Comment on :

Tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib are established therapies for advanced renal cell carcinoma (RCC) [1], while the combination of an anti–vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, has also been approved as a first-line option [2]. Although our armamentarium against this disease has been significantly enriched, there are still several questions to be answered. In this issue of European Urology, Johannsen et al [3] have touched on a clinically relevant issue: the optimal duration of treatment with TKIs. They approached this question by retrospectively reviewing 12 cases of patients who achieved a complete response (CR) with TKI alone or TKI plus surgery and stopped treatment due to side effects. Some of these patients relapsed after discontinuing their treatment. The authors claim that this finding is evidence that discontinuation may not be a safe option. Nevertheless, their conclusion is not supported by this particular study, which suffers from critical limitations (some of which are acknowledged by the authors): small number of patients; retrospective rather than controlled analysis; nonuniform criteria for discontinuing treatment; TKIs used as first-, second-, or even thirdline treatment. Therefore, this study cannot answer any questions but raises important ones. Let us define the magnitude of the problem. The authors chose to study a minority of patients consisting of those with CR. Several studies have consistently shown that such patients represent <10% of cases [2,4]. Furthermore, response by Response Evaluation Criteria in Solid Tumors (RECIST) may be an inappropriate surrogate for efficacy of these agents. The question of optimal duration is important for many more patients, probably any patient with clinical benefit (ie, CR + partial response [PR] + stable disease [SD]). In an incurable disease, the duration of therapy usually represents an equilibrium between the derived benefit and the tolerability of treatment. All available agents for RCC have side effects, which may become serious in a minority of patients [5]. While stopping rules are clearly defined within the context of clinical studies, everyday practice requires considerable experience by the physician with the types of side effects as well as their management so that an effective treatment is not unnecessarily stopped or improperly continued. Certainly treatment discontinuation should be considered in untreatable grade 3 or 4 toxicity, and this practice should not be changed because of the observations of this report. The relapses seen in the five patients would almost certainly have occurred even if treatment had not been discontinued. Whether they occurred earlier cannot be answered by this report. On the contrary, a more significant observation is that many of these patients responded to the reintroduction of the same agent, suggesting that temporary discontinuation of an effective agent may, in fact, be an efficient strategy because the sensitivity to this agent is retained. In conclusion, we are far from using several effective agents in the most efficient way to treat RCC. Clinicians should continue working closely with scientists to identify molecular markers, which will aid us in individualizing therapeutic strategies and will improve on the already significant progress achieved in treating this disease.