Colorectal Carcinoma- An Overview

1. Colorectal Carcinoma- An Overview Dr C. L Chaw ST4, Clinical Oncology Tayside

2. Colorectal Cancer (CRC) • 3rd most common form of cancer and the 3rd leading cause of death in the Western World. • Annual incidence in UK -54/100 000, and 35000 new cases per year,>16000 deaths per year, making it the 2nd most common cause of cancer death in UK • Peak incidence ages: 60-70 yrs old • ♂:♀ ratio for colonic and rectal cancer is 2:3 and 2:1 • Colonic cancer ( 60%) is more common> than rectal cancer (40%)

3. Risk Factors & Aetioloy • Environmental Factors • Genetic • The aetiology is complex, involving interplay of environmental and genetic factors. These factors conspire to change the normal mucosa to a premalignant adenomatous polyp to a frank colorectal cancer over the course of many years

4. Environmental Factors • Diet • Total calories – obesity and ↑ BMI (25-30kg/m2 )↑risk of CRC • ↑ consumption of Meat (red meat) /Fat (saturated) /Protein - ↑ risk of CRC • High Fiber - ↓ risk of CRC • Vegetables/ Fruits – Protective effects due to presence of antioxidants • Lifestyles • Physical inactivity -↑ risk of CRC • Cigarette smoking -↑ risk of CRC • ↑ alcohol consumption -↑ risk of CRC

5. Genetics/Inherited predisposition • +ve family history of CRC, esp in 1st degree relative ≤ 40 yrs old --↑ risk of CRC • 15% of CRC are familial in origins • FAP (Familial Adenomatous Polyposis) • HNPCC (Hereditary Nonpolyposis Colorectal Cancer) /Lynch Syndrome

6. FAP • Autosomal Dominant, mutation of APC gene (5q21) • 1% of all CRC • Development of hundred to thousands of polyps in patients in their teen-30s, almost 100% progress to CRC if not surgically resected • Extracolonic features: benign or malignant • Benign:mandibular osteoma, epidermal cyst • Gardner’s syndrome- desmoid tumour, osteoma and adematous polyps • Malignant: thyroid CA, brain tumours (Turcot’s Syndrome), duodenal and ampullary CA.

7. HNPCC • Autosomal Dominant, mutation of mismatch repair genes –hMLH1,hMLH2, hMSH6, hPMS1 • 3% of all CRC • Presence of up 100 colonic polyps ( hence nonpolyposis), preferentially in right or proximal colon • Type I and Type II (distinguished by extracolonic tumours originating in stomach, small bowel, bile duct. Pelvis, ureter, uterus, bladder, ovary, skin) • Mean age of developing Ca ≈40 yrs old • Lifetime risk of Ca in HNPCC is ≈80% for CRC, 40% for endometrial Ca.

8. HNPCC (Amsterdam Criteria) • Criteria 1: • ≥ 3 family members with CRC, one of whom is 1st degree of the other 2 • 2 successive affected generations • 1 or more cancer diagnosed < 50 years old • FAP excluded • Criteria 2: • ≥ 3 family members with HNPCC related cancer, one of whom is the 1st degree of the other 2 • 2 successive affected generation • 1 or more cancer diagnosed < 50yrs old • FAP excluded Lab testing of MSH 1&2 and PMS 1&2

9. Pathogenesis • Vogelstein model • Multistep to carcinoma formation • Mutation of APC gene –polyposis • K-RAS (40-50%), P53, SMAD mutation • DCC gene helps to initiate metastatic potential • Other pathway through MSI (DNA microsatellite instability) - HNPCC

10. Features of tumour

11. Spread • Adjacent organs – small/ large bowel, bladder, uterus • Transcoelomic spread- peritoneal disease • Regional lymph node involvement ( 40-70%) at presentation – usually follows the supplying blood vessels– pararectal, hypogastric, pre-sacral) • Haematogenous – liver ≥ lung ≥ bone and brain • 25-30% patients at presentations, the tumour will have spread either locally or distant sites, and will be unsuitable for radical treatment

12. Assessment & Management: • History • Presenting complaints • Family history • Systemic enquiries • Physical examination (PR examination) • Investigations • Treatments

13. Signs & Symptoms • Symptoms • Lower GI bleeding • Altered bowel habits • Abdominal pain • Weight loss • Loss of appetite • Obstructive symptoms – vomiting, unable to pass wind, severe abdo pain

14. Signs • Inspection: Jaundice, pallor , (freckles around the lip, buccal mucosal –Peutze Jeghers) • Palpable abdominal / rectal mass–don’t forget about the liver –hepatomegaly – distant mets • PR bleeding – fresh red ( left-sided colon/ rectum), malena (right-sided colon) • Alarming signs –Abdominal distension, peritonism, rebound tenderness, tingling bowel sound – bowel obstruction, perforation. • Pulmonary signs and neurological signs can sometime present if the disease is advanced.

15. Signs

16. Investigations • FBC ( Iron –deficiency anaemia ) • U+E • LFT ( metastatic disease ) • CEA (carcinoembryonic antigen), is raised in 85% of patients with CRC, higher value associated with worse prognosis

17. Investigations • AXR ( if suspicious of SBO/ BO) • Double contrast barium enema • Colonoscopy with biopsy, Flexi/ rigid sigmodoscopy • CT scan –Thorax, abdo • USS liver - liver metastasis • Pelvic MRI –particularly for rectal Ca – To asses CRM (Circumferential resection margin) • Endo-anal USS to asses nodal involvement in rectal Ca

18. Investigations

19. Investigations

20. Investigations

21. Screening • 50-75 years old • FOB; higher false positive rate • Colonoscopy; more specific and better at picking proximal lesion.

22. Staging (TMN & Dukes )

23. Prognosis ( 5-yr survival) • Stage I (Dukes A): 95% • Stage II (Dukes B1/2): 70-80% • Stage III (Dukes C1/2): 40% • Stage IV (Dukes D): 5%

24. Management • Radical/Curative • Non-metastatic disease • Multimodality approaches • Surgery, chemotherapy, radiotherapy • Palliative • Metastatic disease, inoperable disease • Surgery, chemotherapy, radiotherapy • Symptoms control

25. Management (Surgery- Curative) • Depending on site of lesions: • Caecum, ascending colon, hepatic flexure – right hemicolectomy • Transverse colon – extended hemicolectomy • Splenic flexure, descending colon –left hemicolectomy • Sigmoid colon – high anterior resection • Upper rectum- anterior resection • Defunctioning loop ileostomy is anastomosis <12cm from anal margin • Lower rectum- Abdominal –perineal resection • Total mesorectal resection- high rectum

26. Management (Chemothrapy) • Adjuvant Chemotherapy • T3 disease or node positive tumours (Dukes C disease, selective in Dukes B) – 4-13% survival benefits • Serosal involvement, perforated tumours, extramural vascular invasion or involvement of circumferential margin • 5- Flourouracil based chemo, platinum based chemo • Side effects: nausea, myelosuppression, diarrhoea, neuropathy

27. Management ( Radiotherapy ) • Rectal cancer – reduce rate of local recurrence, downstaging of inoperable disease • Pre-operatively or post-operatively • 25Gy in 5#, 45Gy in 25# • Side effects: erythema (local skin reaction), cystitis, diarrhoea, sterility, urge incotinence, bowel dysfunction

28. Management ( Palliative ) • Inoperable disease, medically unfit patients • Defunctiong Colostomy, Surgical/ endoscopic stenting – for obstructing lesions, aiming to improve quality of life • Resection for isolated liver and pulmonary metastasis if patients are fit. • Radiotherapy – palliation of local symtoms, bony pain, rectal bleeding

29. Management ( palliative ) • Chemotherapy • Patients selection- performance status 1-2 • Aiming to improve quality of life and control of disease • Improves survival by 3-6 months • 5-FU based chemo, platinum based.

30. References: • SIGN Guidelines no 67 • Practical Clinical Oncology – Louise Hanna • Cancer, Principle & Practice of Oncology – DeVita, Hellman et al