Transcript Lecture 5-Colorectal Cancer.ppt

R.ALShalfan,K.AlKhayal
Objectives:
1) Epidemiology, Risk Factors
2) Molecular Biology & Pathology
3) Diagnosis , Stages, Screening
4) Therapy
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.
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
Cancer Incidence Report Saudi Arabia 2009
Cancer Incidence Report Saudi Arabia 2009
Risk Factors
 Age
 Adenomas, Polyps
 lifestyle, Diet, Obesity
 Family History of CRC
 Inflammatory Bowel Disease (IBD)
 Hereditary Syndromes
 The incidence of colon cancer rises sharply with
age,beginning at age 50 years.
 The incidence is slightly higher in American men than
women
Colorectal polyps
1. Neoplastic (adenomas).
2. 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.
Modifiable Risk Factors
consumption of red meat
saturated fat
increased risk
refined carbohydrates
alcohol
dietary fiber
vegetables
decreased risk
fruits
antioxidant vitamins
calcium
folate (B Vitamin)
 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.
 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.
Familial cancer
 familial colorectal cancer syndromes are
1.
familial adenomatous polyposis (FAP)
2.
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.
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
Lynch syndrome
 Lynch I
 Lynch II
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.
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.
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
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.
Symptoms associated with CRC
weight loss
loss of appetite
rectal bleeding
change in bowel habits
obstruction
night sweats
abdominal pain & mass
fever
iron-deficiency anemia
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
Site
Investigations
 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. 1998 Mar;6(1):66-78.
Fecal occult blood testing: clinical value and limitations.
 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. 1997 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.
 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. 1994 Jun;8(6):672-6.
Complications in endoscopy of the lower gastrointestinal
tract. Therapy and prognosis.
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.
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
SCREENING
 AVERAGE-RISK SCREENING
 HIGH-RISK SCREENING
staging
staging
Stage 0
Tis, N0, M0
Stage I
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IIIC
Stage IV
T1, N0, M0
T2, N0, M0
T3, N0, M0
T4, N0, M0
T1, N1, M0
T2, N1, M0
T3, N1, M0
T4, N1, M0
Any T, N2, M0
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
staging
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.
 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)
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
 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
Rectal Cancer
 Options
 Low anterior resection
 Transanal local excision
 Abdomino-perineal resection
 Palliative procedure
 Factors influencing choice
2 cm requires
 Level of lesion – distance from dentate line, <
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
 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.
 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.
 FOLFOX is made up of
the drugs
 CapeOx (XelOx) is
made of
 FOL– Folinic
 Cape - capecitabine (Xeloda)
acid (leucovorin)
 F – Fluorouracil (5-FU)
 OX – Oxaliplatin (Eloxatin)
 OX – Oxaliplatin (Eloxatin)
 Recommended for 12
cycles, every 2 weeks
 combination therapy every
3 weeks for 24 weeks
 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.
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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