Colorectal Adenocarcinoma

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 10 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, e.g. lungs, brain and bone, are unusual in the absence of liver metastases.

• Incidence rises sharply with age. Between the ages of 45 and 55, the incidence is about 25 per 100,000. Among those aged 75 and above, the rate is over 300 per 100,000 per year.¹
• Colon cancer is equally common in men and women, but rectal cancer is more common in men.

Risk factors

• Family history of colorectal neoplasia: carcinoma; adenoma under the age of 60 years:²
  • One affected first-degree relative increases risk 2.3-fold.
  • Two or more affected first-degree relatives increase risk 4.25-fold.
  • Index case below 45 years increases risk 3.9-fold.
  • Familial history of colorectal adenoma increases risk 2-fold.
• 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 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, e.g. asbestos exposure.
• History of small bowel cancer, endometrial cancer, breast cancer or ovarian cancer.

• 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. Approximately 55% of patients present with advanced colorectal cancer (spread to the lymph nodes, metastasised to other organs, or so locally invasive that surgery to remove the primary tumour alone is unlikely to be sufficient for cure).¹
• 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.

• Diverticular disease
• Irritable bowel syndrome
• Inflammatory bowel disease
• Local rectal pathology, e.g. haemorrhoids
• Anal cancer
• Ischaemic colitis
• Pneumatosis coli

• Full blood count and liver function tests.
• Proctoscopy with or without sigmoidoscopy if available but don't delay referral.
• 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. At colonoscopy, up to 30% of subjects with distal colonic neoplasms have proximal lesions (up to 20% of these may be advanced).³
• Barium enema may be used if colonoscopy fails to visualise the caecum and/or the patient is unable to tolerate the procedure.
• Computed tomographic (CT) colonography is an effective, safe method for examining the colon and rectum to detect abnormalities such as polyps and cancer.⁴
• Liver ultrasound, (occasionally intrarectal 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 no use in screening but can be helpful in predicting relapse in patients after surgery suitable for further resection).

Pipelle endometrial sampling has a role in screening for hereditary non-polyposis colorectal carcinoma; it is prudent to screen for gynaecological tumours in mutation positive families, irrespective of family history, as 40% of female gene carriers develop endometrial carcinomas.⁵

• Patients over the age of 50 years with any of the following symptoms over a period of six weeks should be urgently and appropriately investigated:
  • Rectal bleeding with a change in bowel habit to looseness or increased frequency.
  • Rectal bleeding without anal symptoms.
  • Palpable abdominal or rectal mass.
  • Intestinal obstruction.
• All patients with iron-deficiency anaemia without other obvious cause should be thoroughly investigated for colorectal cancer.

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 mucosa
  • 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)

Surgery remains the definitive treatment for apparently localised colorectal cancer. Both radiotherapy and chemotherapy can improve survival rates after potentially curative surgery, and chemotherapy prolongs overall survival in patients with advanced disease.⁶

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 perioperative morbidity.²
• Right hemicolectomy: for tumours in the caecum, ascending and proximal transverse colon.
• Left hemicolectomy: if in distal transverse colon or descending colon.
• Sigmoid colectomy: for tumours of the sigmoid colon.
• Anterior resection: if in low sigmoid or high rectum. Anastomosis is achieved at the first operation.
• Abdomino-perineal (A-P) resection: for tumours low in the rectum (less than approximately 8 cm from 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.⁷
• Pre-operative high-dose rate brachytherapy can be used before surgery, 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.⁸

Radiotherapy

For cancer of the rectum, it decreases local recurrence (50% of recurrences of rectal cancer occur in the pelvis) and, in advanced disease, it improves quality of life and increases survival by 6-12 months.²

Chemotherapy

• NICE has 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.⁹
• Capecitabine and oxaliplatin are recommended as possible adjuvant treatments after surgery for stage III (Dukes C) colon cancer:¹⁰
  • Capecitabine is given on its own.
  • Oxaliplatin is given together with 5-fluorouracil and folinic acid.
• Irinotecan and oxaliplatin are recommended as possible treatments for people with advanced colorectal cancer:¹¹
  • Irinotecan is given with 5-fluorouracil and folinic acid to people who have not had chemotherapy for advanced colorectal cancer before, or given on its own to people who have already had chemotherapy.
  • Oxaliplatin is always given with 5-fluorouracil and folinic acid.
• Raltitrexed is not recommended for people with advanced colorectal cancer, unless they are taking part in a clinical trial.¹¹
• Bevacizumab in combination with 5-fluorouracil plus folinic acid, with or without irinotecan, is not recommended for people with metastatic colorectal cancer who have not been treated before.¹²

Palliative therapy

• Resection of metastatic disease (hepatic or pulmonary metastases) can lead to 5-year survival rates of 35-58%.²
• Patients with solitary, multiple, and bilobar disease who have had radical treatment of the primary colorectal cancer, are candidates for liver resection.¹³
• 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.

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.²

• 60% are amenable to radical surgery and 75% of these will be alive at 7 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 5 years after diagnosis. Beyond 5 years, relative survival rates decline only slightly (most of those who live this long are cured).
• Survival rates in the UK have been rising steadily over the past 3 decades.
• Overall 5-year survival rates:²
  • Stage I (T1,T2, N0, M0) 80-95%
  • Stage IIA (T3, N0, M0) 72-75%
  • Stage IIB (T4, N0, M0) 65-66%
  • Stage IIIA (T1,T2, N1, M0) 55-60%
  • Stage IIIB (T3,T4, N1, M0) 35-42%
  • Stage IIIC (any T, Any N, M1) 0-7%

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.²
• Nutritional supplements and medication: vitamin supplements containing folic acid, selenium, calcium, regular use of non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy.