1. Colorectal cancer
R.ALShalfan,K.AlKhayal

2. Objectives: Epidemiology, Risk Factors Molecular Biology & Pathology
3) Diagnosis , Stages, Screening
Therapy

3. EPIDEMIOLOGY one of the most common cancers in the world
US: 4th most common cancer (after lung, prostate, and breast cancers)
2nd most common cause of cancer death (after lung cancer)
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics,2004. CA Cancer J Clin 2004;54:8–29.

6. Our statistics
Accounting for 11.3% of all newly diagnosed cases in year 2009.
Ranked first among male population and third among female population.
Male to female ratio of 125:100.
The median age at diagnosis was 60 years among males 56 years among females.
Cancer Incidence Report Saudi Arabia 2009

7. Cancer Incidence Report Saudi Arabia 2009

8. Cancer Incidence Report Saudi Arabia 2009
There were 1109 cases of colo-rectal cancer
accounting for 11.3% of all newly diagnosed cases
in year This cancer ranked first among male
population and third among female population.
It affected 617 (55.6%) males and 492 (44.4%)
females with a male to female ratio of 125:100.
The overall ASR was 10.5/100,000. ASR for males
was 12/100,000 and for females 9.4/100,000.
The five regions with the highest ASR were
Riyadh region at 15.7/100,000, Eastern region
at 13/100,000, Madinah region at 12.2/100,000,
Tabuk region at 10.6 /100,000 and Makkah region
at 10.6/100,000. The median age at diagnosis was
60 years among males (range years) and
56 years among females (range years).

9. Risk Factors Age Adenomas, Polyps lifestyle, Diet, Obesity
Family History of CRC
Inflammatory Bowel Disease (IBD)
Hereditary Syndromes

10. The incidence of colon cancer rises sharply with age,beginning at age 50 years.
The incidence is slightly higher in American men than women

11. Neoplastic (adenomas).
Colorectal polyps
Neoplastic (adenomas).
Nonneoplastic (hyperplastic, inflammatory, juvenile,and hamartomatous polyps).
The incidence of colorectal malignancy is two to five times higher in patients with adenomatous polyps than in those without them.
Carcinoma is twice as likely to develop in
patients with multiple polyps as in patients with a single polyp.
Evidence suggests the existence of a common inherited susceptibility.

12. Modifiable Risk Factors
consumption of red meat
saturated fat
refined carbohydrates
alcohol
increased risk
dietary fiber
vegetables
fruits
antioxidant vitamins
calcium
folate (B Vitamin)
decreased risk

13. Red meat and fat intake have the most consistently direct association, and fiber intake has the most consistently inverse association with colorectal cancer.
Several mutagenic compounds in cooked meat have been identified.
The role of fiber was originally seen simply as the provision of bulk to dilute potential carcinogens and speed their transit through the colon.
Micronutrients such as folate, methionine, vitamin D, and calcium may provide protection against oxidative stress at the cellular level.

14. Alcohol Consumption, Acetaldehyde may contribute to free radical formation and proliferative growth of mucosal polyps.
Smoking, 18% higher odds of developing colorectal cancers.
higher for cancers in the rectum compared with those in the colon
Risk was significant among persons who smoked more than 30 years and was dose dependent.
Exercise and Obesity,
reduce inflammation and potentially contribute to reduced free radicals
averaged more than 4 hours per week of moderate exercise demonstrate a 22% and 29% reduction in CRC incidence, respectively
Marshall T, et al. A meta-analysis of the association
of physical activity with reduced risk of colorectal
Cancer Colorectal Dis 2005;7(3):204–213.

15. Familial cancer familial colorectal cancer syndromes are
familial adenomatous polyposis (FAP)
hereditary nonpolyposis colon cancer(HNPCC).
Bishop DT, et al. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 1988;319(9):533–537.

16. Hereditary Colorectal Cancer
Familial adenomatous polyposis
FAP account for <1% of all colorectal cancers
Due to mutation of the adenomatosis polyposis coli (APC) gene
Numerous adenomas appear as early as childhood and virtually 100% have colorectal cancer by age 50 if untreated
Hereditary non-polyposis colorectal cancer / Lynch syndrome
More common than FAP and account for ~1-5% of all colonic adenocarcinomas
Due to a mutation in one of the mismatch repair genes
Earlier age onset (39-46) of colorectal cancer and predominantly involve the right colon
HNPCC also increases the risk of
Endometrial, ovarian, breast ca
Stomach, small bowel, hepatobiliary ca
Renal pelvis or ureter ca

17. Lynch syndrome
Lynch I
Lynch II
Bethesda criteria

18. Inflammatory Bowel Disease
The duration of inflammatory bowel disease is a critical factor in predicting the likelihood of adenocarcinoma.
Cancer develops in about 3% of patients during the first 10 years after the onset of colitis and in an additional 20% during each of the next two decades.
In chronically inflamed or colitic patients, dysplasia is believed to progress from inflammation, to low-grade, to indefinite, to high-grade dysplasia.

19. Molecular Biology & Pathology
CRCs arise from a series of histopathological and
molecular changes that transform normal epithelial cells
Intermediate step is the adenomatous polyp
Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler)
In colon cancer, the most important genetic alteration is a
mutation of the K-ras protooncogene, which is associated with
poorer prognosis.

20. Pathways The chromosomal instability (CIN) pathway
characterized by mutations of the APC, p53, and K-ras genes
80% of tumors develop along this pathway.
The microsatellite instability (MIN) pathway
These tumors have aberrant DNA mismatch repair
is responsible for approximately 20% of carcinomas.
Better prognosis

22. Diagnostic approach
Colorectal cancer is diagnosed during the evaluation of a symptomatic patient or during screening or surveillance of asymptomatic patients.
The symptoms of colorectal cancer tend to be nonspecific.
Symptoms depend on cancer location, cancer size, and presence of metastases.

23. Symptoms associated with CRC
weight loss
loss of appetite
night sweats
fever
rectal bleeding
change in bowel habits
obstruction
abdominal pain & mass
iron-deficiency anemia

24. Examination Signs of primary cancer
Abdominal tenderness and distension – large bowel obstruction
Intra-abdominal mass
Digital rectal examination –can be reached by examining finger
Rigid sigmoidoscope
Signs of metastasis and complications
Cachexia,loss of weight ,loss of appetite
Hepatomegaly (mets)
Bone pain

25. Site

27. Investigations Stool DNA Faecal occult blood
Guaiac test (Hemoccult) – based on pseudoperoxidase activity of haematin
50% sensitivity for colorectal cancers and about 98% specificity.
Dietary restrictions – avoid red meat, melons, horse-radish, vitamin C and NSAIDs for 3 days before test
Immunochemical test (HemeSelect, Hemolex) – based on antibodies to human haemoglobins
Used for screening and NOT diagnosis
Stool DNA
PCR-analysis of sloughed mucosal cells in stool,
seeking genetic alterations associated with
colorectal cancer
Gastroenterologist Mar;6(1):66-78.
Fecal occult blood testing: clinical value and limitations.

28. Double contrast barium enema Does not require sedation
More limited in detecting small lesions
(82.9% sensitivity)
All lesions need to be confirmed by colonoscopy and biopsy
Performed with sigmoidoscopy
Second line in patients who failed / cannot undergo colonoscopy.
Rectal lesions may be missed because of interference by the intrarectal occluding balloon.
Gastroenterology Jan;112(1):17-23.
Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice.
Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS.

29. Colonoscopy/sigmoidoscopy Can visualize lesions ~ 5mm
Colonoscopy is highly sensitive at detecting large (>1 cm) colonic polyps, with a miss rate of only 6%, and is moderately sensitive at detecting (0.6 cm) polyps with a miss rate of about 27%.
Performed under sedation
The overall complication rate is 0.4%
bleeding, infection, perforation (1 in 3000), missed diagnosis, failed procedure, anaesthetic/medical risks
bowel prep, abdominal bloating/discomfort afterwards
Rex DK, Cutler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology
1997;112:24–8.
Surg Endosc Jun;8(6):672-6.
Complications in endoscopy of the lower gastrointestinal tract. Therapy and prognosis.

30. CT colonography
CT colonography is not diagnostic; that is, patients with positive findings must undergo a traditional colonoscopy for biopsy or polypectomy
sensitivity and specificity as high as 92% and 94%, respectively, for patients with polyps or lesions greater than 6 mm have been reported.
A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J
Med 1999;341(20):1496–1503.

31. Other Imaging Endorectal ultrasound
Determine: depth, mesorectal lymph node involvements
No bowel prep or sedation required
Help choose between abdominoperineal resection or ultra-low anterior resection
CT and MRI – staging prior to treatment
Blood tests
FBE – anaemia
Coagulation studies – for surgery
UECr - ?take contrast.
Tumour marker CEA
Useful for monitoring progress but not specific for diagnosis

32. SCREENING
AVERAGE-RISK SCREENING
HIGH-RISK SCREENING

36. staging

37. staging Stage 0 Tis, N0, M0 Stage I T1, N0, M0 T2, N0, M0 Stage IIA
T2, N0, M0
Stage IIA
T3, N0, M0
Stage IIB
T4, N0, M0
Stage IIIA
T1, N1, M0
T2, N1, M0
Stage IIIB
T3, N1, M0
T4, N1, M0
Stage IIIC
Any T, N2, M0
Stage IV
Any T, Any N, M1
Table 1   -- TNM Classification for Colorectal Cancer Staging
From the American Joint Committee on Cancer TNM staging system, ed 6

38. staging

39. TREATMENT OF PRIMARY COLON CARCINOMA
The mainstay of therapy for locoregional colon and rectal carcinoma is surgery.
In colon cancer, adjuvant chemotherapy is administered to reduce the risk of recurrence.

41. Recommendation: When approaching colon resection laparoscopically, every effort should be made to localize the tumor preoperatively. Small lesions should be marked endoscopically with permanent tattoos before surgery to maximize the surgeon’s ability to identify the lesion. Surgeons should be prepared to use colonoscopy intraoperatively if lesion localization is uncertain. (++OO, strong).
Recommendation: We recommend that laparoscopic resection follow standard oncologic principles: proximal ligation of the primary arterial supply to the segment harboring the cancer, appropriate proximal and distal margins, and adequate lymphadenectomy. (++++, strong).
Recommendation: We recommend that laparoscopic resection for rectal cancer follow standard oncologic principles: Adequate distal margin, ligation at the origin of the arterial supply for the involved rectal segment, and mesorectal excision. (+++O, strong)

45. Resection Caecum or ascending colon Right hemicolectomy
Vessels divided – ileocaecal and right colic
Anastamosis between terminal ileum and transverse colon
Transverse colon
Close to hepatic flexure  right hemicolectomy
Mid-transverse  extended right hemicolectomy (up to descending) + omentum removed en-bloc with tumour
Splenic flexure  subtotal colectomy (up to sigmoid)
Descending colon
Left hemicolectomy
Vessels divided – inferior mesenteric, left colic, sigmoid

46. Sigmoid colon
High anterior resection
Vessels ligated – inferior mesenteric, left colic and sigmoid
Anastomoses of mid-descending colon to upper rectum
Obstructing colon carcinoma
Right and transverse colon – resection and primary anastomosis
Left sided obstruction
Hartmann’s procedure – proximal end colostomy (LIF) + oversewing distal bowel + reversal in 4-6 months
Primary anastamosis – subtotal colectomy (ileosigmoid or ileorectal anastomosis)
Intraoperative bowel prep with primary anastomosis (5% bowel leak)
Proximal diverting stoma then resection 2 weeks later
Palliative stent

47. Rectal Cancer Options Low anterior resection Transanal local excision
Abdomino-perineal resection
Palliative procedure
Factors influencing choice
Level of lesion – distance from dentate line, <2 cm requires abdomino-perineal resection to obtain adequate margin
Note: only 3% of tumours spread beyond 2cm
Grade – poorly differentiated  larger margin
Patient factors – incotinence
Mesorectal node status – resect if LN mets

48. Adjuvant Chemotherapy
Stage 1 (T1N0 or T2N0): No adjuvant therapy is recommended.
Stage 2: T3N0 with MSI-H: Adjuvant therapy can be omitted.
Stage 2 colon cancer with MSS or MSI-low and with any one of poor prognostic features: Consider 6 months of adjuvant therapy with 5-FU/Leucovorin or Capecitabine. FOLFOX or CapeOx may be considered.

50. Stage 3 (T1-4,N+): 6 months of FOLFOX or CapeOx.
Consider using a single agent (5-FU/Leucovorin or Capecitabine) in patients who are not candidate of Oxaliplatin-based combination therapy.

51. FOLFOX is made up of the drugs
FOL– Folinic acid (leucovorin)
F – Fluorouracil (5-FU)
OX – Oxaliplatin (Eloxatin)
Recommended for 12 cycles, every 2 weeks
CapeOx (XelOx) is made of
Cape - capecitabine (Xeloda)
OX – Oxaliplatin (Eloxatin)
combination therapy every 3 weeks for 24 weeks

52. Adjuvant Radiotherapy
Consider adjuvant radiation therapy for T4 tumors with penetration into fixed adjacent structure (45 to 50.4 Gy in 25 to 28 fractions with or without concurrent 5-FU or Capecitabine) after discussion at MDT rounds.
At the present time best approach for patients with early stage colon cancer and positive resection margin is not known. Positive margin status should be discussed in MDT regarding role of radiation. Effort should be made by surgeon to mark areas of suspicious margin status.

53. COLORECTAL CANCER POSTRESECTION FOLLOWUP
80% of Recurrences occur within 3 years of curative resection.
Any posttreatment plan should include regular followup during at least these 3 years.

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