**3.4 Stage II colon cancer**

The role of adjuvant chemotherapy in stage II is not clearly defined. 5-year disease free survival for these patients is more than 80%. Because of this relatively good prognosis, benefit from adjuvant 5FU-based chemotherapy is small and remains questionable given many of the trials are underpowered. In order to demonstrate a larger benefit or to unravel small differences with statistical significance, a highly efficacious therapy or trials with larger samples are needed. To detect an absolute improvement in survival at 5 years by 4% with more than 90% power, 4700 patients with stage II colon cancer would be required. A retrospective study based on SEER-Medicare linked database explored the outcome of more

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 are not standard practice.

There were a number of meta-analyses which support the use of adjuvant therapy in stage II colon cancer including NSABP, NCCTG and IMPACT. 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 at 8 years [16].

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 regarding therapy.

**167**

*Adjuvant Therapies in Colon Cancer*

given the findings from MOSAIC.

**3.5 Stage III colon cancer**

*3.4.1 Role of oxaliplatin*

*DOI: http://dx.doi.org/10.5772/intechopen.93874*

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,

Patients with node positive colon cancer are at higher risk of recurrence with a 5-year overall survival estimate of 40–60%. Adjuvant therapy is indicated for most patients with stage III disease to eliminate micro metastases and to improve disease free survival and overall survival. Combination 5FU/leucovorin and oxaliplatin regimen is the standard of care unless they are medically unfit to receive intensive

A landmark study in the 1990s established the benefit of adjuvant therapy in resected stage III colon cancer where 5FU/levamisole for 12 months decreased recurrence and improved survival [5]. Results remained significant at 5 years with a 41% reduction in recurrence and 33% reduction in death [24]. However subsequently leucovorin has emerged as an effective potentiator of anti-tumor activity of 5FU, whereas levamisole lacked significant biological activity. 5-FU is metabolized in cancer cells to 5-fluorouridine 5′-monophosphate (FUMP), by uridine monophosphate synthetase, with a resultant active form, 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP). FdUMP then forms a ternary complex with thymidylate synthase in the presence of reduced tetrahydro folate (5,10-CH2-THF) which eventually inhibit DNA replication. Leucovorin is metabolized into 5,10-CH2-THF and enhance formation of thymidylate synthase/5FU ternary complex and anti-tumor activity. Subsequent studies confirmed the lack of utility of levamisole and efficacy of leucovorin in combination with 5FU in adjuvant therapy of colon cancer [25]. Two large randomized studies established the role of oxaliplatin in the adjuvant treatment of stage III colon cancer. Multicentre International Study of

Oxaliplatin/5FU/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIQ ) utilized a 2 hour bolus infusional 5FU followed by 22 hours 5FU infusion along with oxaliplatin in a 2 weekly cycle (FOLFOX4) for 6 months in resected colon cancer patients (60% stage III and 40% stage II). A total of 2246 patients were randomized to receive either FOLFOX4 or 5FU/leucovorin. In the intention to treat population FOLFOX4 significantly improved 5-year disease free survival (73.3% 67.4%) compared to 5FU/leucovorin (HR 0.80, 95% CI 0.68–0.93; p = 0.003). Overall survival at 6 years was 78.5% versus 76.0% (HR 0.84; 95% CI, 0.71–1.00; p = 0.04). In a subgroup analysis, there was 4.2% improvement by the addition of oxaliplatin in 6-year overall survival in stage III disease (72.9% versus 68.7%, HR =0.80; 95% CI =0.65–0.97; p = 0.023), however, no overall survival benefit was evident by the addition of oxaliplatin in stage II cancer (85% versus 83.3%, p = 0.65). In a 10-year updated analysis, results essentially remained consistent. Oxaliplatin was approved for adjuvant treatment of colon cancer and is the standard of care for most patients

chemotherapy where single agent 5FU/Leucovorin may be appropriate.
