INTRODUCTION
Medullary thyroid cancer (MTC) originates from the parafollicular C cells of the thyroid gland and represents 5% of all thyroid cancers [
1]. MTC is a relatively indolent tumor, and the 10-year overall survival (OS) rate is approximately 75% to 80% [
2]. However, patients with unresectable, locally advanced or metastatic MTC have limited therapeutic options, and their 10-year OS rate is reported to be 40% or less [
2]. Owing to limited responsiveness to non-surgical treatments (radioactive iodine therapy, external radiotherapy, and conventional chemotherapy), targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as an important therapeutic option for patients with advanced MTC [
3-
6].
Vandetanib is the most widely used TKI for advanced MTC, targeting the
RET oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR) [
6]. Based on the encouraging results of the international, multicenter, randomized phase III clinical trial (ZETA trial), vandetanib was approved by the Food and Drug Administration and the European Medical Agency for the treatment of patients with symptomatic, unresectable, locally advanced or metastatic MTC [
7]. In the ZETA trial, vandetanib showed a significant prolongation of progression-free survival (PFS) and a high objective response rate (ORR) compared with placebo [
7]. Although the ZETA trial showed the efficacy and safety of vandetanib, only limited data regarding its use outside clinical trials are available [
7,
8]. In this multicenter cohort study, we aimed to evaluate the efficacy and safety of vandetanib in patients with locally advanced or metastatic MTC, when vandetanib was administered in routine clinical practice.
DISCUSSION
This study evaluated the efficacy and toxicity of vandetanib in routine practice in patients with locally advanced or metastatic MTC, during a median follow-up of 32 months. Almost all patients (92%) had distant metastasis and 83% of patients had progressive disease at vandetanib initiation. The ORR and DCR were 42% and 83%, respectively, and these values correspond with the results of the ZETA trial (ORR 45% and DCR 87%) [
7]. The median PFS was 25.9 months, which was slightly shorter than that of patients treated with vandetanib (30.5 months) while longer than that of patients treated with placebo (19.3 months) in the ZETA trial [
7]. With a median dose of 200 mg/day, vandetanib was discontinued in two patients due to skin toxicity. The AEs were generally consistent with the known safety profile of vandetanib, and most were manageable by dose modification and medical therapy.
Vandetanib is the first approved TKI for advanced MTC treatment that selectively targets
RET, VEGFR, and EGFR [
6,
11]. It was approved based on the results of phase II and III trials, which demonstrated a significant durable response and prolongation of PFS [
7,
10,
12]. Thereafter, data from retrospective studies have supported the positive clinical impact of vandetanib [
8,
13]. A retrospective study analyzing 60 MTC patients receiving vandetanib outside any trial reported an ORR of 22% with a median PFS of 16.1 months [
8]. In another retrospective study of 11 patients with progressive metastatic MTC, the rate of PR was 36% and that of SD for 6 months or longer was 27%, but the median PFS was not reached during the median treatment duration of 7 months [
13]. Recent studies have reported prognostic indicators predicting better and longer response to vandetanib in advanced MTC patients [
14-
17]. More advantages of vandetanib therapy have been reported in MTC patients who are younger, have a good ECOG performance status, and have symptomatic disease [
17]. Pre-therapeutic fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography also provides prognostic information in patients with advanced and progressive MTC [
16]. However, the presence of
RET mutations is not a predictor of treatment efficacy of vandetanib, consistent with the results previously shown in clinical trials [
7,
10,
17]. Selective and highly active
RET inhibitors which are currently under clinical trial may provide a promising treatment option for MTC patients with
RET mutations [
18]. Due to the limited number of patients in the current study, we could not identify the clinical features associated with better clinical outcomes after vandetanib treatment.
This study confirms the efficacy of vandetanib in patients with advanced MTC, as shown in the ZETA trial, outside of a clinical trial [
7]. The study population differed between our study and the ZETA trial. Patients enrolled in the ZETA trial were required to have measurable disease but not progressive disease at enrollment [
7]. This inclusion criterium may have allowed the enrollment of many patients with indolent disease in the ZETA trial, as evidenced by a PFS of 19.3 months in the placebo group [
7]. In contrast, the majority of patients (83%) included in our study had progressive disease at the time of vandetanib initiation. The inclusion criteria in this study also did not include progressive disease at enrollment, however, these patients had disease progression, according to RECIST, within 6 months (range, 1 to 6) before vandetanib administration. Another difference was the proportion of MTCs with
RET mutations. The association between
RET mutation and vandetanib efficacy was inconclusive in previous studies [
7,
10,
17], but MTC patients harboring the
M918T mutation showed more aggressive disease and better response rates to vandetanib therapy than those without the
RET918 mutation [
15]. The proportion of patients with cancers harboring a
RET mutation was 8% in our study, while it was 59% in the treatment group of the ZETA trial. Furthermore, in our study, patients previously treated with TKIs were allowed to participate, whereas the ZETA trial did not report data on previous TKI therapy. Despite these differences, the results of our study and the ZETA trial were similar with respect to the ORR and PFS prolongation.
Although the frequency of AEs in our study was higher than that observed in the ZETA trial, no unexpected AEs occurred during treatment. Additionally, most AEs were mild and manageable by dose modification and medical therapies. Dose reduction, interruption, and discontinuation was needed in 33%, 50%, and 17% of patients, respectively. Consistent with the findings of the ZETA trial, the most common AEs were diarrhea, rash, hypothyroidism, decreased appetite, fatigue, and QTc prolongation [
7]. It is significant that the number of patients who required an increase in the daily dose of levothyroxine (75% vs. 49%) and who developed QTc prolongation (50% vs. 14%) was higher in our study than in the ZETA trial. The reason this study has a higher frequency of QTc prolongation than the ZETA trial was because EGC was monitored more frequently and the definition of QTc prolongation was different. In the ZETA trial, scheduled ECGs were performed during screening, at 1, 2, 4, 8, and 12 weeks and every 3 months thereafter [
7]. Meanwhile, in this study, ECGs were monitored at baseline and evaluated at 1 to 2-week intervals for a month, then 1 to 2-month intervals. QTc prolongation was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4 in our study: grade 1, QTc interval 450 to 480 ms; grade 2, 480 to 500 ms; grade 3, ≥501 ms on at least two separate ECGs; and grade 4, ≥501 or >60 ms change from baseline and torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. In the ZETA trial, QTc prolongation was defined as a single measurement ≥550 ms or an increase of ≥100 ms from baseline, two consecutive measurements (within 48 hours of each other) that were ≥500 but <550 ms, or an increase of ≥60 but <100 ms from baseline to a value ≥480 ms [
7]. Therefore, the ZETA trial that used this criteria to identify QTc prolongation may have missed some events since patients whose QTc interval ranged from 450 to 480 ms were not recorded. This evidence suggests that thyroid function, ECGs, and electrolyte levels should be monitored frequently after vandetanib initiation, to allow for early management of AEs before they worsen. It is also noteworthy that cutaneous AEs led to drug discontinuation in two patients in our study. The etiology of rash induced by vandetanib is unclear, but it is likely to be associated with the inhibition of EGFR [
19-
21]. Reduction of quality of life due to rash may play a significant role in adherence to the drug. Therefore, awareness and treatment of cutaneous AEs is needed to improve drug compliance and to maximize the dose while ensuring the best clinical benefits.
Because patients with advanced MTC can present with indolent disease and long life expectancy, the median OS was not reached during the median follow-up of 32 months. Previous data on the ability of vandetanib to improve survival are limited [
7,
10,
12,
17,
22]. OS data were also immature at the data cutoff in the ZETA trial, and an interim analysis showed no significant survival benefits with vandetanib treatment, during a median duration of 24 months of the randomized phase [
7]. These results demonstrate that once vandetanib has been started, the patient is likely to receive this drug for a long time. In addition to doubtful survival benefits and toxicities caused by the chronic use of vandetanib, it is necessary to consider the escape phenomenon and rapid tumor growth after drug withdrawal while determining vandetanib initiation [
6,
22,
23]. Therefore, it is crucial to establish an appropriate risk stratification based on patients with advanced MTC who have benefited with vandetanib administration, and only a selected group of patients should be considered for vandetanib therapy.
The limitations of our study are mainly related to its retrospective nature and the small number of patients. The treatment duration was longer than that in the ZETA trial, but it was relatively short to evaluate the median OS. Further, information on RET mutational status was not available in 25% of patients. Despite these limitations, our study is the first in Korea to evaluate the efficacy and safety of vandetanib in patients with advanced MTC in a real-world setting.
This multicenter, real-world analysis supports the results of the ZETA trial in that vandetanib has clinical benefits with regards to ORR and PFS in patients with advanced MTC. Although all patients experienced any-grade AEs, there were no fatal AEs; all AEs were generally consistent with the known safety profile of vandetanib. In conclusion, vandetanib is an effective treatment option in routine clinical practice with significant efficacy and manageable safety for advanced MTC.