Potential conflict of interest: Nothing to report.
Drug-related adverse events may predict efficacy in sorafenib therapy for hepatocellular carcinoma†
Article first published online: 6 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 2, pages 790–791, August 2012
How to Cite
Zhao, Y., Yang, M., Qi, X., Han, G. and Fan, D. (2012), Drug-related adverse events may predict efficacy in sorafenib therapy for hepatocellular carcinoma. Hepatology, 56: 790–791. doi: 10.1002/hep.25639
- Issue published online: 25 JUL 2012
- Article first published online: 6 JUL 2012
- Accepted manuscript online: 6 FEB 2012 12:07AM EST
- Manuscript Accepted: 18 JAN 2012
- Manuscript Revised: 12 JAN 2012
- Manuscript Received: 28 DEC 2011
To the Editor:
We read with great interest the recent study by Iavarone et al.,1 in which the authors report that the patients receiving a half-dose of sorafenib for >70% of the treatment period had a longer median survival than those maintained on a full dose (21.6 versus 9.6 months). However, the authors failed to further analyze this surprising difference in survival. It is noteworthy that the main reason which caused dose reduction was drug-related adverse events (AEs). Here, we propose that the patients in this study who experienced AEs responded better to sorafenib than those who did not, which indicates that the drug-related AEs may presumably predict the efficacy of sorafenib therapy (Fig. 1).
As we know, most AEs related to sorafenib are downstream effects of suppressed vascular endothelial growth factor (VEGF) signaling in endothelial cells in normal organs.2 It is also suggested that the lack of AEs indicates the absence of an antitumor effect.3 For example, the inhibition of VEGF signaling can not only achieve an antiangiogenic effect, but also decrease the production of the vasodilators nitric oxide (NO) and prostacyclin and consequently result in hypertension.4 The study by Maitland et al.5 also shows that elevated blood pressure is a biomarker for the efficacy of VEGF inhibition.
Furthermore, in recent years some researchers have focused on the correlation between AEs related to small molecular compounds or monoclonal antibodies and response or efficacy (Table 1). More solid evidence on this matter is provided by the recent study of Vincenzi et al.6 The authors found a correlation between the development of a rash during sorafenib therapy and both longer time to progression and better disease control.
|First Author||Publication (Date)||Cancer||Targeted Therapy||Sample Size||Study Design||AEs||Median OS*||Positive Correlation|
|Cunningham||N Engl J Med (2004)||MCC||cetuximab||329||RCT||skin reaction||9.1 m vs. 3.0 m||AEs and longer survival|
|Ravard||Ann Oncol (2009)||MRCC||bevacizumab sorafenib, sunitinib||66||prospective||hypertension (grade ≥2)||N/A||significant AEs and better OR and SD|
|Scartozzi||Ann Oncol (2009)||MCC||bevacizumab||39||retrospective||hypertension||N/A||AEs and both longer PFS and better response rate|
|Vincenzi||Oncologist (2010)||HCC||sorafenib||65||retrospective||early skin reaction (within the first month)||7.9 m vs. 1.2 m||early AEs and longer OS, TTP and better tumor control rate|
|Ravard||Lancet Oncol (2010)||LASCCHN||cetuximab||211||RCT (grade ≥2)||rash||68.8 m vs. 25.6 m||significant AEs and longer survival|
As a result, we consider that the study by Iavarone et al. provides additional evidence for the correlation between AEs related to sorafenib and efficacy. The predictive value of AEs merits better-designed studies.
- 1Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. HEPATOLOGY 2011; 54: 2055-2063., , , , , , et al.
- 2Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96: 1788-1795., .
- 3Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 2007; 25: 2993-2995., , , .
- 4VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008; 8: 579-591., .
- 5Blood pressure as a biomarker for sorafenib, an inhibitor of the VEGF signaling pathway. J Clin Oncol 2006; 24: 87s (suppl; abstr 2035)., , , , , , et al.
- 6Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010; 15: 85-92., , , , , , et al.
Yan Zhao XX*, Man Yang XX*, Xingshun Qi XX*, Guohong Han XX*, Daiming Fan XX* , * Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China, State Key laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.