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Colorectal Cancer

Updated : May 14, 2024





Background

Colorectal cancer is currently the third most fatal cancer, and its prevalence is gradually increasing in developing countries. CRC, also known as colorectal adenocarcinoma, is a type of cancer that develops from the glandular epithelial cells of the large intestine.

Colorectal Cancer develops when specific epithelial cells acquire a succession of genetic or epigenetic changes that give them a selective advantage. These hyper-proliferative cells cause the incidence of a benign adenoma, which can then progress into cancer and spread around the body for decades.

The colon’s major job is to reabsorb water as well as leftover minerals and nutrients in the chyme. The large intestine is home to a diverse microflora that can break down any leftover starches or proteins. The gastrointestinal epithelium is organized as an axis of crypts and villi to aid absorption.

Colon stem and progenitor cells are found in the crypt’s base. These pluripotent cells are responsible for self-renewal. Progenitor cells migrate out of the crypt and up the villus as they mature into specialized epithelial cells. Paneth, goblet, and enteroendocrine cells, as well as enterocytes, are examples of differentiated epithelial cells.

After about 14 days, when these cells reach the top of the villus, they undergo apoptosis, or programmed cell death, and are shed and removed with the feces.

This process is heavily regulated by a gradient of signaling proteins, the most prevalent of which are Wnt, BMP, and TGF-B.CRCs are a fairly diverse set of illnesses caused by a wide range of mutations and mutagens. As all CRCs have the same driving mutations, developing a “catch-all” molecular therapy has been problematic.

Surgery is still the primary line of treatment in situations with early diagnosis, but it is no longer effective in advanced cases when cancer has metastasized, which is the case in approximately 25% of diagnoses.

The rapid growth of medication resistance and cancer recurrence has hindered the efficacy of neoadjuvant, cytotoxic therapy in such individuals. A better understanding of the pattern of CRC development, environmental and genetic risk factors, and the disease’s molecular evolution can help researchers and doctors prevent and cure this lethal neoplasm.

Epidemiology

Every year, CRC affects an estimated 135,439 new patients in the United States, with CRC accounting for 95,520 cases. When colon and rectum cancers are combined, it is the second-largest cause of mortality in the United States, with an estimated 50,260 fatalities.

Since 2004, the CRC incidence rate has been decreasing by 3% per year while increasing by 2% per year among screened adults below the age of 50.The previous data reflects an increase in screening practices and precancerous lesion excisions.

The incidence of CRC varies over the world, with developed countries having greater rates of incidence than developing countries. Low socioeconomic status is linked to an increased risk of CRC, as well as to inadequate risk behavior and lack of access to medical care.

The lifetime average incidence of CRC in white Americans is 5%, but it is higher in 20% more in males than women, and greater than 25% in African Americans in comparison to non-Hispanic whites.

Epidemiologic findings show a steady shift in the anatomic distribution of CRC from the left-distal colon to the right-sided or proximal end, which is once again linked to more successful left-sided screening methods.

Early identification and improved treatment modalities have contributed to a 51 percent decline in CRC mortality in the United States from 1975 to 2014. According to the National Cancer Institute’s estimation, colorectal cancer has a 65% 5-year survival rate.

Anatomy

Pathophysiology

Most colorectal cancers begin as a tumor on the colon’s or rectum’s inner lining. These growths are referred to as polyps.  Some polyps can develop into cancer over many years, however not all polyps turn cancerous.

The likelihood of a polyp developing into cancer is determined by the type of the polyp. Polyps are classified into various types. Adenomatous polyps are polyps that can turn cancerous.

Therefore, adenomas are referred to as a pre-cancerous condition. Tubular, villous, and tubulovillous adenomas are the three forms of adenomas.

Hyperplastic polyps and inflammatory polyps are more common; however, they are not precancerous in most cases. Regular colonoscopies are indicated for individuals who have hyper plastic polyps larger than 1cm.

Traditional serrated adenomas (TSA) and sessile serrated polyps (SSP) are polyps frequently treated as adenomas because their incidence presents an increased risk of colorectal cancer.

Other factors that can increase an individual’s risk of developing colorectal cancer are:

  • If a polyp measuring more than 1 cm is detected,
  • If more than three polyps are detected,
  • If the polyp has dysplasia after it has been removed.

Another precancerous condition is dysplasia. It indicates that the cells in a polyp or the lining of the colon or rectum appear abnormal, but they haven’t turned cancerous yet.

Etiology

The non-cancerous expansion of mucosal epithelial cells is frequently the first sign of CRC. Polyps are benign growths that can grow slowly for 10–20 years before turning malignant. An adenoma or polyp formed from granular cells, which create the mucus that coats the large intestine is the most prevalent type.

Although the risk of cancer increases as the polyp grows larger, only approximately 10% of all adenomas develop into invasive cancers. Adenocarcinoma is an invasive cancer that arises from such polyps and accounts for 96 percent of all CRCs.

CRCs that grow through the colon or rectum’s wall can pass through blood or lymphatic vessels, allowing them to spread to distant organs or lymph nodes. The stage of a CRC diagnosis, and consequently the prognosis, is determined by the extent of the invasion.

Polyps that have not yet entered the colon or rectum wall are classified as in situ cancers and are not reported as CRCs. Cancers that have developed into the wall but not yet spread beyond it are known as local cancers.

Regional cancers have spread to local lymph nodes or tissues, whereas distant cancers have spread to distant organs with capillary beds where they have taken root, such as the lungs or liver, via the bloodstream.

Certain dietary and lifestyle decisions can cause intestinal inflammation and alter intestinal microbiota to stimulate an immune response, both of which can help polyps grow and become cancerous.

Similarly, genetic, or spontaneous mutations in oncogenes and tumor-suppressor genes might give particular mucosal cells a selective advantage, promoting hyper-proliferation and, eventually, carcinogenesis. CRC can be prevented with lifestyle changes, early colorectal screening, and genetic testing.

Genetics

Inherited gene mutations are responsible for a very small percentage of colorectal cancers. Four of these DNA changes and their effects on the growth of cells have been studied.

  • Gardner Syndrome or Familial adenomatous polyposis is caused by mutations of the APC gene. The APC gene is a tumor suppressor gene that helps to control cell development. This “brake” on cell growth is switched off in persons with inherited mutations in the APC gene, causing hundreds of polyps to form in the colon. Over time, cancer will likely develop in one or more of these polyps.
  • Lynch syndrome or hereditary non-polyposis colon cancer is caused by mutations in genes which have the function of helping a cell repair damaged DNA. A mutation in one of the DNA repair genes, such as MLH1, MSH2, MSH6, PMS2, or EPCAM, can result in uncorrected DNA errors. Occasionally, these errors will affect growth-regulating genes, resulting in the development of cancer.
  • Peutz-Jeghers syndrome is a mutation of the STK11 gene which is a tumor suppressor gene.
    MAP or MUTYH-associated polyposis is a result of changes in the MUTYH gene, which serves the function of assisting the cell in checking or “proofreading” DNA. It fixes errors during cell division.

Prognostic Factors

According to the National Cancer Institute’s SEER database, the prognosis of the patient relies heavily on how far the cancer has spread. The 5-year survival rates for colon and rectal cancer are determined by the three stages of its spread, namely the localized, regional, and distant stages.

The figures presented in the SEER database have not taken factors such as age, overall health, and response to treatment into account, considering them might present a different prognosis. They are also exclusively applicable to the stage of the cancer during diagnosis.

The 5-year survival rates for patients diagnosed with colon cancer between 2011-2017 are:

  • Localized: 91%
  • Regional: 72%
  • Distant: 14%

The 5-year survival rates for patients diagnosed with rectal cancer between 2011-2017 are:

  • Localized: 90%
  • Regional: 73%
  • Distant: 17%

Clinical History

Physical Examination

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Surgery: 

  • Primary Tumor Resection: The initial treatment for localized colorectal cancer which involves surgery to remove tumor and nearby lymph nodes. The extent of surgery depends on the location and stage of the cancer. 
  • Lymph Node Dissection: Removal and examination of nearby lymph nodes are crucial to determine the extent of disease spread. 

Chemotherapy: 

  • Adjuvant Chemotherapy: After surgery, patients with certain stages of colorectal cancer may receive adjuvant chemotherapy to reduce the risk of recurrence. The choice of chemotherapy drugs is based on the specific characteristics of the tumor. 
  • Neoadjuvant Chemotherapy: In some cases, chemotherapy may be given before surgery (neoadjuvant) to shrink tumors and facilitate surgical removal. 

Radiation Therapy: 

  • Adjuvant Radiation: Radiation therapy may be used after surgery, particularly in rectal cancer, to reduce the risk of local recurrence. 
  • Neoadjuvant Radiation: Preoperative radiation may be employed in some cases to improve surgical outcomes, especially in rectal cancer. 

Targeted Therapies: 

  • Anti-EGFR and Anti-VEGF Therapies: Targeted drugs, such as cetuximab and bevacizumab, may be used in advanced colorectal cancer to target specific pathways involved in cancer growth. 
  • BRAF Inhibitors: For CRC with specific genetic mutations, such as BRAF V600E, targeted therapy with drugs like vemurafenib may be considered. 

Immunotherapy: 

  • Checkpoint Inhibitors: pembrolizumab and nivolumab, may be used in advanced colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

non-pharmacological treatment of Colorectal Cancer

Lifestyle modifications: 

  • Healthy Diet: Emphasize a diet rich in vegetables, whole grains, fruits, and lean proteins. Limit red and processed meats. Adequate fiber intake is associated with lower risk of colorectal cancer. 
  • Physical Activity: Engage in regular physical activity. Exercise may help to reduce the risk of colorectal cancer and can aid in overall health and well-being. 
  • Limit Alcohol Consumption: Limit alcohol intake, as excessive alcohol consumption has an increased risk of colorectal cancer. For those who drink alcohol, moderation is key. 
  • Quit Smoking: If you smoke, quitting is beneficial not only for reducing the risk of colorectal cancer but also for improving overall health. Smoking is linked to various cancers, including colorectal cancer. 
  • Regular Screening and Surveillance: Adhere to recommended screening guidelines for colorectal cancer. Regular screenings can detect precancerous polyps or early-stage cancer when it is more treatable. Follow-up surveillance is essential for those with a history of colorectal cancer. 
  • Medication Adherence: Adhere to prescribed medications and follow the recommended treatment plan. This includes postoperative medications, chemotherapy, or other treatments as advised by healthcare professionals. 
  • Emotional and Psychological Well-Being: Prioritize mental health. A cancer diagnosis & treatment can be emotionally challenging. Seek support from friends, family, or mental health professionals. 

Use of Chemotherapy in the treatment of Colorectal Cancer

Fluoropyrimidines: 

  • Fluorouracil (5-FU): A classic chemotherapy drug, 5-FU is often used in combination with other agents. It interferes with DNA and RNA synthesis, inhibiting the growth of cancer cells. 
  • Capecitabine (Xeloda): This oral prodrug is converted to 5-FU in the body. It is convenient for outpatient use and has shown efficacy in adjuvant and metastatic settings. 

Platinum-Based Chemotherapy: 

  • Oxaliplatin (Eloxatin): Oxaliplatin is a platinum-based drug that forms DNA cross-links, disrupting DNA replication and leading to cell death. It is commonly used in combination with other chemotherapy agents, such as 5-FU and leucovorin, in the treatment of colorectal cancer. 

Topoisomerase I Inhibitor: 

  • Irinotecan (Camptosar): Irinotecan is a topoisomerase I inhibitor, disrupting DNA repair mechanisms and leading to cell death. It is often used in combination with 5-FU and leucovorin in metastatic colorectal cancer. 

Combination Chemotherapy: 

  • FOLFOX: A common combination regimen that includes 5-FU, leucovorin, and oxaliplatin. FOLFOX is used in both adjuvant and metastatic settings. 
  • FOLFIRI: Another combination regimen that includes 5-FU, leucovorin, and irinotecan. FOLFIRI is often used in metastatic colorectal cancer. 
  • XELOX (Capecitabine + Oxaliplatin): This combination provides the convenience of an oral agent (capecitabine) along with oxaliplatin and is used in various settings. 

Trifluridine/Tipiracil (Lonsurf): 

  • Trifluridine/Tipiracil: Lonsurf is an oral combination therapy that includes trifluridine, a nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine. It is used in metastatic colorectal cancer resistant to standard therapies. 

Use of Targeted therapies in the treatment of Colorectal Cancer

Imiquimod Topical (Aldara and Zyclara): 

Anti-Angiogenesis Agents: 

  • Bevacizumab (Avastin): Bevacizumab is a monoclonal antibody which inhibits the vascular endothelial growth factor (VEGF), that promotes growth of blood vessels. By blocking VEGF, bevacizumab inhibits angiogenesis, the formation of new blood vessels, and may help starve the tumor of its blood supply. 
  • Ziv-aflibercept (Zaltrap): Ziv-aflibercept is another anti-angiogenic agent that targets VEGF. It acts by preventing the binding of VEGF to its receptors, thereby disrupting blood vessel formation. 
  • Ramucirumab (Cyramza): It is a monoclonal antibody that specifically targets the VEGF receptor. It inhibits the binding of VEGF to its receptor, thereby limiting angiogenesis. 

Multikinase Inhibitor: 

  • Regorafenib (Stivarga): Regorafenib is a multikinase inhibitor that targets kinases involved in tumor growth and angiogenesis. It has been approved for the treatment of metastatic colorectal cancer that has progressed after the standard therapies. 

Epidermal Growth Factor Receptor (EGFR) Inhibitors: 

  • Cetuximab (Erbitux): Cetuximab is a monoclonal antibody that targets the EGFR, a protein involved in cell growth and division. It is used to treat metastatic cancer that expresses wild-type KRAS. 
  • Panitumumab (Vectibix): Like cetuximab, panitumumab is an EGFR inhibitor used to treat metastatic colorectal cancer. It is also effective in patients with wild-type KRAS. 

Use of Immunotherapy in the treatment of Colorectal Cancer

Programmed Cell Death Protein 1 (PD-1) Inhibitors: 

  • Pembrolizumab (Keytruda): Pembrolizumab is a PD-1 inhibitor that helps the immune system to recognize and attack cancer cells. It has been approved for use in colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), which are biomarkers indicating a high likelihood of response to immunotherapy. 
  • Nivolumab (Opdivo): Nivolumab is another PD-1 inhibitor that has been approved for use in colorectal cancer with MSI-H or dMMR. Like pembrolizumab, it unleashes the immune system against cancer cells. 

Programmed Cell Death Ligand 1 (PD-L1) Inhibitor: 

  • Dostarlimab (Jemperli): Dostarlimab is a PD-L1 inhibitor used in the treatment of colorectal cancer with MSI-H or dMMR. It helps block the interaction between PD-L1 on cancer cells and PD-1 on immune cells, enhancing the immune response against the tumor. 

Combination Therapy: 

  • Nivolumab and Ipilimumab (Yervoy): This combination involves both a PD-1 inhibitor (nivolumab) and a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor (ipilimumab). It has shown efficacy in certain subtypes of colorectal cancer, particularly those with MSI-H or dMMR. 

Laparoscopic Surgery in the treatment of Colorectal Cancer

  • Laparoscopic Colectomy: This minimally invasive procedure involves the removal of a portion of the colon using small incisions and a camera-equipped instrument (laparoscope). It is often employed for early-stage colon cancer and offers benefits such as shorter recovery times and reduced postoperative pain. 
  • Laparoscopic Proctectomy: For rectal cancer, a laparoscopic proctectomy involves the removal of the rectum and, in some cases, the creation of anastomosis (reconnection of the remaining bowel). This approach may be used for certain cases of rectal cancer, providing a less invasive alternative to open surgery. 

Colostomy and Radiofrequency Ablation (RFA) or Cryoablation in the treatment of Colorectal Cancer

  • Colostomy: In some cases, particularly when a low anterior resection is performed for rectal cancer, a colostomy may be created. A colostomy is a surgical opening in the abdominal wall by which a portion of the colon is brought to the surface, allowing stool to pass into a colostomy bag.  
  • Radiofrequency Ablation (RFA) or Cryoablation: 
  • Radiofrequency Ablation (RFA): RFA is a technique that uses high-frequency currents to heat and destroy cancer cells. It is sometimes used as a local treatment for small liver metastases from colorectal cancer. 
  • Cryoablation: It involves the use of extreme cold to freeze and destroy cancer cells. Similar to RFA, cryoablation may be used for specific cases of liver metastases from colorectal cancer. 

management of Colorectal Cancer

Preoperative (Neoadjuvant) Phase: 

  • The primary goal of the neoadjuvant phase is to shrink tumors and improve the chances of successful surgery. This phase is commonly employed in the treatment of locally advanced rectal cancer. 
  • Chemotherapy: Administered before surgery to reduce tumor size. 
  • Radiation Therapy: It is used in combination with chemotherapy, particularly for rectal cancer, to target and shrink tumors. 

Postoperative (Adjuvant) Phase: 

  • The adjuvant phase aims to eliminate any remaining cancer cells and prevent recurrence of cancer after surgery. 
  • Chemotherapy: Administered after surgery to target residual cancer cells and minimize the risk of recurrence. 
  • Radiation Therapy: In some cases, postoperative radiation may be used to target the area where the tumor was removed. 

Metastatic Phase: 

  • The metastatic phase involves treating cancer that has spread to distant organs or tissues. 
  • Systemic Therapy (Chemotherapy, Targeted Therapy, Immunotherapy): These treatments are used to control the spread of cancer throughout the body and manage symptoms. 
  • Surgery: surgery may be considered to remove isolated metastases, especially in the liver or lungs. 

Palliative Phase: 

  • Palliative care focuses on managing symptoms and providing support for patients with advanced or incurable colorectal cancer. 
  • Symptom Management: Addressing pain, fatigue, nausea, and other symptoms associated with advanced cancer. 
  • Palliative Radiation Therapy: Used to relieve pain or control bleeding in specific areas. 
  • Supportive Care: Providing emotional, psychological, and spiritual support for patients and their families. 

Medication

 

cetuximab

Weekly Dose:
Initial Dose:

400

mg/m^2

Intravenous (IV)

over 2hrs, and Maintenance Dose:250 mg per m2 given IV over 1hr once a week
BIWEEKLY: 500 mg per m2 IV over 2hrs every two weeks
In Combination with Encorafenib:
400 mg per m2 IV is taken as the initial dose over 2hrs, and the Maintenance Dose is 250 mg per m2 IV over 1hr once a week until disease progression or unacceptable toxicity seen
comments:
Cetuximab with or without Irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin), and this should be taken weekly or biweekly
Hence continue the treatment until disease progression or unacceptable toxicity observed



ramucirumab (Rx)

8

mg/kg

Solution

Intravenous (IV)

every 2 weeks

1

hr

Continue the therapy until disease progression or unacceptable toxicity occurs    If the 1st infusion is tolerable, then go with subsequent infusions given over 30 minutes



panitumumab

Administer dose of 6 mg/kg via intravenous route over one hour every 2 weeks:



ipilimumab

ipilimumab 1 mg per kg given IV over 30 minutes every 3 weeks with nivolumab 3 mg per kg given IV over 30 minutes on the same day for 4 doses
After completing four doses of combination, nivolumab is given as a single agent
Continue the therapy until disease progression or unacceptable toxicity occurs



floxuridine

0.25

mg/kg

once a day

Intra-arterial continuous infusion for 14 days for a cycle of 5 weeks, continue for 6 cycles with dexamethasone and heparin
Start floxuridine therapy 2 weeks after 6 cycles of fluorouracil and leucovorin



Dose Adjustments

Reduce the dose by 20% of the usual dose for the following conditions:
o Serum bilirubin 1.2 x ULN or alkaline phosphatase 1.2 x ULN
o Baseline AST is 3 to <4 times the baseline value
Reduce the dose by 50% of the usual dose for the following conditions:
o Serum bilirubin 1.5 x ULN or alkaline phosphatase 1.5 x ULN
o AST is 4 to <5 times the baseline value
Discontinue the dose if any of the following adverse reactions appear:
o White blood count < 3,500/mm3
o Platelet count <1,00,000/mm3
o Vomiting, diarrhea or gastrointestinal bleeding/ulceration

aspirin

Age: >50 years
75-100 mg orally daily



fluorouracil 

400 mg/m² of intravenous pyelogram on 1st day,
then 2400-3000 mg/m² intravenously as a continuous infusion for 46 hours every 2 weeks combined with leucovorin and/or oxaliplatin/irinotecan



regorafenib 

regorafenib is indicated to treat metastatic colorectal cancer in patients who have undergone fluoropyrimidine- / oxaliplatin- / irinotecan-based chemotherapy
A dose of 40 mg is administered four times daily for the initial 21 days of every 28-day cycle
The medication is continued until the disease is reduced to acceptable toxicity



ziv-aflibercept 

Indicated for metastatic colorectal cancer that is resistant to or has advanced after receiving oxaliplatin, it is recommended in conjunction with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI):


4mg/kg intravenous every two weeks
On the day of therapy, give before any FOLFIRI regimen component



oxaliplatin 

Advanced stage of colorectal carcinoma:



Day 1: 85 mg/m² Oxaliplatin Intravenous (IV) + 200 mg/m² leucovorin Intravenous (IV) infused over 2 hours
Following 5-FU 400 mg/m² Intravenous (IV) bolus over 2-4 minutes
Next 5-FU 600 mg/m² Intravenous (IV) infusion over 22 hours

Day 2: WITHOUT oxaliplatin following Same regimen
continue for every 2 weeks

Adjuvant stage III colon cancer:

Course is 12 cycles
continue every 2 weeks,with the above scheduled dose for 6 months
Tumour excision is followed by adjuvant therapy



irinotecan 


Indicated for Colorectal Cancer
It is used as 1st line treatment (leucovorin and 5-fluorouracil) for CRC (metastatic colorectal cancer) and also used for progressed or recurred CRC after fluorouracil-based treatment
Monotherapy
Pre-treatment should be given to patients with antiemetic drugs
For patients who experience cholinergic symptoms, atropine is given
Schedule-1 (every week): 125 mg/m² Intravenously infused over 1 hour 30 min on days 1, 8, 15, 22 and after that, two weeks off, and then repeat it
Schedule-2 (one time every three weeks): 350 mg/m² Intravenously infused over 30-90 min every 3 weeks
As per protocol, adjust the dose
Combination therapy
Pre-treatment should be given to patients with antiemetic drugs
For patients who experience cholinergic symptoms, atropine is given
Schedule-1 (Six weeks cycle) infusion with the leucovorin and 5-fluorouracil: 180 mg/m² Intravenously infused over 30-90 min one time on days 1,15,29 after that, infused with 5-fluorouracil and leucovorin; on day-43 next cycle starts
Schedule-2 (Six weeks cycle) bolus with the leucovorin and 5-fluorouracil: 125 mg/m² on days 1,8,15,22 (infused over 90 minutes); after that, bolus dose with 5-fluorouracil and leucovorin
As per protocol, adjust the dose



tegafur 

Indicated for Advanced colorectal cancer
Three daily divided doses of 300 mg/m2 tegafur in combination with 672 mg/m2 uracil orally with calcium folinate
These doses are administered over a 28-day cycle, followed by a seven-day treatment-free interval



coltuximab ravtansine 

It is not currently approved as medication or as a combination therapy



 

panitumumab

Safety and efficacy not studied 



ipilimumab

Age:>12yrs
ipilimumab 1 mg per kg given IV over 30 minutes every 3 weeks with nivolumab 3 mg per kg given IV over 30 minutes on the same day for 4 doses
After completing four doses of combination, nivolumab is given as a single agent.
Continue the therapy until disease progression or unacceptable toxicity occurs.



nivolumab

Safety and efficacy not established in pediatrics



 

panitumumab

Refer adult dosing



Media Gallary

References

https://www.cancer.org/cancer/colon-rectal-cancer/causes-risks-prevention/what-causes.html”>https://www.cancer.org/cancer/colon-rectal-cancer/causes-risks-prevention/what-causes.html

https://www.ncbi.nlm.nih.gov/books/NBK470380/”>https://www.ncbi.nlm.nih.gov/books/NBK470380/

Colorectal Cancer—Patient Version 

Colorectal Cancer – Gastrointestinal Disorders