About Colorectal Cancer and Treatment 

Cancer is a complex and often misunderstood condition among people. When someone is diagnosed with cancer, it might feel like a death sentence to them. However, the truth might be much more complicated.

Cancer is typically defined as an uncontrolled growth of cells. It can develop at any age, but the chances of cancer risk increase in elderly people as compared to young ones. This is because as we age, the cells in our body require more time to recover from the damage that was built over time due to a slower healing process. However, most of the damage is repaired by the body. But sometimes, the damage can cause cells to proliferate in an unusual way, which might eventually lead to cancer. Spotting cancer at an early stage, precise treatments, and following healthy dietary habits can assist in reducing the risk of developing the most common types such as bowel cancer.

What is colorectal cancer (CRC)?

Bowel cancer or colorectal cancer (CRC) is a type of cancer that affects either colon or rectum of the large intestines depending on where they have initiated. Sometimes, colon and rectum cancers are often grouped together since they have various similar features.

Physiologically, the colon and rectum are the parts of the large intestines in our gastrointestinal system. They are mainly responsible for reabsorbing all the water and salts from the remainder of food that passes through the small intestines. The left waste material then passes through the colon into the rectum. It's stored there until it passes through the anus.

Most colorectal cancers start as a benign or abnormal growth of tissues on the inner walls of the large bowel called polyps. These clumps of cells can grow in two different shapes either as flat (sessile) or with a stalk (pedunculated) similar to a mushroom, varying in sizes ranging from a few millimetres to several centimetres. Although not all polyps grow into cancerous cells some types of polyps (adenomas) may eventually risk cancer if left undetected.

Polyps are the most common colorectal condition, affecting1 in 4 people over the age of 50 years. They can affect any part of the large intestine but are mostly found in the left colon, sigmoid and rectum. However, colorectal cancer is not a single type of tumour. Its development depends on the anatomical location of the mass and differs between the right and left sides of the colon. Tumours in the proximal colon (right side) and distal colon (left side) exhibit different characteristics.¹⁵ Colorectal carcinoma, if raised in the right colon, may cause occult bleeding from polyps, but they are generally non-obstructive with sharp abdominal aches. In comparison to the ascending colon, the left colon tends to cause obstruction followed by constipation alternating with diarrhoea and severe pain in the abdominal region.

How common is it?

World Health Organization reports that Colorectal cancer (Bowel cancer) is the third most common cancer worldwide with the highest mortality rate at advanced stages. According to a study by the International Agency for Research on Cancer, there were over 1.9 million cases of colorectal cancer reported in 2020. Making it the third most common cancer in men and the second most common cancer in women. CRC incidence has been rapidly rising on a global level, especially in developing countries due to westernization and the older population.¹

With an ageing population, the numbers of CRC in elderly patients will likely increase further. The risk of developing colorectal tumors surges as people get older. Individuals 50 years old or more are at 90% at risk of being diagnosed with CRC.²  

The incidence of early colorectal conditions is also on the rise due to modifiable risk factors, which means the number of colorectal cancer cases poses a growing global health challenge. The Global Cancer Observatory estimates that in the year 2040, there will be 1.92 million new cases of colon cancer, 1.16 million new cases of rectal cancer, and 78,000 new cases of anal cancer.

What are the symptoms?

During the early stages of bowel cancer, people may not detect any symptoms at all. As cancer cells continue to grow, they can narrow down and obstruct large intestines resulting in altering the size, shape, and colour of faecal matter. These symptoms are often misunderstood, attributed to hemorrhoids (piles), or simply brushed aside.

Below are the common symptoms which could be indicative of colorectal cancer and should be immediately consulted if they persist for two or more weeks:

• Rectal Bleeding or blood discharge during defecation
• Changes in Bowel habit (constipation, diarrhoea, or feeling of incomplete evacuation)
• Abdominal pain
• Nausea / Vomiting
• Change in stool colour or anal mucus discharge
• Swelling or lump at the anal opening
• Unexplained tiredness
• Rapid weight loss
• Iron deficiency
• Abdominal Bloating

Stages of CRC

Colorectal cancers are generally staged by using a tool known as the TNM staging system. This system helps doctors to differentiate cancer stages and obtain the following information to provide the best treatment to the patients:

1. Tumour (T) – determines the size of the tumour mass and how deeply is grown into the tissue lining of the colon or rectum
2. Lymph Nodes (N) – determines whether the tumour has spread to the lymph nodes or not
3.  Metastasized (M) – this determines if cancer has spread to the other parts of the body

Numbers marked 0-4 or the letter X is assigned to each factor. Using the TNM staging system, a higher number indicates the accurate severity of the tumour. Whereas the letter X shows the information couldn’t be assessed. The results are then combined to evaluate the stage of cancer for each patient.

Colorectal cancer is classified into four main stages, ranging from stage 0 to stage 4. There are sub-stages within a few main stages which are marked by alphabets or letters (Stage ii A or ii B) The main purpose is to be more specifically related to tumour spread within the intestinal wall lining.

The characteristics of CRC stages are mentioned below:

Stage 0 Colorectal Cancer:

Stage 0 is the earliest stage of colorectal cancer also referred to as carcinoma in situ (intramucosal carcinoma). In this cancer cells are contained in the rectum's or colon's inner wall lining. This stage is also marked by this common feature: 

• Abnormal cells are found in the innermost layer (mucosa) of the colon or rectal lining, but these cells have not become cancerous

Stage 1 Colorectal Cancer:

In this stage, colorectal cancer cells are found to penetrate into deeper layers of the colon or rectal lining, but they have not proliferated beyond the wall. This stage is marked by these specified characteristics:

• Carcinomas are located in the innermost layer lining the colon or rectum, and they have grown into the second layer of tissue called the submucosa
• There is a chance that cancer may have also spread to a nearby muscle layer (muscularis propria) but hasn’t reached nearby lymph nodes yet

Stage 2 Colorectal Cancer:

In Stage 2, tumour growth has not advanced to the lymph nodes, but some may have developed through or beyond the colon or rectum wall, sometimes affecting nearby tissues or organs. They are divided into three sub types:

Stage ii A:

In this, cancer has advanced through the layers of the colon or rectum wall and has reached the outermost layer, but to a certain extent.

Stage ii B:

Cancer has grown beyond the outermost layer of the colon or rectum wall but hasn’t affected nearby tissues or organs.

Stage ii C:

Cancer has spread past the outermost layer of the colon or rectum wall and has grown into nearby tissues or organs, but it hasn’t spread to lymph nodes or distant organs.

Stage 3 Colorectal Cancer:

In stage 3, colorectal cancer cells have proliferated to the nearby lymph nodes, but they have not grown beyond the lymph nodes, or to the other organs of the body. They are categorized into three subtypes:

Stage iii A:

• Cancer has spread through the initial two inner layers of the colon or rectum wall (mucosa and submucosa) and may have also reached the third layer (muscularis propria). It may have also reached one to three nearby lymph nodes, or carcinoma can be found near the lymph nodes
• Or there’s a possibility that cancer may have spread through the first two layers of the colon or rectum wall and has affected four to six nearby lymph nodes

Stage iii B:

• Cancer has reached the serosa - outermost layers of the colon or rectum wall. It may have spread through the tissue that covers the abdominal organs (visceral peritoneum) but has not reached nearby organs yet. Cancer cells may affect four to six lymph nodes

Stage iii C:

• In stage 3 C, the tumour has grown past the colon or rectal wall and has spread to the tissue lining of the abdominal organs, but it has not spread to nearby organs. Around four to six lymph nodes can be affected at this stage
• Or cancer has grown past the colon or rectum wall or has spread through the tissue that lines the abdominal organs. Detected in seven or more nearby lymph nodes

Stage 4 Colorectal Cancer:

At Stage 4 of colorectal cancer, the cells may have spread beyond the colon or rectum to distant areas of the body, including tissues and body organs. The specific subtype characteristics include:

Stage iv A: Cancer has reached one area or organ that isn’t near the colon or rectum (such as the liver, lung, ovary or a distant lymph node).

Stage iv B: Cancer has reached more than one area or organ that isn’t near the colon or rectum.

Stage iv C: Cancer has spread to more distant parts of the tissue that covers the abdominal cavities and may have reached other areas or organs as well.

Screening

Screening can prevent the chances of colorectal cancer through the detection and removal of pre-cancerous development. It can assist in detecting the condition at an early stage when treatment is considered most successful. As a consequence, timely screening reduces CRC mortality both by decreasing incidence and increasing survival. 

It is recommended that adults ages 45 years and older should undergo regular screening check-ups either with a high-sensitivity stool-based test or visual examination, depending on patient preference and test availability. As part of the screening procedures, if all positive results are observed on non-colonoscopy screening tests, they should be followed up with a timely colonoscopy because delays in follow-up of abnormal results increase the risk of advanced Colorectal cancer and CRC death. CRC screening according to age is modulated from 50 to 45 years because of rising incidence rates in younger populations. It is favourable to initiate screening and early follow-ups at age 45 than at 50.

This is mostly recommended for those who have a high risk of developing CRC because of family history or certain medical conditions. People should have a conversation with their health care provider about colorectal screening that includes information about cancer family history as well.

There are various recommended techniques for CRC screening, including visionary examinations, which are performed at a health care facility, or high-sensitivity stool-based tests, which can be collected at home.

Below are the tests that have a comparable ability to enhance life expectancy when performed at the appropriate time intervals and with the recommended follow-ups.

• Colonoscopy: Colonoscopy is the most commonly used bowel cancer screening test around the globe. This procedure, which is usually performed by a gastroenterologist or a physician (who is medically concerned with disorders of the digestive system), permits for direct visual examination of the entire colon and rectum. It can also be used as a singular screening test or may be performed as a follow-up to abnormal results from the stool and other visual tests to complete the screening procedures
• Flexible sigmoidoscopy: Sigmoidoscopy was a common screening technique before 2000, but its recent availability is limited because it has been largely replaced by colonoscopy. Sigmoidoscopy is very similar to a colonoscopy except it can examine the entire colon whereas sigmoidoscopy can only visualize the rectum and distal one-third of the colon, and required repeated tests more often. Easy bowel cleansing usually done with enemas is sufficient to prepare the colon for the procedure which is often performed without requiring sedation in a general health care facility. If a polyp or tumour is detected, the patient is then referred for a colonoscopy so that the entire colon can be examined
• Computed tomographic colonography (CTC): Computed tomographic colonography also referred to as virtual colonoscopy, is an imaging technique that provides 2 or 3-dimensional imaging of the entire colon and rectum with the use of a unique X-ray machine connected to a computer. Generally, a complete bowel cleansing is necessary for a successful observation but sedatives are not given to patients.
• CTC is considered a less invasive technique than colonoscopy or sigmoidoscopy which typically takes 10-15 minutes to complete the procedure. A small, flexible tube is inserted into the rectum in order to allow some air to inflate the colon. Then the patient is observed under a CT scanner, which creates multiple images of the interior of the colon
• Stool tests: Most cancerous tumours and some large adenomas bleed intermittently into the intestine. Blood may not be visibly seen but it can be detected through special tests
• Guaiac-based faecal occult blood test (gFOBT): In this testing, a chemical reaction is used to detect blood in the stool. Bleeding from cancers or adenomas may be sporadic or go unnoticeable, so accurate results require annual testing of samples from 3 consecutive bowel eliminations. Patients are typically instructed to avoid non-steroidal anti-inflammatory drugs and red meat consumption for a minimum of 3 days prior to the procedure because they can lead to a false positive testing result when there is no cancer in the body. This is because gFOBT detects blood from any source, including meat in the diet. Vitamin C and large amounts of citrus beverages should also be avoided because of negative test findings when cancer is present (false negative)
• Faecal immunochemical test (FIT): The Faecal immunochemical test also sometimes known as the immunochemical FOBT (faecal occult blood test) or iFOBT (immunological faecal occult blood testing) uses antibodies against haemoglobin to precisely detect hidden blood in the stool when blood is not visibly apparent. It is about twice as similar to most gFOBT products in detecting advanced adenomas and malignancies. Most individuals prefer FIT over gFOBT because of its convenience, little dietary restrictions, and collection of fewer stool samples
• Multitargeted stool DNA Test: This test is referred to as “multitargeted” because it not only detects blood in the stool but also observes multiple genetic mutations in the cellular DNA that are shed into the stool by tumour cells. A multi-targeted stool DNA test has been able to detect cancer and precancerous lesions more often than FIT. However, sometimes results often provide false-positive tests, which may lead to unnecessary colonoscopies

How does age affect CRC prevalence and course?

Colorectal cancer prevalence has significantly increased on a global level in recent times. It was estimated that 1.93 million colorectal cases were diagnosed with 0.94 million deaths caused by colorectal cancer in 2020 worldwide. Sources from GLOBOCAN 2020 represented 10% of cancer incidence on a global scale (total of 19.29 million new cases) and 9.4% of all cancer-caused deaths (total of 9.96 million deaths).

Colorectal cancer is considered the third leading cause of cancer-related to loss of life in both genders worldwide with an estimated 515,637 deaths among males and 419,536 deaths among females. Currently, over 5.25 million (5-year prevalence) people worldwide are living with colorectal cancer only after breast cancer, which causes 7.79 million cancer cases.¹

Extensive efforts and advancements have been made to abstract knowledge of pathophysiological insights related to CRC and expand treatment options which include endoscopic resection, surgical local excision, targeted therapy, radiation, chemo, and immunotherapies in order to double the overall survival of advanced colorectal cancer to three to five years.³

Moreover, there are some significant differences obtained in survival rate, even in most highly developed countries. Diagnosis made at several clinical stages of colorectal cancer may partially explain the marked differences in survival rates. Although, CRC is generally asymptomatic. The first symptoms of CRC, such as rectal bleeding, anaemia, and abdominal pain, usually appear in the later stages when cancer cells are aggressive, malignant, and metastatic, especially in elderly patients.

The exact cause of colorectal cancer is still unknown, but certain risk factors attributes significantly to the CRC prevalence among people. These risk factors are mainly categorized into two types:

Non-modifiable: The risk factors that are non-modifiable mainly involve individuals who suffer from heredity conditions or have a family history of CRC, making it one of the most important risk factors of CRC development. People with a first-degree family relative (parent, sibling, or child) who has been diagnosed with CRC have more chance of developing the disease compared to people with no family history.⁴

A recent study showed that individuals with inherited gene mutations associated with a known high-risk hereditary condition are more expected to acquire colorectal cancer such as Lynch Syndrome and Familial Adenomatous Polyposis (FAP).⁵

Moreover, A gene panel study witnessed CRC indications in people younger than the age of 50 years who have heritable mutations related to BRCA1/ BRCA2 (breast cancer) and found a 1% prevalence. Although their influence on colorectal risk is not well studied but a review reported an association limited to BRCA1 mutation carriers, that may have an increased chance of the disease compared to ones without the mutation.⁶

Other non-modifiable risk factor includes:

Personal medical history such as Chronic inflammatory bowel disease (IBD), diabetes, and h.pylori.

Modifiable Risk Factors: Modifiable risk factors mostly develop due to sedentary lifestyle and poor dietary habits such as:

• Physical inactivity.
• Obesity.
• Smoking / Alcohol usage.
• Red/ processed meat consumption.
• Low fiber diet intake.

Treatment types for different stages of CRC in the elderly

In medical practice, elderly patients with CRC are properly accessed according to their fit to fragility grouping prior to selecting accurate treatment for them. Because most elderly individuals are more likely to have comorbidities than younger patients, such as cardiovascular disease, respiratory illnesses, renal dysfunction, or liver dysfunction, making treatment riskier. Therefore, designing appropriate treatment strategies for elderly CRC patients requires a detailed understanding of the characteristics of colorectal cancer with a minimally invasive approach and quick recovery chances.

General treatment options may be suggested for CRC in elderly patients including surgery for colorectal cancer stage I or II.

Surgery followed by adjuvant chemotherapy for stage III colon cancer or recurrence and in cases of metastatic CRC (mCRC), systemic chemotherapy is referred to alone or in combination with targeted therapies. Low invasive options such as endoscopic resection and laparoscopic surgery are considered for adenomas and early cancer detection.⁷

How does age affect treatment decisions? 

Elderly patients of 60 years or more are considered a heterogeneous group ranging from fit to frail. Some reviews suggested that fit elderly patients can be treated in the same way as younger patients. However, treatment required for frail patients with comorbidities is still a matter of argument. Since many older frail patients are not suggested treatments such as chemotherapy and preoperative radiotherapy under the clinical guidelines to limit adverse events. This can hugely affect the treatment options for an aging population.⁸

Although, various factors by physicians are taken into account, covering the physical fitness of each patient, respecting the wishes of the patient and family, and monitoring treatments with extensive care.

Medicines

Nonsteroidal anti-inflammatory drugs (NSAIDs):

There is reliable evidence that the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in long term on regular basis lowers the possibility of CRC. The reduction in risk appears to be stronger among younger people than age 70 and without excessive body weight.

Aspirin users who do develop CRC appear to have less aggressive tumours and can have better survival chances as compared to non-aspirin users (the survival benefit may be only limited to certain tumour subtypes). However, formal evidence has not been issued so currently it is not recommended to use NSAIDs for CRC prevention because of the potential side effects, such as critical gastrointestinal bleeding.⁹ Decisions regarding aspirin usage must be made after discussing with a health care provider.

Hormones: The evidence regarding the association between steroid hormones, both endogenous (naturally occurring within the body) and exogenous (hormone replacement therapy and oral contraceptives), and CRC is still debatable. Some studies have found that higher natural levels of oestrogen among post-menopausal women are linked with reduced colorectal cancer risk. Recent studies do not support any association between oral contraceptive use and CRC factors.¹⁰

Antibiotics: A few pieces of evidence suggested that oral antibiotic usage may be associated with an increased risk of colorectal cancer. Antibiotics might impact risk by disrupting the critical balance of the gut microbiome.¹¹

Other drugs: Some medications such as oral bisphosphonates, which are used to treat and prevent osteoporosis, might have evidence to reduce CRC risks.¹²

Surgery

Surgery is a method to remove tumour mass and some surrounding healthy tissue during an operative session often called surgical resection. In addition, below are surgical options for colorectal cancer:

• Laparoscopic surgery: With this technique, several viewing scopes are passed into the abdomen after a patient is given anaesthesia (which helps to block awareness of pain). The incisions are small with a quick recovery time than the standardized colon surgery making it the most effective technique
• Colostomy: Rarely, patients with rectal cancer may need to have a colostomy either for temporary rectal healing or lifelong treatment. With modern techniques, radiation therapy and chemotherapy prior to surgery, most people who receive treatment for rectal cancer do not require a permanent colostomy
• Radiofrequency ablation (RFA) or cryoablation: Using radiofrequency ablation to heat tumour masses or freeze (cryoablation) are optional treatments suggested for advanced CRC to the distant organs (lungs or liver). RFA can be held during surgery or through the skin. This option can assist to avoid removing affected tissues that might be removed in regular surgery

Targeted therapy

Targeted therapy is a treatment that aims for cancer’s specific genes or the tissue environment that provide cancer to grow and survive. Targeted therapies mainly block the spread of cancer cells and reduce damage to other body cells.

Following are a few targeted therapy options for colorectal cancer.

Anti-angiogenesis therapy. Anti-angiogenesis therapy is focused on inhibiting angiogenesis, which is a process of making new blood vessels. Tumour requires nutrients delivered by blood vessels to proliferate. Inhibiting angiogenesis can lead tumours to starvation.

Combined targeted therapies: Several tumours have a specific mutation - BRAF V600E, that can be observed by an FDA-approved test. A section of targeted treatments called BRAF inhibitors can be used to aim at tumours with this mutation to treat people with metastatic colorectal cancer.

For advanced colorectal cancers, some targeted drugs are combined with chemotherapy sessions such as Bevacizumab (Avastin), Regorafenib (Stivarga) and epidermal growth factor receptor (EGFR) inhibitors to limit the spread of CRC.

Side effects

Common side effects from surgery and targeted therapy for CRC may include:

• Prolonged Tiredness / Fatigue
• Nausea
• Rashes on the upper body region
• Frequent or urgent bowel movements
• Diarrhea
• Constipation
• Gas or bloating

Palliative care

Palliative care is specialized clinical care for people surviving a serious illness. In this providing care is focused to ensure that patients find relief from the symptoms and stress developed due to illness. The aim is to improve the quality of life for both the patient and the family in an efficient manner.

Palliative care is provided by a trained team of doctors, nurses, and other specialists who collaborate with a patient’s physician to offer an extra layer of support. Palliative care relies greatly on the needs of the patient rather than the patient’s prognosis. It is appropriate at any age or stage of critical condition; however, it is most favourable for older patients.

Outcomes

Currently, the 5-year survival rate for people with colorectal cancer is around 65%. Survival rates for colorectal cancer may vary based on several factors, such as cancer stage.¹³

Detection of colorectal cancer in earlier phases can often be cured. The primary outcome is to analyse risk factors accordingly. A screening technique should identify stages of CRC based on family or personal medical history, lifestyle management, and clinical diagnosis.  Comorbidities in elderly patients and managing appropriate treatments, surgery, targeted therapies, and palliative care at the right period of time can enhance the survival rate among older populations up to 5 or more years.^7,14

Summary

Colon and rectal cancers are among the most common and deadly neoplasms. With an increase in the aging population, their global incidence and mortality are expected to increase in the upcoming decades.¹⁴ The incidence of CRC has been exacerbated due to unhealthy diets and sedentary lifestyles in developed nations. However, successful treatments and early diagnosis have led to a reduction in mortality rates. Increasing awareness of CRC screening can contribute to promoting healthy lifestyles, developing novel strategies, and implementing global awareness programs that can help decrease CRC mortality and morbidity.