INTRODUCTION — Medullary thyroid cancers (MTCs) are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine. They occur both as sporadic tumors and as components of multiple endocrine neoplasia (MEN) type 2. They secrete calcitonin and carcinoembryonic antigen (CEA), both of which can serve as tumor markers. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)
The primary treatment for MTC is extensive and meticulous surgical resection. There is a limited role for external beam radiotherapy. Because the neuroendocrine-derived MTC is not responsive to either radioiodine or thyroid-stimulating hormone (TSH) suppression, these options are not appropriate for treatment of progressive metastatic MTC. (See "Medullary thyroid cancer: Surgical treatment and prognosis".)
Patients with progressive or symptomatic metastatic disease who cannot be treated by surgery or radiotherapy should be considered candidates for systemic therapy. New approaches based upon application of targeted chemotherapies are now available as effective interventions for progressive disease, with additional investigational options 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 chemotherapies for advanced medullary thyroid carcinomas will be reviewed here. Chemotherapies for differentiated and anaplastic thyroid carcinomas are discussed separately. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy" and "Anaplastic thyroid cancer".)
SUGGESTED APPROACH — The availability of kinase inhibitors that can induce tumor shrinkage or stabilize progressive metastatic disease is changing the standard approach to treating metastatic MTC [1-5]. RET mutations are detected in most MTCs, and in these RET-mutated tumors, treatment with an agent that selectively targets RET (eg, selpercatinib, pralsetinib) is preferred [6]. Other potent and selective RET inhibitors such as TPX-0046 and BOS172738 are being tested in clinical trials. (See 'Mutation-selective kinase inhibitors' below.)
Antiangiogenic multikinase inhibitors (aaMKI) with nonselective RET inhibitory activity (eg, vandetanib, cabozantinib) have been used to treat patients with MTC with documented improvements in progression-free survival, although they are generally less potent than selective RET inhibitors. RET-selective inhibitors appear to be more effective and have a far more tolerable side-effect profile, but the data supporting their US Food and Drug Administration (FDA) approvals are considerably less robust than the phase III trials of either cabozantinib or vandetanib. (See 'Multitargeted kinase inhibitors' below.)
Complete responses with these kinase inhibitors are uncommon, but these therapies can potentially provide long-term disease stabilization and delay progression in selected patients. However, no study has yet reported these agents' effects to improve survival.
"Targeted therapies" have significant toxicities and, therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. 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).
In the absence of sufficient clinical trial data comparing both efficacy and safety of any individual drug or combination, the following treatment strategy is based upon clinical experience and data from open label studies. Our approach is consistent with the American Thyroid Association (ATA) Guidelines [3].
●For patients with asymptomatic metastatic tumors generally less than 1 to 2 cm in diameter, growing in diameter less than 20 percent per year, we continue to monitor, treating symptoms like diarrhea with symptomatic support. Known sites of metastatic disease should be imaged by computed tomography (CT) or magnetic resonance imaging (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 carcinoembryonic antigen (CEA) and calcitonin serial measurements.
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing by at least 20 percent per year, or for patients with symptoms related to multiple metastatic foci that cannot be addressed with local intervention (surgery or external beam radiotherapy), we prefer to administer systemic treatment as part of a clinical trial. 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.
•For patients whose tumors bear somatic or germline RET mutations, we suggest a selective RET kinase inhibitor (selpercatinib or pralsetinib), based on high frequency of objective response in open-label, nonrandomized trials and relatively lower levels of adverse effects compared with aaMKIs. (See 'Mutation-selective kinase inhibitors' below.)
•For patients without RET mutations, we suggest an oral aaMKI, such as cabozantinib or vandetanib. Sorafenib, sunitinib, or lenvatinib are reasonable options for patients who fail either or both cabozantinib and vandetanib. (See 'Multitargeted kinase inhibitors' below.)
•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 'Cytotoxic agents' below.)
KINASE INHIBITORS — As in other tumors, constitutively activated tyrosine kinases stimulate tumor proliferation, angiogenesis, invasion, and metastasis. Small molecule inhibitors of select tyrosine kinases have been of interest for the treatment of 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) [7,8]. These agents are used for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease. Most of the kinase inhibitors partially inhibit multiple kinases (antiangiogenic multikinase inhibitors [aaMKIs]) at nanomolar concentrations and often affect multiple signaling pathways. Selpercatinib is a RET-selective kinase inhibitor, though it retains far weaker inhibitory activity against VEGFR that contributes to toxicities. (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, partial responses are reported in approximately 20 to 60 percent of patients; randomized trials of RET-selective inhibitors have not been performed yet. 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.
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 [9].
Mutation-selective kinase inhibitors — RET mutations are detected in most MTCs, and in these RET-mutated tumors, treatment with an agent that selectively targets RET (eg, selpercatinib, pralsetinib) is preferred
Selpercatinib — Selpercatinib is a US Food and Drug Administration (FDA)-approved oral kinase inhibitor used to treat advanced or metastatic medullary thyroid cancer and other types of thyroid cancers that have an alteration (mutation or fusion) in the RET gene [10]. In the open-label LIBRETTO-001 trial of selpercatinib in 143 patients with advanced or metastatic RET-mutant MTC, previously treated or not treated with cabozantinib and/or vandetanib, the overall response rate (ORR) was 69 and 73 percent, respectively [11]. 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 Cushing's syndrome, therapy with selpercatinib can lead to rapid palliation [12].
A phase III randomized trial (NCT04211337), comparing selpercatinib with the clinician’s choice of cabozantinib or vandetanib, has been initiated. Due to the rapid tumor shrinkage seen with selpercatinib, a trial of neoadjuvant therapy (NCT04759911) is recruiting patients with locally advanced primary tumor or nodal metastases.
The nature of the underlying RET mutation may also influence the choice of therapy or outcome. Selpercatinib appears to have excellent inhibitory potential against the "gatekeeper" mutation in RET codon 804, in contrast with vandetanib or cabozantinib. However, "solvent front" mutations in codon 810 may yield resistance to selpercatinib, and such mutations have already been reported to emerge in patients on therapy with RET-selective inhibitors in other tumor types [13].
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). Common side effects occurring in ≥20 percent of patients included dry mouth, diarrhea, constipation, nausea, abdominal pain, rash, hypertension, headache, fatigue, and edema. Severe adverse effects included hypertension (18 percent) and QT prolongation (4 percent). Hypersensitivity reactions occurred in approximately 4 to 5 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 MTC and other types of thyroid cancers that have an alteration (mutation or fusion) in the RET gene [14]. In preliminary results from the open-label ARROW trial, 29 patients with RET-mutant MTC were treated with pralsetinib [14]. The overall response rate was 66 percent (partial response 55 percent, and complete response 10 percent). In 55 patients previously treated with cabozantinib and/or vandetanib, the overall response rate was 60 percent (partial and complete responses 58 and 1.8 percent, respectively) [15,16]. 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).
Multitargeted kinase inhibitors — We prefer that patients with progressive advanced or symptomatic MTC participate in clinical trials of targeted therapies. However, for those patients without a RET mutation, who are unwilling or unable to participate in clinical trials, we suggest either cabozantinib or vandetanib as the initial choice of oral aaMKI.
Vandetanib — Vandetanib is an oral inhibitor that targets VEGFR, RET, and the epidermal growth factor receptor (EGFR) [17]. 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 [18]. 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 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, progression-free survival was significantly prolonged for patients randomly assigned to vandetanib versus placebo (hazard ratio [HR] 0.46, 95% CI 0.31-0.69) [19,20]. 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 has been 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. Patients with both progressive and stable disease were eligible for enrollment, and outcomes were similar in the two groups in a post hoc analysis [21]. 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.
Common side effects occurring in ≥20 percent of patients included diarrhea/colitis, rash, dermatitis, nausea, hypertension, headache, fatigue, anorexia, abdominal pain, hypocalcemia, decreased glucose, and increased alanine aminotransferase (ALT). Severe adverse effects (occurring in ≥5 percent) included diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Torsades de pointes and sudden death have been reported in patients receiving vandetanib [22]. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)
Based upon the results from the phase III trial, vandetanib was made 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, for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease [19,22-24]. In the United States, distribution is restricted to prescribers and pharmacies participating in the REMS program. 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. Electrocardiograms (ECGs) and serum potassium, calcium, magnesium, and TSH should be obtained at two to four weeks and 8 to 12 weeks after starting treatment and every three 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 [25]. 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 approved by the US Food and Drug Administration (FDA) for the treatment of progressive, metastatic MTC [26]. Cabozantinib is an oral, small molecule kinase inhibitor that targets VEGFRs 1 and 2, c-MET, and RET [27]. The inhibitory activity against c-MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC.
In a phase I, dose-escalation study, 10 of 35 MTC patients (29 percent) achieved a confirmed partial response [28]. 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 [26,29]. 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) [30]. The most common side effects, occurring in ≥25 percent of patients, were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant adverse events included fistula formation and osteonecrosis of the jaw. Significant electrocardiographic abnormalities were not observed. 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) [31]. 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) [32].
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 [33]. Although not mandated in its approval, safety monitoring during therapy should include periodic assessment of electrolytes, calcium, and TSH.
Sorafenib — Sorafenib is an oral, small molecule aaMKI that targets VEGFR 2 and 3 and most mutant forms of RET [34]. It could be considered for use in selected patients with advanced MTC who are unable to participate in clinical trials as a second- or third-line therapy.
In a pilot study, five patients with metastatic MTC were treated with sorafenib, starting at 400 mg twice daily [35]. 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 [36]. 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 [37].
In addition to differentiated thyroid cancer, sorafenib is approved in the United States for treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma.
Sunitinib — Sunitinib is an oral, small molecule aaMKI that targets all three VEGFRs and RET [38]. It could be considered for use in highly selected patients with advanced MTC who are unable to participate in clinical trials as a second- or third-line therapy.
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 [39].
●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 [40].
●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 [41].
Sunitinib is approved in the United States for treatment of advanced renal cell carcinoma and also for refractory gastrointestinal stromal tumors.
Lenvatinib — Lenvatinib is an orally administered aaMKI that targets VEGFRs, RET, and fibroblast growth factor receptors (FGFR) 1 to 4. It 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 'Mutation not identified'.)
In a phase II trial, 59 patients with surgically unresectable, progressive MTC were treated with lenvatinib, starting at 24 mg daily [42]. 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' below.)
Given evidence of similar response rates in patients previously treated, lenvatinib may be considered as a second- or third-line aaMKI therapy for patients with progressive, metastatic MTC who have failed other anti-VEGFR therapies.
Side effects and their management — Side effects that are common to all of the VEGF-targeted aaMKIs include hypertension, renal toxicity, bleeding, myelosuppression, arterial thromboembolism, cardiotoxicity, thyroid dysfunction (typically hypothyroidism), 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. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)
Other investigational tyrosine kinase inhibitors — Numerous other kinase inhibitors have been studied in clinical trials during the past several years, but these drugs remain investigational at this time and are not available for routine clinical use. In general, the results of these studies are consistent with the findings described above, supporting the concept that antiangiogenic kinase inhibitors and those that target the mutated RET kinase are useful treatments for advanced metastatic MTC. Rarely, oncogenic mutations other than in the RET or RAS genes can be observed with extended genomic testing, such as activating rearrangements of the ALK gene; in these instances, more selective kinase inhibitors may be considered targeting the rare mutated gene [43,44].
CYTOTOXIC AGENTS — We do not consider traditional cytotoxic agents a first-line therapy for patients with persistent or recurrent MTC. We reserve these agents for patients who are unable to participate in clinical trials or cannot tolerate or fail selective RET kinase inhibitors and aaMKIs. 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, further 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 [45]. 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 [46]. 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 [47]. 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 [48,49].
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 as yet 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 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) [50]. 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 [51]. Three of 10 patients had partial responses, including one with complete resolution of radiographic evidence of disease.
Toxicities in both of these 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 [52,53].
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 bivalent hapten [54]. 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 [55]. 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) [56]. 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 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. (See "Medullary thyroid cancer: Surgical treatment and prognosis".)
●For patients with asymptomatic metastatic tumors generally less than 1 to 2 cm in diameter, growing in diameter less than 20 percent per year, we continue to monitor for disease progression. Known sites of metastatic disease should be imaged by computed tomography (CT) or magnetic resonance imaging (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 carcinoembryonic antigen (CEA) and calcitonin serial measurements. (See 'Suggested approach' above.)
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing by at least 20 percent per year, or for patients with symptoms related to multiple metastatic foci that cannot be addressed with local intervention (surgery or external beam radiotherapy), we prefer to administer systemic treatment as part of a clinical trial where available. (See 'Suggested approach' above.)
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing by at least 20 percent per year, or for patients with symptoms related to multiple metastatic foci who cannot participate in a clinical trial, we suggest an oral kinase inhibitor rather than traditional cytotoxic chemotherapy (Grade 2C). (See 'Suggested approach' above.)
•For initial therapy in patients with RET-mutated tumors, we suggest either selpercatinib or pralsetinib (Grade 2C). (See 'Suggested approach' above and 'Selpercatinib' above.)
•For patients without RET germline or somatic mutations, we suggest cabozantinib or vandetanib (Grade 2C). Sorafenib, sunitinib, or lenvatinib are reasonable options for patients who fail either or both cabozantinib and vandetanib. (See 'Suggested approach' above and 'Vandetanib' above and 'Cabozantinib' above.)
●Complete responses with these kinase inhibitors are uncommon, but these therapies can potentially provide long-term disease stabilization and delay progression in selected patients; no study has yet reported these agents' effects to improve survival. Toxicities of many of these new therapies, although probably less life-threatening than cytotoxic chemotherapies, are common and can be dose limiting, and clinicians must be familiar with recognizing and managing the side effects if they intend to use these agents. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)
●Cytotoxic chemotherapy, of which dacarbazine-based regimens such as cyclophosphamide-vincristine-dacarbazine are preferable, is an alternative option for patients who cannot tolerate or who fail multiple kinase inhibitors. (See 'Suggested approach' above.)
