*3.2.1 Levamisole*

Levamisole is an anti-helminthic drug that is used in veterinary medicine. It was found to have effects on phagocytosis and chemotactic responses of neutrophils as well as on stimulation of lymphocyte proliferation, differentiation and cytotoxicity suggesting an immunomodulatory effect. Preclinical studies suggested an antimetastatic effect in tumor xenograft models.

**165**

*Adjuvant Therapies in Colon Cancer*

*3.2.2 Leucovorin (folinic acid)*

it can cause rash or itch.

low dose leucovorin [7, 8].

**3.3 Stage I colon cancer**

**3.4 Stage II colon cancer**

95%, and adjuvant therapy is not indicated [11].

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

The initial Leicester trial randomized patients after curative surgery either to observation, 5FU, or 5FU plus levamisole. 5FU was administered intravenously for # days following surgery, and then orally once weekly for 6 months; levamisole was administered for only three postoperative days. After 5 years of follow-up, the survival of patients randomized to 5FU plus levamisole was significantly prolonged

Levamisole alone, given intermittently for 1 year, did not produce a survival benefit in an EORTC trial with Dukes C colon cancer patients [4]. In the NCCTG

Two trials the US Intergroup 0035 and the Netherlands Adjuvant Colorectal Cancer Project (NACCP) study both found a significant benefit of 5FU and levamisole in the adjuvant therapy of resected colon cancer compared to observation [6]. A subsequent meta-analysis of these two studies found that after adjustment for the total planned 5FU dose the effect of levamisole became non-significant. Subsequent trials disproved the benefit of levamisole in adjuvant therapy of colon cancer [7, 8].

Leucovorin is an active metabolite of folic acid which works by enhancing enzymatic binding of 5FU onto thymidylate synthetase to prolong the half-life of 5 U and therefore potentiates the 5FU. It is not a cytotoxic agent on its own. Rarely,

Clinical trials compared 5FU-leucovorin regimens to 5FU-levamisole regimens and disproved the benefit of levamisole. The INT-0089 and QUASAR studies have demonstrated that there is no difference in outcome between the use of high dose or

Stage 1 colon cancer is often an incidental finding in those patients undergoing polypectomy. Therefore, pedunculated polyps should be resected with excision of the stalk down to the base. When stage 1 colon cancer is found in a polyp that was completely excised with clear margin of more than 2 mm, further surgical excision may not be required, provided there are no high risk features such as lymphovascular invasion, poor cell differentiation, and malignant invasion beyond stalk. Such patients with high risk features should undergo further excision like segmental resection for complete staging. Sessile polyps with invasive cancers also can be managed with segmental colon resection unless they can be removed in one piece [9]. An estimated 5% of resected polyps and 20% of unresectable polyps contain invasive cancer [10]. Five-year survival rate for stage 1 colon cancer is more than

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

compared with 5FU alone (p = 0.02) or observation (p = 0.045).

trial levamisole was inferior to the combination with 5FU [5].

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

*Colorectal Cancer*

or those who are non-surgical candidates.

**3.1 Drugs used: 5FU, capecitabine, oxaliplatin**

**3. Adjuvant therapies**

*3.1.1 5-Fluorouracil (5-FU)*

inducing coronary artery spasm.

*3.1.2 Capecitabine*

*3.1.3 Oxaliplatin*

*3.2.1 Levamisole*

with this class of cytotoxics.

**3.2 Historic data; levamisole, folinic acid**

static effect in tumor xenograft models.

with good performance status and acceptable comorbidities. This is achieved by surgical resection of the primary tumor, anastomosis of the bowel and removal of 12 or more regional lymph nodes. The aim of oncological resection is the complete removal of the tumor and potential lymphovascular spread with a clear margin of at least 5 cm proximally and distally for colon cancer, and minimal proximal margin of 5 cm and distal of 2 cm for rectal carcinoma. Circumferential/radial margin clearance of at least 1 mm is considered optimal. Endoscopic resection involves complete tumor resection and adjacent tissue in one block. This may be acceptable for those accept vigorous close surveillance and potential need for further surgical resection

5FU is an antimetabolite drug that inhibits DNA and RNA synthesis by acting as a false substrate in purine and pyrimidine synthesis thereby interfering in the S phase of the tumor cell cycle. It is metabolized by the rate limiting enzyme dihydropyrimidine dehydrogenase. The main toxicities are related to mucosal inflammation and this presents clinically as mucositis, stomatitis and diarrhea. It can also cause nausea and myelosuppression. Rarely, it can cause cardiotoxicity presumably by

Capecitabine is an oral fluropyrimidine prodrug which is taken up inside the tumor cells and metabolized to the active 5FU product by thymidine phosphorylase. Repeated oral administration mimicks the pharmacokinetics of protracted infusional 5FU. The side effects are similar to 5FU in term of mucositis and diarrhea but hand-foot syndrome or palmar-plantar erythrodysesthesia with redness, tenderness

Oxaliplatin is a third-generation platinum drug which acts as an alkylating agent

Levamisole is an anti-helminthic drug that is used in veterinary medicine. It was found to have effects on phagocytosis and chemotactic responses of neutrophils as well as on stimulation of lymphocyte proliferation, differentiation and cytotoxicity suggesting an immunomodulatory effect. Preclinical studies suggested an antimeta-

in causing DNA damage by intrastrand crosslinks. The drug is not nephrotoxic or ototoxic but the main side effect is cold related dysesthesia which can lead to cumulative sensory neuropathy. It is moderately emetogenic and myelosuppressive. It exhibits synergy with fluoropyrimidines and so is normally used in combination

and swelling of these areas is a common toxicity experienced.

**164**

The initial Leicester trial randomized patients after curative surgery either to observation, 5FU, or 5FU plus levamisole. 5FU was administered intravenously for # days following surgery, and then orally once weekly for 6 months; levamisole was administered for only three postoperative days. After 5 years of follow-up, the survival of patients randomized to 5FU plus levamisole was significantly prolonged compared with 5FU alone (p = 0.02) or observation (p = 0.045).

Levamisole alone, given intermittently for 1 year, did not produce a survival benefit in an EORTC trial with Dukes C colon cancer patients [4]. In the NCCTG trial levamisole was inferior to the combination with 5FU [5].

Two trials the US Intergroup 0035 and the Netherlands Adjuvant Colorectal Cancer Project (NACCP) study both found a significant benefit of 5FU and levamisole in the adjuvant therapy of resected colon cancer compared to observation [6]. A subsequent meta-analysis of these two studies found that after adjustment for the total planned 5FU dose the effect of levamisole became non-significant. Subsequent trials disproved the benefit of levamisole in adjuvant therapy of colon cancer [7, 8].
