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).

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Figure 1. Different outcomes are attributed to different responses to sorafenib. Dashed arrow shows the possible predictive role of AEs (adverse events).

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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.

Table 1. Relationship Between AEs and Efficacy: A Brief Summary
First AuthorPublication (Date)CancerTargeted TherapySample SizeStudy DesignAEsMedian OS*Positive Correlation
  • *

    The median OS of patients with AEs compared with those without AEs. Abbreviations: AEs, adverse events; HCC, hepatocellular carcinoma; MCC, metastatic colorectal cancer; MRCC, metastatic renal cell carcinoma; LASCCHN, locoregionally advanced squamous-cell carcinoma of the head and neck; OS, overall survival; TTP, time to progression; PFS, progression-free survival; OR, objective response; SD, stable disease; RCT, randomized controlled trial; N/A, not available.

CunninghamN Engl J Med (2004)MCCcetuximab329RCTskin reaction9.1 m vs. 3.0 mAEs and longer survival
RavardAnn Oncol (2009)MRCCbevacizumab sorafenib, sunitinib66prospectivehypertension (grade ≥2)N/Asignificant AEs and better OR and SD
ScartozziAnn Oncol (2009)MCCbevacizumab39retrospectivehypertensionN/AAEs and both longer PFS and better response rate
VincenziOncologist (2010)HCCsorafenib65retrospectiveearly skin reaction (within the first month)7.9 m vs. 1.2 mearly AEs and longer OS, TTP and better tumor control rate
RavardLancet Oncol (2010)LASCCHNcetuximab211RCT (grade ≥2)rash68.8 m vs. 25.6 msignificant 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.


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  • 1
    Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. HEPATOLOGY 2011; 54: 2055-2063.
  • 2
    Kamba T, Mcdonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96: 1788-1795.
  • 3
    van Heeckeren WJ, Ortiz J, Cooney MM, Remick SC. Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 2007; 25: 2993-2995.
  • 4
    Ellis LM, Hichklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008; 8: 579-591.
  • 5
    Maitland ML, Moshier K, Imperial J, Kasza KE, Karrison T, Elliott W, et al. Blood pressure as a biomarker for sorafenib, an inhibitor of the VEGF signaling pathway. J Clin Oncol 2006; 24: 87s (suppl; abstr 2035).
  • 6
    Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010; 15: 85-92.

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.