Colorectal cancer (CRC) is an uncontrollable growth occurring in the colon and rectum¹ that starts in the innermost mucosal layer, grows outward (polyp), and spreads through lymphatics. The polyps, which are sessile, serrated, traditional serrated polyps, polyps with a diameter greater than 1 cm and more than 3 in number, and polyps with a dysplastic nature have the highest risk for CRC. Adenocarcinoma, the most common type of CRC, arises from glandular epithelial cells. Other less common types are carcinoid tumors from hormone-making cells, gastro-intestinal stromal tumors from intestinal cells of Cajal, lymphomas from the immune cells of the digestive tract, and sarcomas that start in blood vessels and connective tissues of the walls of the colon and rectum². Among CRCs, colon cancer is predominant (59.5% of new cases and 61.9% of deaths)³. Incident cases (45.94%) and deaths (49%) are more remarkable in areas with higher income levels⁴. Despite various methods of CRC prevention openly available in scientific literature and the availability of recommendations given by international organizations, the emerging incidence of early-onset CRC cases is posing a public health challenge, as the global incidence of CRC cases is predicted to reach 3.2 million in 2040⁵. This disparity results from various barriers to CRC prevention, among which the most important is a lack of awareness among the general population and a lack of perception towards the importance of prevention among health care providers. To address this gap, the present review focuses on creating awareness by providing a holistic insight into the prevention of CRC.

Search Strategy: We systematically searched PubMed, Web of Science, Elsevier, Wiley Online Library, and Google Scholar databases for articles using keywords and included studies following PRISMA guidelines (Figure 1). 

Study Selection: Inclusion and exclusion criteria: Articles published in peer-reviewed journals in the past 7 years were included. Criteria for inclusion included (i) articles that contained preventive methods for colorectal cancer; (ii) studies that were published in the past 7 years to include recent evidence; and (iii) articles that were available in full text. Criteria for exclusion included (i) studies conducted on cancers other than CRC. (ii) studies conducted on patients already diagnosed with cancer. (iii) studies available in languages other than English. Quality assessment: The quality of the studies was methodologically examined for adequate sample size, selection bias, and standardization of reporting guidelines. Bias was assessed for observational studies done using the New Castle Ottawa scale and for RCTs using the Jadard scoring system. Scores for relevant studies indicated low risk of bias (scores 6 to 8). The studies selected were reviewed by rest of the investigators for eligibility and quality assessment. The extraction of data pertaining to authors, study design, and outcomes was done and synthesized in the form of narrative synthesis, which was later clustered and presented in tabular forms. (Table 1). The extraction of findings from the studies was focused on (i) screening, (ii) early detection, (iii) dietary modification, (iv) lifestyle modification, (v) risk factor management, (v)chemoprevention, and (vi) immunoprevention.

(Figure 1)

Some currently available risk prediction models include APCS (Asia Pacific Colorectal Cancer Screening score) questionnaires⁸ and PRA (Polygenic Risk Assessment) genetic tests⁹. Risk prediction can increase screening uptake, encourage knowledge and lifestyle changes due to an increase in risk perception, and reduce the burden of screening. However, there are challenges such as population variability preventing the development of "one for all model," communication of risk output individually to large populations, and differences in location, socio-economic, cultural, and resource availability of the population. Addressing these challenges is crucial for effective cancer prevention and management.

Non-invasive biomarkers provide convenient screening, aid in increasing screening uptake, and reduce the probability of over screening by invasive methods like colonoscopy.

Biomarkers for CRC:^14,15

Oral Dysbiosis In CRC:^16,17,18

Different studies identified various bacteria associated with CRC, including Fusobacteria, Bacteroidetes, Prevotella, Veillonella, and Treponema denticola, present in individuals with poor oral health. They may play a crucial role in the development, progression, and potential diagnosis of CRC. In PPI (Proton Pump Inhibitor) users, patients with achlorhydria, IBD (Inflammatory Bowel Disease), and the gastric acidic barrier get weakened, leading to the survival of harmful oral-ingested bacteria. They colonize the intestinal tract and may contribute to tumorigenesis by (i) activating inflammatory and NF-?B cascade pathways and (ii) creating an immunosuppressive microenvironment. Fusobacteium nucleatum is most significantly associated with CRC. Actinomyces odontolyticus increased only at an early stage of CRC, while Parvimonas micra, Peptostreptococcus stomatis, Solobacterium moorei, Gemella morbillorum, and Fusobacterium nucleatum increased at both early and late stages [Table 4]. Some of the new diagnostic techniques for identifying oral dysbiosis include PCR, RT-PCR (Reverse Transcriptase-Polymerized Chain Reaction), metagenomics, gel-based electrophoresis, etc.

Early-Onset CRC:^19,20

Early-onset CRC differs from late-onset CRC in age of incidence (<50 years old), location of common occurrence (left distal colon and rectum in 55-80% of people), and frequency of oncogenic mutations. It is poorly differentiated histologically, with a distinct DNA methylation profile. Its polygenic risk score is higher and has worse survival.                                                                                        

Risk factors for early-onset CRC:¹⁹ (Figure 2) Family history and hereditary occurrence are 30% common with familial adenomatosis polyposis (FAP), Lynch syndrome (5%), and other mutations (12-16%). Diabetes can increase the risk of cancer in the colon (38%) and rectum (20%). Chronic inflammatory conditions like IBD (pancolitis) in the 4th decade (30%), and celiac disease are common risk factors. Diet, alcohol, smoking, lack of physical activity, obesity in childhood, and calorie restriction in children are other risk factors. Dietary aspects like high intake of processed and red meat (22%), cooking methods like deep frying which releases glycation end products that are pro-carcinogenic, and usage of food additives like nitrates in processed meat, over-use of synthetic dyes, monosodium glutamate, titanium dioxide (E171) (a food whitening agent) (>1% of food weight), and high fructose corn syrup increase the risk of EOCRC. Maternal stress during pregnancy and childhood perceived stress are also important risk factors. Gut dysbiosis due to increased numbers of Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, and Salmonella enterica causes intestinal dysbiosis, inflammation, evasion of the tumoral immune response, and activation of pro-tumoral signalling. Repeated short-term or long-term exposure to antibiotics also alters the gut microbiota, which increases the risk of EOCRC.

Management of Modifiable Risk Factors:^20,21,22

Diet Modification Recommendations to Prevent CRC:^{6,7,9,28,29,30,31}: Table 6 highlights the dietary recommendations for prevention of CRC. 

Natural Compounds:^43,44

Natural compounds that are found to have protective effects through anti-oxidant, anti-inflammatory, neuroprotective and anticancer actions include: 

1. Curcumin (polyphenol) (turmeric)

2. Resveratrol (stilbenes) (red grapes)

3. EGCG (epigallocatechin) (green tea)

4. Fisetin (hydroxy flavone) (strawberries, apples, onions, and cucumbers)

5. Genistein (isoflavone) in combination with chemotherapeutic agents (ginseng root)

6. Apple polysaccharides (apples)

7. Mushroom glucans (edible mushrooms)

8. Paris saponin 7 (ginseng plant)

9. Soy saponins (soy beans)

10. Soy isoflavones were shown to have significant protective effect in Asian population.⁴⁵

11. Leaf decoctions: 

A.muricata / Graviola / Soursop: The leaf extracts of Graviola contains phytochemicals Annomuricin A, B, C, E & Muricapentocin which is found to have anticancer effects on colon cancer cell-lines in vitro.⁴⁶ Parijaata/Nyctanthes arbor-tristis for antioxidant & antibacterial properties⁴⁷, guava/Psidium guajava L  for antioxidant, antimicrobial actions⁴⁸ showed anti-cancer effects on cancer cell lines. 

12. Terminalia chebula Retz/Hartaki/Kadukkai/Manahei is mild laxative, anti-inflammatory, remedy for hemorrhoids. Hydroalcoholic extracts from this was found to have significant cytotoxicity against HCT-116 colon cancer cells indicating promising anti-cancer activity.⁴⁹

Abnormal frequency of bowel movements is not associated with colon cancer, but it suggests an increased risk for rectal cancer.⁵⁰

At least 30 minutes of physical activity is necessary to maintain health of gastrointestinal tract.

A low certainty of evidence supports a significant effect against CRC incidence with long-term intake of non-steroidal anti-inflammatory drugs (NSAIDS) in low dose. Moderate certainty of evidence supports that aspirin in low doses has protective action as a chemo preventive agent. Magnesium had a significant protective effect when at least 225 mg/day was consumed, supported by low certainty of evidence. Very low certainty of evidence exists to prove the protective effect of vitamin D alone or in combination with calcium. The evidence for Folic Acid, Vitamins E, C, Multivitamins, Beta Carotene, and Selenium as protective agents is very weak. An analysis of micronutrient levels is essential before prescribing the micronutrient supplement.

Immunoprevention is the concept of preventing cancer development using agents that enhance the immune system to survey and destroy tumor cells. The development of tumors is fostered by evading immune cells and creating an immune-suppressive environment for the immune response. Vaccines may help overcome this immunosuppressive environment conducive to cancer growth. The development of such vaccines will be based on tumor-associated antigens and tumor-specific antigens. Multivalent vaccines, complemented with immune adjuvants, help eliminate a larger number of tumor cells. So far, human trials of CRC vaccines have failed due to the administration of vaccines during advanced stages of carcinogenesis because of patients’ inability to mount an effective immune response. But in vivo clinical trials in mouse models well before tumor incidence (presence of genetic risk, polyps) reduced the cancer risk by 100%. Also, the vaccinated mice with genetic susceptibility gave birth to offspring who were free of polyps (antibody transferred through breast feeding). Human trials in a preventive setting need to be conducted to accurately assess the efficacy of CRC vaccines. Recently, the first randomized controlled trial tested the MUC1 vaccine against CRC in a prevention setting, and results are awaited.

The present review, including 32 studies, provides insights on holistic preventive strategies for colorectal cancer. Risk identification among the general population involves developing prediction models relevant to a specific population, followed by risk stratification into high, medium, and low-risk populations^6,7 based on which specific screening strategy¹⁰ would be employed, as in the low-risk population, FIT, non-invasive biomarkers, in the high-risk population, invasive biomarkers, FOBT, FS¹¹, and then colonoscopy¹⁰ for diagnostic conformation. Among early detection biomarkers, stool-based ones¹⁴ are non-invasive and effective. In cases of early-onset CRC, fecal calprotectin, the Cologuard test, the EpiproColon test, and miRNA biomarkers were found to be effective. The recommendation of a healthy diet replacing unhealthy diet components is given elaborately in the present review. Including complex carbohydrates²³ like red, black, and brown rice, positive millets²⁴, plant-based unpolished whole proteins, and sprouted grains can increase fiber intake and provide good glycemic control. For meat intake, avoiding red (beef, pork, lamb, liver, meatballs) and processed (bacon, hot dog, sausage, etc.) meats³⁵, including white meats like chicken, turkey, duck, rabbit, and fish prepared by boiling, steaming, pressure-cooking, and stir-frying methods³⁶ once a week, while deep-frying, barbecued, smoked, and pickled meats should be avoided. For cooking, hydrogenated vegetable oils can be replaced by natural, unfiltered sesame oil and olive oils. Low-fat dairy products like A2 pasteurized milk²⁷, yogurt, natural dairy cheese, and buttermilk³⁰ are found to be protective. Intake of fresh fruits like apples, papaya, citrus fruits, pomegranates, amla, berries, watermelon, and kiwi³⁹ should be regular and frequent. Increased intake of non-starchy, native, and water-rich vegetables, including cruciferous vegetables⁴⁰, has been found to be protective. Regular intake of vegetable juices³⁸ is recommended for people with healthy GIT. Other dietary factors found to be protective include good-quality seeds like pumpkin, sunflower, hemp, chia, sesame, and flax seeds (avoid in cases of allergy), natural probiotic foods like yogurt, fermented rice, and sauerkraut, a cup per day of decaffeinated coffee⁴¹, and rolled or steel-cut oats with fresh fruits²⁶. The review recommends avoiding intake of alcohol, tobacco, soft drinks, canned food, processed and packaged food items, food additives and preservatives, fast foods, nuts like peanuts, which are highly prone to aflatoxin³⁷ presence, and wheat and wheat products in cases of gluten sensitivity. At least 30 minutes of physical activity at least three times per week⁵¹, yoga poses like Parighasana, Ardha matsyendrasana, Salamba setu bandhasana, Ananda balasana (help with IBS), Uttanasana, Utthita Parsvakonasana, Ushtrasana, Dhanurasana, Eka Pada Rajakapotasana, Apanasana, Savasana (help with digestion and colon health), and methods of prasnayam53 like nadisuddhi and kapalbhati have also been found to be helpful for GI health. For chemoprevention⁵⁵, moderate evidence supports low-dose aspirin, and low evidence supports magnesium 225 mg/day as chemopreventive agents for patients with high-risk serrated or adenomatous polyps. New evidence also suggests precise supplementation to address the deficiency of micronutrients. The protective role of natural compounds⁴³, like curcumin, resveratrol, genistein, soursop, etc., is yet to be established in large-scale trials before being recommended as preventive agents. The most recent research on developing immuno-preventive agents⁵⁶ is going on in a promising manner. Recently, a randomized controlled trial on the MUC1 vaccine against CRC in a prevention setting was conducted, and the results are yet to be unfolded. Similar evidence was presented in an umbrella review by Sajesh K. Veettil⁵⁷, where an association was found between lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat. In another umbrella review by Jakub ´Switalski et al., FIT was found to be effective and economical to be used in large-scale population screening of CRC⁵⁸. Quercetin available in onions, elagic acid in green tea, and apples were found to be effective in preventing the recurrence of polyps⁵⁹. The strength of the study lies in exploring prevention strategies in a holistic manner relevant to present-day scenarios applicable to the general population and providing education regarding this at a level understandable to the general population from all streams. The limitation of the study is the smaller number of studies included in multiple aspects of prevention. Elaborate studies, considering a greater number of studies in each aspect of prevention, are needed to be conducted to develop policy recommendations for CRC prevention. Future research may focus on developing risk prediction models relevant to respective populations, developing diet and lifestyle modification methods with measurable outcomes, and testing the performance of cost-effective bio-markers for risk identification in resource limited settings. In conclusion, the study suggested an integrated holistic approach for risk identification and stratification, improving screening uptake with non-invasive biomarkers,  to motivate people to take steps towards prevention. Effective interventions for diet and lifestyle modification, supplementation on a deficiency basis, proper use of phytochemicals for risk factor modification, along with correction of oral dysbiosis⁶⁰, and chemoprevention in high-risk populations, constitute a holistic approach for risk reduction and early intervention to prevent the progression to colorectal carcinoma.