- CAIRO 3 phase III trial showed that bevacizumab and de-escalated

chemotherapy maintenance administrated after chemotherapy and bevacizumab induction significantly improves OS comparing to a treatment holiday strategy [45]. These studies do not allow a clear indication on what is the best option between p53 activator treatment holiday (defined as pause from all treatment) and chemotherapy-free interval with a period of maintenance therapy, and more prospective trial are warranted. Conclusions The role of rechallenge therapy in third-line or fourth-line setting in mCRC is not defined but it could be a possibility for fit patients who do not have any other valid selleck screening library options. Few clinical studies evaluated the role of targeted therapies rechallenge and up to date there are no convincing predictive factors suggesting which drug should be readministered. This choice should be based on several reasonable factors: best response to prior treatment before progression (prolonged stable disease, partial response or complete response), residual toxicity (especially in case of oxaliplatin reintroduction), duration of treatment holiday. In our opinion, intermittent

treatment could be an important strategy in management of mCRC patient when there is not the purpose of gaining an important tumour shrinkage, for avoiding cumulative toxicity and for maintaining chemotherapy sensitiveness even D-malate dehydrogenase if there is not a clear evidence in prolonging OS compared to the intensive treatment. Moreover, few clinical studies assessed the role of rechallenge in the era of targeted therapy and no studies evaluated the activity of bevacizumab as a rechallenge therapy (both as a monotherapy or in combination with standard chemotherapy) so far. However,

it has been demonstrated that targeted therapy could enhance sensitivity to both chemotherapy and radiotherapy [46]. Brite and TML study showed a benefit in the use of bevacizumab beyond disease progression. However, in this case, we cannot regard to bevacizumab administration as a real rechallenge, as there was no treatment interruption after disease progression or any intervening therapy. Further clinical studies should enquire the role of bevacizumab retreatment and the importance of angiogenesis control in heavily pretreated mCRC patients as a possible mechanism of restoring sensitivity to re-administration of standard chemotherapy.