Introduction

 Colorectal cancer is among the leading cause of cancer related death in the western world which is also the third most common cancer diagnosed in both men and women in the United States [2]. The American Cancer Society's most recent estimate indicates a total of 103,170 new cases of colorectal cancer in the United States for 2012 (http:// www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key) [3]. The risk factors for developing colon cancer include age, personal history, family history, racial and ethnic background. Life style and diet related factors also contribute to the development of colon cancer as well [4]. Mostly colorectal cancers occur due to lifestyle and increasing age with only a minority of cases associated with underlying genetic disorders. It typically starts in the lining of the bowel and if left untreated, can grow into the muscle layers underneath, and then through the bowel wall. There are environmental (chemicals, infectious agents, radiation) and genetic (mutations, immune system and hormone dysfunction) factors that can interact in a variety of ways to potentiate carcinogenesis [5, 6]. Activated oncogenes can cause hyperplasia and protect the cancerous cell against apoptosis while tumor suppressor genes can become inactivated in cancer cells, resulting in dysfunctional cellular processes (DNA replication, cell cycle processes, dysplasia, and immune cell interaction) [5, 6]. The goal of cancer therapy is to completely eradicate the cancer without damaging the rest part of the body, and the choice of therapy depends on the state of the patient, location, and stage of the cancer. There are many scientific and alternative methods of colon cancer treatment. 

Treatment trials show their higher or lower effectiveness based on at what stage the cancer was detected in the patients and the age of the patients where outcomes for the elderly have been worse compared to younger patients. Nonetheless, standard-of-care treatment for the elderly patients result in equivalent long-term outcomes to those observed in the younger population; and available data support the use of aggressive surgery and adjuvant therapies in well-selected patients [7]. In patients all the methods should not be tried at once because it may be ineffective and sometimes even harmful. Usually cancer specialists offer timeproven standard methods of cancer treatment and in the case of favorable outcome the patient needs only symptom control during the whole life to prevent metastases or return of the disease.

 The choice of method of colon cancer treatment is very important because each tumor responds to different methods differentially. It is selected according to many factors including tumor type, stage of the disease, patient's age, patient's level of health, and his attitude towards life. Today alternative medicine offers many methods that help a number of people. Scientists also make their researches and present more and more new methods that have all chances to become a panacea. However, specific methods for colon cancer treatment are very limited. In addition, the pathogenesis of colon cancer which involves a combination of many risk factors is poorly understood, and research efforts in these areas are ongoing. 2. Causes, stages, and conventional treatment approaches for colon cancer 2.1 Colon cancer: causes and etiology The majorities of colorectal cancer cases are sporadic with no obvious heritable tendency or family history. Somatic mutation of the adenomatous polyposis coli (APC) is a distinctive marker of approximately 80-85% of the patients with nonhereditary sporadic adenomatous polyposis (SAP). Mutation of the APC gene is thought to be an early step in the development of colorectal cancer [8]. Causes of the APC mutation are not known but may involve diets, smoking, environmental hazards, viruses, and life styles of different individuals [9].

 The accumulation of defective end product of APC gene contributes to subsequent activation of Wnt/β-catenin signaling pathway leading to the transcriptional activation of certain target genes such as c-myc and cyclin D. Following initial genetic change, the process of carcinogenesis involves a series of genetic mutations, phenotypic and pathologic changes such as the loss of p53 tumor suppressor gene toward invasive colorectal carcinoma [10]. A minor group of colon cancer patients (8 to 15% of all cases) is associated Mishra et al. Page 2 Crit Rev Oncol Hematol. Author manuscript; available in PMC 2014 June 01. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript with heritable tendency. About 1-2% of these cases develop familial adenomatous polyposis (FAP). Genetic evidence shows that patients with FAP inherit a germ line mutation of the APC gene and the lifetime incidence of colorectal cancer is almost 100%. They are the most high risk group and if untreated, most of the subjects will eventually develop colorectal cancer in their lifetime [11]. The progress from adenoma to carcinoma pathway in FAP is very similar to that of nonhereditary sporadic colon cancer patients. 

A second group of heritable colorectal cancer patients consists of those who are diagnosed with hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndrome). The genetic defects in HNPCC patients are less specific but are known to be associated with the mutations of a number of DNA mismatch repair genes including MLH1, MSH2, MSH6, PMS1 and PMS2 genes [8]. Although HNPCC cases are larger in size (5% of all hereditary cases), the penetrance of HNPCC is significantly much less than that of FAP [12] and patients with HNPCC usually have a higher 5-year survival rate. A much larger third group of “heritable” colorectal cancer is those with a family history of colorectal cancer but is distinct genetically from either FAP or HNPCC cases. The genetic mutations associated with this group of patients appear to be unique involving different sets of genes. The significant insight obtained from these groups of patients with inherited colorectal cancer has become very important in our understanding of sporadic disease. Specifically, the same genetic alterations leading to hereditary colorectal cancer have also been implicated in the pathogenesis of sporadic non-hereditary colon cancer, and these include APC (Wnt/βcatenin pathway), TGF-β, Notch and hedgehog (Hh) signaling pathways [8, 13]. In addition, other signaling pathways such as epidermal growth factor receptor (EGFR)[14], the ras/raf/ MAPK cascade [15], and activation of Akt kinase and STAT3 transcription factors have been implicated in the oncogenesis of colorectal cancer [16-18]. 

2.2 Different stages of colon cancer and the percentage of patient survival Colorectal cancer is classified into four distinct stages along with a fifth stage called “recurring”. According to American Joint Committee on Cancer, each stage has different treatment options with a five-year survival rates (AJCC 5th edition; http:// www.cancerstaging.org). Stage 0; it is the very early stage of colon cancer where polyps are formed in the mucosal lining of the colon. During colonoscopy, the polyps are eradicated fully by polypectomy. This prevents the advanced stages of colon cancer to occur. Stage I; at this stage polyp develops into a tumor and invades the inner-lining of the mucosa. Usually surgery is the main option for treating the colon cancer at this stage where the cancerous portion of the tissues is separated from the non-cancerous portion. Survival rate is around 95% if colon cancer is detected at this stage. Stage II; it is characterized by whether the cancer has spread beyond colon but not to the lymph nodes through metastasis. This stage is subcategorized into Stage IIA, Stage IIB, and Stage IIC depending on the spreading of cancer to the muscular layer, or outermost layer of the colon or beyond colon. Resection surgery is the only option to threat this stage of colon cancer and the survivalist of the patients at this stage is 85%. Stage III; this stage of colon cancer is diagnosed with cancer has already spread all the wall of the colon and also to the surrounding lymph nodes and the survival rate is around 30-60%. 

This stage of cancer is subcategorized into stage III a, b and c depending on the spreading of the cancer to the inner , middle and outer layer of colon and the surrounding lymph nodes. Along with the surgery, chemotherapy and the other medical therapy is required to treat this cancer. Stage IV; at this stage the cancer has speeded to the other part / organ of the body like liver, ovary, testis, intestines. Survival rate is only 3%. Surgical resection, chemotherapy, radiation therapy and surgical removal of the portion of the other body parts with cancer are opted to treat at this stage of colon cancer. Colonoscopy is recommended for all 50 years or older in their routine checks [19]. Mishra et al. Page 3 Crit Rev Oncol Hematol. Author manuscript; available in PMC 2014 June 01. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 2.3 Conventional methods of treating colon cancer There are several conventional methods for colon cancer treatments that include (a) Polypectomy & Surgery, (b) Radiation therapy, (c) Chemotherapy, and (d) Targeted therapy. a. Polypectomy & Surgery: The main surgical methods include radiation therapy and medication treatment. Surgical removal of the pre-cancerous/cancerous tumor has the potential for full recovery of the patient and can be an effective option for small, localized cancerous growths. Surgical removal of the polyps during colonoscopy is called as polypectomy. While recurrence is possible, surgery is often the only way to treat solid tumors that are resistant to radiation and chemotherapy or is inoperable at the time of diagnosis (e.g. pancreatic carcinoma).

 In addition, for older patients, comprehensive geriatric assessment (CGA) can identify frail patients with significantly increased risk of severe post-surgical complications [20]. b. Radiation therapy: Radiotherapy is the use of ionizing radiation to control the proliferation of malignant cells, and can be used to treat most common cancer types. Because radiation poses a risk to normal tissue, including the formation of radiation-induced cancers, shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose at the cancer site than in the normal tissue. Apart from surgery, other techniques have also been used particularly for oligometastasis. These include selective internal radiotherapy (SIRT), trans-arterial chemoembolisation (TACE), and radiofrequency ablation (RA). RA has played an important role in managing localized disease but data from reports have documented fairly high local recurrence-rate. Newer techniques developed may likely improve the local recurrence rate and could ultimately shift the balance away from surgical resection [21]. c. Chemotherapy: This is also the main method that is implemented in review of cancer treatment. It includes medication-intake such as an alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics, enzymes, hormones and modifiers of biological response that destroy malignant cells, suppress tumor growth or its cells division.

 Unfortunately, there is no medication that can destroy only the malignant cells without damaging the normal tissues and sometimes their side effects are dangerous. The treatment of metastatic cancer mainly relies on chemotherapy, the method or process of administering a pharmaceutical compound to kill tumor cells by direct cytotoxicity leading to tumor regression. These drugs interfere with cell division pathways including DNA replication and chromosomal separation, and are not specific to cancer cells. Targeting all rapidly dividing cells in the body, only a small portion of the drug reaches the target tissue. This poses a risk of harming healthy tissue, especially those tissues that have a high replacement rate (e.g., intestinal lining and immune cells), though these cells usually repair themselves after discontinuation of drug therapy. d. Targeted therapy: Targeted drug delivery systems seek to concentrate anti-cancer agents at the cancer tissue, while reducing the relative concentration of the medication in the proximal tissue. Polymeric micelles increase the accumulation of drugs in tumor tissues utilizing the enhanced permeability and retention effect (EPR-effect) [22].

 A variety of drugs can be incorporated into the inner core by chemical conjugation or physical entrapment, and the diameter of the micelles can be manipulated to ensure that the micelles do not pass through normal vessel walls. Mishra et al. Page 4 Crit Rev Oncol Hematol. Author manuscript; available in PMC 2014 June 01. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 3. Recent advances in treatment methods for colon cancer In combination with the conventional methods of treatment many a time current treatments also include targeted therapies predominantly for advance stages of colorectal cancer. In addition to the above strategies, some additional approaches are listed; 3.1 Immunotherapy Immunotherapy is based on the fact that immune system can help fight against cancer. People with weakened immune systems are more likely to get certain cancers. In other cases, people with normal immune systems still develop cancer where immune system fail to recognize the cancer cells as foreign or the cancer cells do not express their antigens which are different enough from those of normal cells. Sometimes the immune system does recognize the cancer cells, but the responses are not strong enough to induce apoptosis in these cells. Cancer cells themselves may also secret immunosuppressant that may keep the immune system in check. To overcome these, researchers have designed ways to help the immune system recognize cancer cells and strengthen its response so that it can destroy the cancer cells.