**7. Adjuvant therapy in elderly**

Systemic chemotherapy in older adults may possess unique challenges due to comorbidities, and age-related organ dysfunction which may limit their life expectancy. In addition the impact on quality of life from chemotherapy may be more prominent in older adults. Benefit of adjuvant chemotherapy in older adults is well established. A pooled analysis of seven randomized trials of adjuvant chemotherapy (5FU/levamisole or 5FU/leucovorin) in stage II and III found comparable overall survival and disease free survival benefit in patients of over 70 compared to those less than 70 [57]. Similar outcomes were seen in another analysis of prospective data from 85,934 patients [58]. Although it is not clearly determined whether older patients experience more toxicities from chemotherapy, an analysis of 37,568 patients from ACCENT database (Clinical Trials From the Adjuvant Colon Cancer Endpoints Database) reported early mortality was significantly higher among those who are >70 compared to younger patients [59]. A pooled analysis suggested no difference in toxicity from 5FU based therapy in older adults; however, it is important to consider that toxicity from 5FU may vary depending on the schedule, specially gastrointestinal side effects in older adults may be more frequent with bolus regimens compared to short term infusional regimens [60]. In addition capecitabine may be associated with more severe toxicities in older adults, especially in those with diminished renal function. In a phase 3 trial of stage III colon cancer, particular toxicities like diarrhea were higher among patients over 65 with capecitabine [61]. Similarly, in X-ACT trial which examined capecitabine versus bolus 5FU (Mayo clinic), treatment-related toxicity was higher in patients above 70 (51%) compared to those less than 70 (39%) [62].

Although oxaliplatin based adjuvant chemotherapy improves survival in stage III colon cancer, its role in older adults above 70 is debatable. Subset analysis of three large randomized trials failed to demonstrate survival advantage in older patients. In an updated analysis of the MOSAIQ study, addition of oxaliplatin did not improve survival in 315 patients above 70 years (HR 1.16; 95% CI, 0.83–1.7) [22]. NSABP C-07 study enrolled 396 patients over 70 years, and no added benefit was seen with oxaliplatin in either in disease free survival (HR 1.03; 95% CI 0.77–1.36) or overall survival (HR 1.18; 95% CI 0.68–1.62) [23]. Consistently XELOXA study failed to demonstrate benefit of oxaliplatin over capecitabine alone in patients above 70 years (Disease free survival: HR 0.86; 95% CI, 0.64–1.16 and overall survival: HR 0.98; 95% CI, 0.62–1.56) [63]. A pooled analysis of seven randomized trials from ACCENT database with more than 14,500 patients (including 2575 patients over 70 years) suggested no survival advantage of oxaliplatin in those above 70 years (Disease free survival: HR 0.94; 95% CI, 0.78–1.13; Overall Survival: HR, 1.04; 95% CI, 0.85–1.27) [64]. However, it is unclear as to why addition of oxaliplatin was beneficial in metastatic setting and not in early cancer setting. Therefore, with currently available data, oxaliplatin is not recommended for routine use in patients above 70 who need adjuvant therapy, however, in those with high risk cancer and medical fit with good life expectancy, the benefit and risk of oxaliplatin should be discussed.

### **8. Drugs that are not routinely indicated as adjuvant therapy**

Irinotecan, via its active metabolite SN-38 inhibits topoisomerase 1 enzyme, causing inhibition of DNA replication and cell death. Irinotecan has well

**173**

**9. Surveillance**

*Adjuvant Therapies in Colon Cancer*

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

established activity in metastatic colorectal cancer in combination with 5FU/leucovorin and as single agent. However, three phase III randomized controlled trials have failed to show any benefit of irinotecan based regimens [65–67]. Bevacizumab and cetuximab have shown survival advantage in metastatic colon cancer when added to irinotecan or oxaliplatin based regimens. Bevacizumab is a vascular endothelial growth factor inhibitor, failed to show benefit when added to FOLFOX or capecitabine [68–70]. The NCCTG-N0147 trial examined the utility of cetuximab which is a mouse/human chimeric monoclonal antibody that targets the epidermal growth factor receptor, with FOLFOX compared to FOLFOX alone in resected colon cancer [71]. The trial was closed prematurely after the interim analysis showed no benefit of cetuximab. This was confirmed in another European PETACC8 trial which enrolled RAS wild-type patients [72]. Edrecolomab is a murine monoclonal antibody against EpCam antigen. Addition of edrecolomab to standard 5FU based adjuvant therapy did not improve disease-free survival or overall survival in stage III colon cancer [73]. Raltitrexed is a quinazoline folate analogue that acts as a direct and specific thymidylate synthase inhibitor which is often utilized in patients who experience cardiac toxicity with 5FU based therapy. PETACC1 trial examined the role of adjuvant raltitrexed in stage III colon cancer compared to 5FU/leucovorin. This trial was closed prematurely due to high rate of treatment related toxicity and death. However, an independent review found multiple incidences of protocol violations in relation to dose adjustment for renal function. Therefore, it may be appropriate to consider raltitrexed as an alternative to 5FU in patients with high risk stage III colon cancer who experience significant cardiac toxicity. Appropriate discussion about the evidence and potential toxicity is key in such instances [74, 75]. Non-steroidal anti-inflammatory (NSAID) drugs like aspirin or celecoxib have been examined as adjunctive therapies, however large randomized trial data are lacking. Most of the evidence supporting the use of aspirin in secondary prevention of colon cancer recurrence are from observational studies, though not all studies are consistent. Subset analysis of number of such studies have identified potential link to PIK3CA status, prostaglandin-endoperoxidase synthase 2 expression, and BRAF mutations. Although these data are interesting, they need to be confirmed in prospective trials. A large randomized controlled study examined the benefit of celecoxib in more than 2500 patients and there was no disease-free survival or overall survival benefit from the addition of celecoxib. Therefore updated 2013 American Society for Clinical Oncology (ASCO) guidelines did not endorse routine use of aspirin in this setting [76, 77]. Therefore, routine use of NSAIDs is not recommended currently until further studies are available. An association between serum vitamin D levels and resected colon cancer has been postulated; however, there is no high-quality evidence to support the routine use of vitamin D for this indication. Given the adverse of effect of vitamin D deficiency in skeletal system, it

is not unreasonable to replace vitamin D in those who are deficient.

Aim of surveillance after curative resection of primary colorectal cancer is to identify asymptomatic recurrences who may be a potential candidate for curative resection. Although most randomized trials suggest modest survival benefit, not all trials are consistent. The benefit Intensive versus less intensive follow up strategies is still debated. Accordingly, surveillance strategies vary among different expert groups. Multiple meta-analyses have been conducted in an attempt to rationalize the surveillance plan, the latest being Cochrane analysis 2019, which examined the data from 13,216 patients from 19 randomized trials and found there was no

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

*Colorectal Cancer*

in high risk stage II cancers, reflecting the finding in stage III disease. Consistently

Systemic chemotherapy in older adults may possess unique challenges due to comorbidities, and age-related organ dysfunction which may limit their life expectancy. In addition the impact on quality of life from chemotherapy may be more prominent in older adults. Benefit of adjuvant chemotherapy in older adults is well established. A pooled analysis of seven randomized trials of adjuvant chemotherapy (5FU/levamisole or 5FU/leucovorin) in stage II and III found comparable overall survival and disease free survival benefit in patients of over 70 compared to those less than 70 [57]. Similar outcomes were seen in another analysis of prospective data from 85,934 patients [58]. Although it is not clearly determined whether older patients experience more toxicities from chemotherapy, an analysis of 37,568 patients from ACCENT database (Clinical Trials From the Adjuvant Colon Cancer Endpoints Database) reported early mortality was significantly higher among those who are >70 compared to younger patients [59]. A pooled analysis suggested no difference in toxicity from 5FU based therapy in older adults; however, it is important to consider that toxicity from 5FU may vary depending on the schedule, specially gastrointestinal side effects in older adults may be more frequent with bolus regimens compared to short term infusional regimens [60]. In addition capecitabine may be associated with more severe toxicities in older adults, especially in those with diminished renal function. In a phase 3 trial of stage III colon cancer, particular toxicities like diarrhea were higher among patients over 65 with capecitabine [61]. Similarly, in X-ACT trial which examined capecitabine versus bolus 5FU (Mayo clinic), treatment-related toxicity was higher in patients above 70 (51%) compared to those less than 70 (39%) [62]. Although oxaliplatin based adjuvant chemotherapy improves survival in stage III colon cancer, its role in older adults above 70 is debatable. Subset analysis of three large randomized trials failed to demonstrate survival advantage in older patients. In an updated analysis of the MOSAIQ study, addition of oxaliplatin did not improve survival in 315 patients above 70 years (HR 1.16; 95% CI, 0.83–1.7) [22]. NSABP C-07 study enrolled 396 patients over 70 years, and no added benefit was seen with oxaliplatin in either in disease free survival (HR 1.03; 95% CI 0.77–1.36) or overall survival (HR 1.18; 95% CI 0.68–1.62) [23]. Consistently XELOXA study failed to demonstrate benefit of oxaliplatin over capecitabine alone in patients above 70 years (Disease free survival: HR 0.86; 95% CI, 0.64–1.16 and overall survival: HR 0.98; 95% CI, 0.62–1.56) [63]. A pooled analysis of seven randomized trials from ACCENT database with more than 14,500 patients (including 2575 patients over 70 years) suggested no survival advantage of oxaliplatin in those above 70 years (Disease free survival: HR 0.94; 95% CI, 0.78–1.13; Overall Survival: HR, 1.04; 95% CI, 0.85–1.27) [64]. However, it is unclear as to why addition of oxaliplatin was beneficial in metastatic setting and not in early cancer setting. Therefore, with currently available data, oxaliplatin is not recommended for routine use in patients above 70 who need adjuvant therapy, however, in those with high risk cancer and medical fit with good life expectancy, the benefit and risk of oxaliplatin should be discussed.

**8. Drugs that are not routinely indicated as adjuvant therapy**

causing inhibition of DNA replication and cell death. Irinotecan has well

Irinotecan, via its active metabolite SN-38 inhibits topoisomerase 1 enzyme,

3 months of FOLFOX was not non-inferior to 6 months.

**7. Adjuvant therapy in elderly**

**172**

established activity in metastatic colorectal cancer in combination with 5FU/leucovorin and as single agent. However, three phase III randomized controlled trials have failed to show any benefit of irinotecan based regimens [65–67]. Bevacizumab and cetuximab have shown survival advantage in metastatic colon cancer when added to irinotecan or oxaliplatin based regimens. Bevacizumab is a vascular endothelial growth factor inhibitor, failed to show benefit when added to FOLFOX or capecitabine [68–70]. The NCCTG-N0147 trial examined the utility of cetuximab which is a mouse/human chimeric monoclonal antibody that targets the epidermal growth factor receptor, with FOLFOX compared to FOLFOX alone in resected colon cancer [71]. The trial was closed prematurely after the interim analysis showed no benefit of cetuximab. This was confirmed in another European PETACC8 trial which enrolled RAS wild-type patients [72]. Edrecolomab is a murine monoclonal antibody against EpCam antigen. Addition of edrecolomab to standard 5FU based adjuvant therapy did not improve disease-free survival or overall survival in stage III colon cancer [73]. Raltitrexed is a quinazoline folate analogue that acts as a direct and specific thymidylate synthase inhibitor which is often utilized in patients who experience cardiac toxicity with 5FU based therapy. PETACC1 trial examined the role of adjuvant raltitrexed in stage III colon cancer compared to 5FU/leucovorin. This trial was closed prematurely due to high rate of treatment related toxicity and death. However, an independent review found multiple incidences of protocol violations in relation to dose adjustment for renal function. Therefore, it may be appropriate to consider raltitrexed as an alternative to 5FU in patients with high risk stage III colon cancer who experience significant cardiac toxicity. Appropriate discussion about the evidence and potential toxicity is key in such instances [74, 75].

Non-steroidal anti-inflammatory (NSAID) drugs like aspirin or celecoxib have been examined as adjunctive therapies, however large randomized trial data are lacking. Most of the evidence supporting the use of aspirin in secondary prevention of colon cancer recurrence are from observational studies, though not all studies are consistent. Subset analysis of number of such studies have identified potential link to PIK3CA status, prostaglandin-endoperoxidase synthase 2 expression, and BRAF mutations. Although these data are interesting, they need to be confirmed in prospective trials. A large randomized controlled study examined the benefit of celecoxib in more than 2500 patients and there was no disease-free survival or overall survival benefit from the addition of celecoxib. Therefore updated 2013 American Society for Clinical Oncology (ASCO) guidelines did not endorse routine use of aspirin in this setting [76, 77]. Therefore, routine use of NSAIDs is not recommended currently until further studies are available. An association between serum vitamin D levels and resected colon cancer has been postulated; however, there is no high-quality evidence to support the routine use of vitamin D for this indication. Given the adverse of effect of vitamin D deficiency in skeletal system, it is not unreasonable to replace vitamin D in those who are deficient.
