Nozawa et al. report on the activity of Sorafenib rechallenge in patients with advanced RCC. Their data, even though retrospective and therefore intrinsically biased, confirm those of another report [1], suggesting that rechallenging patients with the vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) sunitinib could help achieve a further survival benefit.

At first sight, their results could be regarded as just more retrospective observations, potentially useful (not taking into account local regulatory issues) only in those countries where not all the novel agents are available, or after their use, in those patients who are still clinically suitable for further treatments. Yet, if we take these data together with the recently published results of the AXIS trial [2], which showed the activity of axitinib, another VEGFR-TKI, as a second-line treatment (mainly, but not exclusively, after first-line sunitinib) and also with the retrospective series of the International Metastatic RCC Database Consortium [3], suggesting that VEGFR-TKI-primary-refractory patients will achieve no further benefit from either changing TKI, or shifting to an mTOR inhibitor (with the latter option being even less efficaceous), a couple of key questions are raised. Firstly, how long should we continue to inhibit the VEGF/VEGFRs pathway and, secondly, and equally importantly, does shifting from a VEGFR-TKI to an mTOR inhibitor really mean changing the mechanism of action?

The presently available data suggest that continuing to inhibit angiogenesis is a smart strategy in RCC, and that, shifting from a VEGFR-TKI to a mTOR inhibitor, does not necessarily mean hitting another target. Indeed, we should always take into account that in RCC, a neoplasm that depends heavily on VEGF-driven angiogenesis, owing to the frequent mutation of the VHL tumour suppressor gene, the inhibition of mTOR could ultimately be just a different way to inhibit angiogenesis. If this is true, the only reasonable way to deal with the treatment of advanced RCC patients is by trying to personalize treatment as much as possible, i.e. by trying to simplify a hugely complex scenario [4], which will be even more complex when the results of several ongoing trials are available.