Twenty-four patients (14 males, ten females) were identified from our clinical database to have received TKIs since April 2009. Fourteen patients had DTC and ten had MTC. Their median age was 58.29 (range: 42–74) years. The histological characteristics of the tumors are presented in Table 1. All patients had distant metastases located at one or more sites (liver 37.5%, lung 58%, bone 29.1%, and lower mediastinum 20.8%). The time between diagnosis of thyroid carcinoma and treatment with a TKI varied from a minimum of 6 months to a maximum of 9 years. Previous treatments included thyroidectomy (in all patients) with/without lymph node dissection and administration of RAI (in all DTC patients), external beam radiation, and local therapies for liver metastases (radiofrequency ablation and/or chemoembolization; for details, Table 1). All applied treatment was terminated at least 6 months prior to initiation of TKI therapy.
The duration of TKI treatment ranged from one to 19 cycles. Younger patients tolerated longer treatment (Table 2). The first adverse events appeared after approximately 2 weeks of therapy, and were fatigue, mild diarrhea, and stomatitis. During treatment, the most commonly reported adverse events were diarrhea (81.25%), stomatitis (75%), fatigue (62.5%), and skin adverse effects (81.25%, comprising hand-foot syndrome, skin discoloration, and rash, Tables 2 and 3). A minority of patients developed anemia, neutropenia, and elevated triglyceride levels (Table 2). Although many adverse events were grade 1 and 2, 15 patients (62.5%) reported grade 3 and 4 toxicities (Tables 2 and 3). In particular, one female patient developed painful vulvar ulcers and refused to continue treatment with sunitinib even in lower dose, one man developed many ulcers across the surface of the scrotum while taking sorafenib, and there were one case with renal failure and one case with QT prolongation where both were on vandetanib. Two cases in particular warrant mention. The first was a 73-year-old female patient who developed congestive heart failure (ejection fraction 35%) while on sunitinib. This severe adverse event led to immediate drug withdrawal, with subsequent improvement of cardiac function. The second case was a man with RAI-refractory thyroid cancer in whom intense muscle pain and muscle weakness suddenly appeared 1 month after initiation of sorafenib, along with a nine-fold increase in creatine phosphokinase.
(To view a larger version of Table 2, click here.)
Reduction of the sunitinib dose from 50 to 37.5 mg once daily was required in five patients receiving sunitinib due to neutropenia (two patients), hypertension (two patients), and intense fatigue (one patient); from 400 to 200 mg twice daily for sorafenib in one patient due to scrotal ulcers; and from 300 to 200 mg for vandetanib in two patients (one due to renal failure and one due to QT prolongation). Sequential therapy was attempted with sunitinib followed by sorafenib in two patients due to severe neutropenia caused by sunitinib. Five patients (20.8%) opted to stop treatment after 1–4 cycles, regardless of the severity of the adverse event, because of inability to work long hours, decreased appetite, and restriction of outdoor activities. All adverse events encountered are shown in Table 3.