Colorectal cancer

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Clinical oncology for students > Colorectal cancer


Epidemiology

Colorectal cancer accounts for just under 13% of all cancer diagnoses in Australia. It is the second most common cancer in both men and women.[1][2]


Risk factors

Colorectal cancers occur with highest frequency in Western societies. A diet high in red meat, tobacco and alcohol use, and a sedentary lifestyle have all been implicated as risk factors. Inflammatory bowel disease is associated with significantly increased risk. Familial syndromes such as Familial Adenomatous Polyposis (FAP) and Lynch Syndrome often lead to development of malignancy at a young age.[3]


Cancer biology

Adenocarcinoma makes up over 90% of malignancies arising in the large bowel. Rare tumours, such as carcinoid, lymphoma, melanoma and gastrointestinal stromal tumours, may also occur.[3]

Adenocarcinoma of the colon was the first malignancy in which the multistep nature of carcinogenesis was described. Many cases progress from normal bowel epithelium, dysplasia, polyp formation, and finally invasion into the submucosa. Each stage is associated with progressive mutations in both tumour suppressor genes and oncogenes.[4]

One of the first genes lost in this pathway is APC. This occurs as a somatic mutation in sporadic cancers. In FAP, a germline APC mutation results in 100's or 1000's of polyps, requiring colectomy around age 20. Routine IHC staining for the mismatch repair proteins should be performed, regardless of family history. Lack of staining is suggestive of Lynch syndrome. Loss of MLH1 in older patients is common. In these cases, demonstrating somatic mutations in BRAF excludes Lynch syndrome.[3] (See Genetics of Cancer chapter).


Clinical presentation

The presentation of colorectal cancer is variable. Non-obstructing tumours in the colon may cause anaemia, rectal bleeding and irregular bowel habits. Rectal tumours may give the sensation of tenesmus. Large bowel obstruction requires emergency surgery.[5]

Less commonly, patients may present with symptoms of metastatic disease such as ascites, jaundice or bone pain.


Diagnosis and staging

In patients with a suspicion of colorectal cancer, the first step to perform colonoscopy to obtain histological diagnosis. Locoregional staging of the rectum is best performed using magnetic resonance imaging or endoscopic ultrasound. CT scan of the abdomen allows detection of nodal and liver metastases. FDG-PET scanning is occasionally used to detect otherwise occult sites of spread in patient who are being considered for curative resection of oligometastases.

Modern staging is performed using the TNM system[6]:

• Stage I: Confined to bowel wall

• Stage II: Invading through bowel wall without nodal metastases

• Stage III: Lymph node metastases

• Stage IV: Distant metastases

The historical Dukes Staging system denoted stage A, B and C which correspond to TNM stages I, II and III respectively.

Prognosis

Patients with stage I disease have an excellent prognosis with 5 year survival above 90%. For stage II-III disease, modern treatment has improved five year survival to near 90% and 70% respectively.[6]

Patients with resectable oligometastatic disease have 5 year survivals of 40-50% in case series. Those with extensive metastatic disease have a median survival of 5-6 months with supportive care; this increases to 24 months with modern systemic regimens.[7]


Management

Early stage disease (Stage I)

Stage I disease has a low risk of recurrence if treated with surgery alone, regardless of the location.[5]


Locally advanced (Stage II-III)

The colon and rectum are treated differently.

  • Colon cancer is typically treated with surgical excision followed by adjuvant systemic therapy utilising a fluoropyrimidine chemotherapy based combination for those with nodal involvement.[8][9] There is a lesser degree of benefit of adjuvant chemotherapy in node negative stage II cancer.
  • Rectal cancer is treated with neoadjuvant chemoradiotherapy given concurrently[10], followed by total mesorectal excision.[5]


Metastatic disease (Stage IV)

Patients with metastatic disease are usually considered incurable. Systemic chemotherapy with combination regimens that include drugs such as the fluoropyrimidines, oxaliplatin and irinotecan have demonstrated improvement in median survival in the first and second line setting.[11] Targeted therapies such as bevacizumab[12] and aflibercept[13] have demonstrated further improvement in response rates and survival when combined with chemotherapy. The anti-EGFR monoclonal antibodies and cetuximab[14] and panitumumab[15] are also effective in treating KRAS wild type metastatic colorectal cancers[16]. Regorafenib, an oral multikinase small molecule inhibitor, has also demonstrated a survival benefit over best supportive care in patients with metastatic colorectal cancer refractory to existing therapies.[17]

A small group of patients with solitary metastases in the liver or lung may be cured with surgical resection of their metastasis.[18] Radiotherapy may be also used palliatively to treat symptomatic lesions.


Follow-up

Regular follow-up with imaging of the abdomen, tumour markers and clinical examination is essential and has been shown to improve survival if isolated metastases are detected.[19] Colonoscopic surveillance for new bowel primaries or adenomas that may be premalignant is recommended every 3-5 years.


Screening and prevention

Colorectal cancer is an ideal malignancy for population-based screening, being highly curable in clinically occult early stages. Current evidence supports biennial faecal occult blood tests[20][21] or alternatively colonoscopy every five years from the age of 50.[22] Australia is implementing immunohistochemical stool sampling at ages 50, 55 and 60 with a plan to move to biennial screening in 2018.[23]


Case examples

Case 1

Mr B, a 45 year old man, presents with rectal bleeding of 4 months duration. Examination demonstrates a mass 7 cm above the anal verge, and biopsy confirms adenocarcinoma.


  • What important staging information is required before an appropriate treatment plan can be developed?

A: The extent of the disease needs to be established by means of imaging. In this situation a CT scan of the chest abdomen would be appropriate as well as a pelvic MRI or endorectal ultrasound.


  • Assuming Mr B has a localised tumour, what would your recommended treatment be?

A: If staging shows that the tumour is confined to the bowel wall (Stage I) then resection should be carried out. Stage II and III should be considered for preoperative chemoradiotherapy prior to surgical resection.


  • Describe how you would follow up Mr B in the event of a complete response to therapy.

A: Surveillance with CEA levels and CT imaging as well as colonoscopies are required.


Case 2

Mrs C, a 68 year old previously fit woman presents to hospital with faeculent vomiting on a background of weight loss, symptomatic anaemia and low back pain.


  • What urgent measures are required for this woman?

A: IV fluids, nasogastric tube, correct anaemia with blood transfusion, abdominal X-ray or CT scan of the abdomen.

She is stabilised and CT imaging of the abdomen is obtained. The scan shows a large obstructing mass in the caecum with dilated small bowel. Multiple liver metastases are seen affecting most lobes as well as some lytic lesions in the lumbar spine.


  • What treatment options are available?

A. i) Resection of caecal primary lesion ii) Palliative radiotherapy to the vertebral metastasis iii) Systemic chemotherapy with biological therapy


  • What is her expected outcome? How would you convey this news to the patient?

A: The cancer is not curable and her prognosis is a median survival of 24 months with systemic treatment.

B: Ensure the patient has support people present and discuss their diagnosis in a private area. Flag that you have serious news, and ensure that you tell the patient the relevant facts. Make sure there is time for the patient to ask any questions.

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Cancer incidence and mortality worldwide: GLOBOCAN 2008 v2.0. Lyon, France: International Agency for Research; 2010 Jan 1. Report No.: IARC CancerBase No. 10. Available from: http://globocan.iarc.fr.
  2. Australian Institute of Health and Welfare. Bowel cancer for Australia. Canberra: Australian Institute of Health and Welfare; 2012.
  3. 3.0 3.1 3.2 Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon, France: International Agency for Research on Cancer; 2000 [cited 2014 May 20] Available from: http://w2.iarc.fr/en/publications/pdfs-online/pat-gen/bb2/BB2.pdf.
  4. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993 Apr 1 [cited 2014 May 20];9(4):138-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8516849.
  5. 5.0 5.1 5.2 Australian Cancer Network Colorectal Cancer Guidelines Revision Committee. Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. Sydney: The Cancer Council Australia/Australian Cancer Network; 2005 Dec 8 [cited 2014 May 20] Available from: http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp106_0.pdf.
  6. 6.0 6.1 Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging handbook. New York: Springer; 2010 [cited 2014 May 20].
  7. Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ 2000 Sep 2;321(7260):531-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10968812.
  8. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009 Jul 1;27(19):3109-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19451431.
  9. Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007 Jun 1;25(16):2198-204 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17470851.
  10. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004 Oct 21 [cited 2014 May 20];351:1731-1740 Abstract available at http://www.nejm.org/doi/full/10.1056/NEJMoa040694.
  11. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000 Aug;18(16):2938-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10944126.
  12. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004 Jun 3;350(23):2335-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15175435.
  13. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012 Oct 1;30(28):3499-506 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22949147.
  14. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007 Nov 15;357(20):2040-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18003960.
  15. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010 Nov 1;28(31):4697-705 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20921465.
  16. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008 Oct 23;359(17):1757-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18946061.
  17. Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, Humblet Y, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). J Clin Oncol 2012 Jan 1 [cited 2014 May 20];30(15):3502 Abstract available at http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/3502.
  18. Morris EJA, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, et al. Surgical management and outcomes of colorectal cancer liver metastases. BJS 2010 Jun 2 [cited 2014 May 20];97(7):1110-1118 Abstract available at http://www.bjs.co.uk/details/article/892375/Surgical-management-and-outcomes-of-colorectal-cancer-liver-metastases-.html.
  19. Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2007 Jan 24;(1):CD002200 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17253476.
  20. Mandel JS, Church TR, Ederer F, Bond JH. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999 Mar 3;91(5):434-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10070942.
  21. Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996 Nov 30;348(9040):1472-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8942775.
  22. Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993 Dec 30;329(27):1977-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8247072.
  23. Australian Government Department of Health. National bowel cancer screening program. [homepage on the internet] Australia: Australian Government Department of Health; 2014 May 13 [cited 2014 May 20; updated 2014 May 13]. Available from: http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/bowel-about.