*Targeted Photodynamic Therapy as Potential Treatment Modality for the Eradication of Colon… DOI: http://dx.doi.org/10.5772/intechopen.84760*

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 appear promising [15].

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

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 with better outcomes [18, 19].

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 survival [23].

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

*Multidisciplinary Approach for Colorectal Cancer*

deskbound seated occupations [5].

diagnosed [9].

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

bined with surgery to treat the disease [12].

blood or lymph vessels and so spread to other parts of the body forming secondary cancer metastasizes [1]. Adenocarcinomas polyps originate within intestinal cells that produce mucus to lubricate the inside of either the colon or rectum and this is the most common form of CRC, with approximately 96% of cases, being diagnosed annually [3]. Other less common types of CRC tumors that can originate in colorectal tissues or cells include: lymphomas, sarcomas, gastrointestinal carcinoid or stromal tumors [3]. The risk of developing of CRC is often attributed to either a variety of environmental factors or genetic predispositions. Approximately 25% of diagnosed CRC cases can be attributed to inherited syndromes, while the remaining 75% cases are due to external environmental contributing factors [4, 5]. The most common CRC inherited syndromes include familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancers (HNPCC) [4]. While common triggering environmental factors include: diets which are low in fiber and high in fat and red meat, low physical activity, obesity, heavy alcohol consumption, cigarette smoking and

Even though numerous advances have been made in relation to early diagnosis and treatment of CRC, tumor reoccurrence and metastatic spread are two critical factors which affect the survival rate of patients [6]. Dependent on the stage at which they have been diagnosed, approximately 25% of patients with CRC at time of diagnosis have metastases (due to late detection) and 50% of patients diagnosed with CRC will develop metastases, either at presentation or during follow-up [7, 8].

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

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 com-

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

**42**

expansion and invasiveness, the metastatic cellular potential of CRC to spread is high [24]. Lastly, another important factor in CRCs resistance to conventional therapies and metastasis, is the presence of cancer stem cells, since these cells have the ability to go by undetected (due to their slow growth) and so enhances CRC treatment resistance, as well as allows this type of cancer to initiate new tumor growth and so metastasize [6].

Thus, currently conventional treatments are not very successful at curing CRC and patients are at high risk of developing secondary cancers, due to the ease at which this cancer can migrate through the blood and lymphatic systems to other parts of the body, such as the liver, lungs and digestive system [8, 25]. Thus, there is dire need to investigate other alternative therapies for the treatment of CRC.
