Treatment Compliance and Severe Adverse Events Limit the Use of Tyrosine Kinase Inhibitors in Refractory Thyroid Cancer

Overall response

Overall response, including stable disease and partial response, was estimated for the 17 of the 24 patients who continued treatment for more than three cycles (Table 2). Two patients with DTC showed improvement of lung metastases after 6 months of TKI administration as documented by CT, which improved further as treatment was continued. Metastatic sites favoring response were the lungs. At the time of collecting the data, all patients with DTC were alive; however, six of the ten MTC patients had died. There were no deaths related to TKI therapy.

Tumor markers

Median TSH was 0.26 (range: 0.01–1.44) μIU/mL at baseline and 0.48 (0.09–3.6) μIU/mL at 3 months. In three patients, an increase in thyroxine dose was decided. Thyroglobulin levels at baseline on thyroxine were 148 (1.3–7,572) ng/mL and at 3 months were 108 (1.3–1,629) ng/mL, while the calcitonin levels were 8,107 (874–8,920) pg/mL at baseline and 4,901 (441–5,068) pg/mL at 3 months.

A high treatment dropout rate was observed in this study, mainly due to drug toxicity along with reluctance of patients to continue treatment. Younger patients tolerated longer treatment, indicating that these patients were perhaps more motivated and willing to receive and continue therapy. The patients presented a high frequency of minor and major adverse events while on treatment. A preferential effect of TKI therapy on metastatic disease to the lung was observed.¹⁶ Finally, a non-significant trend for reduction of both thyroglobulin and calcitonin serum levels after the use of TKIs was also observed. Because a considerable number of patients (13 of 24) discontinued therapy due to side effects and not disease progression, calculation of progression-free survival or even overall survival would not provide an insight into the efficacy of TKI treatment in this cohort.

With the exception of anaplastic thyroid cancer, patients with MTC and DTC have in most cases a good prognosis, with a 5-year survival exceeding 60% for MTC¹⁷ and 90% for DTC.¹⁸ In this study, the survival of MTC cases was shorter than for DTC patients. Furthermore, while the disease is progressing, patients usually maintain a good quality of life. As a result, they have the expectation that applied therapies would not interfere with their normal everyday life and activities.

In the present study, we used sorafenib for the treatment of MTC patients (when vandetanib was not approved for the treatment of MTC) based on data concerning its activity at the RET and vascular endothelial growth factor receptors¹⁹ and from two studies published at that time showing a response in 40% of patients²⁰ and stable disease in 50% of MTC patients.⁸ After approval of vandetanib, patients with MTC received this drug. On the other hand, sunitinib, known as a multitargeted inhibitor at that time,²¹ was administered to RAI-refractory DTC patients in an open-label Phase II study and showed a 13% partial response rate and a 68% disease stabilization rate.²² Very recently, data have been presented from DECISION, a randomized, double-blind Phase III trial examining the efficacy and safety of sorafenib versus placebo in RAI-refractory DTC patients.²³ Four hundred and seventeen patients from 77 centers in the USA and Europe were randomized to receive either sorafenib or placebo. The study indicated that sorafenib improved progression-free survival by 5 months over placebo. In another randomized, double-blind Phase III study that included 331 patients with MTC, 231 patients received vandetanib and 100 received placebo. In that study, prolongation of progression-free survival was observed in patients who received vandetanib when compared with those who received placebo.¹⁰ A direct comparison with the earlier findings cannot be made because the design of our study did not include a placebo group or calculation of progression-free survival.

Looking at the efficacy and adverse events between DTC and MTC patients, we can conclude that: sunitinib or sorafenib therapy in DTC patients was more efficacious than sorafenib or vandetanib in MTC patients, given that partial response and stable disease was seen only in DTC patients and adverse events were similar between DTC and MTC patients (Table 2).

Cardiac and hematological side effects were the most clinically important adverse events presented during therapy, and were the most significant medical reasons for withdrawing treatment. In general, cardiac toxicities, from changes on the electrocardiogram and left ventricular ejection fraction abnormalities to severe congestive heart failure and acute coronary syndromes, should be suspected and monitored for during TKI therapy.^24,25 In our cohort, hematological toxicity of all grades was seen in five of our 24 patients and grade 3–4 events occurred in two patients. Epistaxis, seen in three patients, was an additional reason to withdraw treatment. These results are comparable with the published data for all-grade hematological toxicity of 60%–70% and grade 3–4 toxicity of 6%–8%.²⁶In addition, we observed hand-foot syndrome in 58.33% of patients, which is similar to published data reporting rates of 60%–91%.²⁷ These skin reactions tend to appear early on in treatment and improve after the first six cycles,²⁸ and were also seen in the present study. Finally, fatigue, which probably represents a multifactorial toxicity during use of TKIs,²⁹ is debilitating and at times difficult to overcome, as suggested by our findings.