Better outcomes observed in chemoradiation in adjuvant settings raised the question of possible neoadjuvant chemoradiation for treatment of patients with locally advanced rectal cancer. In 2004, German Rectal Cancer Study Group (GRCSG) examined the role preoperative chemoradiation in rectal cancer patients with T3 or T4 stages or node positivity [51]. They randomized 823 patients in two groups; the neoadjuvant arm received a total 50.4 Gray dose

free survival differences in between these two groups.

significant decrease in local recurrence rate (5.6 % vs 10.9%, *P* < 0.001).

*Neoadjuvant Chemoradiation Therapy (Combined Modality Therapy)*

*Neoadjuvant Radiotherapy*

rectal cancer in USA.

#### *Development of Adjuvant Therapy*

The standard care of rectal cancer remains surgery with a total mesorectal excision. However locally advanced disease were relapsing significantly higher than early stage disease after surgery-only approach [43]. Rectal cancer transmurally invades the rectal wall directly and can spread through the lymphatic system to regional lymph nodes. These characteristics of locally advanced disease put the patients at higher risk of local and distant recurrence which is associated worse overall survival. Given the high rate of the recurrent disease, combination treatment approaches have evolved in locally advance rectal cancer over the last two decades. First, adjuvant radiotherapy and then combined modality therapy (chemotherapy concur‐ rently with radiation therapy) was integrated in standard care to enhance survival outcomes of locally advanced rectal cancer.

An early prospectively randomized clinical trial was conducted to assess the question of the adjuvant benefit roles of radiation, chemotherapy, or combined modality therapy (chemoradiation) in the treatment of locally advance rectal cancer by the Gastrointestinal Tumor Study Group (GTSG) in 1985 [44]. In this study, patients after having curative surgery (202 in total), were enrolled and randomized into four different groups includ‐ ing; patients received no adjuvant treatment, patients treated with adjuvant radiotherapy either at dose of 40 or 48 Gray, patients received adjuvant chemotherapy with semustine and 5-fluorouracil, and a final group treated with combination of chemotherapy and radiotherapy. All patients were followed up to for 80 months. Although there was no significant difference for OS in four groups, authors found significantly better diseasefree survival in combination therapy arm compared to resection-alone [44]. In same study, recurrence rate was highest in resection-alone with 55%, while the lowest relapse was observed in combination therapy group (33%). The follow-up results of this study con‐ firmed a significantly improved overall survival reported in combination treatment group compared to surgery alone group [45]. By the end of the 10 year follow up, 10-year survival rates were 26% vs. 45% in control group vs. combination treatment group and was showing the superiority of combination treatment group. Independently, The National Surgical Adjuvant and Breast and Bowel Project (NSABP) released the result of R-01 that compar‐ ing adjuvant radiation or chemotherapy to surgery alone and provided superior overall and disease-free survival in chemo group respect to the surgery alone (*P* = 0.03, *P* = 0.006 respectively) [46]. No significant survival benefit observed in radiation alone group.

The North Central Cancer Treatment Group (NCCTG) reported a trial comparing the adjuvant radiation versus the combined chemoradiation. In this study, total 209 patients randomized in two arms. The combined modality arm was found to have 34% reduced overall recurrence compared to the radiation alone. (*P* < 0.003) [47]. Decreased recurrence incidence was observed in both local (25% versus 13% *P* < 0.02) and distant relapse (43% versus 29.5% *P* < 0.003). After this study National Surgical Adjuvant Breast Program (NSABP) examined the impact of the adjuvant chemotherapy alone versus chemoradiotherapy on overall survival and disease free survival in protocol R-02. In this study, all female patients received 5-flurouracil and leuco‐ vorin whereas male patients either received MOF regimen including 5-flurouracil, semustine, vincristine or 5-flurouracil combined with leucovorin. Radiotherapy was given in 25 fractions at a daily 18 Gray dose. Although there was a significant decrease in cumulative local relapse incidence after 5-year follow-up (13% versus 8%, *P* = 0.02), they observed no overall or diseasefree survival differences in between these two groups.

#### *Neoadjuvant Radiotherapy*

Compared the large bowel the close proximity of rectum to other local organs such as uro‐ genital system requires different surgical techniques and significantly increases the likelihood of local relapse after surgery when compared to colon cancer [42]. For this reason, in addition to total mesorectal excision combination therapeutic options have arisen to decrease local recurrence. Subsequently, these multimodality therapy approaches have become standard-ofcare in locally advanced rectal cancer. In this book chapter, we aimed to summarize scientific

The standard care of rectal cancer remains surgery with a total mesorectal excision. However locally advanced disease were relapsing significantly higher than early stage disease after surgery-only approach [43]. Rectal cancer transmurally invades the rectal wall directly and can spread through the lymphatic system to regional lymph nodes. These characteristics of locally advanced disease put the patients at higher risk of local and distant recurrence which is associated worse overall survival. Given the high rate of the recurrent disease, combination treatment approaches have evolved in locally advance rectal cancer over the last two decades. First, adjuvant radiotherapy and then combined modality therapy (chemotherapy concur‐ rently with radiation therapy) was integrated in standard care to enhance survival outcomes

An early prospectively randomized clinical trial was conducted to assess the question of the adjuvant benefit roles of radiation, chemotherapy, or combined modality therapy (chemoradiation) in the treatment of locally advance rectal cancer by the Gastrointestinal Tumor Study Group (GTSG) in 1985 [44]. In this study, patients after having curative surgery (202 in total), were enrolled and randomized into four different groups includ‐ ing; patients received no adjuvant treatment, patients treated with adjuvant radiotherapy either at dose of 40 or 48 Gray, patients received adjuvant chemotherapy with semustine and 5-fluorouracil, and a final group treated with combination of chemotherapy and radiotherapy. All patients were followed up to for 80 months. Although there was no significant difference for OS in four groups, authors found significantly better diseasefree survival in combination therapy arm compared to resection-alone [44]. In same study, recurrence rate was highest in resection-alone with 55%, while the lowest relapse was observed in combination therapy group (33%). The follow-up results of this study con‐ firmed a significantly improved overall survival reported in combination treatment group compared to surgery alone group [45]. By the end of the 10 year follow up, 10-year survival rates were 26% vs. 45% in control group vs. combination treatment group and was showing the superiority of combination treatment group. Independently, The National Surgical Adjuvant and Breast and Bowel Project (NSABP) released the result of R-01 that compar‐ ing adjuvant radiation or chemotherapy to surgery alone and provided superior overall and disease-free survival in chemo group respect to the surgery alone (*P* = 0.03, *P* = 0.006 respectively) [46]. No significant survival benefit observed in radiation alone group.

The North Central Cancer Treatment Group (NCCTG) reported a trial comparing the adjuvant radiation versus the combined chemoradiation. In this study, total 209 patients randomized

progression in the field of treatment of locally advanced rectal cancer.

*Development of Adjuvant Therapy*

290 Colorectal Cancer - Surgery, Diagnostics and Treatment

of locally advanced rectal cancer.

Absence of clinical evidence to use radiotherapy in adjuvant settings urged the researchers to test the efficacy of radiotherapy in preoperative settings. Swedish investigators conducted a phase III clinical trial to understand the possible role of neoadjuvant radiotherapy (i.e. preoperative radiation therapy) [48]. They enrolled 1,168 patients and randomly assigned to receive either conventional surgery alone or surgery with preceded neoadjuvant radiotherapy designed as a total dose of 25 Gy in five fractions. After five years follow up, recurrence rate was found 11% in neoadjuvant radiotherapy group, whereas it was observed as high as 27% in patients with surgery alone (*P* < 0.001). Additionally, the authors reported significantly better five year-survival in radiotherapy arm (58% compared to 48%, *P* = 0.004). Since con‐ ventional surgery was performed in this study, the additive role of the radiation in TME was still not clear. In 2007, this question was addressed by Dutch Colorectal Cancer Group. They conducted a randomized clinical trial enrolled the patients into TME alone and 5 fractions radiotherapy with total 25 Gray dose plus total mesorectal excision [49]. After a median 6.1 years follow- up, no significant overall survival difference was demonstrated. Moreover, there was no significant difference in distal recurrence incidence. On the other hand, they found a significant decrease in local recurrence rate (5.6 % vs 10.9%, *P* < 0.001).

Currently, two different preoperative radiotherapy protocols are commonly preferred in locally advanced rectal cancer treatment including conventional (50.4 Gray administered in 28 fractions) and short-term treatment (25 Gray in 5 fractions). Although both models have been shown to decrease local recurrence, there are debates on prolonged side effect in short-term radiotherapy modality [50]. While short-term neoadjuvant radiation treatment is commonly used in European countries, conventional radiation is standard-of-care of locally advance rectal cancer in USA.

#### *Neoadjuvant Chemoradiation Therapy (Combined Modality Therapy)*

Better outcomes observed in chemoradiation in adjuvant settings raised the question of possible neoadjuvant chemoradiation for treatment of patients with locally advanced rectal cancer. In 2004, German Rectal Cancer Study Group (GRCSG) examined the role preoperative chemoradiation in rectal cancer patients with T3 or T4 stages or node positivity [51]. They randomized 823 patients in two groups; the neoadjuvant arm received a total 50.4 Gray dose radiation in 28 fractions and 5-flurouracil 120-hour continuous infusion during the first and fifth weeks of radiation at a dose of 1,000 mg per square meter of body surface then followed by surgery after completing the chemoradiation. Patients also received four cycles of 5 flurouracil (500 mg per square meter body surface) which was designed as five time weekly during the four weeks. The adjuvant group also received the same treatment except additional a boost of 5.4 Gray radiation after total mesorectal excision. No significant difference was reported for five year-survival in between neoadjuvant and adjuvant group (74% vs 76% respectively, *P* = 0.80). Interestingly, five years cumulative incidence of local recurrence was significantly lower in neoadjuvant group than the adjuvant. (6% versus 13% respectively, *P* = 0.006). Moreover they observed less acute and long term toxicity in neoadjuvant arm of the study compared the adjuvant arm (*P* = 0.001 versus *P* = 0.01).

prolonged treatment related toxicities and improved sphincter preservation observed in

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

5-flurouracil has become the recommended first-line chemotherapy in locally advanced rectal cancer patients based on the GTSG and NCCTG data [44,47].The most commonly preferred administration mode of 5-flurouracil is continuous intravenous infusion( 225-300mg/m2

To compare the bolus administration with continuous intravenous infusion, the NCCTG randomized 660 patients in two arms. Both arms received concurrent radiotherapy. First group received bolus 5-flurouracil on three consecutive days as s rapid infusion of 500 mg/m2

survival was 63% in continuous infusion group while it was 53% in the bolus arm (*P* = 0.01). Significant difference for 4-year overall survival was also observed in the same study. Fouryear overall survival was 70% as compared to 60% in continuous infusion and bolus group respectively (*P* = 0.005). Interestingly, no benefit was observed for local relapse in continuous infusion group (*P* = 0.110). While leukopenia was more common in bolus group, diarrhea

Since superior outcomes observed in continuous intravenous administration of 5-flurouracil in chemoradiation regimens, an equivalent fluropyrimidine, capecitabine was studied for locally advanced rectal cancer treatment. Oral administration of capecitabine which has very similar pharmacokinetics to continuous intravenous 5-flurouracil provided more convenient treatment for patients if they are able to tolerate oral administration. In a phase I clinical study, the recommended dose of the capecitabine was determined as 1800 mg/m2 daily given orally in two divided doses combined with 50.4 Gray preoperative radiation [56]. A prospectively randomized study of 1,987 patients was enrolled into two groups; a) patients who received capecitabine orally, b) patients who were administered bolus 5-flurouracil modulated with leucovorin [58]. In the results of this study, non-inferior disease-free survival was observed in capecitabine group. The capecitabine improved relapse-free survival (*P* = 0.04). Moreover, fewer adverse effects were seen with capecitabine treatment compared to bolus 5-flurouracil

The NSABP R-04 trial compared the use of capecitabine to continuous infusion 5-flurouracil with or without oxaliplatin during combined modality therapy in locally advance rectal cancer. 5-fluorouracil was given as a 225 mg/m2 daily protracted venous infusion during radiation and

only. There was no significant different regarding pathologic complete response, surgical downstaging or sphincter-saving surgery. Local recurrence and overall survival have yet to

More recently, in a randomized phase III study, German researchers compared the efficacy of capecitabine with 5-flurouracil as neoadjuvant radiosensitizing agent [60]. In this study, 392

orally in two divided doses daily on the days of radiation

daily).

293

while

/day). Four-year relapse free

http://dx.doi.org/10.5772/57481

preoperative treatment also favor the neoadjuvant chemoradiation modality [54].

*Current Drugs for Neoadjuvant Therapy of Rectal Cancer*

the other group received as protracted infusion (225 mg/m2

incidence was found higher in continuous infusion group.

plus leucovorin arm (*P* < 0.001) [58].

capecitabine was given at 1650 mg/m2

be reported [59].

*5-Fluorouracil*

*Capecitabine*

In another study, European Organization for Research and Treatment of Cancer (EORTC) randomized 1,011 patients with locally advanced rectal cancer into four different groups: a) preoperative radiotherapy designed as 45 Gy in five weeks, b) preoperative radiotherapy plus two course of 5-flurouracil and leucovorin (350 mg/m2 /day and 20 mg/m2 /day), c) preoperative radiotherapy plus postoperative four course of 5-flurouracil and leucovorin, and d) preoper‐ ative radiotherapy and two course of bolus 5-flurouracil and leucovorin, plus postoperative four course of postoperative 5-flurouracil and leucovorin. In early preliminary results of the study, authors reported a significant benefit towards preoperative chemoradiotherapy groups for tumor size, lymph node involvement, pathological complete response (*P* < 0.0001, *P* = 0.046, *P* < 0.001). [52]. Later in follow up results, no significant difference was observed in OS between neoadjuvant chemoradiotherapy and neoadjuvant radiotherapy (P=0.085). On the other hand, local recurrence was significantly lower in preoperative chemoradiation groups (*P* = 0.002) [53]. Chemotherapy protocol which was given in this study was an uncommon protocol possibly is a contributing factor for absence of survival difference in between chemoradiation and radiation alone group in preoperative settings.

To better understand the additive role of neoadjuvant chemoradiation for patients with locally advanced rectal cancer, NSABP R-03 trial was conducted. Two hundreds and sixty-seven patients enrolled in two arms; patients who received neoadjuvant or adjuvant chemoradiation. Neoadjuvant group received a bolus of 5-flurouracil with leucovorin for six weeks followed by radiation given as a total 45 Gray dose in 25 fractions with an additional 5.4 Gray boost. Then, patients were resected and postoperatively received 24 more weeks of weekly 5-FU and LV. Patients in adjuvant arm also received same courses of treatment in the same order except initial surgical resection. The most striking finding of this study was superior 5-year diseasefree survival observed in neoadjuvant arm (64.7% vs 53.4%, P=0.011). Although there was not a significant difference in OS (P = 0.65), There was trend for observed five-year overall survival as 74.7% vs 65.6% in the neoadjuvant and adjuvant arms respectively [54]. Overall, all these clinical trials support the use neoadjuvuvant chemotheradiation as standart-care-of locally advance colorectal cancer. Although there is no clear result proving as an evidence for the superior OS compared to adjuvant chemoradiation, decreased local recurrence incidence with neoadjuvant treatment promises better local disease control. Moreover decreased acute and prolonged treatment related toxicities and improved sphincter preservation observed in preoperative treatment also favor the neoadjuvant chemoradiation modality [54].

*Current Drugs for Neoadjuvant Therapy of Rectal Cancer*

#### *5-Fluorouracil*

radiation in 28 fractions and 5-flurouracil 120-hour continuous infusion during the first and fifth weeks of radiation at a dose of 1,000 mg per square meter of body surface then followed by surgery after completing the chemoradiation. Patients also received four cycles of 5 flurouracil (500 mg per square meter body surface) which was designed as five time weekly during the four weeks. The adjuvant group also received the same treatment except additional a boost of 5.4 Gray radiation after total mesorectal excision. No significant difference was reported for five year-survival in between neoadjuvant and adjuvant group (74% vs 76% respectively, *P* = 0.80). Interestingly, five years cumulative incidence of local recurrence was significantly lower in neoadjuvant group than the adjuvant. (6% versus 13% respectively, *P* = 0.006). Moreover they observed less acute and long term toxicity in neoadjuvant arm of the

In another study, European Organization for Research and Treatment of Cancer (EORTC) randomized 1,011 patients with locally advanced rectal cancer into four different groups: a) preoperative radiotherapy designed as 45 Gy in five weeks, b) preoperative radiotherapy plus

radiotherapy plus postoperative four course of 5-flurouracil and leucovorin, and d) preoper‐ ative radiotherapy and two course of bolus 5-flurouracil and leucovorin, plus postoperative four course of postoperative 5-flurouracil and leucovorin. In early preliminary results of the study, authors reported a significant benefit towards preoperative chemoradiotherapy groups for tumor size, lymph node involvement, pathological complete response (*P* < 0.0001, *P* = 0.046, *P* < 0.001). [52]. Later in follow up results, no significant difference was observed in OS between neoadjuvant chemoradiotherapy and neoadjuvant radiotherapy (P=0.085). On the other hand, local recurrence was significantly lower in preoperative chemoradiation groups (*P* = 0.002) [53]. Chemotherapy protocol which was given in this study was an uncommon protocol possibly is a contributing factor for absence of survival difference in between chemoradiation

To better understand the additive role of neoadjuvant chemoradiation for patients with locally advanced rectal cancer, NSABP R-03 trial was conducted. Two hundreds and sixty-seven patients enrolled in two arms; patients who received neoadjuvant or adjuvant chemoradiation. Neoadjuvant group received a bolus of 5-flurouracil with leucovorin for six weeks followed by radiation given as a total 45 Gray dose in 25 fractions with an additional 5.4 Gray boost. Then, patients were resected and postoperatively received 24 more weeks of weekly 5-FU and LV. Patients in adjuvant arm also received same courses of treatment in the same order except initial surgical resection. The most striking finding of this study was superior 5-year diseasefree survival observed in neoadjuvant arm (64.7% vs 53.4%, P=0.011). Although there was not a significant difference in OS (P = 0.65), There was trend for observed five-year overall survival as 74.7% vs 65.6% in the neoadjuvant and adjuvant arms respectively [54]. Overall, all these clinical trials support the use neoadjuvuvant chemotheradiation as standart-care-of locally advance colorectal cancer. Although there is no clear result proving as an evidence for the superior OS compared to adjuvant chemoradiation, decreased local recurrence incidence with neoadjuvant treatment promises better local disease control. Moreover decreased acute and

/day and 20 mg/m2

/day), c) preoperative

study compared the adjuvant arm (*P* = 0.001 versus *P* = 0.01).

two course of 5-flurouracil and leucovorin (350 mg/m2

292 Colorectal Cancer - Surgery, Diagnostics and Treatment

and radiation alone group in preoperative settings.

5-flurouracil has become the recommended first-line chemotherapy in locally advanced rectal cancer patients based on the GTSG and NCCTG data [44,47].The most commonly preferred administration mode of 5-flurouracil is continuous intravenous infusion( 225-300mg/m2 daily). To compare the bolus administration with continuous intravenous infusion, the NCCTG randomized 660 patients in two arms. Both arms received concurrent radiotherapy. First group received bolus 5-flurouracil on three consecutive days as s rapid infusion of 500 mg/m2 while the other group received as protracted infusion (225 mg/m2 /day). Four-year relapse free survival was 63% in continuous infusion group while it was 53% in the bolus arm (*P* = 0.01). Significant difference for 4-year overall survival was also observed in the same study. Fouryear overall survival was 70% as compared to 60% in continuous infusion and bolus group respectively (*P* = 0.005). Interestingly, no benefit was observed for local relapse in continuous infusion group (*P* = 0.110). While leukopenia was more common in bolus group, diarrhea incidence was found higher in continuous infusion group.

#### *Capecitabine*

Since superior outcomes observed in continuous intravenous administration of 5-flurouracil in chemoradiation regimens, an equivalent fluropyrimidine, capecitabine was studied for locally advanced rectal cancer treatment. Oral administration of capecitabine which has very similar pharmacokinetics to continuous intravenous 5-flurouracil provided more convenient treatment for patients if they are able to tolerate oral administration. In a phase I clinical study, the recommended dose of the capecitabine was determined as 1800 mg/m2 daily given orally in two divided doses combined with 50.4 Gray preoperative radiation [56]. A prospectively randomized study of 1,987 patients was enrolled into two groups; a) patients who received capecitabine orally, b) patients who were administered bolus 5-flurouracil modulated with leucovorin [58]. In the results of this study, non-inferior disease-free survival was observed in capecitabine group. The capecitabine improved relapse-free survival (*P* = 0.04). Moreover, fewer adverse effects were seen with capecitabine treatment compared to bolus 5-flurouracil plus leucovorin arm (*P* < 0.001) [58].

The NSABP R-04 trial compared the use of capecitabine to continuous infusion 5-flurouracil with or without oxaliplatin during combined modality therapy in locally advance rectal cancer. 5-fluorouracil was given as a 225 mg/m2 daily protracted venous infusion during radiation and capecitabine was given at 1650 mg/m2 orally in two divided doses daily on the days of radiation only. There was no significant different regarding pathologic complete response, surgical downstaging or sphincter-saving surgery. Local recurrence and overall survival have yet to be reported [59].

More recently, in a randomized phase III study, German researchers compared the efficacy of capecitabine with 5-flurouracil as neoadjuvant radiosensitizing agent [60]. In this study, 392 patients were randomized into two groups. Patients in capecitabine arm were enrolled to receive two cycles of capecitabine (2,500 mg/m2 days 1-14, repeated day 22), then followed by chemoradiotherapy (50 4 Gray plus capecitabine 1650 mg/m2 days 1-38 and additionally three cycles of capecitabine). Two cycles of bolus 5-flurouracil (500 mg/m2 days 1-5, repeated day 29), followed by chemoradiotherapy (50 4 Gray plus infusional 5-flurouracil 225 mg/m2 daily), finally two cycles of bolus 5-FU were administered patients in 5-flurouracil arm. Results were promising for non-inferiority with significantly better 5-year OS in capecitabine group (76% as compared to 67%, *P* = 0.05). Similarly disease-free survival was also higher in capecitabine group (75% versus 67%, *P* = 0.07).

*Targeted Therapies*

radiotherapy 650 mg/m2

to receive initial intravenous dose of 400 mg/m2

embolism, and one pulmonary infection with sepsis.

initiation of radiation followed by 250 mg/m2

survival (*P* = 1.0, *P* = 0.363 respectively)

significant hematologic toxicity.

Monoclonal antibodies targeting the critical survival signaling pathways such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are currently under the investigation to determine their role in neoadjuvant chemoradiaton treatment in rectal cancers. The potential role of cetuximab and bevacizumab in the treatment

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

In a phase I/II clinical study the safety and potential benefit of cetuximab in neoadjuvant chemoradiation investigated in locally advanced rectal cancer patients. Forty patients enrolled

[65]. Observed pathologic complete response was only in two patients (5%), while diarrhea was seen in 65% of the patients. Grade 3 diarrhea was detected in 15% of cases. In one patient three grade 4 toxic effect was reported by authors; one myocardial infarction, one pulmonary

In the EXPERT-C trial, combination of cetuximab and capecitabine plus oxaliplatin was studied in neoadjuvant settings. One hundred sixty-five patients enrolled in two arms to receive four cycles of capecitabine/oxaliplatin and then capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab [66]. In this study the most striking finding was significantly improved OS in cetuximab plus group (*P* = 0.034). Additionally, a better radiologic response was determined in cetuximab group. On the other hand there was no difference either in pathologic complete response rate or progression-free

Another fully humanized monoclonal antibody, that binds circulating anti-vascular epithelial growth factor, bevacizumab, has also been investigated in combination neoadjuvant treatment of rectal cancer. In a phase I/II study, bevacizumab combined with preoperative 5-FU and radiotherapy in 32 locally advanced rectal cancer patients [67]. Patients were administered four cycles of bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 5-FU (225 mg/m2

hours) during cycles 2 to 4; radiotherapy in 28 fractions with a total dose of 50.4 Gy over 5.5 weeks. Surgery was performed 7 to 10 weeks after completion of all therapies. No grade4 toxicity was detected and the most frequent toxicity was diarrhea. Pathologic complete response was achieved in 5 out of 32 patients. In another phase II study, bevacizumab was explored in a combination treatment of capecitabine and radiotherapy [68]. Twenty-five rectal cancer patients received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily during the radiation). Surgical resection was performed a median of 7.3 weeks later initial treatment. An encouraging pathologic complete response rate was reported in 8 of 25 patients (32%). Six of 24 patients showed less than 10% viable tumor cells in final pathological specimens. No patient was reported with grade 3 gastrointestinal toxicity or

cetuximab which was given 1 week before the

http://dx.doi.org/10.5772/57481

295

/24

/week for 5 weeks and capecitabine during the

orally twice daily and 825 mg/m2 twice daily, as a second dose level

of locally advanced rectal cancer has been tested in phase I and phase II clinical trials.

#### *Oxaliplatin*

Given the promising results of oxaliplatin treatment of colon cancer in adjuvant setting [15] and metastatic disease [61] its possible additive effect to the neoadjuvant treatment of rectal cancer has been investigated. In a phase II clinical trial, oxaliplatin (at 50 mg/m2 on days 1, 8, 22, and 29) plus capecitabine (1,650 mg/m2 on days 1 to 14 and 22 to 35) with radiotherapy (50.4 Gray in 28 fraction) was tested both for activity and safety [62]. Pathologic complete response was achieved in 17% patients whereas 53/103 patients showed more than 50% tumor regres‐ sion. Although results were not superior to standard 5-FU treatment phase III trials were warranted. The randomized phase III Studio Terapia Adiuvante Retto ( STAR)-01 trial has tested to outcomes of addition of oxaliplatin (60 mg/m2) to chemoradiation (225 mg/m2 /day plus 50.4 Gray in 28 daily fractions) comparing with standard chemoradiation [62]. Addition of oxaliplation did not increase pathologic complete response rate (16% versus 16% ) but rather increased grade 3 to 4 adverse events in oxaliplatin arms (*P* < 0.001).

Recently published German CAO/ARO/AIO-04 randomised phase III trial also investigated the role of oxaliplatin in neoadjuvant chemoradiation [63]. In the study control group was treated with standard 5-flurouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (1000 mg/m2 days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2 days 1-5 and 29). Oxaliplatin arm received preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (250 mg/m2 days 1-14 and 22-35) and oxaliplatin (50 mg/m2 days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 days 1 and 15), leucovorin (400 mg/m2 days 1 and 15), and again infusional 5-flurouracil. Authors reported better pathologic complete response outcomes in oxaliplatin treatment arm compared to standard group (17% vs 13% respectively, *P* = 0.038). Controversially, ACCORD 12/0405- PRODIGE 2 trial reported no benefit with additional oxaliplatin [64]. In this study control patients were assigned to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m2 twice daily (5 days per week). The experimental arm of the study received 50 Gray in 25 fractions radiation with capecitabine 800 mg/m2 twice daily (5 days per week) and oxaliplatin 50 mg/m2 (once weekly). Although there was trend toward oxaliplatin plus group for pCR it was not significant (19.2% s 13.9% P=0.09). Preoperative grade 3 and 4 toxicities were observed significantly higher in oxalipatin plus arm *(P* < 0.001). Since there is no consensus in clinical trials for benefit with additional oxaliplatin it is not currently standard-of-care of locally advanced rectal cancer.

#### *Targeted Therapies*

patients were randomized into two groups. Patients in capecitabine arm were enrolled to

finally two cycles of bolus 5-FU were administered patients in 5-flurouracil arm. Results were promising for non-inferiority with significantly better 5-year OS in capecitabine group (76% as compared to 67%, *P* = 0.05). Similarly disease-free survival was also higher in capecitabine

Given the promising results of oxaliplatin treatment of colon cancer in adjuvant setting [15] and metastatic disease [61] its possible additive effect to the neoadjuvant treatment of rectal cancer has been investigated. In a phase II clinical trial, oxaliplatin (at 50 mg/m2 on days 1, 8,

Gray in 28 fraction) was tested both for activity and safety [62]. Pathologic complete response was achieved in 17% patients whereas 53/103 patients showed more than 50% tumor regres‐ sion. Although results were not superior to standard 5-FU treatment phase III trials were warranted. The randomized phase III Studio Terapia Adiuvante Retto ( STAR)-01 trial has tested to outcomes of addition of oxaliplatin (60 mg/m2) to chemoradiation (225 mg/m2

plus 50.4 Gray in 28 daily fractions) comparing with standard chemoradiation [62]. Addition of oxaliplation did not increase pathologic complete response rate (16% versus 16% ) but rather

Recently published German CAO/ARO/AIO-04 randomised phase III trial also investigated the role of oxaliplatin in neoadjuvant chemoradiation [63]. In the study control group was treated with standard 5-flurouracil-based combined modality treatment, consisting of

Oxaliplatin arm received preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil

15), leucovorin (400 mg/m2 days 1 and 15), and again infusional 5-flurouracil. Authors reported better pathologic complete response outcomes in oxaliplatin treatment arm compared to standard group (17% vs 13% respectively, *P* = 0.038). Controversially, ACCORD 12/0405- PRODIGE 2 trial reported no benefit with additional oxaliplatin [64]. In this study control patients were assigned to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions

oxaliplatin plus group for pCR it was not significant (19.2% s 13.9% P=0.09). Preoperative grade 3 and 4 toxicities were observed significantly higher in oxalipatin plus arm *(P* < 0.001). Since there is no consensus in clinical trials for benefit with additional oxaliplatin it is not currently

preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (1000 mg/m2

surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2

of the study received 50 Gray in 25 fractions radiation with capecitabine 800 mg/m2

29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2

days 1-14 and 22-35) and oxaliplatin (50 mg/m2

29), followed by chemoradiotherapy (50 4 Gray plus infusional 5-flurouracil 225 mg/m2

days 1-14, repeated day 22), then followed by

on days 1 to 14 and 22 to 35) with radiotherapy (50.4

days 1-38 and additionally three

days 1-5, repeated day

daily),

/day

days 1-5 and

days 1 and

twice daily

days 1-5 and 29).

days 1, 8, 22, and 29), followed by

twice daily (5 days per week). The experimental arm

(once weekly). Although there was trend toward

receive two cycles of capecitabine (2,500 mg/m2

294 Colorectal Cancer - Surgery, Diagnostics and Treatment

group (75% versus 67%, *P* = 0.07).

22, and 29) plus capecitabine (1,650 mg/m2

with concurrent capecitabine 800 mg/m2

(5 days per week) and oxaliplatin 50 mg/m2

standard-of-care of locally advanced rectal cancer.

*Oxaliplatin*

(250 mg/m2

chemoradiotherapy (50 4 Gray plus capecitabine 1650 mg/m2

cycles of capecitabine). Two cycles of bolus 5-flurouracil (500 mg/m2

increased grade 3 to 4 adverse events in oxaliplatin arms (*P* < 0.001).

Monoclonal antibodies targeting the critical survival signaling pathways such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are currently under the investigation to determine their role in neoadjuvant chemoradiaton treatment in rectal cancers. The potential role of cetuximab and bevacizumab in the treatment of locally advanced rectal cancer has been tested in phase I and phase II clinical trials.

In a phase I/II clinical study the safety and potential benefit of cetuximab in neoadjuvant chemoradiation investigated in locally advanced rectal cancer patients. Forty patients enrolled to receive initial intravenous dose of 400 mg/m2 cetuximab which was given 1 week before the initiation of radiation followed by 250 mg/m2 /week for 5 weeks and capecitabine during the radiotherapy 650 mg/m2 orally twice daily and 825 mg/m2 twice daily, as a second dose level [65]. Observed pathologic complete response was only in two patients (5%), while diarrhea was seen in 65% of the patients. Grade 3 diarrhea was detected in 15% of cases. In one patient three grade 4 toxic effect was reported by authors; one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis.

In the EXPERT-C trial, combination of cetuximab and capecitabine plus oxaliplatin was studied in neoadjuvant settings. One hundred sixty-five patients enrolled in two arms to receive four cycles of capecitabine/oxaliplatin and then capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab [66]. In this study the most striking finding was significantly improved OS in cetuximab plus group (*P* = 0.034). Additionally, a better radiologic response was determined in cetuximab group. On the other hand there was no difference either in pathologic complete response rate or progression-free survival (*P* = 1.0, *P* = 0.363 respectively)

Another fully humanized monoclonal antibody, that binds circulating anti-vascular epithelial growth factor, bevacizumab, has also been investigated in combination neoadjuvant treatment of rectal cancer. In a phase I/II study, bevacizumab combined with preoperative 5-FU and radiotherapy in 32 locally advanced rectal cancer patients [67]. Patients were administered four cycles of bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 5-FU (225 mg/m2 /24 hours) during cycles 2 to 4; radiotherapy in 28 fractions with a total dose of 50.4 Gy over 5.5 weeks. Surgery was performed 7 to 10 weeks after completion of all therapies. No grade4 toxicity was detected and the most frequent toxicity was diarrhea. Pathologic complete response was achieved in 5 out of 32 patients. In another phase II study, bevacizumab was explored in a combination treatment of capecitabine and radiotherapy [68]. Twenty-five rectal cancer patients received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily during the radiation). Surgical resection was performed a median of 7.3 weeks later initial treatment. An encouraging pathologic complete response rate was reported in 8 of 25 patients (32%). Six of 24 patients showed less than 10% viable tumor cells in final pathological specimens. No patient was reported with grade 3 gastrointestinal toxicity or significant hematologic toxicity.

In a recent study, bevacizumab was tested in a combined treatment including the oxaliplatin, 5-FU, and radiotherapy in 26 patients [69]. Patients were initially treated with 1 month of induction bevacizumab and FOLFOX6, then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m2 /week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). This trial was terminated early because of high incidence of significant grade 3 toxicity. Authors reported 19 (75%) of 25 patients experienced grade 3 toxicities. Five (20%) out of 25 patients had pathologic response. The effect of bevacu‐ zimab was also studied with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor in a combination treatment of 5-flurouracil and external beam radiation in 21 patients [70]. Seven (47%) of 15 patients who completed the therapy and had surgery achieved pathologic complete response. Reported toxicities were including lympho‐ penia 6 (40%), diarrhea 4 (24%), rash 2 (12%), cardiac ischemia 1(6%), transaminitis (6%) and mucositis (6%).

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Obtained promising pathologic response and observed safety results by the addition of monoclonal antibodies in neoadjuvant chemoradiation encourages to further explore the role of these drugs in treatment of locally advanced rectal cancer. On the other hand these targeting agents are yet to be standard-care-of rectal cancer in neoadjuvant settings.

## **7. Conclusions**

The clinical advances over the last two decades have led to demonstrable improvements in the outcomes of patients with colorectal cancer and are a testament to the success of multidisci‐ plinary cancer care. Continued development of novel therapeutics in the metastatic setting will undoubtedly lead to changes in our surgical adjuvant treatments. Refinement in predictive and prognostic studies will allow us greater ability to tailor the appropriate therapy for patients, and allow for greater patient's participation in the shared decision process.

## **Author details**

I.H. Sahin and C.R. Garrett

University of Texas MD Anderson Cancer Center Houston, Texas, USA

## **References**

[1] Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians. 2012 Jul-Aug; 62(4):220-41. PubMed PMID: 22700443.

In a recent study, bevacizumab was tested in a combined treatment including the oxaliplatin, 5-FU, and radiotherapy in 26 patients [69]. Patients were initially treated with 1 month of induction bevacizumab and FOLFOX6, then received 50.4 Gy of radiation and concurrent

continuous infusion 5-FU (200 mg/m(2)/day). This trial was terminated early because of high incidence of significant grade 3 toxicity. Authors reported 19 (75%) of 25 patients experienced grade 3 toxicities. Five (20%) out of 25 patients had pathologic response. The effect of bevacu‐ zimab was also studied with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor in a combination treatment of 5-flurouracil and external beam radiation in 21 patients [70]. Seven (47%) of 15 patients who completed the therapy and had surgery achieved pathologic complete response. Reported toxicities were including lympho‐ penia 6 (40%), diarrhea 4 (24%), rash 2 (12%), cardiac ischemia 1(6%), transaminitis (6%) and

Obtained promising pathologic response and observed safety results by the addition of monoclonal antibodies in neoadjuvant chemoradiation encourages to further explore the role of these drugs in treatment of locally advanced rectal cancer. On the other hand these targeting

The clinical advances over the last two decades have led to demonstrable improvements in the outcomes of patients with colorectal cancer and are a testament to the success of multidisci‐ plinary cancer care. Continued development of novel therapeutics in the metastatic setting will undoubtedly lead to changes in our surgical adjuvant treatments. Refinement in predictive and prognostic studies will allow us greater ability to tailor the appropriate therapy for

[1] Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians. 2012 Jul-Aug;

patients, and allow for greater patient's participation in the shared decision process.

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/week for 6 weeks), and

bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m2

296 Colorectal Cancer - Surgery, Diagnostics and Treatment

agents are yet to be standard-care-of rectal cancer in neoadjuvant settings.

mucositis (6%).

**7. Conclusions**

**Author details**

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[61] Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxa‐ liplatin combinations in patients with previously untreated metastatic colorectal can‐ cer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 Jan 1;22(1):23-30. PubMed PMID: 14665611. Epub 2003/12/11. eng.

[62] Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor re‐ sponse to preoperative chemoradiation with or without oxaliplatin in locally ad‐ vanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical On‐ cology. 2011 Jul 10;29(20):2773-80. PubMed PMID: 21606427. Epub 2011/05/25. eng.

[63] Rodel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. Preopera‐ tive chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxa‐ liplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. The lancet oncology. 2012

[64] Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally ad‐ vanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. Jour‐ nal of clinical oncology : official journal of the American Society of Clinical

Jul;13(7):679-87. PubMed PMID: 22627104. Epub 2012/05/26. eng.

PMID: 15305186. Pubmed Central PMCID: 2747703. Epub 2004/08/12. eng.

1;63(2):346-53. PubMed PMID: 15913913. Epub 2005/05/26. eng.

13(6):579-88. PubMed PMID: 22503032. Epub 2012/04/17. eng.

1;25(1):110-7. PubMed PMID: 17194912. Epub 2006/12/30. eng.

3503) 2011.

302 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Chapter 13**

**Adjuvant Treatment in Colorectal Cancer**

Worldwide, more than 1 million people develop colorectal cancer (CRC) annually [1]. CRC is a major health problem in the Western world and the second most common cause of cancer mortality [2]. To improve performance, the role of chemotherapy for CRC has increased dramatically over the last decade. Of course surgery remains the cornerstone of treatment, the vast majority of CRC patients now receive chemotherapy with multiple agents that are currently approved for the treatment in the appropriate setting. However, it is a complex process to select the optimal chemotherapy for each patient and practice evidence gap is still a problem. We found large differences in patterns of institution, region and country. The results suggest that the lack of evidence for CRC chemotherapy prac‐ tice still exists around the world. [3] Recently, standardization of cancer treatment, including chemotherapy, has become of particular importance for the quality of cancer therapy. It is important to know whether the overhaul performed normalization of CRC chemothera‐ py. Measures and quality indicators are needed and several studies on indicators of quality of cancer care have been reported. However, measures to assess the standardization of cancer therapy are not well established. In this study, we evaluated the usefulness of the oncology market research to assess the evidence gap in practice CRC chemotherapy. We also discuss the role of the method to measure the effect of normalization of CRC chemo‐

Although surgery remains the cornerstone of treatment, the vast majority of CRC pa‐ tients now receive chemotherapy to reduce the risk of metastatic spread by eradicating microscopic tumor foci that are distant from the primary tumor and undetectable in

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Krassimir Ivanov, Nikola Kolev, Ivan Shterev,

Additional information is available at the end of the chapter

Tanya Kirilova

**1. Introduction**

therapy. [4, 5]

http://dx.doi.org/10.5772/56914

Anton Tonev, Valentin Ignatov, Vasil Bojkov and

## **Adjuvant Treatment in Colorectal Cancer**

Krassimir Ivanov, Nikola Kolev, Ivan Shterev, Anton Tonev, Valentin Ignatov, Vasil Bojkov and Tanya Kirilova

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56914

### **1. Introduction**

Worldwide, more than 1 million people develop colorectal cancer (CRC) annually [1]. CRC is a major health problem in the Western world and the second most common cause of cancer mortality [2]. To improve performance, the role of chemotherapy for CRC has increased dramatically over the last decade. Of course surgery remains the cornerstone of treatment, the vast majority of CRC patients now receive chemotherapy with multiple agents that are currently approved for the treatment in the appropriate setting. However, it is a complex process to select the optimal chemotherapy for each patient and practice evidence gap is still a problem. We found large differences in patterns of institution, region and country. The results suggest that the lack of evidence for CRC chemotherapy prac‐ tice still exists around the world. [3] Recently, standardization of cancer treatment, including chemotherapy, has become of particular importance for the quality of cancer therapy. It is important to know whether the overhaul performed normalization of CRC chemothera‐ py. Measures and quality indicators are needed and several studies on indicators of quality of cancer care have been reported. However, measures to assess the standardization of cancer therapy are not well established. In this study, we evaluated the usefulness of the oncology market research to assess the evidence gap in practice CRC chemotherapy. We also discuss the role of the method to measure the effect of normalization of CRC chemo‐ therapy. [4, 5]

Although surgery remains the cornerstone of treatment, the vast majority of CRC pa‐ tients now receive chemotherapy to reduce the risk of metastatic spread by eradicating microscopic tumor foci that are distant from the primary tumor and undetectable in

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

perioperative assessment of tumor extension. [5] Five-year survival of patients are mainly determined by the histological stage of the tumor at the time of resection. The most important prognostic factor for survival in patients without visceral metastases is the stage of the tumor determined by the depth of penetration of the tumor in the bowel wall and the number of lymph nodes [4] (lymph nodes >12 examined). Result of the meta - analy‐ sis of over 10 studies showed that each - two-month delay of adjuvant chemotherapy resulted in a 14% decrease in overall survival, suggesting that adjuvant chemotherapy should be administered as soon as possible [5].

**2. Treatment guidelines for CRC**

treated as clinical issues with many references.

study.

Some guidelines for the treatment of CRC have been developed to promote the standardization of CRC treatment. Only two drugs, panitumumab and cetuximab first line were still causing discord. Bevacizumab or capecitabine combined with oxaliplatin is used for the treatment of advanced and recurrent CRC, while the FOLFOX regimen is used in patients with a high risk of recurrence in the adjuvant chemotherapy. In this major revision, current controversies are

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 307

Adjuvant 5-FU chemotherapy is the standard treatment used in patients with stage III (Dukes C) and high-risk stage II (Dukes B) tumors. Capecitabine and bolus 5FU regimes have proven efficacy and are associated with a low risk of severe toxicity. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of random‐ ized trials in 2246 patients with stage 2 or 3 of the CRC to receive LV5FU2 or FOLFOX-4 chemotherapy. The operating system after 6 years of follow-up for all patients was 78.5% for FOLFOX-4 against 76% for LV5FU2. Subgroup analysis showed stage-specific 6-year OS rate of 72.9% against 68.7% in patients with stage 3 of the CRC and 86.9% compared with 86.8% in patients with stage 2 CRC for FOLFOX-4 and LV5FU2, respectively. The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5FU adjuvant chemothera‐ py, but used a different calendar 5FU and oxaliplatin doses delivered also less than in the MOSAIC study (nine against twelve). The first results showed a similar improvement in disease-free survival (DFS) than that observed in the MOSAIC trial. A recently presented the final results confirm improved DFS, but showed shorter survival time after recur‐ rence in the oxaliplatin arm and an improvement in overall survival has not been seen. A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while patients over 70 years, no benefit was observed consistently. The analysis of the ACCENT data‐ base, including 10, 449 patients less than 70 years and 2170 patients over 70 years from six randomized trials have demonstrated a significant interaction between age and treatment effect. No differences in results were noted between experimental (combination) chemother‐ apy and chemotherapy in patients with fluoropyrimidine control over 70 years. Adding oxaliplatin to 5FU increases the overall incidence of grade 3 toxicity and is associated with the occurrence of peripheral sensory neuropathy. Over 90% of patients experience tempora‐ ry symptoms typically induced cold, with a minority of patients with persistent symp‐ toms affecting activities of daily living (grade 2 and 3 toxicity). In the MOSAIC study, grade 3 peripheral sensory neuropathy was noted in 12.5% of patients treated with oxaliplatin for the treatment. After 48 months of follow-up, rates of toxicity were grade 11.9% 1, % [22] 8 degree and 0.7% grade 3, respectively. Similar data were presented for the NSABP C-07

Decisions regarding the use of adjuvant chemotherapy combinations are more complex. The incidence of approximately 3% of significant long-term peripheral neuropathy and MS MT Seymour Braun could interfere with the activities of the daily life of the patient influences decision-making in relation to the small additional benefit accrued to receive the

The introduction of new cytotoxic agents such as oral fluoropyrimidines, oxaliplatin and irinotecan in chemotherapy (CT) regimens have improved the response rate, disease-free survival (DFS) and overall survival (OS) in patients with metastatic colorectal cancer. [6, 7] This has encouraged the trials in the adjuvant treatment of non-metastatic disease, especially in patients with stage III tumors. Table 1 shows the most common regimens used for the CT adjuvant. Surgery alone is usually curative for colon cancer stage II, but about 20% to 30% of these patients develop recurrence and die of metastatic disease. [8] This under‐ pins the need for prognostic factors such as microsatellite instability (MSI), which are potentially predictive of tumor response to cytotoxic agents. [7] Prognostic factors are particularly useful in the context of stage II colorectal cancer, where the benefits of cytotoxic adjuvant therapy are more controversial than in stage III disease. The identification of accurate and validated predictive and prognostic markers help clinicians in choosing appropriate use of adjuvant chemotherapy in patients with stage II CRC.

MSI is a change in the length of microsatellite DNA due to the insertion or deletion of repeating units – from 1to 5 nucleotides caused by defects in mismatch repair genes or methylation of their promoters. [9] Tumors with MSI are more often proximal, poorly differentiated, mucinous, and show a significant lymphocytic infiltration. [9] Colon cancers with high-frequency MSI have clinical and pathological features that distinguish them from microsatellite stable tumors and MSI is a marker of favorable outcome and a predictor for the benefit decreased from fluorouracil - based adjuvant chemotherapy in patients with stage II or colon cancer stage III with microsatellite stable tumors or tumors with lowfrequency microsatellite instability. [10] Silence or mutation of mismatch repair (MMR) genes can lead to protein deficiency MMR and MSI 10. This is observed in patients with Lynch syndrome, and it is a rare cause of hereditary colon cancer 2 to 4% of the 11 cases. Somatic mutation is reported in 19% of CRC [12], while silencing of MMR genes can be observed in up to 52% of sporadic colon cancers [13].

In sporadic CRC, three tumor phenotypes were defined: microsatellite stable (MSS), lowfrequency MSI (MSI-L) and high frequency MSI (MSI-H). It has been reported that MSI-H are more frequently found in stage II disease than in stage III disease 14. This may partly explain the benefit decreased from 5 - fluorouracil adjuvant chemotherapy (5FU) in patients with stage II. Tente identify patients who might benefit from adjuvant chemotherapy led to the devel‐ opment of multigene tests as several Oncotype DX etc. Unfortunately, there is no evidence that any of them can predict the potential benefit of adjuvant chemotherapy. [13]

## **2. Treatment guidelines for CRC**

perioperative assessment of tumor extension. [5] Five-year survival of patients are mainly determined by the histological stage of the tumor at the time of resection. The most important prognostic factor for survival in patients without visceral metastases is the stage of the tumor determined by the depth of penetration of the tumor in the bowel wall and the number of lymph nodes [4] (lymph nodes >12 examined). Result of the meta - analy‐ sis of over 10 studies showed that each - two-month delay of adjuvant chemotherapy resulted in a 14% decrease in overall survival, suggesting that adjuvant chemotherapy

The introduction of new cytotoxic agents such as oral fluoropyrimidines, oxaliplatin and irinotecan in chemotherapy (CT) regimens have improved the response rate, disease-free survival (DFS) and overall survival (OS) in patients with metastatic colorectal cancer. [6, 7] This has encouraged the trials in the adjuvant treatment of non-metastatic disease, especially in patients with stage III tumors. Table 1 shows the most common regimens used for the CT adjuvant. Surgery alone is usually curative for colon cancer stage II, but about 20% to 30% of these patients develop recurrence and die of metastatic disease. [8] This under‐ pins the need for prognostic factors such as microsatellite instability (MSI), which are potentially predictive of tumor response to cytotoxic agents. [7] Prognostic factors are particularly useful in the context of stage II colorectal cancer, where the benefits of cytotoxic adjuvant therapy are more controversial than in stage III disease. The identification of accurate and validated predictive and prognostic markers help clinicians in choosing

MSI is a change in the length of microsatellite DNA due to the insertion or deletion of repeating units – from 1to 5 nucleotides caused by defects in mismatch repair genes or methylation of their promoters. [9] Tumors with MSI are more often proximal, poorly differentiated, mucinous, and show a significant lymphocytic infiltration. [9] Colon cancers with high-frequency MSI have clinical and pathological features that distinguish them from microsatellite stable tumors and MSI is a marker of favorable outcome and a predictor for the benefit decreased from fluorouracil - based adjuvant chemotherapy in patients with stage II or colon cancer stage III with microsatellite stable tumors or tumors with lowfrequency microsatellite instability. [10] Silence or mutation of mismatch repair (MMR) genes can lead to protein deficiency MMR and MSI 10. This is observed in patients with Lynch syndrome, and it is a rare cause of hereditary colon cancer 2 to 4% of the 11 cases. Somatic mutation is reported in 19% of CRC [12], while silencing of MMR genes can be

In sporadic CRC, three tumor phenotypes were defined: microsatellite stable (MSS), lowfrequency MSI (MSI-L) and high frequency MSI (MSI-H). It has been reported that MSI-H are more frequently found in stage II disease than in stage III disease 14. This may partly explain the benefit decreased from 5 - fluorouracil adjuvant chemotherapy (5FU) in patients with stage II. Tente identify patients who might benefit from adjuvant chemotherapy led to the devel‐ opment of multigene tests as several Oncotype DX etc. Unfortunately, there is no evidence that

any of them can predict the potential benefit of adjuvant chemotherapy. [13]

appropriate use of adjuvant chemotherapy in patients with stage II CRC.

observed in up to 52% of sporadic colon cancers [13].

should be administered as soon as possible [5].

306 Colorectal Cancer - Surgery, Diagnostics and Treatment

Some guidelines for the treatment of CRC have been developed to promote the standardization of CRC treatment. Only two drugs, panitumumab and cetuximab first line were still causing discord. Bevacizumab or capecitabine combined with oxaliplatin is used for the treatment of advanced and recurrent CRC, while the FOLFOX regimen is used in patients with a high risk of recurrence in the adjuvant chemotherapy. In this major revision, current controversies are treated as clinical issues with many references.

Adjuvant 5-FU chemotherapy is the standard treatment used in patients with stage III (Dukes C) and high-risk stage II (Dukes B) tumors. Capecitabine and bolus 5FU regimes have proven efficacy and are associated with a low risk of severe toxicity. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of random‐ ized trials in 2246 patients with stage 2 or 3 of the CRC to receive LV5FU2 or FOLFOX-4 chemotherapy. The operating system after 6 years of follow-up for all patients was 78.5% for FOLFOX-4 against 76% for LV5FU2. Subgroup analysis showed stage-specific 6-year OS rate of 72.9% against 68.7% in patients with stage 3 of the CRC and 86.9% compared with 86.8% in patients with stage 2 CRC for FOLFOX-4 and LV5FU2, respectively. The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5FU adjuvant chemothera‐ py, but used a different calendar 5FU and oxaliplatin doses delivered also less than in the MOSAIC study (nine against twelve). The first results showed a similar improvement in disease-free survival (DFS) than that observed in the MOSAIC trial. A recently presented the final results confirm improved DFS, but showed shorter survival time after recur‐ rence in the oxaliplatin arm and an improvement in overall survival has not been seen. A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while patients over 70 years, no benefit was observed consistently. The analysis of the ACCENT data‐ base, including 10, 449 patients less than 70 years and 2170 patients over 70 years from six randomized trials have demonstrated a significant interaction between age and treatment effect. No differences in results were noted between experimental (combination) chemother‐ apy and chemotherapy in patients with fluoropyrimidine control over 70 years. Adding oxaliplatin to 5FU increases the overall incidence of grade 3 toxicity and is associated with the occurrence of peripheral sensory neuropathy. Over 90% of patients experience tempora‐ ry symptoms typically induced cold, with a minority of patients with persistent symp‐ toms affecting activities of daily living (grade 2 and 3 toxicity). In the MOSAIC study, grade 3 peripheral sensory neuropathy was noted in 12.5% of patients treated with oxaliplatin for the treatment. After 48 months of follow-up, rates of toxicity were grade 11.9% 1, % [22] 8 degree and 0.7% grade 3, respectively. Similar data were presented for the NSABP C-07 study.

Decisions regarding the use of adjuvant chemotherapy combinations are more complex. The incidence of approximately 3% of significant long-term peripheral neuropathy and MS MT Seymour Braun could interfere with the activities of the daily life of the patient influences decision-making in relation to the small additional benefit accrued to receive the oxaliplatin. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluat‐ ing shorter periods of oxaliplatin-based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the noninferiority of short periods of treatment, as well as consideration of the evaluation criteria of quality of life. The relative benefit of chemotherapy is also a key factor in the choice of treatment for patients in the adjuvant setting. Patients with stage 3 are a heterogeneous group and decisions based on age, the relative risk of recurrence (N1 N2 against disease), and the additional benefit that can be achieved by adding oxaliplatin need to be carefully considered. Given the new data in patients over 70 years, it seems likely that chemothera‐ py oxaliplatin are used less frequently in this group. Patients with disease stage 2 have an excellent prognosis with or without chemotherapy 5FU-based and high-risk patients functions are selected for processing. Both C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5-FU in patients with stage 2 disease, but a trend towards improved DFS was noted. However, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotoxicity. [23]

regimen (5FU bolus followed by LV 15 minutes) with double - monthly infusion LV5FU2 (LV for 2 hours, followed by bolus 5-FU, followed by a continuous infusion of 5-FU over 2 days) in 905 patients with stage II (43%) or III (57%) colon cancer showed that the regime was less toxic LV5FU2, especially regarding hematological and gastrointestinal events (P <0.001) [19]. No significant difference in DFS and OS was observed in one of two regi mens median follow-up 6 years. Two other studies have shown that the two ways of 5FU bolus administration combined with LV with or without levamisole and a continuous infusion of 5-FU are equivalent. Saini and colleagues conducted a multicenter randomized trial comparing the efficacy and toxicity of 12 weeks of 5FU delivered by continuous intrave‐ nous infusion against the standard bolus 5-FU and LV for 6 months as adjuvant treat‐ ment in colorectal cancer. The two schemes are equivalent, but the plan 12 weeks was less toxic [20]. The analysis of data from several trials in which patients were randomly resection of the tumor or tumor resection followed by adjuvant 5-FU/LV showed that the benefit of adjuvant chemotherapy was observed in patients with stage III [21, 22], which suggests that because of nodal status of these patients are at higher risk. Both studies showed that the addition of oxaliplatin to 5-FU/LV as adjuvant therapy in stage II and elderly patients showed no significant DFS or OS [23, 24] benefits even in patients with characteristics high risk - T4 tumors, intestinal obstruction, venous invasion, etc. This suggests that, despite the failure of our definition of high-risk patients with stage II, 5-FU/LV regimen may be preferable. QUASAR investigators reported their analysis of 3238 patients, the majority of them were in stage II colon cancer. Patients were randomized to receive 5-FU/LV or observation. The relative risk of death from all causes in the 5-FU/LV arm versus observa‐ tion was 0.82 (95% CI, 0.70 to 0.95, p = 0.008). The relative risk of recurrence was 0.78 (95% CI, 0.67-0, 91, p = 0.001) [7]. The investigators did not separate patients into individuals high or low risk. Risk factors are obstruction or bowel perforation, elevated preoperative CEA, poorly differentiated tumors, removal of CDC patients and MSI-S. The impact of adjuvant chemotherapy and the potential benefit of this new could not be clearly demon‐

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 309

Two oral prodrugs of 5FU - capecetabine and uracil / tegafur (UFT), has demonstrated efficacy in metastatic disease, which is comparable with bolus 5-FU/LV regimens [25, 26]. After oral administration, capecitabine is rapidly absorbed with plasma concentrations peaking after 1.5 hours [27]. Pharmacokinetics is largely dose - dependent. The pharmacol‐ ogy of capecitabine is not significantly influenced by gender, race, performance status, body surface area, albumin or hepatic dysfunction [28]. The half-life of capecitabine is between 0.49 and 0.89 hours, whereas the half-life of the metabolite (5-FU) extends from 0.67 to 1.15 hours [29]. Regarding renal excretion primarily (more than 70% of metabolites), capecita‐ bine is against - in patients with severe renal impairment (creatinine clearance less than 30

strated in this study of patients with stage II.

**4. Oral fluoropyrimidines**

mL / min).

#### **3. 5FU**

In 1990, Moertel and colleagues first reported the value of adjuvant chemotherapy in patients with stage III colon cancer (Dukes C, Tx N + M0). [15] This study showed an increase in overall survival and progression-free survival in patients receiving 5FU/ Levamisole - based chemotherapy for 1 year against levamisole alone or without chemother‐ apy. With a median follow - up of 6.5 years, patients treated with 5-FU / levamisole showed a 40% reduction in recidivism and an estimated reduction of 33% of overall mortality [16]. 5-FU is a pyrimidine analogue, which inhibits thymidylate synthase (TS) (involved in the de novo synthesis of thymidine) and is involved in incorporation into RNA and DNA with the inhibition of DNA synthesis and function [17]. With 5FU bolus injection maximum concentration is reached in the plasma and bone marrow 100-1000 times higher than with continuous infusion. More than 85% of the administered drug is inactivated by dihydropyr‐ imidine dehydrogenase (DPD), expressed mainly in the liver. Some mutation in DPD in about 2% in the general population can lead to serious life-threatening toxicity [17]. Leucovorin (LV) or folinic acid enhance the antitumor activity of 5FU. Today, there is a lack of LV in the United States, despite the absence of specific data confirming this statement. The QUASAR study investigators demonstrated that patients treated with 175 mg of LV similar survival and 3 - year recurrence rate of LV 25 mg when administered as a bolus 5-FU as adjuvant therapy for CRC 7. Similar results have been reported in the parameters in metastatic CRC patients - there was no difference in survival or response rate in patients receiving 5FU bolus high - dose or low-dose LV [18]. Therefore, when LV is not available without LV treatment is reasonable. Comparison of monthly bolus FU / LV

regimen (5FU bolus followed by LV 15 minutes) with double - monthly infusion LV5FU2 (LV for 2 hours, followed by bolus 5-FU, followed by a continuous infusion of 5-FU over 2 days) in 905 patients with stage II (43%) or III (57%) colon cancer showed that the regime was less toxic LV5FU2, especially regarding hematological and gastrointestinal events (P <0.001) [19]. No significant difference in DFS and OS was observed in one of two regi mens median follow-up 6 years. Two other studies have shown that the two ways of 5FU bolus administration combined with LV with or without levamisole and a continuous infusion of 5-FU are equivalent. Saini and colleagues conducted a multicenter randomized trial comparing the efficacy and toxicity of 12 weeks of 5FU delivered by continuous intrave‐ nous infusion against the standard bolus 5-FU and LV for 6 months as adjuvant treat‐ ment in colorectal cancer. The two schemes are equivalent, but the plan 12 weeks was less toxic [20]. The analysis of data from several trials in which patients were randomly resection of the tumor or tumor resection followed by adjuvant 5-FU/LV showed that the benefit of adjuvant chemotherapy was observed in patients with stage III [21, 22], which suggests that because of nodal status of these patients are at higher risk. Both studies showed that the addition of oxaliplatin to 5-FU/LV as adjuvant therapy in stage II and elderly patients showed no significant DFS or OS [23, 24] benefits even in patients with characteristics high risk - T4 tumors, intestinal obstruction, venous invasion, etc. This suggests that, despite the failure of our definition of high-risk patients with stage II, 5-FU/LV regimen may be preferable. QUASAR investigators reported their analysis of 3238 patients, the majority of them were in stage II colon cancer. Patients were randomized to receive 5-FU/LV or observation. The relative risk of death from all causes in the 5-FU/LV arm versus observa‐ tion was 0.82 (95% CI, 0.70 to 0.95, p = 0.008). The relative risk of recurrence was 0.78 (95% CI, 0.67-0, 91, p = 0.001) [7]. The investigators did not separate patients into individuals high or low risk. Risk factors are obstruction or bowel perforation, elevated preoperative CEA, poorly differentiated tumors, removal of CDC patients and MSI-S. The impact of adjuvant chemotherapy and the potential benefit of this new could not be clearly demon‐ strated in this study of patients with stage II.

## **4. Oral fluoropyrimidines**

oxaliplatin. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluat‐ ing shorter periods of oxaliplatin-based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the noninferiority of short periods of treatment, as well as consideration of the evaluation criteria of quality of life. The relative benefit of chemotherapy is also a key factor in the choice of treatment for patients in the adjuvant setting. Patients with stage 3 are a heterogeneous group and decisions based on age, the relative risk of recurrence (N1 N2 against disease), and the additional benefit that can be achieved by adding oxaliplatin need to be carefully considered. Given the new data in patients over 70 years, it seems likely that chemothera‐ py oxaliplatin are used less frequently in this group. Patients with disease stage 2 have an excellent prognosis with or without chemotherapy 5FU-based and high-risk patients functions are selected for processing. Both C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5-FU in patients with stage 2 disease, but a trend towards improved DFS was noted. However, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of

In 1990, Moertel and colleagues first reported the value of adjuvant chemotherapy in patients with stage III colon cancer (Dukes C, Tx N + M0). [15] This study showed an increase in overall survival and progression-free survival in patients receiving 5FU/ Levamisole - based chemotherapy for 1 year against levamisole alone or without chemother‐ apy. With a median follow - up of 6.5 years, patients treated with 5-FU / levamisole showed a 40% reduction in recidivism and an estimated reduction of 33% of overall mortality [16]. 5-FU is a pyrimidine analogue, which inhibits thymidylate synthase (TS) (involved in the de novo synthesis of thymidine) and is involved in incorporation into RNA and DNA with the inhibition of DNA synthesis and function [17]. With 5FU bolus injection maximum concentration is reached in the plasma and bone marrow 100-1000 times higher than with continuous infusion. More than 85% of the administered drug is inactivated by dihydropyr‐ imidine dehydrogenase (DPD), expressed mainly in the liver. Some mutation in DPD in about 2% in the general population can lead to serious life-threatening toxicity [17]. Leucovorin (LV) or folinic acid enhance the antitumor activity of 5FU. Today, there is a lack of LV in the United States, despite the absence of specific data confirming this statement. The QUASAR study investigators demonstrated that patients treated with 175 mg of LV similar survival and 3 - year recurrence rate of LV 25 mg when administered as a bolus 5-FU as adjuvant therapy for CRC 7. Similar results have been reported in the parameters in metastatic CRC patients - there was no difference in survival or response rate in patients receiving 5FU bolus high - dose or low-dose LV [18]. Therefore, when LV is not available without LV treatment is reasonable. Comparison of monthly bolus FU / LV

operation) and the risk of neurotoxicity. [23]

308 Colorectal Cancer - Surgery, Diagnostics and Treatment

**3. 5FU**

Two oral prodrugs of 5FU - capecetabine and uracil / tegafur (UFT), has demonstrated efficacy in metastatic disease, which is comparable with bolus 5-FU/LV regimens [25, 26]. After oral administration, capecitabine is rapidly absorbed with plasma concentrations peaking after 1.5 hours [27]. Pharmacokinetics is largely dose - dependent. The pharmacol‐ ogy of capecitabine is not significantly influenced by gender, race, performance status, body surface area, albumin or hepatic dysfunction [28]. The half-life of capecitabine is between 0.49 and 0.89 hours, whereas the half-life of the metabolite (5-FU) extends from 0.67 to 1.15 hours [29]. Regarding renal excretion primarily (more than 70% of metabolites), capecita‐ bine is against - in patients with severe renal impairment (creatinine clearance less than 30 mL / min).

LV. After a median follow-up of 6.9 years, both treatments showed similar efficacy in terms of DFS and OS [30]. The HR for DFS of capecitabine compared 5-FU/LV was 0.88 (95% CI, 0.77 to 1.01), the upper limit of the 95% is well below the predefined non-inferiority margin of 1.20 (p <0.0001) [30]. The 5-year DFS rate for capecitabine and 5-FU/LV were 60.8% and 56.7%, respectively. These monitoring data confirm that, as adjunctive therapy for patients with colon cancer resected stage III oral capecitabine is at least equivalent to iv bolus treatment of 5- FU/LV in terms of 5 - year DFS, the primary endpoint of X-ACT study. Infusional 5-FU regimens are now often favored because they offer similar efficacy or improved slightly bolus 5-FU/LV regimes and are generally better tolerated [31]. However, the plasma concentration profile of capecitabine is administered twice daily for 14 days, closer to that of a continuous infusion of 5-FU bolus injections as daily or weekly 5FU.La capecitabine Profile improved safety compared to bolus 5-FU/LV in terms of significantly lower rates of diarrhea, stomatitis,

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 311

UFT and oral LV was evaluated in the adjuvant setting in the NSABP C-06 trial. More than 1000 patients with colon cancer were randomized to receive either oral or intravenous UFT with LV 5FU with LV. 47% of patients had colon cancer stage II, and 53% had colon cancer stage III. Median follow-up was 62.3 months time. There was no significant difference in disease-free survival - or overall showing that the UFT is an acceptable alternative to parenteral 5-FU/LV [32]. No difference in toxicity profiles of the two regimens has been reported.

The hypothesis that the antitumor activity of the combination agent, including oxalipla‐ tin, irinotecan, bevacizumab, cetuximab in metastatic cure rates would result in increased adjuvant proved to be often wrong. Oxaliplatin is a platinum compound and third generation of the safe administration of evidence of clinical activity has been reported 33. Platinum compounds exert their effect through the development of covalent adducts with cellular DNA, which is not portable - specific cycle [34]. Platinum derivative oxaliplatin is described as having a "tri-exponential" reason for removing the half - life being successive‐ ly 0.28 hours, 16.3 hours and 273 hours [35]. The fact that the third half-life of oxaliplatin hundreds of hours, the accumulation of the drug in the tissues can reasonably be expect‐ ed. In this regard, one study examined the long - term retention of platinum 8-75 months after treatment with cisplatin and oxaliplatin [36]. Narrow therapeutic index of oxalipla‐ tin and adverse reactions are mainly reported in the hematopoietic system, peripheral nerves, and gastrointestinal tract [35]. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of randomized 2246 patients with stage II or III CRC will LV5FU2 or FOLFOX-4 (which is LV5FU2 chemotherapy plus oxaliplatin on day 1]. The 5-year DFS rate of Phase II and III patients were 73.3% and 67.4% in the FOL‐ FOX-4 groups and LV5FU2, respectively (RR 0.80, 95% CI, 0.68-0, 93, p = 0.003) [37]. Subgroup analysis showed stage - specific 6 years OS rate of 72.9% against 68.7% in patients with stage III CRC (HR 0.80, 95% CI, 0.65-0, 97, P = 0.023) and 85.0% against 83.3% in patients with stage II CRC (P = 0.65] in the FOLFOX-4 and LV5FU2, respectively [38]. As

neutropenia, nausea, alopecia, febrile neutropenia [30].

**5. Adjuvant therapy combination**

**Table 1.** Types of therapeutical agents and their mechanism of action

The X-ACT (Xeloda (capecitabine) in adjuvant therapy of colon cancer) Phase III trial in patients (N = 1.987) compared capecitabine (2500 mg / m 2 / day, 14 to 21 days) for bolus 5-FU/ LV. After a median follow-up of 6.9 years, both treatments showed similar efficacy in terms of DFS and OS [30]. The HR for DFS of capecitabine compared 5-FU/LV was 0.88 (95% CI, 0.77 to 1.01), the upper limit of the 95% is well below the predefined non-inferiority margin of 1.20 (p <0.0001) [30]. The 5-year DFS rate for capecitabine and 5-FU/LV were 60.8% and 56.7%, respectively. These monitoring data confirm that, as adjunctive therapy for patients with colon cancer resected stage III oral capecitabine is at least equivalent to iv bolus treatment of 5- FU/LV in terms of 5 - year DFS, the primary endpoint of X-ACT study. Infusional 5-FU regimens are now often favored because they offer similar efficacy or improved slightly bolus 5-FU/LV regimes and are generally better tolerated [31]. However, the plasma concentration profile of capecitabine is administered twice daily for 14 days, closer to that of a continuous infusion of 5-FU bolus injections as daily or weekly 5FU.La capecitabine Profile improved safety compared to bolus 5-FU/LV in terms of significantly lower rates of diarrhea, stomatitis, neutropenia, nausea, alopecia, febrile neutropenia [30].

UFT and oral LV was evaluated in the adjuvant setting in the NSABP C-06 trial. More than 1000 patients with colon cancer were randomized to receive either oral or intravenous UFT with LV 5FU with LV. 47% of patients had colon cancer stage II, and 53% had colon cancer stage III. Median follow-up was 62.3 months time. There was no significant difference in disease-free survival - or overall showing that the UFT is an acceptable alternative to parenteral 5-FU/LV [32]. No difference in toxicity profiles of the two regimens has been reported.

## **5. Adjuvant therapy combination**

**Therapy Mechanism of Action Indications Potential Common Toxicities**

Multiple uses in combination with other agents, both in the adjuvant (postop) and palliative setting

Multiple uses in combination with other agents, both in the adjuvant (postop) and metastatic setting

setting

setting

Used alone or in

combination with 5FU, LV (FOLFIRI) in the metastatic

Used in combination with either FOLFOX or FOLFIRI in the metastatic setting

Used with irinotecan or as a single agent in the metastatic setting

Used as a single agent in the metastatic setting

The X-ACT (Xeloda (capecitabine) in adjuvant therapy of colon cancer) Phase III trial in patients (N = 1.987) compared capecitabine (2500 mg / m 2 / day, 14 to 21 days) for bolus 5-FU/

Used in combination with 5FU, leucovorin (LV) (FOLFOX) in the adjuvant (postop) and metastatic

Gastrointestinal (nausea,

Gastrointestinal (nausea,

Palmar-plantar syndrome (hand-foot syndrome)

Peripheral neuropathy Gastrointestinal (nausea,

Myelosuppression Hypersensitivity

late diarrhea) Fatigue

Alopecia

Hypertension

Acneform rash Hypersensitivity Hypomagnesemia

Acneform rash Hypomagnesemia

Fatigue

Fatigue

Myelosuppression

Cholinergic (acute diarrhea) Gastrointestinal (nausea,

Arterial thrombotic events Impaired wound healing Gastrointestinal perforation

diarrhea) Myelosuppression

Fatigue

diarrhea) Myelosuppression

Fatigue

diarrhea) Fatigue

5- Fluorouracil (5FU) Blocks the enzyme

310 Colorectal Cancer - Surgery, Diagnostics and Treatment

synthesis

Capecitabine Blocks thymidylate synthase

Oxaliplatin Inhibits DNA replication and

Irinotecan Inhibits topoisomerase I, an

Bevacizumab Monoclonal antibody which

Cetuximab Monoclonal antibody to

Panitumumab Monoclonal antibody to

site

thymidylate synthase (TS), which is essential for DNA

(orally administered prodrug

transcription by forming inter- and intra-strand DNA adducts/cross-links

enzyme that facilitates the uncoiling and recoiling of DNA during replication

binds to VEGF ligand

EGFR (chimeric) that blocks the ligand-binding site

EGFR (fully humanized) that blocks the ligand-binding

VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.

**Table 1.** Types of therapeutical agents and their mechanism of action

converted to 5FU)

The hypothesis that the antitumor activity of the combination agent, including oxalipla‐ tin, irinotecan, bevacizumab, cetuximab in metastatic cure rates would result in increased adjuvant proved to be often wrong. Oxaliplatin is a platinum compound and third generation of the safe administration of evidence of clinical activity has been reported 33. Platinum compounds exert their effect through the development of covalent adducts with cellular DNA, which is not portable - specific cycle [34]. Platinum derivative oxaliplatin is described as having a "tri-exponential" reason for removing the half - life being successive‐ ly 0.28 hours, 16.3 hours and 273 hours [35]. The fact that the third half-life of oxaliplatin hundreds of hours, the accumulation of the drug in the tissues can reasonably be expect‐ ed. In this regard, one study examined the long - term retention of platinum 8-75 months after treatment with cisplatin and oxaliplatin [36]. Narrow therapeutic index of oxalipla‐ tin and adverse reactions are mainly reported in the hematopoietic system, peripheral nerves, and gastrointestinal tract [35]. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of randomized 2246 patients with stage II or III CRC will LV5FU2 or FOLFOX-4 (which is LV5FU2 chemotherapy plus oxaliplatin on day 1]. The 5-year DFS rate of Phase II and III patients were 73.3% and 67.4% in the FOL‐ FOX-4 groups and LV5FU2, respectively (RR 0.80, 95% CI, 0.68-0, 93, p = 0.003) [37]. Subgroup analysis showed stage - specific 6 years OS rate of 72.9% against 68.7% in patients with stage III CRC (HR 0.80, 95% CI, 0.65-0, 97, P = 0.023) and 85.0% against 83.3% in patients with stage II CRC (P = 0.65] in the FOLFOX-4 and LV5FU2, respectively [38]. As

expected, the toxicity of the regimen FOLFOX-4 was higher than that observed in the LV5FU2 arm. All - cause mortality in the first 60 days was the same in both arms.The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5-FU adjuvant chemotherapy, but using a different calendar 5FU and also provide fewer doses of oxaliplatin in the MOSAIC study (nine against twelve). FLOX regimen in this trial was studied - oxaliplatin was given on weeks 1, 3, and 5 more per week 5-FU/LV bolus of 1-6 weeks, repeated at 8 week cycle, depending on the standard weekly 5-FU/LV treatment. Over 2000 patients were randomized to receive 5-FU/LV and FLOX treatment. Stage II patients were 29% and stage III patients was 71%. The median duration of follow up was 34 months. The hazard ratio of FLOX against 5-FU/LV was 0.79 (95% CI, 0.67 to 0.93], with a risk reduction of 21% in favor of FLOX [39]. As expected, treatment toxicity FLOX was higher than that observed in the 5-FU/LV arm. 15 deaths were recorded in the treatment with FLOX and 14 deaths 5-FU/LV. Update this study showed that the benefit of FLOX in DFS was observed in 7 - year median follow - but there was no significant difference in overall survival when the two arms were compared 24 (HR, 0.88, 95% CI, 0.74 to 1.05, P = 0.1428). A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while in patients over 70 years, no benefit was observed consistently. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluating shorter periods of oxaliplatin - based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the non-inferiority of short periods treatment.Both NSABP C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5- FU in patients with stage II disease, but a trend towards improved DFS was noted.Howev‐ er, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotox‐ icity. Analysis of a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus 5-FU/LV as adjuvant treatment for colon cancer stage III showed that XELOX was an improvement of 3 years compared to 5-FU/LV DFS rate [40, 41]. Patients receiving XELOX had less adverse reactions such as diarrhea, alopecia, and more neurosensory toxicity, vomiting and hand-foot syndrome than patients receiving FU / LV. All these studies suggest that FOLFOX, XELOX FLOX and can be used interchangeably in contexts adjuvant. Irinotecan is a semisynthetic analogue of camptothecin, originally isolated from the China / Tibet ornamental tree Camptotheca acuminata.It is a chemotherapy agent that causes destruction of cells in S phase-specific topoisomerase I poison in the cell [42]. CALGB 89803 trial by Saltz and colleagues randomized 1264 patients to receive standard weekly bolus 5- FU / LV bolus regimen or weekly irinotecan and 5-FU bolus / LV. The primary endpoints of the study were overall survival and disease-free survival. Surprisingly, they found no difference in either DFS (0.84] or OS (P = 0.74] between the two treatment arms with lethal and non-lethal toxicity increased by the addition of irinotecan to standard 5FU / LV pattern 43.This trial showed the need for randomized controlled trials adjuvant because advances in the treatment of metastatic disease does not necessarily translate into advances in adjuvant therapy. Phase III trial was conducted by large investigators PETACC-3. They

investigated whether the addition of irinotecan to LV5FU2 would improve disease-free survival in patients with colon cancer. After surgery, patients with stage II and III colon cancer were randomized to receive surgery LV5FU2 (LV 200 mg / m 2 infused over 2 hours, followed by 5-FU as a 400 mg / m 2 bolus and then one of 600 mg / m 2 by continuous infusion over 22 hours on days 1 and 2 every 2 weeks for 12 cycles) with or without irinotecan (180 mg / m 2 infused over 30 to 90 minutes, day 1, every 2 weeks) [44]. After a median follow-up of 66.3 months, the rate at 5 years was 56.7% with DFS irinotecan/ LV5FU2 and 54.3% for LV5FU2 alone (p = 0.106). They observed that the addition of irinotecan to LV5FU2 was associated with an increased incidence of adverse reactions and neutropenia. They concluded that irinotecan added to LV5FU2 as adjuvant therapy does not confer a statistically significant improvement in overall survival or DFS in patients with colon cancer stage III versus LV5FU2 alone. For the moment, there are no data support‐ ing the use of irinotecan-containing regimens in adjuvant stage II and III patients. Analy‐ sis PETACC-3 trial could not confirm the expected benefit of adding irinotecan in MSI-H patients. Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF) which is used to inhibit the function of VEGF in vascular endothelial cells and thereby inhibit tumor angiogenesis-dependent solid tumors for growth and metastasis [45]. Bevacizumab has demonstrated clinical activity to in‐ crease in the standard CT metastatic settings.This led to the consideration of this agent in the adjuvant chemotherapy in the NSABP C-08 trial. More than 2500 patients, most of whom had stage III were randomized to receive FOLFOX6 modified 6 months, alone or with bevacizumab [46]. In the bevacizumab arm, bevacizumab was administered for more than 6 months, for a total of 1 year of bevacizumab.The primary endpoint of the study was 3 years DFS. The relative risk of FOLFOX plus bevacizumab versus FOLFOX alone was 0.89 (95% CI, 0.76 to 1.04, p = 0.15). This study did not demonstrate the benefits of the use of bevacizumab in the adjuvant treatment of stage II and III CRC and for this reason the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer. Cetuximab is a monoclonal antibody capable of inhibiting the degradation and transmembrane receptor EGFR epidermal growth factor 47.Inhibition of EGFR is of major importance because EGFR control many important activities of tumor cells, includ‐ ing tumor growth and neo - angiogenesis, inhibition of the apoptotic response to chemother‐ apy and radiotherapy. In a Phase III, randomized, Alberts and colleagues evaluated the potential benefit of cetuximab added to the sixth amended plan FOLFOX.Ils randomized over 2500 patients to receive 12 cycles of FOLFOX every two weeks with or without cetuximab. The mutational status of the KRAS gene was decided at the central level. The median follow-up of 28 months. Three-year disease-free survival for FOLFOX alone was 74.6% against 71.5% with the addition of cetuximab (HR, 1.21, 95% CI, 0.98 to 1.49, P = 0 08) in patients with wild-type KRAS, and 67.1% against 65.0% (HR 1.12, 95% CI, 0.86 to 1.46, p = 0.38) in patients with mutated KRAS 48.The trial did not demonstrate any benefit when adding cetuximab to FOLFOX regimen. More patients with grade 3 or higher adverse events (72.5% versus 52.3%, odds ratio (OR) 2.4, 95% CI, 2.1 to 2.8, p <.001) and failure to carry Good 12 cycles (33% versus 23%, OR 1.6, 95% CI, 1.4 to 1.9, p <0, 001) were significant‐

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 313

investigated whether the addition of irinotecan to LV5FU2 would improve disease-free survival in patients with colon cancer. After surgery, patients with stage II and III colon cancer were randomized to receive surgery LV5FU2 (LV 200 mg / m 2 infused over 2 hours, followed by 5-FU as a 400 mg / m 2 bolus and then one of 600 mg / m 2 by continuous infusion over 22 hours on days 1 and 2 every 2 weeks for 12 cycles) with or without irinotecan (180 mg / m 2 infused over 30 to 90 minutes, day 1, every 2 weeks) [44]. After a median follow-up of 66.3 months, the rate at 5 years was 56.7% with DFS irinotecan/ LV5FU2 and 54.3% for LV5FU2 alone (p = 0.106). They observed that the addition of irinotecan to LV5FU2 was associated with an increased incidence of adverse reactions and neutropenia. They concluded that irinotecan added to LV5FU2 as adjuvant therapy does not confer a statistically significant improvement in overall survival or DFS in patients with colon cancer stage III versus LV5FU2 alone. For the moment, there are no data support‐ ing the use of irinotecan-containing regimens in adjuvant stage II and III patients. Analy‐ sis PETACC-3 trial could not confirm the expected benefit of adding irinotecan in MSI-H patients. Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF) which is used to inhibit the function of VEGF in vascular endothelial cells and thereby inhibit tumor angiogenesis-dependent solid tumors for growth and metastasis [45]. Bevacizumab has demonstrated clinical activity to in‐ crease in the standard CT metastatic settings.This led to the consideration of this agent in the adjuvant chemotherapy in the NSABP C-08 trial. More than 2500 patients, most of whom had stage III were randomized to receive FOLFOX6 modified 6 months, alone or with bevacizumab [46]. In the bevacizumab arm, bevacizumab was administered for more than 6 months, for a total of 1 year of bevacizumab.The primary endpoint of the study was 3 years DFS. The relative risk of FOLFOX plus bevacizumab versus FOLFOX alone was 0.89 (95% CI, 0.76 to 1.04, p = 0.15). This study did not demonstrate the benefits of the use of bevacizumab in the adjuvant treatment of stage II and III CRC and for this reason the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer. Cetuximab is a monoclonal antibody capable of inhibiting the degradation and transmembrane receptor EGFR epidermal growth factor 47.Inhibition of EGFR is of major importance because EGFR control many important activities of tumor cells, includ‐ ing tumor growth and neo - angiogenesis, inhibition of the apoptotic response to chemother‐ apy and radiotherapy. In a Phase III, randomized, Alberts and colleagues evaluated the potential benefit of cetuximab added to the sixth amended plan FOLFOX.Ils randomized over 2500 patients to receive 12 cycles of FOLFOX every two weeks with or without cetuximab. The mutational status of the KRAS gene was decided at the central level. The median follow-up of 28 months. Three-year disease-free survival for FOLFOX alone was 74.6% against 71.5% with the addition of cetuximab (HR, 1.21, 95% CI, 0.98 to 1.49, P = 0 08) in patients with wild-type KRAS, and 67.1% against 65.0% (HR 1.12, 95% CI, 0.86 to 1.46, p = 0.38) in patients with mutated KRAS 48.The trial did not demonstrate any benefit when adding cetuximab to FOLFOX regimen. More patients with grade 3 or higher adverse events (72.5% versus 52.3%, odds ratio (OR) 2.4, 95% CI, 2.1 to 2.8, p <.001) and failure to carry Good 12 cycles (33% versus 23%, OR 1.6, 95% CI, 1.4 to 1.9, p <0, 001) were significant‐

expected, the toxicity of the regimen FOLFOX-4 was higher than that observed in the LV5FU2 arm. All - cause mortality in the first 60 days was the same in both arms.The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5-FU adjuvant chemotherapy, but using a different calendar 5FU and also provide fewer doses of oxaliplatin in the MOSAIC study (nine against twelve). FLOX regimen in this trial was studied - oxaliplatin was given on weeks 1, 3, and 5 more per week 5-FU/LV bolus of 1-6 weeks, repeated at 8 week cycle, depending on the standard weekly 5-FU/LV treatment. Over 2000 patients were randomized to receive 5-FU/LV and FLOX treatment. Stage II patients were 29% and stage III patients was 71%. The median duration of follow up was 34 months. The hazard ratio of FLOX against 5-FU/LV was 0.79 (95% CI, 0.67 to 0.93], with a risk reduction of 21% in favor of FLOX [39]. As expected, treatment toxicity FLOX was higher than that observed in the 5-FU/LV arm. 15 deaths were recorded in the treatment with FLOX and 14 deaths 5-FU/LV. Update this study showed that the benefit of FLOX in DFS was observed in 7 - year median follow - but there was no significant difference in overall survival when the two arms were compared 24 (HR, 0.88, 95% CI, 0.74 to 1.05, P = 0.1428). A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while in patients over 70 years, no benefit was observed consistently. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluating shorter periods of oxaliplatin - based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the non-inferiority of short periods treatment.Both NSABP C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5- FU in patients with stage II disease, but a trend towards improved DFS was noted.Howev‐ er, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotox‐ icity. Analysis of a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus 5-FU/LV as adjuvant treatment for colon cancer stage III showed that XELOX was an improvement of 3 years compared to 5-FU/LV DFS rate [40, 41]. Patients receiving XELOX had less adverse reactions such as diarrhea, alopecia, and more neurosensory toxicity, vomiting and hand-foot syndrome than patients receiving FU / LV. All these studies suggest that FOLFOX, XELOX FLOX and can be used interchangeably in contexts adjuvant. Irinotecan is a semisynthetic analogue of camptothecin, originally isolated from the China / Tibet ornamental tree Camptotheca acuminata.It is a chemotherapy agent that causes destruction of cells in S phase-specific topoisomerase I poison in the cell [42]. CALGB 89803 trial by Saltz and colleagues randomized 1264 patients to receive standard weekly bolus 5- FU / LV bolus regimen or weekly irinotecan and 5-FU bolus / LV. The primary endpoints of the study were overall survival and disease-free survival. Surprisingly, they found no difference in either DFS (0.84] or OS (P = 0.74] between the two treatment arms with lethal and non-lethal toxicity increased by the addition of irinotecan to standard 5FU / LV pattern 43.This trial showed the need for randomized controlled trials adjuvant because advances in the treatment of metastatic disease does not necessarily translate into advances in adjuvant therapy. Phase III trial was conducted by large investigators PETACC-3. They

312 Colorectal Cancer - Surgery, Diagnostics and Treatment

ly higher with cetuximab.Increased toxicity was observed in patients aged 70 years or older. Therefore, the role of cetuximab in the adjuvant treatment is insignificant for the moment.

**3.** overall survival (OS), which is the length of time patients are alive after diagnosis or

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 315

Postoperative, or "adjuvant" systemic therapy has become standard for stage III colon cancer. Adjuvant therapy should also be strongly considered in stage II patients. It is generally recommended for any medically fit patient with stage II cancer with unfavorable factors, including colonic perforation, poorly differentiated histology, colonic obstruction, lympho vascular invasion, or inadequately sampled lymph nodes [61]. The optimal choice of adjuvant chemotherapy has recently changed from a 6-month course of 5FU-based chemotherapy alone to a 6-month course of infusional 5FU plus LV and oxaliplatin (FOLFOX) based on a large trial of adjuvant systemic therapy for resected stage II or III colon cancer [62].This trial demon‐ strated an increase in disease-free survival at 3 years from 72.9 to 78.2% (*p* = 0.002) with addition of oxaliplatin to FU/LV. Five-year disease-free survival remained significant (HR: 0.80; *p* = 0.003) and at 6 years there was an overall survival benefit for stage III patients (68.3% versus 72.9%) [64].Toxicities were comparable between the two groups, with the exception that oxaliplatin is associated with a much higher rate of paresthesia: 12.4% versus 0.2% grade 3 (serious) toxicity. This neurotoxicity persisted at a grade 3 level in 1.1% of treated patients at

Many advances have occurred recently in the treatment of metastatic CRC. Active agents, in addition to the original 5FU, that have been approved by the Food & Drug Administration (FDA) for mCRC include irinotecan, capecitabine, oxaliplatin, bevacizumab, cetuximab, and panitumumab. The goals of systemic therapy of mCRC include palliation of symptoms, prolongation of life, and in selected cases of liver-only metastases, tumor regression to facilitate surgical resection of these metastases. The median survival of a patient with mCRC has improved during the last decade from less than 1 year, with only 5FU-based therapy, to ~2

5FU, often modified by LV, has been clinically used for half a century as a standard agent for mCRC [64]. This was the only available agent until 1996, when irinotecan was approved. Over the last decade, chemotherapies such as oxaliplatin and capecitabine and targeted agents such as bevacizumab, cetuximab, and panitumumab have been approved. 5FU blocks the enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Leucovorin (LV), also known as folinic acid, enhances the antineoplastic effects of 5FU. Both LV (FOL = folinic acid) and 5FU (F = fluorouracil) can be combined with irinotecan (IRI) or oxaliplatin (OX) with the treatment acronyms FOLFIRI or FOLFOX, respectively. These alternative treatments consist of admin‐ istration of a bolus of 5FU, LV, and either oxaliplatin or irinotecan. The patient is then sent home with a 2-day infusion of low-dose 5FU, administered by a small, lightweight, portable pump, usually worn on a belt or shoulder strap, infused through a centrally placed catheter. The patient or health care provider can simply disconnect the catheter after the 2-day infusion. Capecitabine is an oral fluoropyrimidine with a similar mechanism of action and similar

initiation of treatment for metastatic disease.

**8. Postoperative management**

one-year of follow-up.

efficacy as 5FU.

years, with multiagent systemic therapy.

## **6. Chemotherapy in elderly**