Vandetanib: too dangerous in medullary thyroid cancer

Treatment of medullary thyroid cancer is mainly based on surgery. Life expectancy exceeds 10 years in almost half of patients with inoperable advanced or metastatic disease. Cytotoxic chemotherapy is generally ineffective when this malignancy progresses. Vandetanib (Caprelsa, AstraZeneca), a multiple kinase inhibitor, is authorised in the European Union for use in this setting. Its clinical evaluation is mainly based on a double-blind, randomised, placebo-controlled trial in 331 patients, 70% of whom had progressed within the previous 6 months. Median follow-up (2 years) is too short to detect an impact on overall survival (about 85% in both groups). Analyses based on other outcomes (progression-free survival and pain) are unreliable, due to the large amount of missing data. The adverse effect profile of vandetanib is unfavourable: it includes diarrhoea and other gastrointestinal disorders, cardiovascular disorders, and cutaneous, neuropsychological, haemorrhagic and metabolic disorders. Visual disturbances have also been observed. Vandetanib also prolongs the QT interval: 3 cases of torsades de pointes and 9 sudden deaths have already been reported. Renal failure increases this risk. Numerous pharmacokinetic interactions are likely to occur, notably via cytochrome P450 isoenzyme CYP 3A4. Vandetanib reduces the effectiveness of levothyroxine. Vandetanib should not be combined with other drugs that prolong the QT interval. The long half-life of vandetanib (about 3 weeks) must be taken into account when managing interactions and adverse effects. There is no firm evidence that vandetanib has a favourable harm-benefit balance in patients with inoperable advanced or metastatic medullary thyroid cancer.