New Treatment Options for Metastatic Thyroid Cancer
Thyroid cancer is the ninth most common malignancy in the U.S. At the time of diagnosis, thyroid cancer is mostly confined to the thyroid gland and regional lymph nodes. However, around 4% of patients with thyroid cancer present with metastatic disease. When compared with localized and regional thyroid cancer, 5-year survival rates for metastatic thyroid cancer are significantly worse (99.9%, 97.6%, and 54.7%, respectively).1 Treatment options for metastatic thyroid cancer are limited and largely depend on the pathology and the type of thyroid cancer.
Thyroid cancer can be divided into differentiated, medullary, and anaplastic subtypes based on pathology. The treatment for metastatic differentiated thyroid cancer (DTC) consists of radioactive iodine therapy, thyroid-stimulating hormone (TSH) suppression (thyroxine hormone) therapy, and external beam radiotherapy. Systemic therapy is considered in patients with metastatic DTC who progress despite the above treatment modalities. In the case of metastatic medullary thyroid cancer (MTC), patients who are not candidates for surgery or radiation are considered for systemic therapy, because MTC does not respond to radioactive iodine or TSH suppressive therapy. On the other hand, metastatic anaplastic thyroid cancer is a very aggressive subtype with no effective therapy available to date. Palliation of symptoms is the main goal for these patients, which can be achieved by loco-regional resection and palliative irradiation.2,3
This review focuses on the newer treatment options for metastatic DTC and MTC that are based on inhibition of cellular kinases.
Differentiated Thyroid Cancer
Differentiated thyroid cancer is the most common histologic type of thyroid cancer, accounting for 95% of all thyroid cancers and consists of papillary, follicular, and poorly differentiated thyroid cancer.2,3 Surgery is the treatment of choice for DTC. Based on tumor size and its local extension in the neck, treatment options include unilateral lobectomy and isthmectomy, total thyroidectomy, central neck dissection, and more extensive resection.2,3 After surgery, radioactive iodine is recommended in patients with known metastatic disease; locally invasive tumor, regardless of size; or primary tumor > 4 cm, in the absence of other high-risk features.2 This should be followed by TSH suppressive hormone therapy.2
About 7% to 23% of patients with DTC develop distant metastases.4 Two-thirds of these patients become refractory to radioactive iodine.5 Prognosis remains poor in these patients, with a 10-year survival rate from the time detection of metastasis of only 10%.5-7 Treatment options are limited. However, recently the understanding of cell biology in terms of key signaling pathways called kinases has been elucidated. The kinases that can stabilize progressive metastatic disease seem to be attractive therapeutic targets in treating patients whose disease no longer responds to radioiodine and TSH suppressive hormone therapy.
Papillary thyroid cancers frequently carry gene mutations and rearrangements that lead to activation of the mitogen-activated protein kinase (MAPK), which promotes cell division. The sequential components leading to activation of MAPK include rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS.8,9 Similarly, overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS genes, is found in follicular adenomas, follicular cancers, and occasionally papillary cancers.10-14 Increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) might have a role in thyroid carcinoma as well.15
These kinases (the serine kinase BRAF and tyrosine kinases RET and RAS, and the contributory roles of tyrosine kinases in growth factor receptors such as the VEGFR) stimulate tumor proliferation, angiogenesis, invasion, metastasis, and inhibit tumor cell apoptosis. Kinase inhibitors target these signaling kinases, affecting tumor cell biology and its microenvironment.16,17
A wide variety of multitargeted kinase inhibitors (MKIs) have entered clinical trials for patients with advanced or progressive metastatic thyroid cancers. Two such agents, sorafenib and lenvatinib, are approved by the FDA for use in selected patients with refractory metastatic DTC, whereas many other drugs remain investigational for this disease. In phase 2 and 3 trials, most of the treatment responses for MKIs were partial. Complete responses were rare, and no study has reported a complete analysis of overall survival (OS) outcomes. Results from some new randomized trials indicate an improvement in progression-free survival (PFS) compared with placebo, and additional trials are underway.
Sorafenib
Sorafenib was approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.18 Sorafenib is an oral, small molecule MKI. It works on VEGFRs 1, 2, and 3; platelet-derived growth factor receptor (PDGFR); common RET/PTC subtypes; KIT; and less potently, BRAF.19 The recommended dose is 400 mg orally twice a day.
In April 2014, Brose and colleagues published the phase 3 DECISION study on sorafenib.20 It was a multicenter, randomized, double-blinded, placebo-controlled trial of 417 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the previous 14 months.20 The results of the trial were promising. The median PFS was 5 months longer in the sorafenib group (10.8 mo) than in the placebo group (5.8 mo; hazard ratio [HR], 0.59; 95% conidence interval [CI], 0.45-0.76; P < .0001). The primary endpoint of the trial was PFS, and crossover from placebo to sorafenib was permitted upon progression. Overall survival did not differ significantly between the treatment groups (placebo vs sorafenib) at the time of the primary analysis data cutoff. However, OS results may have been confounded by postprogression crossover from placebo to open-label sorafenib by the majority of placebo patients.
In subgroup analysis, patients with BRAF and RAS mutations and wild-type BRAF and RAS subgroups had a significant increase in median PFS in the sorafenib treatment group compared with the placebo group (Table 1).20
Adverse events (AEs) occurred in 98.6% of patients receiving sorafenib during the double-blind period and in 87.6% of patients receiving placebo. Most AEs were grade 1 or 2. The most common AEs were hand-foot-skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Toxicities led to dose modification in 78% of patients and permanent discontinuation of therapy in 19%.20 Like other BRAF inhibitors, sorafenib has been associated with an increased incidence of cutaneous squamous cell carcinomas (5%), keratoacanthomas, and other premalignant actinic lesions.21
Lenvatinib
In February 2015, lenvatinib was approved for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.22 Lenvatinib is a MKI of VEGFRs 1, 2, and 3; fibroblast growth factor receptors 1 through 4; PDGFR-α; RET, and KIT.23,24 The recommended dose is 24 mg orally once daily.
Schlumberger and colleagues published results from the SELECT trial, a randomized, double-blinded, multicenter phase 3 study involving 392 patients with progressive thyroid cancer that was refractory to iodine-131.25 A total of 261 patients received lenvatinib, and 131 patients received a placebo. Upon disease progression, patients in the placebo group were allowed to receive open-label lenvatinib. The study’s primary endpoint was PFS. Secondary endpoints were the response rate (RR), OS, and safety. The median PFS was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (HR, 0.21; 99% CI, 0.14-0.31; P < .001). The RR was 64.8% in the lenvatinib group (4 complete and 165 partial responses) and 1.5% in the placebo group (P < .001). There was no significant difference in OS between the 2 groups (HR for death, 0.73; 95% CI, 0.50-1.07; P = .10). This difference became larger when a potential crossover bias was considered (rank-preserving structural failure time model; HR, 0.62; 95% CI, 0.40-1.00; P = .05).25
In a subgroup analysis, median PFS was about 14 months in the absence of prior anti-VEGFR therapy and 11 months of prior therapy. The treatmentrelated AEs were 97.3% in the lenvatinib group, and 75.9% were grade 3 or higher. Common treatmentrelated AEs of any grade in the lenvatinib group included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The study drug had to be discontinued because of AEs in 14% of patients who received lenvatinib and 2% of patients who received placebo. In the lenvatinib group, 2.3% patients had treatment-related fatal events (6 patients).25
Summary
Patients with DTC who progress after radioactive iodine therapy, TSH suppressive therapy, and external beam radiotherapy should be considered for systemic therapy. Systemic therapy consists of MKIs, which can stabilize progressive metastatic disease. These newer drugs have significant toxicities. 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 good baseline performance status, such as being ambulatory at least 50% (Eastern Cooperative Oncology Group performance score of 2) of the day to tolerate these treatments.
Patients who have disease progression or are unable to tolerate sorafenib and lenvatinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include vandetinib, pazopanib, and sunitinib, which finished phase 2 trials and showed some partial responses.26-30 If the patients are unable to tolerate MKIs, they can try doxorubicin-based conventional chemotherapy regimens.31
Medullary Thyroid Cancer
Medullary thyroid cancer is a neuroendocrine tumor arising from the thyroid parafollicular cells, accounting for about 4% of thyroid carcinomas, most of which are sporadic. However, some are familial as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes, which are transmitted in an autosomal dominant fashion.32,33 Similar to DTC, the primary treatment option is surgery. Medullary thyroid cancer can be cured only by complete resection of the thyroid tumor and any local and regional metastases. Compared with DTC, metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither concentrates iodine nor is TSH dependent.34,35
The 10-year OS rate in MTC is ≤ 40% in patients with locally advanced or metastatic disease.32,36,37 In hereditary MTC, germline mutations in the c-ret proto-oncogene occur in virtually all patients. In sporadic MTC, 85% of patients have the M918T mutation, and somatic c-ret mutations are seen in about 50% of patients.38-42
Similar to DTC, due to the presence of mutations involving RET receptor tyrosine kinase, molecular targeted therapeutics with activity against RET demonstrate a potential therapeutic target in MTC.43-45 Other signaling pathways likely to contribute to the growth and invasiveness of MTC include VEGFR-dependent tumor angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumor cell proliferation.46
In 2011 and 2012, the FDA approved tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib for metastatic MTC. Similar to treatment for DTC, systemic therapy is mainly based on targeted therapies. Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy.
Vandetanib
Vandetanib is approved for unresectable, locally advanced or metastatic sporadic or hereditary MTC.47 The daily recommended dose is 300 mg/d. It is an oral MKI that targets VEGFR, RET/PTC, and the EGFR.48
The ZETA trial was an international randomized phase 3 trial involving patients with unresectable locally advanced or metastatic sporadic or hereditary MTC.48 In a ZETA trial study by Wells Jr and colleagues, patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. After objective disease progression, patients could elect to receive openlabel vandetanib. The primary endpoint was PFS, determined by independent central Response Evaluation Criteria in Solid Tumors assessments.
A total of 331 patients were randomly assigned to receive vandetanib (231 patients) or placebo (100 patients). At data cutoff, with median follow-up of 24 months, PFS was significantly prolonged in patients randomly assigned to vandetanib vs placebo (30.5 mo vs 19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR was significantly higher in the vandetanib group (45% vs 13%). The presence of a somatic RET M918T mutation predicted an improved PFS.
Common AEs (any grade) noted with vandetanib vs placebo include diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%). Torsades de pointes and sudden death were reported in patients receiving vandetanib. Data on OS were immature at data cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival analysis will take place when 50% of the patients have died.48
Vandetanib is currently approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about serious heart-related risks. Electrocardiograms and serum potassium, calcium, magnesium, and TSH should be taken at 2 to 4 weeks and 8 to 12 weeks after starting treatment and every 3 months after that. Patients with diarrhea may require more frequent monitoring.
Cabozantinib
In 2012, the FDA approved cabozantinib for the treatment of progressive, metastatic MTC.49 It is an oral, small molecule TKI that targets VEGFRs 1 and 2, MET, and RET. The inhibitory activity against MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC.50 The daily recommended dose is 140 mg/d. A phase 3 randomized EXAM trial in patients with progressive, metastatic, or unresectable locally advanced MTC.51 Three hundred thirty patients were randomly assigned to receive either cabozantinib 140 mg or placebo once daily. Progressionfree survival was improved with cabozantinib compared with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI, 0.19-0.40). Partial responses were observed in 27% vs 0% in placebo. A planned interim analysis of OS was conducted, including 96 (44%) of the 217 patient deaths required for the final analysis, with no statistically significant difference observed between the treatment arms (HR, 0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to continue until at least 217 deaths have been observed.
There was markedly improved PFS in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS mutations (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10).51
The most common AEs, occurring in ≥ 25% of patients, were diarrhea, stomatitis, hand and foot syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant AEs also included fistula formation and osteonecrosis of the jaw.
Summary
Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy. Though not curative, TKIs can only stabilize disease progression. Initiation of TKIs should be considered in rapidly progressive disease, because these drugs are associated with considerable AEs affecting the quality of life (QOL).
Patients who progressed or were unable to tolerate vandetanib or cabozantinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include pazopanib, sunitinib, and sorafenib, which finished phase 2 trials and showed some partial responses.29,52-57 If patients are unable to tolerate MKIs, they can try conventional chemotherapy consisting of dacarbazine with other agents or doxorubin.58-60
Conclusions
Molecular targeted therapy is an emerging treatment option for patients with metastatic thyroid cancer (Table 2). The authors suggest that such patients participate in clinical trials in the hope of developing more effective and tolerable drugs and recommend oral TKIs for patients with rapidly progressive disease who cannot participate in a clinical trial. For patients who cannot tolerate or fail one TKI, the authors recommend trying other TKIs before initiating cytotoxic chemotherapy.
Before initiation of treatment for metastatic disease, an important factor to consider is the pace of disease progression. Patients who are asymptomatic and have the very indolent disease may postpone kinase inhibitor therapy until they become rapidly progressive or symptomatic, because the AEs of treatment will adversely affect the patient’s QOL. In patients with symptomatic and rapidly progressive disease, initiation of treatment with kinase inhibitor therapy can lead to stabilization of disease, although at the cost of some AEs. More structured clinical trials are needed, along with an evaluation of newer molecular targets for the management of this progressive metastatic disease with a dismal prognosis.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.