatment with a specific RET inhibitor) (algorithm 1).

•RET mutation identified – For initial therapy in patients with RET-mutated tumors who meet criteria for treatment, we recommend selpercatinib (a selective RET kinase inhibitor) rather than cabozantinib or vandetanib (antiangiogenic multikinase inhibitors [aaMKIs]) (Grade 1B). Selpercatinib improved progression-free survival in open-label, randomized and nonrandomized trials compared with cabozantinib or vandetanib. There were fewer adverse events of grade 3 or higher in the selpercatinib group, and fewer patients discontinued treatment due to adverse events. (See 'RET mutation identified: Selective RET kinase inhibitor' above and 'Selpercatinib' above.)

•RET mutation not identified – We prefer to administer systemic treatment as part of a clinical trial where available. If oncogenic mutations other than in the RET gene (eg, mutations in RAS gene, activating rearrangements of the ALK gene) are identified with extended genomic testing, participation in a clinical trial of more selective kinase inhibitors targeting the rare, mutated gene may be considered. If a clinical trial is not feasible, patients are generally treated with an aaMKI. (See 'RET mutation not identified' above.)

For patients without a RET or other targetable mutation who are unwilling or unable to participate in clinical trials, we suggest cabozantinib or vandetanib rather than another aaMKI (Grade 2C). Sorafenib, sunitinib, or lenvatinib are reasonable options for patients who have disease progression on cabozantinib and/or vandetanib. (See 'Vandetanib' above and 'Cabozantinib' above and 'Disease progression' above.)

●Evaluate response to therapy – Patients with metastatic disease are monitored for progression with serum calcitonin and carcinoembryonic antigen (CEA) levels measured every three to six months as well as CT and/or MRI of the neck, chest, and abdomen. The frequency of repeating imaging studies is dependent on clinical factors (eg, magnitude and rate of rise of the calcitonin and CEA values, location of lesions, overall burden of disease). Complete responses with these kinase inhibitors are uncommon, but these therapies can potentially provide long-term disease stabilization and delay progression in selected patients. (See 'Evaluate response to therapy' above.)

•Stable disease – For patients with stable disease, continue the same therapy with continued monitoring. (See 'Stable disease' above.)

•Disease progression – For patients who progress on initial therapy, a trial of other kinase inhibitors is warranted (algorithm 1). A biopsy can be performed on a progressing or resistant lesion with genomic testing to identify potential mechanism of resistance. Selection of another first-generation selective RET inhibitor or an investigational second-generation agent should then be based upon that updated mutational profile. For patients who cannot tolerate or who fail multiple kinase inhibitors, cytotoxic chemotherapy is an option. (See 'Disease progression' above.)

●Adverse effects – Toxicities of many of these new therapies are common and can be dose limiting. Clinicians must be familiar with recognizing and managing the side effects if they intend to use these agents. (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".)