**6. Duration of therapy**

The recommendations for duration of adjuvant therapy for colon cancer are evolving. Early adjuvant trials treated patients for 12 months with 5FU/levamisole which was the standard of care in 1990s. Subsequent studies revealed 6 months of therapy was at least comparable to 12 months which became the standard of care in late 1990s [25, 52]. MOSAIQ an NSABP C-07 trials utilized 6 months of oxaliplatin and 5FU based regimen which remained as standard practice until recently the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration study explored non-inferiority of 3 months of adjuvant therapy versus 6 months. IDEA collaboration study was a prespecified exploratory combined analysis of six separate international randomized trials of 6 versus 3 months of oxaliplatin based adjuvant therapy. Although non-inferiority of 3-months was not proven in the intention to treat population, sub-group analysis revealed patients those who received capecitabine and oxaliplatin (CAPOX) for 3 months, 5-year disease free survival was non-inferior to 6 months, however 3 months of 5FU and oxaliplatin FOLFOX did not meet the non-inferiority margin [53, 54]. Among low risk patients (T1–3,N1) the 5-year overall survival benefit between 3 versus 6 months therapy was 89.6% versus 88.9% (absolute difference of 0.7%) whereas the absolute difference was 2.7 among higher risk patients (T4N2 and above). Therefore, in lower risk patients, 3 months of therapy is acceptable if CAPOX regimen was chosen, while 6 months of therapy should be offered with FOLFOX regimen for others with stage III disease with clear discussion with patients regarding the small added benefit and risk of long-term neuropathy. 5FU/Leucovorin without oxaliplatin is offered as adjuvant therapy in stage III colon cancer sometimes, when patients are medically unfit or elderly. Six months adjuvant therapy is the standard recommendation in this situation, given absence of prospective data comparing 3 months versus 6 months. Similarly, 6 months of 5FU based adjuvant therapy is standard in stage II colon cancer. However, patients with high risk stage II disease are sometimes treated with oxaliplatin based regimen. TOSCA trial investigated 3 months versus 6 months of adjuvant therapy in stage II and III colon cancer where one-third of them were stage II [55]. In the overall population, 6 months was superior to 3 months, however, 3 months of CAPOX regimen was non-inferior to 6 months. There were 1254 patients with high risk stage II disease in the IDEA collaborative study (including TOSCA study) which investigated the optimal duration of adjuvant therapy [56]. Investigators concluded that 3 months of CAPOX may be non-inferior to 6 months

in high risk stage II cancers, reflecting the finding in stage III disease. Consistently 3 months of FOLFOX was not non-inferior to 6 months.
