Chemotherapy plus Vandetanib or chemotherapy alone in advanced non-small cell lung cancer: a meta-analysis of four randomised controlled trials
Xiao, Y.-Y.; Zhan, P.; Yuan, D.-M.; Liu, H.-B.; Lv, T.-F.; Shi, Y.; Song, Y.
Clinical Oncology 25(1): E7
2013
ISSN/ISBN: 1167-7422 PMID: 23185843 Document Number: 669529
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. Most patients with advanced non-small cell lung cancer (NSCLC) require systemic chemotherapy. Vandetanib, targeting epidermal growth factor receptor and vascular endothelial growth factor receptor signalling in NSCLC, has recently been evaluated in combination chemotherapy in advanced NSCLC. However, the advantage of chemotherapy plus vandetanib over chemotherapy alone in advanced NSCLC remains largely unknown. A meta-analysis of randomised controlled trials was carried out to compare the efficacy and toxicity of chemotherapy plus vandetanib with chemotherapy alone in advanced NSCLC. The PubMed database, American Society of Clinical Oncology, European Society for Medical Oncology and the Cochrane Library and references of published trials were searched. Two reviewers independently assessed the quality of the trials. Data were extracted and the overall response rate, pooled progression-free survival, overall survival with 95% confidence intervals and main toxicity were analysed. Four randomised controlled trials involving 2160 patients with advanced NSCLC were ultimately analysed. Compared with chemotherapy alone, chemotherapy plus vandetanib significantly increased the overall response rate (relative risk = 1.96, 95% confidence interval = 1.53--2.52) and progression-free survival (hazard ratio = 0.79, 95% confidence interval = 0.71-0.87), but there was no significant difference in overall survival (hazard ratio = 0.91, 95% confidence interval = 0.79-1.03). Patients who received chemotherapy plus vandetanib had more rash, diarrhoea, hypertension and QTc prolongation (odds ratio = 2.32, 95% confidence interval = 1.93-2.79; odds ratio = 1.64, 95% confidence interval = 1.37-1.97; odds ratio = 4.08, 95% confidence interval = 2.51-6.01, odds ratio = 17.77, 95% confidence interval = 3.54-61.66, respectively), and less nausea and vomiting (odds ratio = 0.70, 95% confidence interval = 0.58-0.85; odds ratio = 0.69, 95% confidence interval = 0.55-0.86, respectively). The incidences of haemorrhage, fatigue and cough were comparable between the two groups. Although similar in overall survival, chemotherapy plus vandetanib showed particular advantages over chemotherapy alone in terms of progression-free survival and overall response rate. The toxicity was comparable between the two groups. Therefore, chemotherapy plus vandetanib might be a safe and valid therapeutic option for advanced NSCLC patients.