Colorectal Cancer

About two thirds of all colorectal tumours develop in the colon and the remainder in the rectum. Most tumours are adenocarcinomas which evolve from polyps, which may be present for ten years or more before malignancy develops. Colorectal cancer is locally invasive but metastatic spread may be evident before local growth produces symptoms. The most common site for metastatic spread is the liver. Other sites (eg, the lungs, brain and bone) are unusual in the absence of liver metastases.

Early diagnosis is essential for effective treatment to provide the greatest chance of survival.

Prevalence

Colorectal cancer is the third most common cancer after breast and lung cancer. Colorectal cancer is the second most common cause of cancer death

The age-standardised incidence rate per 100,000 population in 2008 was 47.2 (29.4 colon, 17.8 rectum). The figures were higher for men than women for both colon and rectal cancers. Occurrence is strongly related to age, with almost three quarters of cases of colorectal cancer occurring in people aged 65 or over.

Risk factors

Family history of colorectal neoplasia: carcinoma; adenoma under the age of 60 years.

Past history of colorectal neoplasm: carcinoma, adenoma.

Inflammatory bowel disease: ulcerative colitis, Crohn’s colitis.

Polyposis syndromes: familial adenomatous polyposis (Gardner’s syndrome), Turcot’s syndrome, attenuated adenomatous polyposis coli, flat adenoma syndrome, hamartomatous polyposis syndromes (Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden’s syndrome).

Hereditary non-polyposis colorectal cancer (HNPCC).

Hormonal factors: nulliparity, late age at first pregnancy, early menopause. Diet: rich in meat and fat; poor in fibre, folate and calcium.

Sedentary lifestyle, obesity, smoking, high alcohol intake.

Diabetes mellitus.

Previous irradiation,

Occupational hazards – eg, asbestos exposure.

History of small bowel cancer, endometrial cancer, breast cancer or ovarian cancer.

Appearance

The presentation depends on the site of the cancer:

Right colon cancers: weight loss, anaemia, occult bleeding, mass in right iliac fossa, disease more likely to be advanced at presentation.

Left colon cancers: often colicky pain, rectal bleeding, bowel obstruction, tenesmus, mass in left iliac fossa, early change in bowel habit, less advanced disease at presentation.

The most common presenting symptoms and signs of cancer or large polyps are rectal bleeding, persisting change in bowel habit and anaemia.

All patients with symptoms suspicious of colorectal cancer must have a thorough abdominal examination and rectal examination.

In some patients, symptoms do not become apparent until the cancer is far advanced.

Jaundice and hepatomegaly indicate advanced disease with extensive liver metastases. Peritoneal metastases with ascites are often also present. 20-25% of patients have clinically detectable liver metastases at the time of the initial diagnosis and a further 40-50% of patients develop liver metastases within three years of primary surgery.

Rarer clinical signs include: pneumaturia, gastrocolic fistula, ischiorectal or perineal abscesses, deep vein thrombosis.

Distinguished interpretation

Diverticular disease

Irritable bowel syndrome

Inflammatory bowel disease.

Local rectal pathology –eg- haemorrhoids.

Anal cancer

Ischaemic colitis.

Pneumatosis coli.

Investigations

Colonoscopy should be offered to patients without major comorbidity to confirm the diagnosis of colorectal cancer. If a lesion suspicious of cancer is detected, a biopsy sample should be sent for histology.

Flexible sigmoidoscopy or barium enema can be used as an alternative to colonoscopy for patients with major comorbidity.

Computed tomographic (CT) colonography can also be used as an alternative if the local radiology service can demonstrate competency in this technique. If a lesion suspicious of cancer is detected on CT colonography, a colonoscopy with biopsy to confirm the diagnosis should be performed.

FBC and LFTs.

Proctoscopy with or without sigmoidoscopy if available

Flexible sigmoidoscope can reach deep enough into the bowel to detect about 60% of tumours.

Colonoscopy is the gold standard for diagnosis of colorectal cancer.

Barium enema may be used if colonoscopy fails to visualise the caecum and/or the patient is unable to tolerate the procedure.

CT colonography is an effective, safe method for examining the colon and rectum to detect abnormalities such as polyps and cancer.

Liver ultrasound (occasionally intra-rectal ultrasound) and CT or magnetic resonance imaging (MRI) are useful in staging. MRI is more specific than CT in showing liver metastases.

Positron emission tomography (PET) is valuable for detection of recurrent colorectal cancer, but has little effect on staging of primary cancer.

No consensus has been reached about the most sensitive method for detection of liver metastases of colorectal cancer. A meta-analysis showed that PET is the most sensitive modality and is also especially valuable for detection of extrahepatic disease. However, no randomised study has yet proved the value of PET in this setting and therefore CT and MRI remain the diagnostic standards. Elevated pre-treatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance (CEA is of no use in screening but can be helpful in predicting relapse in patients after surgery suitable for further resection).

Urgent consultation with specialist

Aged 40 years and older, reporting rectal bleeding with a change of bowel habit towards looser stools and/or increased stool frequency persisting for six weeks or more.

Aged 60 years and older, with rectal bleeding persisting for six weeks or more without a change in bowel habit and without anal symptoms.

Aged 60 years and older, with a change in bowel habit to looser stools and/or more frequent stools persisting for six weeks or more without rectal bleeding.

Of any age with a right lower abdominal mass consistent with involvement of the large bowel.

Of any age with a palpable rectal mass (intraluminal and not pelvic)

Men of any age with unexplained iron-deficiency anaemia and a haemoglobin of 11 g/100 ml or below.

Who are non-menstruating women with unexplained iron-deficiency anaemia and a haemoglobin of 10 g/100 ml or below.

Staging

Contrast-enhanced CT of the chest, abdomen and pelvis should be used to estimate the stage of disease for patients with colon cancer. MRI should be used to assess the risk of local recurrence (as determined by anticipated resection margin, tumour and lymph node staging) in all patients with rectal cancer. Endorectal ultrasound should be offered if MRI shows disease amenable to local excision or if MRI is contra-indicated.

The Dukes’ staging classification is now gradually being replaced by the tumour/node/metastases (TNM) classification:

TX: primary cannot be assessed.

T0: no evidence of primary carcinoma in situ (Tis) – intraepithelial or lamina propria only.

T1: invades submucosa.

T2: invades muscularis propria.

T3: invades subserosa or non-peritonealised pericolic tissues.

T4: directly invades other tissues and/or penetrates visceral peritoneum.

NX: regional nodes cannot be assessed.

N0: no regional nodes involved.

N1: 1-3 regional nodes involved.

N2: 4 or more regional nodes involved.

MX: distant metastasis cannot be assessed.

M0: no distant metastasis.

M1: distant metastasis present (may be transcoelomic spread).

Colorectal cancer can then be staged as follows:

Stage 0: carcinoma in situ (CIS).

Stage 1: cancer growth through the inner lining of the bowel, or into the muscle wall, but no further. There is no cancer in the lymph nodes (T1, N0, M0 or T2, N0, M0).

Stage 2: further local spread of the cancer but no lymph nodes are affected (N0) and the cancer has not spread to another area of the body (M0):

Stage 2a: cancer growth into the outer covering of the bowel wall (T3, N0, M0).

Stage 2b: cancer growth through the outer covering of the bowel wall and into tissues or organs next to the bowel (T4).

Stage 3: lymph node involvement:

Stage 3a: cancer growth into the muscle layer, and between 1 and 3 nearby lymph nodes contain cancer cells (T1, N1, M0 or T2, N1, M0).

Stage 3b: cancer growth into the outer lining of the bowel wall or into surrounding body tissues or organs, and between 1 and 3 nearby lymph nodes contain cancer cells (T3, N1, M0 or T4, N1, M0).

Stage 3c: cancer growth of any local size but has spread to 4 or more nearby lymph nodes (any T, N2, M0).

Stage 4: cancer has spread to other parts of the body (eg, liver or lungs) (any T, any N, M1).

Grading

Colorectal cancer can also be graded according to the cancer cell differentiation:

Grade 1 (low grade): well differentiated.

Grade 2 (moderate grade): moderately differentiated.

Grade 3 (high grade): poorly differentiated.

Wellness Program

Surgery remains the definitive treatment for apparently localised colorectal cancer. Both radiotherapy and chemotherapy can improve survival rates after potentially curative surgery.

If colonic stents are considered for patients presenting with acute large bowel obstruction, CT of the chest, abdomen and pelvis should be offered to confirm the diagnosis of mechanical obstruction, and to determine whether the patient has metastatic disease or colonic perforation.

Surgery

May be performed either to attempt cure (removing the draining lymphatic field) or to relieve symptoms:

One of the most important advances for surgery of rectal cancer has been the concept of total mesorectal excision, which reduces local recurrences and peri-operative morbidity.

Right hemicolectomy: for tumours in the caecum, ascending and proximal transverse colon.

Left hemicolectomy: if in the distal transverse colon or descending colon.

Sigmoid colectomy: for tumours of the sigmoid colon.

Anterior resection: if in the low sigmoid or high rectum. Anastomosis is achieved at the first operation.

Abdomino-perineal (AP) resection: for tumours low in the rectum (less than approximately 8 cm from the anal canal). Permanent colostomy and removal of rectum and anus.

Laparoscopic surgery (including laparoscopically assisted surgery) may be considered as an alternative to open surgery for some people with colorectal cancer.

Pre-operative high-dose rate brachytherapy can be used in patients with cancer in the middle or lower third of the rectum to shrink the tumour. There is evidence for short-term safety and efficacy in reducing tumour bulk but evidence about the advantages of the procedure as an adjunct to surgery and its effect on long-term survival is currently inadequate.

All patients with resectable liver metastases should be considered for surgical resection

Radiotherapy

For cancer of the rectum, radiotherapy decreases local recurrence (50% of recurrences of rectal cancer occur in the pelvis) and it improves quality of life and increases survival by 6-12 months for patients with advanced disease.

Radiofrequency ablation should be considered for colorectal liver metastases in patients unfit or otherwise unsuitable for hepatic resection, or in those who have previously had hepatic resection.

For patients who have previously been treated with chemotherapy, there is evidence that selective internal radiation therapy (SIRT) can prolong time to progression of non-resectable colorectal metastases in the liver.

Chemotherapy

One of the following sequences of chemotherapy should be considered unless contra-indicated:

FOLFOX (= folinic acid plus fluorouracil plus oxaliplatin) as first-line treatment, then single agent irinotecan as second-line treatment; or

FOLFOX as first-line treatment, then FOLFIRI (= folinic acid plus fluorouracil plus irinotecan) as second-line treatment; or

XELOX (= capecitabine plus oxaliplatin) as first-line treatment, then FOLFIRI as second-line treatment.

Raltitrexed should only be considered for patients with advanced colorectal cancer who are intolerant to 5-fluorouracil and folinic acid, or if these drugs are not suitable.

It is recommended that capecitabine or tegafur with uracil (and folinic acid), to be taken by mouth, should be among the first options considered for a person with metastatic colorectal cancer.

Capecitabine and oxaliplatin are recommended as possible adjuvant treatments after surgery for stage III (Dukes C) colon cancer:

Capecitabine is given on its own.

Oxaliplatin is given together with 5-fluorouracil and folinic acid.

Cetuximab in combination with FOLFOX or FOLFIRI is recommended for the first-line treatment of metastatic colorectal cancer only when all of the following criteria are met:

The primary colorectal tumour has been resected or is potentially operable.

The metastatic disease is confined to the liver and is unresectable.

The patient is fit enough to undergo surgery to resect the primary colorectal tumour and to undergo liver surgery if the metastases become resectable after treatment with cetuximab.

Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine is not recommended for the treatment of metastatic colorectal cancer.

Palliative therapy

Resection of metastatic disease (hepatic or pulmonary metastases) can lead to five-year survival rates of 35-58%.

Patients with solitary, multiple, and bilobar disease who have had radical treatment of the primary colorectal cancer, are candidates for liver resection.

For patients with metastatic colorectal cancer, chemotherapy aims to improve survival and quality of life.

About 15% of patients with liver metastases initially judged to be unresectable will become resectable after systemic chemotherapy, with excellent long-term survival.

Follow-up after apparently curative resection

A minimum of two CT scans of the chest, abdomen, and pelvis in the first three years; and Regular serum CEA tests (at least every six months in the first three years).

Future trends

Current research into cancer immunology may lead to advances in gene therapy and prognostic markers useful in identifying those tumours with a high recurrence rate.

Prognosis (Outlook)

Around half of people diagnosed with colorectal cancer survive for at least five years after diagnosis.

60% are amenable to radical surgery and 75% of these will be alive at seven years (or will have died from non-tumour-related causes).

Survival rates relative to age-matched groups without colorectal cancer, are now about 45% at five years after diagnosis. Beyond five years, relative survival rates decline only slightly (most of those who live this long are cured).

Survival rates have been rising steadily over a period of three decades.

Obviation

Lower risk has been linked with:

Lifestyle: infrequent consumption of meat, matching calorie consumption to need, low dietary fat, active lifestyle, not smoking, frequent consumption of vegetables and possibly fruit, high-fibre diet. Nutritional supplements and medication: vitamin supplements containing folic acid, selenium, calcium, regular use of non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy.

Several studies have found that taking aspirin each day reduces the risk of developing colorectal cancer.