A rescue through a cetuximab based
therapy may then determine a further disease response (Figure 1). Figure 1 K-Ras WT clone restored during intervening chemotherapy allow the gain of new sensibility to anti-EGFR chemotherapy. In this sense an interval therapy based on a different treatment, which is not

influenced by K-Ras status or is more efficacious in K-Ras mutated CRC, could facilitate the re-emersion of wt clones (Table 2). Table 2 Biological and clinical data suggesting a possible role of rechallenge see more in management of mCRC Role of rechallenge in mCRC K-ras status concordance and heterogeneity K-ras mutation is an early pathogenic step in colorectal cancer development and the possibility of late acquisition of K-Ras mutation is not clarified. The following therapy could allow K-Ras WT clone to re-predominate

Treatment holiday Holiday from a drug could allow reversion to a previous epigenetic profile. Moreover treatment holiday could facilitate recovery from cumulative toxicity induced by chemotherapy. To our knowledge few studies evaluated role of treatment holiday and they reported results. An in vitro model suggested that K-Ras mutated cell lines are more sensitive to Oxaliplatin [34]. Consistently, a retrospective study evaluating K-Ras status in 90 patients treated with FOLFOX-6 as first-line or second-line MK5108 treatment showing that PFS was longer in mutated K-Ras population than in wt K-Ras patients (10 vs 8 months, respectively; p = 0.001) [35]. Clinical evidence of activity of standard chemotherapy rechallenge The RE-OPEN phase II study assessed the efficacy of the re-introduction of oxaliplatin (administered in FOLFOX regimen) for 18 patients with metastatic colorectal cancer refractory to standard chemotherapy regimens including oxaliplatin, irinotecan and fluorouracil. Disease control rate (DCR) after 12 weeks was observed in seven patients (38.9%) [36]. Treatment holiday Dynein and chemotherapy-free

interval strategies Rationale The introduction of biologic compounds in combination with standard chemotherapy in the treatment of mCRC has extended median overall survival of patients up to 2 years and beyond. Moreover a sequential treatment approach using all active agents can allow to reach long-term control of disease changing mCRC from an acute to chronic condition. In this new scenario, the find more quality of life and the avoidance of cumulative toxicity became one of the most important end point of mCRC management. Several randomized phase III studies evaluated the role of chemotherapy in mCRC but most of them planned treatment to be continued until disease progression or development of intolerable toxicity.