The Heterogeneous Landscape of Colorectal Cancer: Implications for Treatment
By Dr (Prof) GS Moirangthem, Director – CEO, Karkinos Manipur Cancer Care Institute
& Leimajam Rabina Chanu Medical Coordinator, Karkinos Manipur Cancer Care Institute
The human intestine is approximately eight meters long. It consists of 2 main parts: small intestine of 6 meters in length and a large intestine, known as the colon, of 2 meters in length. Whatever is required by the body, such as protein, vitamins, fat, nutrients, minerals, fluid, etc., are absorbed in the small intestine. Whatever is not absorbed, such as water, electrolytes, mostly potassium, and solid waste in the form of stools, moves to the colon. The main function of the colon is the absorption of water, electrolytes, and some vitamins, fermentation of the indigestible materials by bacteria, storage, and then transportation of faecal matter to the rectum, which is sub-classified into an upper, middle, and lower portion having a length of 4 cm each with a total of 12 cm in length. The fully formed stool then moves to the anal canal, which is about 3.7 cm in length and leaves the body through the anus.
Main symptoms of colorectal cancer (CRC)
The symptoms of colorectal cancer depend on the type and location of the tumour. In general, the individual gradually becomes anaemic, lethargic, and loses appetite. Grossly, there are roughly two types of colon cancer: ulcerative, which involves mostly the right half of the colon, and annular, which affects mostly the left side of the colon.
The symptomatology of right-sided colon cancer is more of vague pain in the abdomen, malabsorption syndrome such as diarrhoea, mixed with blood, and that of left-sided colon is more obstructive in nature in the form of abdominal distention, feeling of a lump, not passing stools and flatus for days together and incomplete sense of defecation with blood in stools time to time.
As for rectal cancer, the symptomatology is slightly different from colon cancer. Here, the patients will definitely have tenesmus, an incomplete sense of defaecation, and they will feel like going to the washroom repeatedly. The frequent passing of small amounts of stools mixed with blood and mucus is one of the most important symptoms of rectal cancer. This symptom is commonly mistaken for symptom of piles and this misdiagnosis leads to significant loss of time. By this time, cancer would have manifested to progress into an advanced stage.
Causes & predisposing factors
The main contributing factor is our personal habits. These days, the Indian diet has a Western influence. There has been higher consumption of red meat, strong spices, intoxicants such as alcohol and nicotine through cigarette smoking, etc., and very little consumption of fibrous foods such as vegetables and water. Owing to this, the individual develops constipation, and colon faecal contact time is prolonged. The chance of developing colon cancer is higher in this category of people. Consuming large quantities of vegetables, fibrous foods, and water increases faecal matter’s transit time in the colon, thereby helping minimize the incidence of colorectal cancer.
There are some pre-disposing factors of the colon. If we don’t treat it in time, these factors almost invariably develop colorectal cancer later. For example, there are 3 types of adenomas, a non-cancerous lesion initially — i) Villous, ii) Tubulovillous, iii) Tubular. Out of these types, the risks of developing cancer in villous adenoma are as high as 35% to 40% if the size of the adenoma is larger than 4 cm, the tubulovillous is about 20% to 25%, and that of tubular is as low as 5%. The other predisposing factors for developing colon cancer are multiple polyposis coli and inflammatory bowel diseases such as ulcerative colitis, Crohn’s colitis, and Lynch Syndrome.
Compared with the Western world, the incidence of colorectal cancer (CRC) is far less in India. However, the incidence of CRC is gradually rising in India. As per the National Tumour Registry, the Incidence rate of 4 per 1000000 people in the early past has gradually risen to 5.8 in 2004 – 2005 and 6.9 in 2012 – 2014 per 1000000 people. The rising rates can be attributed to changing lifestyles that include the consumption of calorie-rich and high-fat diets, excessive intake of red meat and processed foods, and less physical activity.
To reduce the risk of colorectal cancer, consider these lifestyle changes:
- Fiber-rich diet: Incorporate plenty of fruits, vegetables, and whole grains into your diet.
- Stay active: Regular exercise can help maintain a healthy weight and reduce risk.
- Healthy eating: Limit red meat, oily foods, and excessive spices.
- Watch for warning signs: If you experience significant weight loss, anaemia, weakness, lethargy, abdominal lumps, anorectal bleeding, or changes in bowel habits, consult a doctor immediately.
Suspected colon cancer: Immediate steps
If colon cancer is suspected, immediate medical attention is necessary. Consult a GI surgeon, oncologist, or general surgeon specializing in colorectal diseases.
Initial evaluation will include assessing symptoms like anaemia, abdominal lumps, and changes in bowel habits. A simple rectal examination can often identify or rule out mid and low-rectal cancers.
Further investigations may include:
- Haemoglobin levels: Low haemoglobin levels can be a sign of bleeding in the colon.
- Occult blood test: A positive stool test for occult blood can indicate bleeding in the digestive tract.
- FIT (Faecal Immunochemical Test): A positive FIT result suggests the presence of blood in the stool.
- CEA (Carcinoma Embryonic Antigen): Elevated CEA levels can be a marker of colon cancer.
If these tests indicate a potential problem, a colonoscopy will be recommended. This procedure allows direct colon visualization to identify abnormalities like adenomas, polyps, or ulcerative colitis.
Early detection and prevention
If precancerous conditions like adenomas or polyps are identified, the physician may recommend preventive surgery to remove the affected area and reduce the risk of cancer development.
Remember, early detection and treatment are crucial for successful outcomes in colon cancer. Don’t hesitate to seek medical advice if you have any concerns.
Screening for Colorectal Cancer (CRC)
The gold standard for colorectal cancer screening is colonoscopy, a procedure that allows for direct visualization of the colon. However, due to its invasive nature and the need for specialized equipment, it’s not suitable for mass screening.
For large-scale screening, simpler tests are often used:
- Tumour Marker CEA: Elevated levels of CEA can be a potential indicator of colorectal cancer.
- FIT (Faecal Immunochemical Test): A positive FIT result suggests the presence of blood in the stool.
- FOBT (Faecal Occult Blood Test): Another test to detect blood in the stool.
Individuals with anaemia, elevated CEA, or positive FIT/FOBT results should be considered at higher risk and may require further investigation, including colonoscopy.
Emerging Technologies:
While not currently recommended for routine screening, research is ongoing into new technologies that may improve colorectal cancer detection:
- Genetic Analysis: Analysing stool samples for genetic markers associated with colorectal cancer.
- Gut Microbiome Analysis: Examining changes in the gut microbiome to identify potential risk factors.
Repeat screening or follow-up
The general guidelines for getting a screening colonoscopy for asymptomatic individuals is once in 10 years. However, people whose noncancerous polyps were removed colonoscopically are preferably called for repeat procedures every 5 years. Or in the meantime, when the individual’s routine screening indicates symptoms or when other general screening methods indicate low haemoglobin and high level of tumour marker CEA, positive Fit & FOBT Test, further investigation is warranted. Like FOBT, FIT is a simple, non-invasive screening test that can detect traces of blood in stool samples collected at home.
However, unlike FOBT, which uses a chemical reagent to detect blood, FIT uses antibodies that specifically react to human haemoglobin, an oxygen transport protein found in red blood cells. FIT is more sensitive than FOBT and can detect lower-level blood in the stools. Even so, a FIT level alone cannot diagnose CRC conclusively.
Colorectal cancer is a complex disease characterized by both genetic variations and distinct stages of tumour development.
The adenoma-carcinoma sequence, a common pathway leading to colorectal cancer, is driven by three primary molecular mechanisms:
- Chromosomal Instability (CIN): This involves errors in chromosome number and structure, leading to genetic imbalances that contribute to tumour growth.
- Microsatellite Instability (MSI): This occurs when DNA repair mechanisms are defective, resulting in errors in short, repetitive DNA sequences called microsatellites.
- CpG Island Methylator Phenotype (CIMP): This involves abnormal DNA methylation, which can silence tumour-suppressor genes and promote cancer development.
These three molecular pathways can interact and contribute to the development of colorectal cancer in various ways, highlighting the disease’s heterogeneity and complexity.
Most sporadic CRC (85%) exhibit chromosomal instability with changes in chromosome number and structures. The remaining sporadic cases (15%) have high-frequency Microsatellite Instability (MSI) phototypes which can be distinguished into 3 types — high Microsatellite Instability (MSI – H), low Microsatellite Instability (MSI – L), and Micro stellate Static stability (MSS). At present, the MSI – L and MSS are clubbed together as far as clinical implications are concerned.
Based on different molecular mechanisms of MSI in colorectal cancer, it can be divided into CRC with no obvious family genetic history and Lynch syndrome with non-polyposis, with family genetic history. The Lynch syndrome is an autosomal dominant tumour syndrome caused by mutation in MMR strains, and it constitutes about 5% of colorectal cancers. It used to be called hereditary non-polyposis colorectal cancer. It can also involve other parts of the body, such as endometrial cancer, ovarian cancer, and many different types, such as cancer of the stomach, small intestine, pancreas, bile duct, urinary tract, and brain, before the age of 50 years.
The high MSI implies genetic instability in tumour cells and more resistance to chemotherapy. However, unstable tumours also mean no need for chemotherapy in T3NO disease.
Regarding the clinical implications of Microsatellite Instability, there is no need for chemotherapy for any CRC clinical stage 1, irrespective of the microsatellite status, whether it is MSI—H or low or stable. However, for clinical stage II (T3NO), there is always controversy regarding the role of chemotherapy and whether to administer it or not. However, chemotherapy in the form of capecitabine is administered for CRC clinical stage III and above, irrespective of the state of the microsatellite, whether it is high, low, or stable.
The MSI High implies genetic cases of tumor cells, and family members mandatorily need genetic testing.
Treatment
The surgical removal of the cancer is the most common form of treatment for many stages of colorectal cancer. The right hemicolectomy for right-sided colon cancer, the left hemicolectomy for (L) sided colon cancer, Anterior resection for rectosigmoid, upper and mid rectal cancer, low and ultra-low resection for lower rectal cancer, and abdominoperineal resection (APR), etc. are the procedures recommended for resectable CRC.
Depending on the stage, neo-adjuvant chemotherapy, chemo-radiation (before surgery) to downsize the tumour, post-surgery chemotherapy/chemoradiation, and immunotherapy using immune checkpoint inhibitors for Lynch syndrome and for those CRC having MSI – H and mismatch repair deficiency are other modalities of treatment either as an adjunct to surgery or as a primary procedure.
The precision and targeted therapy using drugs that act against the genetic mutation in metastatic colorectal cancer is another field of recent advances for the overall improvement of prognosis. To cite an example, the drug Encorafenib (Braftfovi), which targets the BRAF protein, is approved for the treatment of some patients with colorectal cancer. This drug is used in combination with Cetuximab (ERBITUX) in adults with metastatic colorectal cancer whose tumour has a certain mutation in the BRAF gene and who have already undergone treatment.
In this era of Molecular Biology, scientists can detect defective genes well before the tumour is clinically detected, radiologically, sociologically, and colonoscopically in a particular individual or in families with a history of Lynch Syndrome. The question is now about its clinical implications. Are we legally and ethically permitted to do prophylactic colectomy for an individual who has a defective gene and for any family member of patients suffering from Lynch syndrome for fear that they are likely to develop CRC at a later stage? Do we have to simply categorize these groups of individuals as having high risks for developing CRC at a later stage, and they are subjected to regular follow-up and monitoring?
Prognosis of colorectal cancer
According to the National Cancer Institute’s Surveillance Epidemiology and End Results Programme (SEER) database, the five-year survival rate for localized colorectal cancer is 90.6%, regional cancer is 73%, and distance is 13% to 14%. Fortunately, colon cancer is relatively low-growing, with benign polyps typically taking 10-15% years to develop into cancer. During this time, colon cancer often does not produce any significant symptoms and signs, which is the reason why individuals who belong to high-risk categories and those who have undergone colonoscopic polypectomy for noncancerous polyps must be subjected to regular follow-up and screening for CRC.
