Oncologist. The. The Community Oncologist: Case Report. A Case of Advanced Medullary Thyroid Carcinoma Successfully Treated with Sunitinib

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1 The Oncologist The Community Oncologist: Case Report A Case of Advanced Medullary Thyroid Carcinoma Successfully Treated with Sunitinib MARIA JOÃO BUGALHO, a c RITA DOMINGUES, b ALEXANDRA BORGES d a Serviço de Endocrinologia, b Centro de Investigação de Patobiologia Molecular, and d Serviço de Radiologia, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal; c Clínica Universitária de Endocrinologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal Key Words. Sunitinib Thyroid Carcinoma Disclosures: Maria João Bugalho: None; Rita Domingues: None; Alexandra Borges: None. The article discusses sunitinib (Pfizer) for the treatment of medullary thyroid carcinoma. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Context. Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from C cells of the thyroid; it is a RET associated cancer that can be sporadic or familial in origin. Advances in understanding the genetic changes associated with the development of MTC explain the growing interest in the therapeutic potential of tyrosine kinase inhibitors. Sunitinib is an orally administered multikinase inhibitor likely to target multiple pathways in the tumor, stromal, and endothelial compartments. Its role in the treatment of MTC patients has not yet been established. Objective. To present the case of a patient with a sporadic and unresectable MTC who was successfully treated with sunitinib. Patient and Results. A 55-year-old man with locally advanced MTC, without germinal and/or somatic RET mutations, was started on sunitinib (50 mg/day for 28 days, followed by 14 days of no treatment). At the time of writing, he had received four consecutive cycles. At the end of the first cycle, his serum calcitonin level had dropped by 81%. In the following cycles, a long-lasting minor response was observed. An early and dramatic tumor reduction, particularly of a cervical lymph node conglomerate, was observed and confirmed by the Response Evaluation Criteria in Solid Tumors. Conclusion. Sunitinib may play a role in the management of patients with locally advanced MTC or distant metastatic disease, for which no effective systemic therapy exists. Moreover, the absence of RET mutations does not seem to be an exclusion criterion for sunitinib treatment. The Oncologist 2009;14: INTRODUCTION Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth and angiogenesis. Mutations and overexpression of RTKs have been implicated in the development of different tumors. Activating mutations in the RET proto-oncogene, which encodes a tyrosine ki- Correspondence: Maria João Bugalho, M.D., Ph.D., Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Rua Professor Lima Basto, , Lisboa, Portugal. Telephone: ; Fax: ; mjbugalho@ipolisboa.min-saude.pt Received August 23, 2009; accepted for publication October 13, 2009; first published online in The Oncologist Express on November 3, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 1084 Medullary Thyroid Carcinoma and Sunitinib nase receptor, are the underlying cause of almost all familial forms of medullary thyroid carcinoma (MTC) [1] and of a great number of sporadic MTC cases [2 4]. Sunitinib (sunitinib malate, SU11248, Sutent ; Pfizer, Inc., New York) is an oral multitargeted RTK inhibitor (RTKI) with antitumor and antiangiogenic activity [5]. It is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR)-1 to VEGFR-3, fetal liver tyrosine kinase receptor 3, Kit (stem-cell factor receptor), platelet-derived growth factor receptor (PDGFR)-, and PDGFR- [6 8]. Sunitinib is approved as monotherapy for the treatment of renal cell carcinoma and imatinib-refractory/intolerant gastrointestinal stromal tumor. Human studies have established 50 mg daily dosing, given on an intermittent schedule, as a well-tolerated dose with manageable and reversible adverse events [9]; recently, a continuous oncedaily dosing regimen of 37.5 mg was reported, with a manageable safety profile [10]. It was proven to be a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase [11] and has been used selectively for patients with advanced or metastatic differentiated thyroid carcinoma or MTC [12 14]. Herein, we present the case of a locally advanced MTC successfully treated with sunitinib off the ongoing, openlabel, phase II trials (ClinicalTrials.gov identifiers, NCT and NCT ). CASE REPORT /CLINICAL PRESENTATION The patient, a 55-year-old white man, was referred to our institution in May 2007 with a diagnosis of MTC. The diagnosis was based on a cervical lymph node biopsy with ensuing immunohistochemistry staining and high levels of serum calcitonin. He was otherwise asymptomatic, had a good performance status, and denied other medical problems or family history of malignancy. Occasionally, he felt numbness and functional limitation of the right arm. On physical examination, a right cervical lymph node conglomerate was observed. A computed tomography (CT) scan revealed a normal thyroid gland with a small nodule (13 mm in largest diameter) in the inferior pole of the right lobe and a right supraclavicular conglomerate of lymph nodes along with multiple enlarged lymph nodes in the tracheoesophageal groove and right paratracheal space with compressive effects. The case was considered locally advanced and unresectable. Molecular analysis of RET ruled out the presence of germline mutations and identified the patient as homozygous for the IVS14 24 A variant. Thus, this case was considered as sporadic. Later on, screening for somatic RET mutations was conducted in tumor DNA obtained from an archival paraffin block; we were able to amplify exons 5, Figure 1. Biochemical evidence of antitumor activity measured as calcitonin levels. (A): Starting and final values observed in each cycle. (B): Decay curve. 10, 12, and No somatic mutations were found by direct sequencing of polymerase chain reaction products. Progressively, complaints such as discomfort, local pain, and functional limitation of the right arm became permanent. Fourteen months later, there was objective evidence of disease progression. A bronchoscopy, performed following an episode of dyspnea, documented severe tracheal obstruction. The patient was then considered for therapy with sunitinib. After approval by the institutional review board and written informed consent, treatment was started in February 2009 (50 mg/day for 28 days, followed by 14 days of no treatment). RESULTS After only 15 days of treatment, the patient s serum calcitonin level dropped by 62%, and at the end of the first cycle it had dropped by 81%. In the following cycles, a longlasting minor response was observed. At the time of writing, the patient had received four cycles. Results are shown in Figure 1. During the 2-week-off period of each cycle, his serum calcitonin level increased slightly but did not reach the highest value of the previous cycle. In parallel with the calcitonin decrease, sunitinib induced shrinkage of the right cervical lymph node conglomerate. Evidence for an objective response, according to the Response Evaluation Criteria in Solid Tumors (RECIST), was further provided by a CT scan qualifying the patient as a partial responder (Fig. 2). Concerning adverse events, glossitis developed during the first 2 weeks and worsened slightly to grade 2 during weeks 3 and 4 of the first cycle. It was fully reversible during the 2-week-off period and recurred in subsequent cycles as grade 0 1 toxicity; it was managed with supportive care. Occasionally, the patient mentioned polyarthralgias. Hematologic toxicity was not observed and thyroid function remained normal.

3 Bugalho, Domingues, Borges 1085 Figure 2. Computed tomography scans showing objective response according to the Response Evaluation Criteria in Solid Tumors. (A, B): Before initiation of therapy. (C, D): At the end of the fourth cycle. DISCUSSION The RET proto-oncogene has been identified as the susceptibility gene for the inherited forms of MTC [1], and somatic mutations are present in a large number of sporadic MTCs [2 4]. The gene encodes the Ret protein, an RTK that activates the Ras-Raf mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase Akt pathways. Surgery is the only potentially curable treatment for patients with MTC, and only when the tumor is confined to the thyroid. There is no effective systemic therapy for metastatic or unresectable disease, as was the case in the patient presented herein. Given the molecular pathophysiology of MTC, RTKIs appear to be natural candidates for treatment of MTC patients [15, 16]. Sunitinib has inhibitory activity against VEGFR-1 to VEGFR-3, PDGFR, and Ret. Preliminary analyses from an open-label, phase II clinical trial (ClinicalTrials.gov identifier, NCT ), to test its efficacy in differentiated thyroid cancer and MTC, documented disease stabilization in 83% of MTC patients [14]. A second, open-label, phase II trial is currently ongoing (ClinicalTrials.gov identifier, NCT ). The efficacy and tolerability of motesanib, a highly selective inhibitor of VEGFR-1 to VEGFR-3, PDGFR, and Kit, was investigated in a phase II study enrolling patients

4 1086 Medullary Thyroid Carcinoma and Sunitinib Figure 3. Photographs documenting evolution of the cervical lymph node conglomerate. with advanced MTC. A significant number of patients achieved stable disease, but only 2% achieved an objective response [17]. Vandetanib (ZD6474, Zactima ; AstraZeneca Pharmaceuticals, Wilmington, DE) is another RTKI that potently inhibits VEGFR-2 and VEGFR-3, Ret, and at a higher concentration epidermal growth factor receptor [18, 19]. An international, phase II, randomized, double-blinded, placebocontrolled, multicenter study in unresectable locally advanced or metastatic MTC patients is currently ongoing. In the present case, sunitinib induced a rapid response in serum calcitonin levels and, moreover, had clinically relevant antitumor activity leading to a meaningful objective response according to the RECIST. Blocking Ret may lead to direct inhibition of calcitonin gene expression, independent of tumor volume changes [20]; therefore, serum calcitonin levels should not be regarded as the sole marker of response to treatment. In the present case, treatment with sunitinib resulted in an important decrease in serum calcitonin in parallel with a significant tumor reduction and amelioration of symptoms. REFERENCES 1 Eng C, Clayton D, Schuffenecker I et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276: Wohllk N, Cote GJ, Bugalho MM et al. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1996;81: Romei C, Elisei R, Pinchera A et al. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab 1996;81: Moura MM, Cavaco BM, Pinto AE et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer 2009;100: Chow LQM, Eckhardt SG. Sunitinib: From rational design to clinical efficacy. J Clin Oncol 2007;25: Mendel DB, Laird AD, Xin X et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and The most noticeable response occurred in a cervical lymph node conglomerate (Fig. 3). Given the absence of RET mutations, results are likely to depend on the inhibition of other proteins enhancing MAPK signaling and/or inhibition of proangiogenic factors. The use of RTKIs in the neoadjuvant and adjuvant settings holds promise for the management of advanced MTC patients. The choice of the optimal RTKI will rely on a better definition of the molecular subtype of each tumor. ACKNOWLEDGMENTS We are grateful to Dr. Rafael Cabrera, from the Pathology Department of Instituto Português de Ocologia/Lisboa, for preparing tumor samples. We also thank the nurses Alexandra Braga and Susana Mendonça for their valuable technical assistance. AUTHOR CONTRIBUTIONS Conception/Design: Maria João M Bugalho Data analysis and interpretation: Maria João M Bugalho, Alexandra Borges Manuscript writing: Maria João M Bugalho Molecular analysis of RET: Rita Domingues platelet-derived growth factor receptors: Determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 2003;9: Murray LJ, Abrams TJ, Long KR et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003;20: Faivre S, Delbaldo C, Vera K et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24: Rini BI. Sunitinib. Expert Opin Pharmacother 2007;8: Escudier B, Roigas J, Gillessen S et al. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27: Kim DW, Jo YS, Jung HS et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 2006;91: Kelleher FC, McDermott R. Response to sunitinib in medullary thyroid cancer. Ann Intern Med 2008;148:567.

5 Bugalho, Domingues, Borges Dawson SJ, Conus NM, Toner GC et al. Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma. Anticancer Drugs 2008;19: Cohen EE, Needles BM, Cullen KJ, et al. Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol 2008;26(15 suppl): de Groot JWB, Links TP, Plukker JTM et al. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev 2006;27: Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 2009;94: Schlumberger MJ, Elisei R, Bastholt L et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009;27: Carlomagno F, Vitagliano D, Guida T et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002;62: Sathornsumetee S, Rich JN. Vandetanib, a novel multitargeted kinase inhibitor, in cancer therapy. Drugs Today (Barc) 2006;42: Akeno-Stuart N, Croyle M, Knauf JA et al. The RET kinase inhibitor NVP- AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res 2007;67: