Table 3 Clinical evidences evaluating different strategies for treatment of mCRC

EGFR therapy rechallenge

- A multicenter phase II prospective study confirmed the activity of cetuximab rechallenge plus irinotecan-based therapy after an intervening chemotherapy [30]

- A phase II prospective study did not show any response to panitumumab administrated after progression on prior cetuximab-based therapy [31]

Chemotherapy stop-and go strategy

- OPTIMOX 1 study shows that ceasing oxaliplatin after 6 cycles, followed by leucovorin–5-FU alone, achieves RR, PFS, and OS equivalent to that with continuing oxaliplatin until progression or toxicity [38]

- OPTIMOX 2 study shows that continuing treatment with a maintenance chemotherapy led to a longer PFS, compared with pausing treatment [39]

- COIN study did not show a non inferiority of chemotherapy free interval versus continuous treatment but treatment holiday significantly reduced cumulative toxic effects, and improved quality of life [41]

Biological treatment of chemotherapy-free interval

- NORDIC VIII phase III trial showed that cetuximab maintenance do not improve survival data comparing to intermittent treatment [42].

- COIN B phase II trial showed that cetuximab maintenance significantly improved chemotherapy free interval and PFS [43].

- MACRO TTD phase III trial confirmed the efficacy of a maintenance therapy with bevacizumab after a predefined period of chemotherapy induction [44].

- 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].