**3.5 Stage III colon cancer**

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

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

with stage III colon cancer. The FOLFOX4 regimen is associated with more toxicity compared to 5FU/leucovorin, notably grade 3/4 neutropenia was 41% in FOLFOX4 compared to 5% in 5FU/leucovorin and grade 3/4 diarrhea was 11% versus 7%. Oxaliplatin was associated with cold related dysesthesia and mostly reversible peripheral sensory neuropathy. Grade 3 neuropathy was reported in 12% of patients who received FOLFOX4. Although considered reversible, minority of patients may suffer long term or permanent sensory loss. About 30% of patients still had residual numbness at 12 months (5.9% grade 2/3) with another 24% experiencing some degree of neuropathy at 18 months from the end of treatment (3.9% grade 2/3).

A large second study confirmed the efficacy of oxaliplatin in adjuvant therapy for stage III colon cancer. NSABP C-07 enrolled 2409 patients with stage III (71%) and stage II (29%) colon cancer. They were randomized to receive either combination 5FU/leucovorin/oxaliplatin (FLOX) or 5FU/leucovorin. A weekly bolus 5FU Roswell Park regimen was used here instead of infusional 5FU. FLOX regimen improved disease-free survival compared to control arm (69.4% versus 64.2%; HR 0.82; 95% CI 0.72–0.93; p = 0.002), however overall survival differences were not statistically different. (HR 0.88; 95% CI 0.72–1.02; P = 0.08) No interaction was seen between treatment on the stage, however treatment effect did vary by age overall survival significantly improved in patients younger than 70 (HR 0.80; 95% CI 0.68–0.95; p = 0.01) with no effect seen in older patients [23]. However, FLOX regimen was associated with high incidence of grade 3/4 diarrhea (38% versus 32%) and hospitalization (5.5% versus 3%). Given the lack of survival benefit and toxicity with bolus 5FU regimen, infusional 5FU regimens like FOLFOX have become standard of care.

The XELOXA trial supported the benefit of oxaliplatin in combination with capecitabine. In this randomized trial, 1866 patients with stage III colon cancer were either treated with capecitabine/oxaliplatin or bolus 5FU/leucovorin regimen (Mayo clinic or Roswell Park) for 6 months. After a median follow up of 7 years disease free survival (63% versus 56%, HR 0.80; 95% CI; 0.69–0.93; p = 0.004) and overall survival (73% versus 67%, HR 0.83; 95% CI 0.70–0.93; p = 0.04) improved significantly compared to 5FU/leucovorin.

In all three trials oxaliplatin was associated with significant neurotoxicity which can be acute or chronic. Acute cold related neurotoxicity present as paresthesia or dysesthesia of hands and feet or muscular cramps including laryngospasm. This is often reversible but tends to recur with each treatment. On the other hand chronic neuropathy causes primarily a sensory neuropathy in limbs is thought to be due to accumulation of platinum products in dorsal root ganglia in a dose -dependent manner. About 10–15% of patients experience severe neuropathy after cumulative dose of 780–850 mg/m<sup>2</sup> . Other clinical factors are implicated in the onset of neuropathy, but none shows strong association. Patents with existing other comorbidities such as diabetes, hypertension and smoking may be associated with higher incidence of neuropathy from oxaliplatin, these results were not statistically significant. But patients with diabetes seem to develop neuropathy at lower cumulative dose [26]. Another report suggests that incidence neuropathy may be less XELOX 3-wekely (130 mg/m<sup>2</sup> ) regimen than FOLFOX 2-weekly (85 mg/m<sup>2</sup> ) regimen [27]. Therefore, choice of oxaliplatin in the adjuvant treatment of colon cancer should be based on individual assessment of risk of recurrence and other clinical factors.

## *3.5.1 Role of radiation*

Adjuvant and neoadjuvant radiotherapy is routinely used in the treatment of rectal cancer and has an impact on reducing the local recurrence rate and

**169**

*Adjuvant Therapies in Colon Cancer*

received radiotherapy.

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

for resectable colorectal cancer metastases.

**4.1 Mismatch repair enzyme deficiency**

after treatment with 5FU [35, 36].

**4. Molecular markers**

therefore improving local control. However, the use of this modality in non-rectal colon cancer is controversial and not supported by randomized controlled trials. It is however considered in the situation of T4 tumor which invades surrounding structures such as the bladder or the abdominal wall where there is a perceived high risk of local recurrence of the tumor. A retrospective analysis of 21,789 patients with T4 colon cancer using the US SEER (Surveillance, Epidemiology and End Results) database found 1001 patient who received radiotherapy [28]. After adjustment for sex, age, N stage and tumor grade the relative risk of death from cancer at 5-years was 0.88 (95CI 0.8008–0.9779, p = 0.0165) in patients who

**3.6 Role of adjuvant therapy for resected colorectal cancer metastases**

Liver is the commonest site of metastases in colon cancer. Unlike many other solid organ cancers, metastasectomy improves survival in colorectal cancer, where 5-year overall survival may reach 50%. The best postoperative management strategy is not well defined, however, often perioperative chemotherapy is utilized in the form of FOLFOX or CAPOX with agents like irinotecan, anti-EGFR, or anti-VEFG therapy often added for eligible patients in the neoadjuvant setting if downstaging was necessary. In the EORTC 40983 trial, perioperative chemotherapy was associated with 7.3% absolute increase in 3-year progression-free survival, however there was no difference in overall survival [29, 30]. Another Japanese study also did not show overall survival benefit with adjuvant chemotherapy [31]. Given the established role of adjuvant therapy in stage III colon cancer, despite lack of strong evidence many expert groups support perioperative or postoperative chemotherapy

Colon cancers that lack mismatch repair enzyme (dMMR) exhibit high microsatellite instability (MSI-High) and are associated with better prognosis compared to those with proficient mismatch repair enzymes (pMMR). Consistently, frequency of dMMR is higher in stage II colon cancer (20%) compared stage III (12%) and stage IV (4%) [32]. In a seminal study by Ribic et al., reported the prognostic differences between dMMR and pMMR in 570 patients from 5 different trials of 5FU based adjuvant chemotherapy (stage II and III) [33]. Five-year overall survival was significantly better in dMMR compared to pMMR(HR 0.31; 95% CI, 0.14–0.72;p = 0.004). Furthermore, there was no survival difference between dMMR and pMMR among those who received adjuvant chemotherapy (HR 1.07; 95% CI, 0.62–1.86; p = 0.80). The benefit of adjuvant chemotherapy was restricted to those with pMMR only. Although not all studies are consistent, a systemic review of 32 trials supported the above finding [34]. The key enzyme involved 5FU metabolism in cancer cells, thymidylate synthase, is found to be overexpressed in dMMR colon cancers which confer resistance to 5FU based therapy. Therefore, most patients with stage II colon cancer would not benefit from 5FU (only) based adjuvant therapy. Nevertheless, the role of dMMR in adjuvant therapy for stage III colon cancer is less clear. Despite lack of prospective data, retrospective studies support the use of oxaliplatin based adjuvant therapy, although Sinicrope et al. reported reduced distant recurrence in stage III cancers

### *Adjuvant Therapies in Colon Cancer DOI: http://dx.doi.org/10.5772/intechopen.93874*

*Colorectal Cancer*

become standard of care.

significantly compared to 5FU/leucovorin.

after cumulative dose of 780–850 mg/m<sup>2</sup>

may be less XELOX 3-wekely (130 mg/m<sup>2</sup>

rence and other clinical factors.

*3.5.1 Role of radiation*

with stage III colon cancer. The FOLFOX4 regimen is associated with more toxicity compared to 5FU/leucovorin, notably grade 3/4 neutropenia was 41% in FOLFOX4 compared to 5% in 5FU/leucovorin and grade 3/4 diarrhea was 11% versus 7%. Oxaliplatin was associated with cold related dysesthesia and mostly reversible peripheral sensory neuropathy. Grade 3 neuropathy was reported in 12% of patients who received FOLFOX4. Although considered reversible, minority of patients may suffer long term or permanent sensory loss. About 30% of patients still had residual numbness at 12 months (5.9% grade 2/3) with another 24% experiencing some degree of neuropathy at 18 months from the end of treatment (3.9% grade 2/3). A large second study confirmed the efficacy of oxaliplatin in adjuvant therapy for stage III colon cancer. NSABP C-07 enrolled 2409 patients with stage III (71%) and stage II (29%) colon cancer. They were randomized to receive either combination 5FU/leucovorin/oxaliplatin (FLOX) or 5FU/leucovorin. A weekly bolus 5FU Roswell Park regimen was used here instead of infusional 5FU. FLOX regimen improved disease-free survival compared to control arm (69.4% versus 64.2%; HR 0.82; 95% CI 0.72–0.93; p = 0.002), however overall survival differences were not statistically different. (HR 0.88; 95% CI 0.72–1.02; P = 0.08) No interaction was seen between treatment on the stage, however treatment effect did vary by age overall survival significantly improved in patients younger than 70 (HR 0.80; 95% CI 0.68–0.95; p = 0.01) with no effect seen in older patients [23]. However, FLOX regimen was associated with high incidence of grade 3/4 diarrhea (38% versus 32%) and hospitalization (5.5% versus 3%). Given the lack of survival benefit and toxicity with bolus 5FU regimen, infusional 5FU regimens like FOLFOX have

The XELOXA trial supported the benefit of oxaliplatin in combination with capecitabine. In this randomized trial, 1866 patients with stage III colon cancer were either treated with capecitabine/oxaliplatin or bolus 5FU/leucovorin regimen (Mayo clinic or Roswell Park) for 6 months. After a median follow up of 7 years disease free survival (63% versus 56%, HR 0.80; 95% CI; 0.69–0.93; p = 0.004) and overall survival (73% versus 67%, HR 0.83; 95% CI 0.70–0.93; p = 0.04) improved

In all three trials oxaliplatin was associated with significant neurotoxicity which can be acute or chronic. Acute cold related neurotoxicity present as paresthesia or dysesthesia of hands and feet or muscular cramps including laryngospasm. This is often reversible but tends to recur with each treatment. On the other hand chronic neuropathy causes primarily a sensory neuropathy in limbs is thought to be due to accumulation of platinum products in dorsal root ganglia in a dose -dependent manner. About 10–15% of patients experience severe neuropathy

the onset of neuropathy, but none shows strong association. Patents with existing other comorbidities such as diabetes, hypertension and smoking may be associated with higher incidence of neuropathy from oxaliplatin, these results were not statistically significant. But patients with diabetes seem to develop neuropathy at lower cumulative dose [26]. Another report suggests that incidence neuropathy

ment of colon cancer should be based on individual assessment of risk of recur-

Adjuvant and neoadjuvant radiotherapy is routinely used in the treatment of rectal cancer and has an impact on reducing the local recurrence rate and

) regimen [27]. Therefore, choice of oxaliplatin in the adjuvant treat-

. Other clinical factors are implicated in

) regimen than FOLFOX 2-weekly

**168**

(85 mg/m<sup>2</sup>

therefore improving local control. However, the use of this modality in non-rectal colon cancer is controversial and not supported by randomized controlled trials. It is however considered in the situation of T4 tumor which invades surrounding structures such as the bladder or the abdominal wall where there is a perceived high risk of local recurrence of the tumor. A retrospective analysis of 21,789 patients with T4 colon cancer using the US SEER (Surveillance, Epidemiology and End Results) database found 1001 patient who received radiotherapy [28]. After adjustment for sex, age, N stage and tumor grade the relative risk of death from cancer at 5-years was 0.88 (95CI 0.8008–0.9779, p = 0.0165) in patients who received radiotherapy.
