Colorectal cancer

Colon cancer is a malignant disease developing in one of its sections (colon, rectum, rectosigmoid junction) responsible for absorption of nutrients and excretion of feces.

Colorectal cancer is a common cancer, ranking second in frequency among all malignant neoplasms in the world.

Polyps can be easily detected and removed early during colonoscopy. This greatly reduces the risk of developing cancer. This is why it is important to diagnose and treat precancerous lesions.

Epidemiology

Bowel cancer occurs most commonly in the elderly. Ages 65 to 80 years account for about 25% of cases, 65 to 70 years account for 24%, and 55 to 65 years account for 22%.

Each year, more than half a million people worldwide develop colorectal cancer.  About 70% of cases are detected in the late 3-4 stages of development.

Provoking factors

The main predisposing factors to the development of colon cancer are:

• Heredity.
• Older age.
• Chronic intestinal diseases (Crohn's disease, ulcerative colitis, benign lesions on the inner lining of the intestinal mucosa, such as diverticula or polyps).
• Another cancer (breast, uterine, ovarian cancer).
• Diabetes mellitus type 2.
• Overweight, obesity.
• Influence of unfavorable environmental factors, occupational hazards.
• Predominance of meat products and animal fat with deficiency of vegetable fiber in the diet. Such meals lead to a decrease in intestinal motility and longer contact of carcinogens and mutagens with the intestinal mucosa.
• Chronic alcohol abuse.
• Smoking.

Colon cancer classification and stages

A malignant process goes through several stages of development. They differ in the degree of infiltration into the intestinal wall, the lymph node involvement and spread to other organs (metastases).

Cancer stage	Tumor characteristics
Zero stage	Does not extend beyond the bowel (carcinoma in situ).
I	Has grown into the intestinal wall, but has not spread beyond the muscle layer or into neighboring lymph nodes.
II	Has spread through the colon wall (IIA), beyond its muscular layers (IIB), or into neighboring tissues (IIC), without lymph node involvement.
III	Has spread beyond the intestinal wall, into the lymph nodes and into the abdominal organs.
IV	Has metastasized to distant organs (liver, lungs, ovaries).

The international TNM classification distinguishes 4 main stages of colorectal disease, where T characterizes the tumor, M is the presence of metastases, N is the lymph node status.

Stage	T	N	M
0	Carcinoma in situ	0	0
I	Stages 1-2, from the epithelial to the muscle layer	0	0
II	Stages 3-4, growing through the colon wall into neighbouring structures	0	0
IIa	3	0	0
IIb	4а, peritoneal growth	0	0
IIc	4b into the neighbouring structures	0	0
III	Any	1,2	0
IIIa	1,2	1,2a,2b	0
IIIb	1,2/2,3/3,4а	2a	0
IIIc	4b/4a/3,4a	2b	0
IV	Any	Any	I
IVa	Any	Any	Ia
IVb	Any	Any	Ib

Colon cancer symptoms

The manifestations of the disease are divided into early (local) and late (systemic, which occur when the disease spreads).

Local symptoms

In the early stages, colorectal cancer is practically asymptomatic. As the tumor grows, the following early (local) symptoms may appear:

• streaks of blood in the feces (fresh or congealed blood);
• intestinal spasms;
• abdominal discomfort, bloating;
• pelvic pain.

Non-specific symptoms of colon cancer

As the condition progresses, general symptoms appear: weakness, loss of strength, performance impairment, weight loss (from 8 to 20%), loss of appetite, subfebrile temperature, intermittent diarrhea with constipation.

Ascending colon cancer

Symptoms of the ascending colon involvement include abdominal pain of indistinct localization, signs of anemia, feelings of bloating. Quite often complications such as bleeding and intestinal obstruction develop. Less frequent symptoms are vomiting and weight loss.

Rectal cancer

During the initial disease stages, there are very few or no signs. One of the first patient complaints is the feeling that the bowel is not completely emptied. When the disease develops, symptoms can be divided into groups:

• Abnormal discharges from the anus.
• Impaired intestinal function.
• Pain syndrome.
• Changes in the general condition.

Blood in the feces is reported by the majority of patients. Abnormal discharge appears at the beginning of defecation. Severe bleeding is rare. The admixture of mucus in the feces is associated with the lesion of the mucous membrane villi. When the tumor sprouts into the lumen of the intestine, functional disorders of the intestine are observed.

As the process worsens, and the perifocal inflammation develops, there are false urges to defecate (tenesmus) and diarrhea. The first are the leading symptom in patients in whom the tumor is located in the ampulla (upper part) of the rectum, diarrhea is most often found in cancer of the upper ampullary section.

Pain syndrome and its character depend on the location of the tumor process. The most pronounced pain is characteristic of the lower ampullary cancer. Such localization leads to sacral nerve root compression. Pain increases with defecation, irradiates (spreads) to the coccygeal area. When the tumor is found in the upper ampullary region, the pain has an inconstant, contraction-like character and is most often associated with the developing colon obstruction.

The patient general condition does not worsen for a long time. Then posthemorrhagic anemia and weight loss appear.

Cancer of the middle intestine

The symptoms are nonspecific in nature. They depend on the localization of the tumor and its growth type.

In right-sided lesions of the large intestine, the symptoms are associated with impaired absorption. If the lesion is found in the left half, its manifestations are caused by poor intestinal permeability.

A symptom characteristic of all tumor locations is abdominal pain. Its intensity varies from insignificant to intolerable. Painful sensations develop due to the disruption of the large intestine and the developing inflammatory process. These processes gradually lead to wall stenosis.

At the next stage, symptoms associated with impaired intestinal function appear, which include constipation, diarrhea, their alternation, increased gas formation and rumbling in the abdomen.

Colorectal cancer diagnosis

The main method of diagnosing colorectal cancer is endoscopic examination (colonoscopy). It allows not only a visual inspection of the rectum and colon up to the transition to the small intestine, but also taking tissue samples from suspicious areas for subsequent histological examination.

These molecular biological characteristics allow for more accurate differentiation of colorectal tumors.  At advanced stages of the disease, they often become the main factor determining the choice of first-line and subsequent therapy. Therefore, current clinical guidelines include analyzing the mutational status of RAS and BRAF genes, as well as MSI status, before starting colorectal carcinoma treatment.

If there is a narrowing of part of the bowel through which the endoscope cannot pass, computed tomography (CT colonoscopy) may additionally be used for imaging. However, this technology excludes the possibility of obtaining tissue samples.

If the cancer diagnosis is confirmed, additional studies are done to determine the degree of tumor spread. In particular, the following exams are used to detect metastases in lymph nodes and other organs:

• ultrasound examination of the abdominal cavity;
• chest X-ray or CT;
• CT scan of the abdomen and pelvis.

If metastases to the genitourinary and reproductive organs are suspected, a gynecological examination or endoscopic examination of the bladder (cystoscopy) may also be required.

Blood laboratory tests provide information about the patient's general condition and the function of certain organs. Changes such as anemia, changes in blood proteins, elevated levels of certain enzymes, or increased blood cell counts may additionally indicate tumor disease.

This marker is particularly important for monitoring disease progression. It is elevated in almost one third of all bowel cancer patients, but decreases after surgery. A subsequent increase in CEA indicates recurrence.

Colon cancer treatment

The main colon cancer therapy is surgery, i.e. surgical resection of the affected part of the organ. In the early stages of the disease, complete cure can be achieved in this way.

If it is possible to remove the entire tumor, a partial or total resection of the colon with removal of regional lymph nodes and mesentery is performed. In advanced cases with the presence of metastases, combined treatment with preoperative and/or postoperative therapy (radiation, drugs) is necessary.

Surgical treatment of carcinoma of the large intestine

Surgery can be applied at all stages of the disease. At the initial stages, it is the first-line therapy, that is, it is considered in the first place. In the first, second and even third stages, surgery can still have a so-called curative purpose (that is, there is a possibility of curing the disease in this way). As for the fourth stage, 20 years ago it was believed that surgery in the presence of distant metastases of colorectal cancer is exclusively palliative. But in recent years, data have been obtained that in about 25 percent of patients with hepatic metastasis, surgery still has a curative potential. 

In general, surgery for colorectal cancer includes:

• Removal of the malignant mass within healthy tissues, which means that the resection margines should be at a sufficient distance from the tumor. To find out whether this goal has been achieved, histologic examination of the removed tissue is performed.
• Resection of nearby lymph nodes, which are to be examined in the laboratory to determine whether the cancer has spread into them.

At later stages of the disease surgical removal of metastases (e.g. in the lungs or liver) may be considered. However, the benefits of such treatment depend on the localization and number of secondary neoplasms, as well as the patient’s general health state.

Colorectal cancer surgery techniques

In exceptional cases (if it was detected early), the tumor can be removed in a relatively small endoscopic procedure (colonoscopy). However, much more often doctors have to resort to open surgery or a minimally invasive (laparoscopic) surgery.

In principle, both techniques, the conventional (open) access through an incision in the abdomen, and laparoscopy (intervention through small incisions in the abdomen using an optical camera and special instruments) are equally present in the arsenal of modern medicine.

The conventional access gives the surgeon a good view of the abdominal cavity and the ability to palpate abnormally altered tissue areas during surgery. This contributes to the most complete removal of the tumor without damaging the nearby vital body structures.

The number of colorectal cancer procedures using a more gentle, laparoscopic technique (the so-called “keyhole technique”), which requires much smaller incisions in the abdomen, has increased significantly in recent years.  These have a number of advantages for the patient (no scarring, less pain, shorter surgery time, quicker recovery), but are not suitable for each and every patient.

Colorectal cancer surgery types

What kind of surgery is to be performed to remove the malignant formation of the large intestine depends on its location.

If the tumor is located in the right colon, a right-sided hemicolectomy is performed. All parts of the colon located in this area (the cecum, appendix, ascending colon, transverse colon) are removed, leaving about 10-12 cm of ileum, which is then connected to the small intestine by anastomosis.

If the left side of the large intestine is affected, the left half of the transverse colon and descending colon are removed, and part of the greater omentum and the terminal end of the sigmoid colon are retained within 10-12 cm. It is connected to the right side of the large intestine. For prophylactic purposes, all nearby lymph nodes are removed.

If the tumor is located in the sigmoid colon, the latter is resected, and the descending colon is sutured to the rectum to restore bowel continuity.

In the case of a lesion in the outermost part of the large intestine, that is, the rectum, the following options are possible:

• Removal of the malignant mass, tumor excision.
• Transanal excision of the wall.
• Complete removal of the organ with lower anterior resection.
• Removal of the organ without preserving the anal sphincter with colostomy placement.

At an early stage of rectal cancer development, transanal layer-by-layer removal of the mass is performed. This method is considered sparing, since it makes it possible to preserve the organ.

Indications for organ-preserving resection of rectal carcinoma are:

• small size of the tumor (not more than 3 cm);
• the tumor is movable and not adherent to the surrounding tissues;
• no more than ⅓ of the colon is affected by the cancer.

Partial resection may be accompanied by removal of the underlying tissue and lymph nodes.

In cases of rectal cancer without penetration into surrounding tissues (T1-T2), total removal of the organ is performed without preoperative radiation therapy. When the tumor is located in the upper ampulla of the rectum, partial removal with a rim of surrounding healthy tissue is done.

For 2-3 stage cancer located in the lower ampulla, a combination of preoperative preparation and organ removal is used.

If the mass is found in the middle ampulla, pre-operative radiation is performed, and radiation or chemotherapy is administered after surgery.

Chemotherapy

Chemotherapy for colorectal cancer may be used after surgical resection of the tumor to prevent recurrence.

In inoperable forms, chemo is done as palliative care, that is, it is aimed at increasing the duration and improve the quality of life.

According to current clinical guidelines, the colorectal cancer chemotherapy should be based on 5-fluorouracil and folic acid (5-FU/FA regimen) or a combination with oxaliplatin (FOLFOX regimen).

Recently, active agents that are taken as tablets and are converted to 5-fluorouracil only in the body (capecitabine, UFT) have also become available. Capecitabine can be used as monotherapy or in combination with oxaliplatin.

The modern improvement of drug therapy of colorectal cancer consists in combining cytostatics with targeting drugs that block the action of tumor-specific growth factors - epidermal (EGF) and vascular (VEGF).

Possible chemotherapeutic regimens:

• oxaliplatin/leucovorin/5-fluorouracil;
• oxaliplatin/capecitabine+bevacizumab;
• irinotecan/leucovorin+bevacizumab/cetuximab/panitumumumab

Radiation therapy

Radiation may be used before surgery (preoperative or neoadjuvant therapy) to reduce the size of the mass and thus facilitate its surgical removal. It may also be administered after surgery to prevent continued tumor growth in the rectum.

The radiation therapy schedule depends on how much of the colon is affected by the neoplasm, and the extent of the cancerous process.

• In the presence of a primary tumor in the colon, radiation exposure is applied to the entire volume of the formation, lymph nodes are included in the process when the size is more than 1.5 cm.
• At 2-3 stages of cancer, the impact is on the entire area of the lesion, retreating on the sides of 1.5-2 cm, affecting the peritoneal space, fiber. Radiation exposure extends to all lymph nodes detected on CT or MRI near the tumor.
• For 3-4 stages, the radiation area includes neighboring organs, iliac lymph nodes, fiber, vessels.

Prevention

Diet

To prevent recurrences of the disease, it is necessary to adhere to the rules of rational nutrition. Exclude meat from the diet. Consume more plant foods containing fiber, pectin, vitamins and trace elements. Proteins of animal origin are replaced by vegetable proteins.

Motor activity

Increasing motor activity is of great importance in the prevention of the disease. Hypodynamia and sedentary lifestyle are among the provoking factors in the development of the disease. This can be both exercises for home, and therapeutic physical training. Important are breathing techniques, deep diaphragmatic breathing.

Removal of polyps

If polyposis growths are detected in the colon, it is recommended to remove them with subsequent determination of the histological type of cells. This is of fundamental importance in the prevention of the disease.

Prognosis

The best prognosis for colorectal cancer is when the tumor is detected early. In such cases, surgical treatment brings the best results. The survival rate at the first stage of the disease is more than 95%. At the second stage it is 50-70% and less than 30% at the third stage. After palliative colon surgery, the survival rate is approximately 6-12 months.

Second opinion

In the case of such a complex and dangerous disease as colorectal cancer, a second opinion of a reputable and experienced specialist can help to get answers to a number of questions that are of key importance for treatment strategy. First of all, it concerns the issue of the principal possibility of surgical treatment, as well as the choice of the best surgery type and technique.  Remote advice can also improve the drug treatment (chemotherapy or targeted therapy) plan in terms of the latest scientific and clinical practice. In this regard, the depth of the histological and immunohistochemical analysis of tumor tissue should be brought into focus. An independent expert can point out at missing tests which can significantly influence the choice of medicines. Another important aspect, particularly in advanced bowel cancer, is the advisability of liver metastases surgical removal. In this case, for example, in Germany it is strongly recommended to get a second opinion from specialists at a major specialized center with sufficient experience in this field.

References

1. Johns L. E., Houlston R. S. A systematic review and meta-analysis of familial colorectal cancer risk // Am J Gastroenterol. ‒ 2021. ‒ T. 96, No 10. ‒ C. 2992-3003.
2. Tenesa A., Dunlop M. G. New insights into the aetiology of colorectal cancer from genome-wide association studies // Nat Rev Genet. ‒ 2019. ‒ T. 10, No 6. ‒ C. 353-8.
3. Huxley R. R., Ansary-Moghaddam A., Clifton P., Czernichow S., Parr C. L., Woodward M. The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence // Int J Cancer. ‒ 2019. ‒ T. 125, No 1. ‒ C. 171-80.
4. Rasool S., Kadla S. A., Rasool V., Ganai B. A. A comparative overview of general risk factors associated with the incidence of colorectal cancer // Tumour Biol. ‒ 2021. ‒ T. 34, No 5. ‒ C. 2469-76.
5. Raskov H., Pommergaard H. C., Burcharth J., Rosenberg J. Colorectal carcinogenesis--update and perspectives // World J Gastroenterol. ‒ 2020. ‒ T. 20, No 48. ‒ C. 18151-64.
6. Group M. S. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study // Radiology. ‒ 20017. ‒ T. 243, No 1. ‒ C. 132-9.
7. Glynne-Jones R., Wyrwicz L., Tiret E., Brown G., Rödel C., Cervantes A., Arnold D. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up // Annals of Oncology. ‒ 2021.
8. Holland-Frei Cancer Medicine Cloth. / Bast Jr R. C., Croce C. M., Hait W. N., Hong W. K., Kufe D. W., Piccart-Gebart M., Pollock R. E., Weichselbaum R. R., Wang H., Holland J. F.: John Wiley & Sons, 2021.