*5.1. Surgery*

Colorectal cancers may be cured by surgery (hemicolectomy) [2], but only if the entire tumor is localized and no cells have spread to other sites (adenocarcinoma in situ) [22,32]. Moreover, in most of the cases, complementary therapies (adjuvants) are needed before or after surgery and vary from traditional to novel. Traditional chemotherapies are based on 5-FU, which inhibits cancer cell division. Nobody doubts that traditional adjuvant treatments have improved the prognosis of patients; however, they are not beneficial for all cases. For instance, not all women with breast cancer derive benefit from 5-FU-based adjuvant chemotherapy. Many older women (age > 70) with hormone receptor-positive early stage breast cancer treated with adjuvant chemotherapy will not accrue a survival advantage [33]. For CRC, it was demonstrated that extra cycles of traditional chemotherapy, either before or after chemoradiotherapy, have been shown not to improve survival compared with chemoradiotherapy alone. An argumen<sup>t</sup> for less chemotherapy is also presented by results from trials investigating neoadjuvant or preoperative therapy in esophageal and gastric cancers. In randomized trials, which enrolled patients with esophageal and gastro-esophageal junction adenocarcinoma, no survival benefit with four cycles of the ECX regimen (epirubicin, cisplatin, and capecitabine) were reported beyond that achieved with two cycles of fluorouracil and cisplatin. These results support the use of a shorter duration of preoperative chemotherapy [34].

5-FU can cause local and systematic toxicity (DNA damage) to healthy cells, generating undesired side e ffects, and favor the mutation of them to malignant cells. These problems can be overcome by using novel approaches such as targeting specific cancer-relevant proteins (such as oncogenic tyrosine kinases), immunotherapy, and reactive oxygen species (ROS)-modulated therapies, which are more specific in generating cancer cell apoptosis and reducing the side e ffects associated with traditional chemotherapy [35,36].
