*3.4.1 Role of oxaliplatin*

*Colorectal Cancer*

are not standard practice.

at 8 years [16].

than 3000 patients without any adverse features depending whether they received chemotherapy within 3 months after surgery or not. Interestingly, 27% of patients received adjuvant therapy in this group without much evidence to support it [12]. They reported a 5-year survival of 75% for those who did not receive chemotherapy versus 78% in those who received therapy. High grade, younger age, low comorbidities and white race were more likely to receive chemotherapy. After adjusting for known variables there was no difference in survival (HR 0.91, 95% CI 0.77–1.09). A number of trials have tried to address the role of adjuvant therapy in stage II colon cancer with conflicting results. QUASAR (Quick and Simple and Reliable), a large UK study investigated the role of adjuvant 5FU in this randomized controlled trial [13]. This study enrolled more than 3000 patients with (91%) stage II cancers (node-negative) which also included 30% rectal cancer. After a median follow up of 5.5 years, there was about 20% reduction in the relative risk of death (any cause mortality HR 0.82; 95% CI 0.70–0.95; p < 0.008) in those treated with chemotherapy compared to placebo controlled arm which translated into small but significant absolute survival benefit of 3.6% (95% CI 1.0–6.0). Despite significant results, number of pitfalls in this trial has raised questions with regard to the benefit seen. The median number of lymph nodes removed in this study was 6 (in more than 60% of patients <12 lymph nodes were removed) which is well below current standards. In addition, there was a group of patients who received radiation therapy (14%) and another proportion received portal vein infusion therapy (6%), which

There were a number of meta-analyses which support the use of adjuvant

International Multicenter Pooled Analysis of Colon Cancer Trial (IMPACT) was a pooled analysis of randomized trials, showed a 2% improvement in 5-year overall survival. In another analysis of more than 150,000 patients with stage II colon cancer from National Cancer Database reported survival advantage of adjuvant therapy (HR 0.76; p < 0.001) [14]. Gill et al. analyzed pooled individual patient data of 3302 patients with stage II and stage III colon cancers. Although there was a statistically significant improvement in disease free survival (by 4%), overall survival difference (absolute benefit of 5%) was not significant [15]. The Adjuvant Colon Cancer End Points (ACCENT) collaboration analyzed individual patient data with regard to long term outcome after adjuvant therapy. Among 6900 patients with stage II cancers, there was 5% improvement survival

Given the conflicting data, adjuvant therapy in stage II colon cancer remains controversial. Several clinicopathological features and molecular markers are associated with poor prognosis in stage II colon cancers. These include T4 primary, bowel obstruction of peroration, poorly differentiated phenotype (including signet ring cells and mucinous) high pre-operative carcinoembryonic antigen (CEA), inadequate lymph node sampling (<13 nodes), lymphovascular space invasion and perineural invasion [17, 18]. Although most expert groups consider these factors as high risk features in stage II colon cancer, some discrepancy exist among their definition for high risk stage colon cancer [19–21]. While most expert groups recommend to consider these adverse factors when considering adjuvant therapy, there is limited evidence to suggest that the presence of one or risk factors are more likely to benefit from adjuvant therapy. In the landmark MOSAIQ trial, 434 patients were considered high risk stage II colon cancer. Although there was trend towards better disease-free survival in the FOLFOX arm compared to 5FU arm, overall survival was essentially similar [22]. The decision regarding adjuvant therapy in this setting will need to be individualized and take into account the patient's preferences

therapy in stage II colon cancer including NSABP, NCCTG and IMPACT.

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regarding therapy.

Two large phase III trials explored the role of oxaliplatin in stage II colon cancer; MOSAIC and NSABP C-07 which have virtually shown the lack of benefit of oxaliplatin in stage II colon cancer [22, 23]. Forty percent and 27% of patients were stage II in MOSAIC and NSABP C07 trials, respectively. An updated 10-year follow up report of MOSAIC confirmed the lack of benefit from oxaliplatin in stage II colon cancer. In fact there was a trend towards adverse outcome in low-risk stage II in MOSAIC, while there is a non-significant trend of improvement in disease free survival (7%) and overall survival (2%) [22]. No disease-free survival or overall survival benefit was seen in NSABP C-07 trial in patients with stage II colon cancer [23]. Therefore oxaliplatin is unlikely to benefit most patients with stage II colon cancer; however, it may be appropriate to discuss oxaliplatin in those with extremely high risk features, given the findings from MOSAIC.
