Colorectal cancer

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Colorectal cancer (CRC) remains a significant cause of death in the developed world and an increasing burden in the developing world [1]. When detected and treated at an early stage, CRC is potentially curable through a combination of surgery and adjuvant chemotherapy.

Unfortunately, most tumours do not cause any symptoms until they are locally advanced or metastatic. A significant proportion of tumours removed at surgery have already invaded the bowel serosa, a finding that carries an adverse prognosis. The proportion of late stage colorectal cancers has decreased, at least in the UK, with the advent of FOB testing.

Contents

Epidemiology

Lifetime risk of between 1:18 and 1:20. More common in males. 35000 cases annually in the UK, of which 50-55% will eventually die from the disease. Second highest cancer death after lung cancer[2]

Other links to Cancer Statistics:

  • US: American Cancer Society [3] | Centers for Disease Control and Prevention [4] | National Cancer Institute (SEER) [5]
  • UK: Cancer Research UK [6] | National Statistics Office [7] | Scottish figures [8]

Aetiology

CRC age of diagnosis.png

Risk factors:

Unmodifiable Factors

  • Age
  • Male gender

Family history

For specific genetic syndromes, see genetics below.

Genetics

Twin studies suggest that genetics contributes about 35% to disease causation, while the remaining contributory factors are thought to be mainly environmental.[9][10]

Only about 5% of CRC is thought to be due to major inherited susceptibility genes (as in HNPCC and FAP). In contrast to these highly penetrant genes, there may be a smaller genetic predisposition in a proportion of other cases. It is important to identify the high-risk cases, in order to implement surveillance within families.

Lifestyle Factors

Based mainly on epidemiological studies with caveats about the difficult of excluding confounding factors. Associations with increased relative risk include:

Carcinogenesis

The vast majority of colorectal cancers are sporadic and result from an accumulation of defects in various key cellular functions, loss of which allows uncontrolled growth and eventually metastasis. However, a small proportion of colorectal cancers are clearly hereditary and these have provided useful insights into the process of colorectal cancer development, particularly familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC).

In addition, the ability to examine the bowel using colonoscopy has the allowed the study of precursor lesions to build up a picture of the molecular events that may occur. Several different pathways can lead to inactivation of genes vital to normal cell growth regulation. Adenoma-adenocarcinoma sequence Key genes k-ras, p53, APC.

Prevention & Screening

Chemoprevention

See:

Screening

See also colorectal cancer screening

Population Screening

As one of the most common cancers in the UK, population screening for colorectal cancer would appear to be an obvious solution. Following various pilot schemes, a nation-wide programme using faecal occult blood testing is gradually being rolled out. Nonetheless, screening has several limitations due to the methods used.

High Risk Patients

The overall evidence is in favour of screening certain sub-groups

These groups are also likely to have net benefit if they take aspirin at their highest risk age range as this is now known to be protective, but the risk benefit analysis is complex if the sole benefit is in preventing cancer death as it is only able to shift the risk benefit equation towards benefit when combined with primary cardiovascular prevention which does not give net benefit in middle age by itself[13].

Anatomy

CRC distribution.jpg

Most lesions in the left side of the colon. Drainage of affected area by mesenteric veins and lymphatics. For rectal cancers, spread via mesorectum.

Presentation

Symptoms dependent on size and location of the tumour. Small lesion may be asymptomatic.

Investigation

Investigation is initially aimed at establishing (or excluding) the diagnosis of cancer. Tissue diagnosis is mandatory making colonoscopy the preferred investigative modality. In addition to permitting diagnosis, it allows simultaneous biopsy and removal of polyps. Double-contrast barium enema combined with flexible sigmoidoscopy is also acceptable, but does not allow tissue biopsy. CT colonography is newer technique and is likely to replace barium enema.

In frail patients that cannot tolerate colonoscopy and, therefore, whom surgery is unlikely to be offered, a plain CT of the abdomen and pelvis may suffice, although subsequent diagnosis will be primarily aimed at palliation.

Staging

Having established the presence of cancer, a staging CT is required to exclude metastases, particularly in the liver or lung. For rectal cancers, an MRI is preferred as it is superior for the imaging of the soft tissues planes in the pelvis and will help to determine if neo-adjuvant radiotherapy is required.[14]

PET scans have an increasing role in excluding micrometastases.

Blood Tests

Staging

Several different systems, but broadly similar concepts. Local and systemic spread.

Colorectal Cancer Staging
Classification In situ Stage I/A Stage II/B Stage III/C Stage IV/D Comments
TNM Tis N0 M0 I: T1 N0 M0
T2 N0 M0
IIA: T3 N0 M0
IIB: T4 N0 M0
IIIA: T1/2 N1 M0
IIIB: T3/4 N1 M0
IIIA: Tany N2 M0
IV: Tany Nany M1
Dukes' staging A: No breach of muscularis propria B: Breach of muscularis propria C: LN metastases n.a.
Modified Dukes' A:Limited to mucosa B1: Invasion of submucosa, but not beyond muscularis
C1:Regional lymph node spread
C2: Regional LN and apical LN +ve
D: Distant metastases
Astler-Coller A: No breach of muscularis propria B: Invasion of submucosa or muscularis propria C1/2: As B, but with LN involvement n.a.
Modified Astler-Coller A:Limited to mucosa B1: Invasion of submucosa, but not beyond muscularis
B2: Through muscularis
B3: Adherent or invading adjacent organs.
C1-3: As B, but with LN involvement n.a.
AJCC stage A: Invasion to submucosa B1: invasion, but not through muscularis propria
B2: invasion through muscularis
B3: equiv. to T4 in TNM
C1-C3: equivalent to corresponding grade B, but with LN involvement D: Distant metastases 100

Prognosis

Info bulb.png
Duke Stage5 Yr Survival[15]Yr Survival[16]
A93%90%
B9070
C5930

Short-term survival related to peri-operative course. Longer term survival is influenced primarily oncological factors such as stage and adequate tumour clearence at time of original surgery.[17] Clearly, other co-morbidities are relevant as many older patients may die of causes unrelated to cancer, even with successful treatment.[18]

Survival has improved with time.[19]

Better survival rates seen in US compared to UK. Unclear if improvement due to increased awareness or better clinico-pathological staging (see Stage migration).

Treatment

Neoadjuvant

  • Radiotherapy for low rectal tumours
    • Down stages tumours in terms of to permit surgical resection, but may not alter prognosis associated with pre-radiotherapy stage.
    • An ileostomy may be performed in certain cases, particularly in very large rectal cancers requiring radiotherapy.
    • Short-course vs long-course?
    • With chemoherapy too?
  • Aspirin looks likely to be very useful in those with certain PIK3CA gene mutations associated with their colorectal cancer[20]

Surgery

  • Segmental resection of affected area and its lymph nodes.
  • Low rectal tumours near the sphincter complexes can be difficult to treat. Low anterior resections can be curative, but if close to the dentate line and the sphincters, it becomes technically more difficult and bowel control and continence can be poor (but may be improved with coloplasty). In these situations, obtaining a cure may be safer by performing an abdomino-perineal resection and a permanent stoma.
  • Low anterior resections where the formation of the anastomosis is technically difficult can be covered with a temporary defunctioning stoma.
  • A single liver metastases does not preclude curative resection and a later or simultaneous metastatectomy (liver lobectomy) can be considered.
  • A total colectomy or proctocolectomy is indicated for patients with polyposis syndromes, e.g. Familial adenomatous polyposis.

Chemotherapy

Can be adjuvant following surgical resection or palliative.

Combination of one or more of the following:

See also NICE Guidelines.[21][22]</sub>)

Palliation

Areas of On-going Research

References

  1. Boyle P, Langman JS. ABC of colorectal cancer: Epidemiology. BMJ. 2000 Sep 30;321(7264):805-8.
  2. Cancer Research UK web-page of mortality
  3. American Cancer Society web-site
  4. Centers for Disease Control and Prevention
  5. National Cancer Institute (SEER)
  6. Cancer Research UK web-site
  7. National Statistics Office web-site
  8. Scottish Health Statistics web-site
  9. Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Burt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. The New England journal of medicine. 1988;319:533-7.
  10. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England journal of medicine. 2000;343:78-85.
  11. Stürmer T, Buring JE, Lee IM, Gaziano JM, Glynn RJ. Metabolic abnormalities and risk for colorectal cancer in the physicians' health study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006 Dec; 15(12):2391-7.(Link to article – subscription may be required.)
  12. Friedenreich C, Norat T, Steindorf K, Boutron-Ruault MC, Pischon T, Mazuir M, Clavel-Chapelon F, Linseisen J, Boeing H, Bergman M, Johnsen NF, Tjønneland A, Overvad K, Mendez M, Quirós JR, Martinez C, Dorronsoro M, Navarro C, Gurrea AB, Bingham S, Khaw KT, Allen N, Key T, Trichopoulou A, Trichopoulos D, Orfanou N, Krogh V, Palli D, Tumino R, Panico S, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Monninkhof E, Berglund G, Manjer J, Ferrari P, Slimani N, Kaaks R, Riboli E. Physical activity and risk of colon and rectal cancers: the European prospective investigation into cancer and nutrition. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006 Dec; 15(12):2398-407.(Link to article – subscription may be required.)
  13. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010 Nov 20; 376(9754):1741-50.(Link to article – subscription may be required.)
  14. MERCURY Study Group. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007 Apr;243(1):132-9.
  15. ANZ Journal of Surgery 2002; 72:352-356. Survival from Colorectal Cancer in Victoria: 10-Year Follow-Up of the 1987 Management Survey.
  16. Surgical Tutor.org.uk
  17. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. Journal of the National Cancer Institute 2004;96:1420-5. (Direct link – subscription may be required.)
  18. Gross CP, McAvay GJ, Krumholz HM, Paltiel AD, Bhasin D, Tinetti ME. The effect of age and chronic illness on life expectancy after a diagnosis of colorectal cancer: implications for screening. Annals of internal medicine. 2006 Nov 7; 145(9):646-53.
  19. McArdle CS, McKee RF, Finlay IG, Wotherspoon H, Hole DJ. Improvement in survival following surgery for colorectal cancer. Br J Surg. 2005 Aug;92(8):1008-13.
  20. Liao X, Lockhead P, Nishihara R et al. Aspirin use, tumour PIK3CA mutation, and colorectal-cancer survival N Eng J Med 2012;367:1596-606 DOI:10.1056/NEJMoa1207756
  21. NICE Guidelines on irinotecan, oxaliplatin and raltitrexed for advanced colorectal cancer
  22. NICE Guidance on bevacizumab and Cetuximab
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