ArticlesVandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial
Introduction
Differentiated thyroid carcinoma, which includes papillary, follicular, and poorly differentiated carcinomas, accounts for about 90% of all cases of thyroid cancer. Papillary and follicular carcinomas are generally associated with a favourable prognosis; however, recurrence occurs in 10–15% of patients after surgery.1 Distant metastases are detected in less than 10% of patients at diagnosis, but are the main cause of mortality.2 In unresectable persistent, recurrent, and metastatic disease, treatment consists of radioiodine (131I) therapy in patients with demonstrable metastatic radioiodine uptake and levothyroxine therapy to suppress secretion of thyroid-stimulating hormone (TSH). These methods provide complete remission in a third of patients with metastatic disease.3 Local treatments, including surgery, radiotherapy, radiofrequency ablation, cryotherapy, and cement injection might also be effective. Compared with papillary and follicular carcinomas, poorly differentiated carcinoma is associated with an increased risk of recurrence and distant metastases, a low frequency of radioiodine uptake and response, and a rapid rate of progression. Effective therapies for patients with differentiated thyroid carcinoma who do not respond to radioiodine treatment are lacking, with conventional chemotherapy proving relatively ineffective.1, 2, 3
Aberrant signalling pathways have been implicated in the onset, progression, and invasiveness of differentiated thyroid carcinoma. The most common genetic changes in papillary thyroid cancer are point mutations in BRAF and RAS and rearrangement of the RET proto-oncogene.4, 5 In follicular thyroid cancer, mutations in RAS and rearrangement of the PPARγ and PAX8 genes (to create the PPFP fusion gene) are common changes.6 In poorly differentiated carcinomas, the most frequent genetic abnormalities are mutations in RAS and PIK3CA and overexpression of EGFR. VEGF receptor-dependent tumour angiogenesis might also contribute to the growth and invasiveness of metastatic differentiated thyroid carcinoma.7
Vandetanib (AstraZeneca, Macclesfield, UK) is a once-daily oral anticancer drug that selectively targets RET, VEGF receptor, and EGFR tyrosine kinases.8, 9 Initial phase 1 dose-escalation studies with a broad range of advanced tumours showed that vandetanib monotherapy was generally well tolerated at daily doses up to 300 mg.10, 11 Vandetanib is now approved in Canada, Europe, Switzerland, and USA for the treatment of for the treatment of medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease; approval was made on the basis of phase 3 data showing that vandetanib can significantly prolong progression-free survival (PFS) in this setting.12 Other multikinase inhibitors targeting the VEGF receptor, RET, and other tyrosine kinases are associated with response rates of 14–59% in differentiated thyroid carcinoma,13, 14, 15, 16 although no placebo-controlled studies have been reported to date. We aimed to assess efficacy of vandetanib in patients with locally advanced or metastatic differentiated thyroid carcinoma in a randomised phase 2 setting.
Section snippets
Patients
We undertook our randomised, double-blind, placebo-controlled phase 2 study at 16 medical centres in Belgium, Denmark, France, Norway, Spain, Sweden, and Switzerland. We enrolled patients aged 18 years or older with histologically confirmed locally advanced (surgically unresectable) or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated, without an anaplastic component). Poorly differentiated thyroid cancer was classified according to the Turin
Results
Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 145 patients to receive vandetanib 300 mg (72 patients) or placebo (73 patients; figure 1, table 1). At data cutoff on Dec 2, 2009, all patients had discontinued randomised treatment. The main reasons for discontinuation were disease progression, 12 months of stable disease, and adverse events (figure 1). 28 (39%) of 72 patients randomly allocated vandetanib and 59 (81%) of 73 patients randomly allocated placebo received open-label
Discussion
Our trial investigated the efficacy and safety of vandetanib in patients with locally advanced or metastatic papillary thyroid cancer and follicular thyroid cancer, and is the first randomised phase 2 study of a kinase inhibitor in patients with differentiated thyroid carcinoma (panel). We noted significant PFS prolongation with vandetanib 300 mg compared with placebo. The median duration of PFS for patients in the placebo group was 5·9 months, which is consistent with a population with
References (26)
- et al.
Contemporary post surgical management of differentiated thyroid carcinoma
Clin Oncol (R Coll Radiol)
(2010) - et al.
Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors
Ann Oncol
(2005) - et al.
A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors
J Thorac Oncol
(2006) - et al.
Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study
Lancet Oncol
(2010) - et al.
Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors: an open-label, phase I, rising multiple-dose study
Clin Ther
(2011) - et al.
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group
Eur J Cancer
(1999) - et al.
Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy
J Clin Endocrinol Metab
(2006) - et al.
Approach to the patient with advanced differentiated thyroid cancer
Eur J Endocrinol
(2012) - et al.
BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas
J Clin Endocrinol Metab
(2004) - et al.
RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture
Eur J Endocrinol
(2006)