Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Colorectal cancers may also be called colon cancer or rectal cancer, depending on where the cancer originated in the large intestine. But these two cancer types are often grouped together because they have many common features. Colorectal cancer is the third most common cancer (approximately 10% of all cancers) in developed countries (in men and women) and the third in cancer-related deaths. Overall, the lifetime risk of developing colorectal cancer is approximately 1 in 23 (4.3%) in men and 1 in 25 (4.0%) in women.

Most of the colorectal cancers (95%) are adenocarcinomas. These cancers start in gland cells that make mucus. Unless a specific type of colorectal cancer is mentioned, colorectal cancer is referred as Adenocarcinoma. Adenocarcinomas are generally (80%) well differentiated (grade 1) type. If there is extracellular mucin accumulation in Adenocarcinoma, it is called “Mucinous (Colloid) Adenocarcinoma” and this type of tumor usually develops in patients with Lynch syndrome or ulcerative colitis. Intracellular mucin accumulation creates signet ring cell carcinoma. Mucinous and Signet Ring Cell Carcinomas of the colon are considered poorly differentiated (grade 3) tumors.

Most colorectal cancers start from small protrusions called "polyps" in the mucosa, and the transformation into cancer usually takes many years. But not all polyps turn into cancer. The likelihood or risk of a polyp turning into cancer depends on the type of polyp. Adenomatous (tubular, villous, or tubulovillous) polyps, also called adenomas, sometimes develop into cancer. Therefore, they are considered precancerous. The risk of cancerization is 5% in tubular adenomas and around 40% in villous adenomas. The process leading to cancer in adenomatous polyps; hyperproliferation, small adenoma, large adenoma (+mild dysplasia), large adenoma (+severe dysplasia/Cis) and invasive cancer sequences and takes an average of 10-15 years. Hyperplastic and inflammatory (pseudo) polyps, which are more common, are generally not precancerous. Cancerization is also rare in hamartomatous polyps, another type of polyps however, they play an important role for colorectal cancer and various non-colorectal cancers increment when seen together with some genetic cancer syndromes (e.g., Peutz-Jeghers syndrome, Cowden syndrome).

As in other cancers, colorectal cancers can be caused by DNA changes (mutations) that activate oncogenes or inhibit tumor suppressor genes. However, inherited mutations are responsible for a small fraction (15-20%) of colorectal cancers. Most of the DNA mutations that cause cancer are acquired mutations and these occur throughout a person's lifetime and are not passed on to their children. Certain risk factors likely play a role in causing these acquired mutations, but it is unknown what causes most of them. In most cases, the first mutation occurs in the APC (adenomatous polyposis coli) gene. The mutation leads to increased cell growth and proliferation due to the loss of "brake" on cell growth. Later, mutations can occur in other genes that can cause cells to grow and spread uncontrollably. Risk factors that can increase a person's likelihood of developing colorectal polyps or colorectal cancer can be grouped into two main groups: "modifiable (lifestyle-related) risk factors" and "non-modifiable risk factors". Colorectal cancer risk factors that we can change include:

• Being overweight or obese
• Not being physically active
• Certain types of diets 
• Low vitamin D levels
• Smoking 
• Alcohol use
• Night shift work (controversial).

Colorectal cancer risk factors that cannot be change are:

• Having one of the hereditary cancer syndromes 
• Family history of colorectal cancer or adenomatous polyp
• Being of high risk of colorectal cancer racial and ethnic origin 
• Advanced age
• Male gender
• Having a history of colorectal polyps or colorectal cancer 
• Inflammatory bowel disease (IBD) 
• Type 2 diabetes (and insulin resistance)
• Presence of other cancers 
• History of radiation therapy
• Other (weak) risk factors – Factors such as cystic fibrosis, acromegaly, renal transplantation history, androgen hormone therapy, cardiovascular disease, uretero-colic anastomosis (uretero-sigmoidostomy), cholecystectomy (controversial), low socioeconomic level, chronic constipation and intestinal microbiota disorder (antibiotics!) have also been reported as risk factors. But in general, these are considered weak risk factors.

SYMPTOMS, DIAGNOSIS & STAGING

Colorectal cancer may not always cause symptoms. When it is symptomatic, although it varies according to the location and extent of the tumor, the following symptoms can be found:

• Rectal bleeding: Bright red blood on the stool, blood mixed with the stool, burgundy red blood, or dark brown or black stool appearance.
• Change in bowel habits (diarrhea, constipation, increased number of defecations): Slimy diarrhea is due to increased mucus secretion and can be seen not only in cancer but also in patients with large villous adenoma.
• Thinning of stool diameter (having stools as thin as a pencil)
• Constantly feeling the need to pass stool (tenesmus) and not being able to relax after defecation (incomplete evacuation): It is because the rectum is filled with a mass instead of stool.
• Abdominal pain, discomfort
• Vomiting (without obstruction)
• Abdominal swelling (increased abdominal diameter)
• Unwanted weight loss, loss of appetite, indigestion
• Weakness, fatigue, paleness: due to anemia
• Difficulty breathing: due to cancer spread to the lungs, anemia, or fluid accumulation in the abdomen.
• Jaundice: an indication of cancer spread to the liver.
• Indication of intestinal obstruction: Sudden onset of abdominal distension, inability to pass gas-stool and vomiting
• Perforation due to acute abdomen condition
• Shock due to severe bleeding.

Your doctor will first inquire about your medical history regarding symptoms and possible risk factors, including family history. If you have symptoms suggestive of colorectal cancer or an abnormal screening test result or if you are in a high-risk group for colorectal cancer, the doctor will recommend one or more of the following examinations and tests to help diagnose or rule out cancer:

• Physical examination 
• Tests to look for blood in the stool
• Tumor markers 
• Colonoscopy 
• Biopsy
• Imaging tests. 

An overview of the current (AJCC 2018) pathological stages (pTNM) of colorectal cancer is as follows:

• Stage 0: Carcinoma in situ (refers to precancerous cells are in mucosa, the innermost layer of colon or rectum wall).
• Stage I: Cancer has grown into the wall of bowel (T1 or T2) but hasn’t spread beyond the muscular coat or into nearby (regional) lymph nodes (N0). There is no spread to distant areas (M0).
• Stage II: The cancer has spread farther into the wall of bowel or spread to a nearby organ (T3 or T4a/b) but hasn’t spread to regional lymph nodes (N0). There is no spread to distant areas (M0). There are three types of Stage II colorectal cancer: IIA, IIB, IIC
• Stage III: The cancer has spread to regional lymph nodes (N1 veya N2). There is no spread to distant areas (M0). Like Stage II colorectal cancer, Stage III colorectal cancer has three sub-stages: IIIA, IIIB, IIIC
• Stage IV: The cancer has spread (metastasized) to one or more distant organs (such as liver, lungs, bone, ovaries, distant lymph nodes) or distant parts of the peritoneum (M1). There are three sub-stages of Stage III colorectal cancer: IVA, IVB, IVC.

Apart from the TNM staging system, there is the Dukes classification, which was developed by British pathologist Cuthberg Dukes in 1932 and has historical significance. The original Duke classification was modified in 1953 by the American researchers Astler and Coller. Later, in 1967, Turnbull revised it again to include metastatic tumors. The “Astler-Coller and Turnbull” staging system is now more commonly referred to as the “Modified Astler Coller (MAC)” classification and is not widely used.

TREATMENT & PROGNOSIS

Stage 0 Colon Cancer Treatment

Stage 0 colon cancer is treated with polypectomy (removal of the polyp through the colonoscope), local excision (removal of the cancerous area through a colonoscope) or partial colectomy (removal of a portion of the colon) on case-by-case bases.

Stage I Colon Cancer Treatment

Treatment approach varies whether the tumor developed in the polyp or not and even if it has developed in the polyp, depends on some other factors:

• Cancers that develop (detected) in the polyp: If the polyp removed by polypectomy or local excision is a pedunculated polyp and completely removed, if the cancer does not extend to the stem of the polyp and there are no cancer cells at the edges of the removed part (1 mm closer to the edge), no further treatment is needed. Surgery (partial colectomy) is required if; the cancer in the polyp is high grade (G3), lymphovascular space invasion (LVI) is positive, presence of cancer cells at the margins of the polyp or difficult to show whether there are cancer cells at the edges, or the polyp cannot be completely removed or needs to be removed in multiple pieces. Partial colectomy should also be performed in cancer developed from a sessile (non-pedunculated) polyp.
• Cancers not detected in the polyp: Partial colectomy (surgery to remove the cancerous part of the colon and nearby lymph nodes) is standard treatment.

In all Stage I cancers, "observation only" is recommended without chemotherapy or other adjuvant treatment after removal of the tumor.

Stage II Colon Cancer Treatment

Surgery (partial colectomy) is needed to remove part of the colon that contains cancer along with nearby lymph nodes. It can be difficult to decide on adjuvant (post-operative) chemotherapy for colon cancers at this stage. Adjuvant chemotherapy may be recommended in the presence of the following factors:

• If the cancer is high grade (Grade 3)
• If there is lymphovascular space involvement (LVI)
• If less than 12 lymph nodes have been surgically removed (in which case it can be difficult to be certain the absence of lymph metastasis)
• If tumor cells are detected at or near the edge of the surgically removed tissue (which means there may be tumor left behind)
• If the cancer has been cancer diagnosed as a result of obstruction or perforation (puncture)
• If MSI-H/dMMR is not detected in MSI and MMR tests performed on tumor cells: For MSI-H/dMMR Stage II cases, follow-up (observation) is generally recommended without adjuvant chemotherapy. For microsatellite stable (MSS) or pMMR Stage II cases, adjuvant chemotherapy is controversial, while some clinics routinely give the tests, other clinics only give it to patients with high risk factors for recurrence (mentioned above).

Stage III Colon Cancer Treatment

Stage III colon cancers have spread to regional lymph nodes but have not yet spread to other parts of the body. Surgery (partial colectomy) to remove the cancerous part of the colon along with the nearby lymph nodes, followed by adjuvant chemotherapy (rarely adjuvant radiotherapy: in some cases, e.g., positive margin, residual disease) is standard treatment for this stage.

Some patients with more advanced disease may be eligible for preoperative (neoadjuvant) systemic therapy (chemotherapy or immunotherapy for MSI-H/dMMR) or chemoradiation. Re-evaluation for surgery can be done for patients with good treatment response and if the tumor is found to be resectable, surgery is performed (followed by chemotherapy again), if it is not found suitable for surgery (if it has not become resectable), systemic treatment is continued. The most commonly used regimens in neoadjuvant chemotherapy are FOLFOX and CAPEOX. Pembrolizumab (Keytruda®) or Nivolumab (Opdivo®) are used in immunotherapy. Chemotherapy options applied as part of chemoradiation are 5-FU/leucovorin (infusion), Capecitabine or 5-FU/leucovorin (bolus: single dose or short-term administration).

For some patients whose general health is not good enough to undergo surgery, primary systemic therapy or chemoradiation treatments may be considered.

If the person presents with intestinal obstruction, there are several options. These are:

• Colectomy (colon resection): “One-Stage Colectomy” (intestinal surgery to remove the tumor and relieve obstruction in one session and without colostomy) or “Colectomy + Colostomy” (colostomy can be closed in another session).
• Diversion Colostomy: this is followed by a second surgery to remove the tumor
• Endoscopic Stent: this is followed by a second surgery (colectomy) to remove the tumor.

Stage IV (Metastatic) Colon Cancer Treatment

In most cases, surgery is unlikely to completely cure these cancers however, if the tumor (primary tumor and liver/lung metastases) can still be surgically removed that would be the treatment of choice. Chemotherapy is given after the surgery. In approximately 20% of those with metastatic disease have metastases that are limited only to the liver and 20% of the liver metastases can be surgically removed. If the liver metastases cannot be removed because of their large size or number, chemotherapy can be given before surgery (neoadjuvant). If the tumors shrink, surgical removal can be attempted later and chemotherapy can be given again after surgery (in some cases, hepatic artery infusion chemotherapy/HAIC can be used). Local treatments called ablation, embolization and stereotactic radiotherapy (SBRT: stereotactic body radiation therapy) are other options that eliminate tumors in the liver. Local therapies can be used in addition to or in place of surgery. In the presence of metastatic disease, if possible, the primary (colon) tumor should be removed as it may cause complications such as obstruction and bleeding. If the tumor cannot be removed, a bypass procedure (colostomy/ileostomy) can be performed. Treatment options for metastatic disease which include surgery are:

• Surgery* (+/- local treatment) → Chemotherapy (*: colon and metastasis surgery in the same session or at two consecutive times).
• Chemotherapy (2-3 months) or Immunotherapy (for MSI-H/dMMR tumors) → Surgery* (+/- local treatment) → Chemotherapy (*: colon and metastasis surgery in the same session or at two consecutive times).
• Colon surgery → Chemotherapy (2-3 months) → Metastasectomy (+/- local treatment) → Chemotherapy.

With an occurrence rate of 13%, peritoneal metastasis is the third most common colorectal metastatic disease after liver and lung metastases. Colorectal peritoneal metastasis (CPM) alone is also observed in about 30% of recurrences. Since the 1990’s, an aggressive curative approach has been proposed for selected patients with CPM. This treatment includes cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and should be performed in highly specialized (tertiary) centers.

Most patients with stage IV cancer will receive systemic therapy (as a primary treatment or in addition to surgery) to control the cancer. This treatment includes chemotherapy and/or targeted (smart) drug therapies and/or immunotherapy. The following biomarkers need to be researched to decide which, or which ones would be appropriate:

• RAS and BRAF mutations
• HER2 amplification (if RAS or BRAF mutation is present it wouldn’t be necessary)
• MSI/MMR status (if previously has not worked).

For advanced cancers, radiation therapy may also be used to help prevent or relieve cancer symptoms such as pain. This form of treatment can also be used to treat areas of spread such as the lungs or bone. It may shrink tumors for a while but is unlikely to cure cancer.

In cases presenting with intestinal obstruction, there are colectomy (+/- colostomy), diversion (diverting) colostomy and endoscopic stent options for obstruction. The most appropriate treatment is chosen depending on the patient’s condition.

Recurrent Colon Cancer Treatment

In general, similar actions are taken to Stage IV disease. Enrolling patients in clinical trials is also considered as an option.

Stage 0 (Tis, N0, M0) Rectal Cancer Treatment

Villous adenomas with advanced carcinoma in situ (high grade dysplasia) (except those involving the rectum) are usually treated with surgical procedures such as polypectomy (removal of the polyp by colonoscopy), local excision or trans anal resection. A solid surgical margin of 1 cm should be ensured.

Treatment Of Early (Stage I) Rectal Cancer

Early rectal cancer includes Stage I (T1/2, N0, M0) cancers. Treatment may vary depending on whether the cancer is detected in the polyp or not.

• Stage I cancers detected in the polyp: If the tumor is a T1 tumor detected in a pedunculated polyp and removed completely in one piece during colonoscopy, if the cancer is not high grade and the surgical margins are found to be clean in the removed part (good polypectomy results), local excision is sufficient, and no other treatment is required. Otherwise (if detected in a sessile polyp, if T2 tumor, if it is G3, if not removed in one piece, if the surgical margins are positive or not possible to evaluate the surgical margins correctly), the local recurrence rate is as high as 30-40% and therefore surgery is required.
• Stage I cancers that are not detected in the polyp: Surgery is usually the main treatment for Stage I cancers that are not detected in the polyp, except the patients who received primary chemoradiation therapy because they are not healthy enough to undergo surgery. Small (T1) lesions can be removed via the anus (transanal surgery) using transanal resection or transanal endoscopic microsurgery (TEM). However, if the tumor is T2 in the postoperative pathology, depending on the location of the tumor in the rectum a second surgery (transabdominal surgery) such as low anterior resection (LAR), proctectomy with colo-anal anastomosis or abdominoperineal resection (APR) should be the approach of choice. For cancers that were initially considered to be T2, the transabdominal surgical method (whichever of the 3 above-mentioned operations is appropriate)suitable for the location of the tumor is applied directly. Typically, no additional treatment is required after these surgeries, unless pathological examination of the surgically removed tissue revealed more advanced cancer (Stage II-III) than what was initially considered prior to the surgery (Stage I). Otherwise, adjuvant chemoradiation and/or chemotherapy (exclusively, depending on the case before or after chemoradiation ) can be given (only observation can be sufficient for some low-risk Stage II tumors without chemotherapy).

Treatment Of Locally Advanced (Stage II-III) Rectal Cancer

Locally advanced rectal cancer includes Stage II-III (T3/4 or regional lymph node involvement) tumors.

Most often treatment starts with chemoradiation (5FU/leucovorin or Capecitabine = long-course chemoradiation given in addition to radiotherapy given in 25 fractions -2Gyx25=50Gy-) or radiotherapy (start with radiotherapy alone = short-course radiation therapy/SCRT given at higher doses over a shorter period of time, typically 5 sessions -5GyX5=25Gy-, without chemotherapy). The success rates of the short and long protocol are similar. Neoadjuvant therapy can shrink the cancer and often makes larger tumors easier to remove. It also reduces the risk of cancer recurrence in the pelvis. Stage II patients can be approached by applying adjuvant chemoradiation after surgery instead of starting the treatment with neoadjuvant chemoradiation. The advantages of "chemoradiotherapy first " are tumor shrinkage, increase the possibility of sphincter-sparing procedure, disappearance of lymph nodes and "downstaging" and less radiation damage to the small intestine. The disadvantages are the possibility of not staging correctly, overtreatment in low-stage tumors, and anastomosis and wound complications due to impaired wound healing after radiotherapy. In stage III disease, it is almost always more effective to give radiation before surgery and tends to cause less problems than administration after surgery. Therefore, it is the accepted (standard) approach in most centers. Chemoradiation is usually followed by surgery to remove rectal cancer and nearby lymph nodes, such as lower anterior resection (LAR), proctectomy with colo-anal anastomosis (extended/ultra lower anterior resection), or abdominoperineal resection (APR). Depending on the cancer location in the rectum one of the three procedures are chosen. Furthermore, if the cancer has reached nearby organs, a more extensive operation known as pelvic exenteration may be required. After surgeries, chemotherapy is usually given for about 6 months. The most commonly used regimens are FOLFOX (5-FU/leucovorin + Oxaliplatin) and CAPEOX (Capecitabine + Oxaliplatin). 

For people who cannot receive chemoradiation for any reason, surgery (depending on the situation LAR colo-anal anastomosis proctectomy or APR) may be the first line of treatment. This may sometimes be followed by radiation therapy and/or chemotherapy.

Although in previous studies it has been emphasized that delaying surgery for 4-12 weeks in patients with moderate risk (T3-N0-M0 or T1/2/3-N1-M0 without mesorectal fascia involvement) rectal cancer who received neoadjuvant SCRT (total 25Gy in 5 fractions) increases the rate of pathological complete response (pCR) (10.3% vs. 0.3%) and reduces the postoperative “first 30-day complication” rate (40.6% vs 52.7%); a current study suggest that there was no significant difference between the delayed surgery (SCRT-delay) and the surgery performed within 1 week following SCRT (SCRT-direct surgery) in terms of length of stay in the hospital, admission to the intensive care unit, surgical complications (anastomotic leakage, infection, abscess, etc.), re-operation and death. Only pCR rates were higher in the SCRT-delay group (Reference: Verweij ME, et al. BJS 2023; 110: 839-45).

Metastatic Rectal Cancer Treatment

Stage IV rectal cancers have spread to distant organs such as the liver or lung, or to distant areas of the peritoneum.

If the entire cancer has a chance to be removed (for example, if there are only a few tumors in the liver or lungs), a multimodal treatment approach that necessarily includes surgery would be the most appropriate approach. This can be done in several ways, depending on the timing (order) of treatment modalities:

• Surgery + Chemotherapy (+/-Radiotherapy)
• Chemotherapy + Surgery + Chemoradiation
• Chemoradiation + Surgery + Chemotherapy.

Surgery can be performed to remove rectal cancer and metastases simultaneously (in a single session) or it can be done in different sessions. Surgery to remove rectal cancer will be inferior anterior resection (LAR), proctectomy with colo-anal anastomosis or abdominoperineal resection (APR), depending on where the cancer is located in the rectum.

If metastases in the liver are too large or too numerous to be surgically removed, they can be partially or completely regressed with local treatments such as ablation or embolization.

If the liver is the only area where the cancer has spread, you may be treated with regional chemotherapy (hepatic artery infusion chemotherapy-HAIC) administered with a catheter inserted into the artery going directly to the liver. This may shrink the liver cancer better than systemic (intravenous or oral) chemotherapy.

If the cancer is more extensive and cannot be completely removed with surgery (and there is no need for surgery for intestinal obstruction, etc.), it will likely be treated with chemotherapy and/or targeted drugs (non-surgical). If these treatments shrink the cancer, at this point it can be possible to consider surgery to remove all the cancer. If the cancer does not shrink with the drugs used, a different drug combination can be tried. For people with certain gene changes in cancer cells, treatment with an immunotherapy drug such as Pembrolizumab (Keytruda®) or Nivolumab (Opdivo®) can be another option after the initial chemotherapy. Even if metastases do not respond to drug therapy, one or more of the following treatments may be required to prevent long-term problems such as intestinal bleeding or obstruction and to relieve some symptoms (e.g., tenesmus):

• Surgical removal of cancer (not metastases) in the rectum
• Surgery to bypass rectal cancer (directive colostomy)
• Laser therapy for rectal cancer
• Inserting a stent into the rectum to keep it open
• Chemoradiotherapy.

With an occurrence rate of 13%, peritoneal metastasis is the third most common colorectal metastatic disease after liver and lung metastases. Colorectal peritoneal metastasis (CPM) alone is also observed in about 30% of recurrences. Since the 1990’s, an aggressive curative approach has been proposed for selected patients with CPM. This treatment includes cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and should be performed in highly specialized and tertiary care centers.

Recurrent Rectal Cancer Treatment

If the cancer recurs in the pelvis (local recurrence) surgical treatment is chosen to remove the cancer, if possible. This surgery is usually more extensive than the first surgery. In some cases, radiation therapy and/or chemotherapy may be given during or after surgery (intraoperative radiotherapy).

If the cancer recurs in a distant part of the body (distant recurrence), it is the same as in the treatment of Stage IV rectal cancer. The option of inclusion in clinical trials for the treatment of this group of patients should also be considered.

Treatment Success and Prognosis (outlook)

Many prognostic factors have been reported in colorectal cancers. These are:

• Extent of disease (TNM stage): This is the most important prognostic factor.
• T stage and tumor diameter
• N stage and number of involved lymph nodes
• Surgical margins
• Histological type
• Tumor grade
• LVI (lymphatic and venous invasion) status
• RAS/BRAF/PTEN/TP53 mutations
• Obstruction (occlusion) or perforation
• Factors with uncertain or controversial effect: Distal rectal tumors are considered to have a relatively poor prognosis. Poor prognosis has been reported in HIV-positive or immunocompromised individuals. There are conflicting results regarding the prognostic value of serum biochemical tests and CEA and Ca19.9 levels. The impact of factors such as age, obesity, hereditary cancer syndrome, anastomotic leakage and wound infection on prognosis are controversial.

You can visit our current website “oncosurgery.com.tr” for further information about colorectal cancer and its surgery.