NEOADJUVANT LENVATINIB IN ADVANCED UNRESECTABLE MEDULLARY THYROID CARCINOMA: A CASE REPORT

Abstract

Objective:

Medullary thyroid carcinoma, a rare form of thyroid cancer, is typically managed with surgical excision. However, in patients with locally-invasive tumors, an aggressive surgical attempt may result in unnecessary morbidity. Neoadjuvant tyrosine kinase inhibition has been utilized to downstage tumors prior to surgical excision but its role in thyroid cancer treatment is not well-established. We describe the potential role that lenvatinib, a tyrosine kinase inhibitor, may have as a neoadjuvant agent in advanced locoregional medullary thyroid carcinoma.

Methods:

Our patient presented with a large left thyroid mass and bulky left lateral neck lymphadenopathy. Imaging studies revealed a hypervascular and locally-invasive tumor with metastatic central and left lateral lymphadenopathy. A lymph node biopsy cytologic evaluation and plasma calcitonin concentration of 32,926 pg/mL were consistent with medullary thyroid carcinoma. Rearranged during transfection germline mutation testing was negative. A multidisciplinary team of physicians deemed the patient a poor surgical candidate and recommended 4 months of neoadjuvant lenvatinib therapy to reduce tumor burden with a subsequent reassessment of resectability. Given the tumor's hypervascularity, lenvatinib was chosen due its potent vascular endothelial growth factor receptor inhibition, as well as its availability at our institution.

Results:

Lenvatinib therapy resulted in rapid regression of tumor volume (approximately 70% reduction) as documented by computed tomography and ultrasound. Surgery after 4 months of treatment resulted in a 99% reduction in serum calcitonin and imaging studies 6 months later showed no residual disease.

Conclusion:

Lenvatinib has potential as a neoadjuvant agent in advanced medullary thyroid carcinoma, and permitted tumor resection in this previously inoperable patient.

INTRODUCTION

Medullary thyroid carcinoma (MTC) is a rare, potentially fatal form of thyroid cancer arising from the neural crest, specifically calcitonin-producing parafollicular C cells of the thyroid gland. Rearranged during transfection (RET) proto-oncogene mutations have long been associated with the pathogenesis of MTC, but much more recently, Ras gene mutations have been identified in sporadic MTCs with wild-type RET (1). Additionally, aggressive MTC tumors tend to be highly vascular with angiogenesis mediated by vascular endothelial growth factor (VEGF), fibro-blast growth factor, and platelet-derived growth factor (2). While surgical excision is typically the preferred first intervention and sole curative treatment modality for MTC, in some patients with locally bulky and invasive disease, an aggressive surgical attempt at tumor resection may result in permanent airway, esophagus, nerve, or blood vessel injury.

Neoadjuvant therapy is used to downstage advanced cancers in order to increase the odds of successful, low morbidity surgical outcomes. The neoadjuvant approach is integral in the management of cancers affecting breast, lungs, and bladder (3–5), often obviating the need for morbid and risky surgeries associated with large and invasive tumors. Despite an established track record with many adenocarcinoma types, neoadjuvant therapy in thyroid cancer is not well-established and the data supporting its use is limited. Although neoadjuvant chemotherapeutic agents have shown some effectiveness in the treatment of differentiated thyroid carcinoma (DTC) (6), their use has been limited due to a well-known profile of toxicity and suboptimal patient tolerance.

The advent of novel tyrosine kinase inhibitors (TKIs) heralded a new era in the management of advanced thyroid cancer. Currently, 2 multitargeted TKIs, vandetanib and cabozantinib, have been FDA approved for the treatment of MTC (7,8). Sorafenib and lenvatinib are FDA approved drugs for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC) (9,10). All 4 drugs were approved based on a statistically significant increase in progression-free survival over placebo however, these studies were not designed to evaluate overall survival (7–10). Despite the emergence of evidence supporting the efficacy of TKIs, their role in a neoadjuvant setting has yet to be thoroughly explored.

In this case report, we describe a 66-year-old female who presented with invasive central neck disease and bulky left lateral neck metastatic lymphadenopathy and was treated with neoadjuvant lenvatinib for 4 months prior to biochemically and structurally successful surgery. Lenvatinib was chosen due to the hypervascularity of the tumor with evidence in mind of its potent vascular endothelial growth factor receptor (VEGFR) inhibition in comparison to other tyrosine kinase inhibitors (Table 1), and availability at our institution.

Table 1.

Half Maximal Inhibitory Concentration (IC50) of FDA-Approved Drugs for Advanced Thyroid Carcinoma with Respect to Different VEGFR Subtypes (nmol/L) ^a

Drug	VEGFR1	VEGFR2	VEGFR3
Vandetanib	–	40	110
Cabozantinib	–	0.035	–
Sorafenib	26	90	20
Lenvatinib	22	4	5.2

Abbreviations: FDA = United States Food and Drug Administration; VEGFR = vascular endothelial growth factor receptor; VEGFR1 = vascular endothelial growth factor receptor 1; VEGFR2 = vascular endothelial growth factor receptor 2; VEGFR3 = vascular endothelial growth factor receptor 3.

^aData extracted from reference 14.

CASE REPORT

A 66-year-old Caucasian female was evaluated due to left lateral neck masses that had been growing over 18 months. Upon review of systems the patient described lateral neck discomfort and denied globus sensation, dysphagia, dysphonia, or dyspnea. The patient described 40 pounds of unintentional weight loss without flushing or diarrhea over a 2-year period. Ultrasound evaluation revealed normal movement of the vocal folds. Family history was negative for thyroid malignancy. Physical examination was remarkable for grossly enlarged left lateral neck lymph nodes. Office ultrasonography revealed a hypervascular, 8.3 cm, taller-than-wide, hypoechoic mass replacing the left thyroid and possibly invading the trachea and esophagus. Multiple hypervascular left level II, III, IV, and VI metastatic lymph nodes measuring up to 6.9 cm were identified. FNA biopsy of the level II to III, 6.9 cm lymph node revealed malignant cells with punctate nuclear chromatin and plasmacytoid features. Immunohistochemical stains were positive for calcitonin and carcinoembryonic antigen (CEA). The Veracyte Genomic Sequencing Classifier identified a gene expression signature suggesting MTC. Subsequent biochemical analysis of the patient's serum revealed a calcitonin concentration of 32,926 pg/mL (normal, 0 to 5 pg/mL) and a CEA concentration of 281 ng/mL (normal, 0 to 4.7 ng/mL). Contrasted computed tomography (CT) scans of neck, chest, and abdomen revealed 270-degree encirclement of the trachea by the left thyroid mass with possible membranous trachea invasion and possible esophageal invasion (Fig. 1). Staging work-up did not reveal evidence of distant metastatic disease. Thyroid function tests, serum metanephrines, and serum quantitative thyroglobulin were all within normal limits. Genetic testing did not reveal a germline RET mutation.

Fig. 1.

Axial contrast-enhanced computed tomography scans prelenvatinib therapy (top left), 4 months postlenvatinib therapy (top middle), and 5 months post-surgery (top right). Note the 270-degree encirclement of the trachea by the left thyroid mass with potential membranous trachea and esophageal invasion prior to lenvatinib therapy (top left) timeline (middle) calcitonin and CEA concentrations versus time (bottom). CEA = carcinoembryonic antigen US = ultrasound.

The patient was determined to be inoperable by a multidisciplinary team of physicians due to the potentially invasive nature of her disease on CT imaging. She was referred to medical oncology for consideration of neoadjuvant TKI therapy. Lenvatinib 10 mg twice daily was initiated. Transient headaches and hand-foot syndrome prevented further up-titration of the lenvatinib dose.

After 2 weeks of lenvatinib, the patient noted a remarkable reduction in the size of her left neck adenopathy. At week 6, serum calcitonin and CEA concentrations fell to 5,332 pg/mL (84% reduction) and 55 ng/mL (75% reduction), respectively (Fig. 1). At week 14, a neck ultra-sound study revealed a 73% reduction in the volume of the largest left lateral compartment lymph node. Follow-up CT and ultrasound examination revealed the trachea and esophagus to be uninvolved by the tumor. The lymph nodes appeared remarkably devascularized (Fig. 2). In preparation for surgery at 20 weeks of therapy, lenvatinib was discontinued over a 2-week period to reduce the risk of tracheoesophageal fistula formation and impaired wound healing. The patient noted rapid regrowth of her lymphadenopathy during this interval and lenvatinib was restarted with near-immediate regression of lymph node size for a second time. Surgery was finally accomplished after a 3 day TKI holiday and included a left thyroid lobectomy with resection of the left recurrent laryngeal nerve (which ran into the thyroid and through the thyroid-confined tumor) along with a unilateral (left) central compartment and selective left neck dissection, resulting in complete gross tumor and lymph node resection (Fig. 3) with excision margins negative for MTC. Notably, the esophagus, trachea, and great vessels were free of gross tumor invasion on surgical inspection. Final pathologic analysis was consistent with the American Joint Committee on Cancer Stage 4A MTC (ypT4a, pN1b, cM0) and all margins were free of tumor. There was no pathologic evidence of tumor necrosis. As a result of the requisite left recurrent laryngeal nerve resection, hoarseness was observed postoperatively and improved on 3- and 6-month follow-up examinations. There were no other significant intraoperative or postoperative complications. CT of neck, lungs, and liver, and ultrasound imaging of the neck for local and distant metastasis were negative at 6 months postoperatively. In the 12th postoperative week, the patient's calcitonin concentration fell to 4.9 pg/mL (a 99.9% reduction from baseline) and the CEA concentration dropped to 1.7 ng/mL (a 99.9% reduction from baseline Fig. 1). The patient continues to do well clinically after 6 months of regular follow-up examinations. TKI therapy has not been reintroduced.

Fig. 2.

Sagittal contrast-enhanced computed tomography scans prelenvatinib (left) and 4 months postlenvatinib therapy (right). Note the marked reduction in radiodensity (165.05 HU versus 61.54 HU) suggesting devascularization of the tumor. HU = Hounsfield unit.

Fig. 3.

A, Left hemithyroidectomy surgical specimen including left recurrent laryngeal nerve posteriorly and level VI lymph nodes. B, Left level VI/III metastatic lymph node. C, Left lateral lymphadenectomy specimen levels II, III, and IV.

DISCUSSION

We identified one case report of TKI use in a neoadjuvant setting with advanced MTC. Randolph et al (11) described a case of a chemoradiotherapy-resistant tumor presumed to be anaplastic thyroid carcinoma (ATC) treated successfully with TKIs prior to surgery. Their patient was treated with sunitinib for 19 months with a significant reduction in tumor volume that allowed for successful surgical resection. On final pathologic analysis, the tumor was found to be MTC rather than ATC. Thus, a TKI intended as palliation for cytologically misdiagnosed ATC was inadvertently employed as a neoadjuvant therapy in an MTC patient, with subsequent serendipitous effects on tumor resectability. This was the basis for the neoadjuvant approach in our MTC patient. Based on preoperative imaging, our multidisciplinary team believed that immediate surgery would likely result in tracheal, esophageal, and left recurrent laryngeal nerve, as well as left lateral neck nerve morbidity.

Lenvatinib is an oral multikinase inhibitor of VEGFR 1 to 3, fibroblast growth factor receptor 1 to 4, platelet-derived growth factor receptor alpha, the ret protooncogene (RET), and the KIT proto-oncogene (12–14). VEGF overexpression mediates angiogenesis and tumor progression in MTC (2). Several TKIs target VEGFR, although with variable affinities (Table 1) (15). Of the 4 FDA-approved drugs for DTC and MTC, lenvatinib is the most effective broad-spectrum VEGFR inhibitor, requiring relatively low drug concentrations to inhibit all 3 VEGFR subtypes. Although lenvatinib has activity against RET, it is unclear if anti-RET activity offered any therapeutic benefit in this patient. In one MTC study, there was no difference in lenvatinib treatment response according to RET mutational status however, high baseline levels of VEGF correlated with greater tumor shrinkage (15).

Although VEGFR is an appropriate target to inhibit angiogenesis and tumorigenesis, VEGF is also essential for wound healing. Current literature contains few reports of impaired healing or wound dehiscence following therapy with anti-VEGF TKIs (6). In a phase III trial of lenvatinib in RR-DTC, Schlumberger et al (10) reported that 6 of 118 deaths in the trial were determined to be treatment-related, and none of these were related to surgical or wound problems. The rate of fistula formation of any grade was 1.5% with significant fistula formation (grade 3 or higher), only occurring in 0.8% of treated patients (10). Of note, the package insert for lenvatinib reports a 0.8% rate of impaired healing and a 0.4% of wound dehiscence (16). Thus, with such a low incidence of interference with wound healing and fistula formation, lenvatinib appears to be a potentially suitable neoadjuvant agent that could facilitate effective surgery for both RR-DTC and MTC.

Lenvatinib exhibits a short response time and a high objective response rate in clinical trials. Schlumberger et al (8) reported a median time to the objective response of 2 months (95% confidence interval [CI], 1.9 to 3.5 months), prolonged progression-free survival (PFS hazard ratio for progression or death, 0.21 99 % CI, 0.14 to 0.31 P<.001) by 14.7 months (lenvatinib median PFS, 8.3 months) compared with placebo (median PFS, 3.6 months), and an overall response rate (ORR) of 64.8%, compared with an ORR of 1.5% in placebo-treated patients (8). In our patient, we observed rapid tumor shrinkage in response to lenvatinib therapy and a similarly rapid tumor regrowth within 2 weeks after short-term discontinuation prior to surgery. Data on the use of lenvatinib in MTC is currently limited to a phase II single arm trial that showed promising results. The study reported the median PFS was 9 months and an estimated PFS at 6 months was 67%. The ORR, after a minimum 8-month follow-up, was 36% (all partial responses), without significant differences to age, sex, or prior anti-VEGF therapy (17).

CONCLUSION

In summary, this case illustrates the potential benefit neoadjuvant TKI therapy may offer patients with locally advanced disease. Neoadjuvant lenvatinib allowed for successful tumor resection resulting in a biochemical and structural disease-free status at 6 months of follow-up. It is important to note that standard of care for MTC is surgical excision. We suggest the use of TKIs to be reserved for progressive, recurrent, or locally-invasive MTC, with a possible neoadjuvant approach for only the most locally-advanced cases. For highly vascularized and invasive MTC, lenvatinib should be considered as a neoadjuvant agent by virtue of its broad-spectrum VEGFR inhibition. Finally, with the advent of prospective neoadjuvant TKI trials for advanced DTC, we propose inclusion of patients with advanced locoregional MTC.

Abbreviations

ATC

Anaplastic thyroid carcinoma

CEA

carcinoembryonic antigen

CT

computed tomography

DTC

differentiated thyroid carcinoma

MTC

medullary thyroid carcinoma

ORR

overall response rate

PFS

progression-free survival

RET

rearranged during transfection

RR-DTC

radioiodine-refractory differentiated thyroid carcinoma

TKI

tyrosine kinase inhibitor

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor