**2. Resistance of CRC to conventional treatments**

The most common conventional treatments for CRC include surgical resection, chemotherapy or radiation therapy [9]. These treatments are either used in combination or alone depending on the stage at which the disease has been detected and diagnosed [9].

In early stages (0 to I) of CRC diagnosis, the most common treatment practice is surgical resection of the CRC polyps, without any further need for treatment [10]. In stages II to III of CRC detection, surgical resection with lymph node dissection to examine for presence of cancer cell spread, is standard practice [11]. Patients with stage IV CRC disease often require chemotherapy and/or radiation therapy combined with surgery to treat the disease [12].

Typical standard CRC chemotherapy treatment regimens include; FOLFOX: leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (Eloxatin), FOLFIRI: leucovorin, 5-FU, and irinotecan (Camptosar), CAPEOX or CAPOX: capecitabine (Xeloda) and oxaliplatin, FOLFOXIRI: leucovorin, 5-FU, oxaliplatin, and irinotecan, one of the previous combinations, plus either a drug that targets VEGF, (bevacizumab [Avastin], ziv-aflibercept [Zaltrap], or ramucirumab [Cyramza]), or a drug that targets EGFR (cetuximab [Erbitux] or panitumumab [Vectibix]) or 5-FU and leucovorin, with or without a targeted drug, Capecitabine, with or without a targeted drug, Irinotecan, with or without a targeted drug, Cetuximab alone, Panitumumab alone, Regorafenib (Stivarga) alone, Trifluridine and tipiracil (Lonsurf) [13].

Thus, 5-FU-based chemotherapy remains the mainstay of therapy for patients with CRC, however in recent year's chemotherapy drugs such as oxaliplatin, irinotecan and capecitabine have been developed and generally conventional chemotherapy treatment for advanced CRC combines 5-FU and leucovorin with oxaliplatin or irinotecan [14]. The greatest strides over recent years in chemotherapy treatments have been combining these drugs with monoclonal antibodies such as Bevacizumab and Cetuximab in order to target vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) which are

**43**

survival [23].

*Targeted Photodynamic Therapy as Potential Treatment Modality for the Eradication of Colon…*

respectively overexpressed in CRC cells [14, 15]. Angiogenesis, plays an important role in CRC tumor development and metastasis, is partly mediated by vascular endothelial growth factor (VEGF), thus by combining chemotherapeutic drugs with Bevacizumab monoclonal antibodies, VEGF overexpressed receptors can be targeted to enhance drug uptake and so improve treatment [14, 15]. Likewise, since EGFR plays and important role in tumorigenesis, it is often found to be overexpressed in a high percentage of patients with late-stage colorectal cancer and by combining chemotherapeutic drugs with Cetuximab monoclonal antibodies, chemotherapeutic drug targeting and uptake can be promoted [14, 15]. Moreover, by utilizing chemotherapy monoclonal antibody treatments for CRC, resistance to EGFR inhibitors may be partially mediated, by activating VEGF-dependent signaling, and so drug delivery strategies that combine anti-EGFR and anti-VEGF agents

Overall, the choice of these various chemotherapy treatment regimens for CRC depends on various factors such as previous treatments received, if the regime is no longer working and the patients overall health [13]. For some patients with certain genetic marker changes in their CRC cells another treatment option after chemo-

Nevertheless, despite the improved CRC response rates with these various advanced strategies, the overall survival rate for metastatic CRC remains only slightly over 12% [18]. One of the major causes for this poor survival rate is due to the fact that nearly half of all metastatic CRC patients are resistant to 5-FU-based chemotherapies, which demises their overall treatment and recovery [14]. The reason for the development of chemotherapeutic drug resistance in CRC cells is that they have the ability to enhance DNA repair mechanisms, deregulate signaling pathways, as well as increase drug metabolism [16]. Generally, 90% CRC patients report drug resistance to chemotherapies, resulting in poor treatment due to oncogene mutations, which deregulate signaling pathways [16]. This deregulation of signaling pathways, results in increased aerobic glycolysis, fatty acid synthesis, and glutamine metabolism causing a decrease in chemotherapeutic drug induced apoptosis [17]. Moreover, drug efflux transporter proteins are often found to be overexpressed in drug-resistant CRC cells, which decrease the successful uptake of chemotherapeutic drugs in cancer cells [6, 18]. Thus, if metastases has occurred, chemotherapy will probably not be curative and so only help in improving prognosis via tumor shrinkage [19]. Thus continuous research is required into CRC in order to unravel these multiple drug resistance mechanisms and so develop improved treatment regimens

Radiation therapy is usually utilized pre-CRC surgical resection in stages II to IV, depending on the degree of metastasis, to shrink un-respectable tumors or to try and help control the cancer that has spread to other parts of the body [11, 20]. However, radiation therapy has numerous unwanted side effects in patients receiving such treatments, which include: nausea, stool leakage, fatigue, sexual problems, skin irritation, rectal irritation and diarrhea [21]. Moreover, some CRC patients have noted resistance to radiation therapy, whereby in response to radiation DNA damage, Ataxia Telangiectasia Mutated (ATM) genes and anti-apoptotic factors phosphatases of regenerating liver-3 (PRL-3) become activated in cancer cells and so begin to regulate cancer cell pro-survival and resistance [22]. Additionally, these genes have been noted to be overexpressed in CRC patients whom have previously received radiation therapy and their cancer has reoccurred, shortening their

Moreover, in addition to resistance to conventional treatments, the metastasis spread of CRC is of major concern. Primary CRC tumors are highly prone to TGF-β, PIK3CA, and TP53 gene mutations and since these genes are responsible for clonal

therapy to be considered is immunotherapy with pembrolizumab [13].

*DOI: http://dx.doi.org/10.5772/intechopen.84760*

appear promising [15].

with better outcomes [18, 19].
