Transcript Worldwide Statistics for Colorectal Cancer (CRC)

Malignant disease of colon and
rectum
Seyed vahid hosseini
Professor of surgery
Department of surgery
Colo-rectal ward
Worldwide Statistics for Colorectal
Cancer (CRC)
• Estimated 875,000 cases in 1996
•
 8.5% of all new cases of cancer
• Incidence rates vary by ~20-fold
•
 highest in North America, Western Europe,
•
Australia, New Zealand, Japan
•
 lowest in India, Northern Africa
• Estimated deaths for 1998: 556,000
Estimated New Cancer Cases
of 10 Leading Sites by Gender
for the US 2000
Colorectal Cancer Statistics in
the US
• Second overall leading cause of cancerrelated deaths in the US
• Estimated 130,000 new cases and 56,300
deaths in the year 2000
• Declining trends between 1990 and 1996
 Incidence reate: ~2.1% per year
 Mortality rates: ~1.7% per year
Average Annual Age-Specific US
Incidence and Mortality Rates of
CRC, 1992-1996
Risk Factors for Colorectal
Cancer (CRC)
•
•
•
•
•
•
Aging
Personal history of CRC or adenomas
High-fat, low-fiber diet
Inflammatory bowel disease
Family history of CRC
Hereditary colon cancer syndromes
Risk of Colorectal Cancer
(CRC)
5%
General population
Personal history of
colorectal neoplasia
15%–
20%
Inflammatory
bowel disease
15%–40%
70%–80%
HNPCC mutation
>95%
FAP
0
20
40
60
Lifetime risk (%)
80
100
Familial Risk for Colorectal
Cancer
100
70%
80
Approximat
e
lifetime
CRC risk
(%)
60
40
20
2%
6%
8%
One 1°
One 1°
and two
2°
10%
17%
0
None
One 1° Two 1°
age
<45
Aarnio M et al. Int J Cancer 64:430, 1995
Houlston RS et al. Br Med J 301:366, 1990 Affected
St John DJ et al. Ann Intern Med 118:785, 1993
HNPCC
mutation
family members
Causes of Hereditary
Susceptibility to CRC
Sporadic
(65%–
85%)
Familial
(10%–30%)
Rare CRC
Hereditary
syndromes
nonpolyposis colorectal
(<0.1%)
Familial adenomatous cancer (HNPCC) (5%)
polyposis (FAP) (1%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Clinical Features of FAP
•
•
•
•
Estimated penetrance
for adenomas >90%
Risk of extracolonic
tumors (upper GI,
desmoid, osteoma,
thyroid, brain, other)
CHRPE may be
present
Untreated polyposis
leads to 100% risk of
cancer
Genetics of FAP
•
•
•
Autosomal dominant inheritance
Caused by mutations in APC tumor suppressor
gene on chromosome 5q
Up to 30% of patients have de novo germline
mutations
•
Most families have unique mutations
•
Most mutations are protein truncating
•
Genotype/phenotype relationships emerging
Attenuated FAP

Later onset (CRC ~age
50)

Few colonic adenomas

Not associated with
CHRPE

UGI lesions

Associated with
mutations at 5' and 3'
ends of APC gene
Indications for APC Gene
Testing
•
•
Molecular diagnosis of FAP in patients
who present with:
–
polyposis (>100 adenomas)
–
attenuated FAP
Predictive testing for FAP in blood
relatives of persons with FAP or known
APC mutations
Giardiello FM et al. N Engl J Med, 336:823, 1997
Clinical Features of HNPCC
•
•
•
Early but variable age at
CRC diagnosis (~45
years)
Tumor site in proximal
colon predominates
Extracolonic cancers:
endometrium, ovary,
stomach, urinary tract,
small bowel, bile ducts,
sebaceous skin tumors
Amsterdam Criteria





3 or more relatives with verified CRC in
family
One case a first-degree relative of the other
two
Two or more generations
One CRC by age 50
FAP excluded
Failure to meet these criteria
does not exclude HNPCC
Vasen HFA et al. Dis Colon Rect 34:424, 1991
Cancer Risks in HNPCC
100
80
%
with
cancer 60
Colorectal 78%
Endometrial 43%
40
Stomach 19%
Biliary tract 18%
Urinary tract 10%
Ovarian 9%
20
0
0
20
40
Aarnio M et al. Int J Cancer 64:430, 1995
60
80
Age (years)
Microsatellite Instability (MSI)
•
•
•
10%–15% of sporadic tumors have MSI
95% of HNPCC tumors have MSI at multiple
loci
Routine MSI assays soon available
Normal
Electrophoresis gel
MSI tumor
Adenomatous polyp
•Adenomatous polyp
•Can take 5-10 years for polyp to develop
•Up to 10% of polyps develop into cancer
•Size and histology are risk factors for polyp
to cancer progression
Summary
Risk factors for colon cancer

Inherited

Acquired (sporadic)-adenomatous polyp, IBD
Genetic basis for colon cancer

Inherited (FAP, HNPCC, to be defined)

Sporadic polyp-different pathways
Preclinical models for colon cancer
Summary (continued)
Applications of chemoprevention initially in
animal models and inherited forms of colon
cancer, and then to general population
Determine efficacy of chemoprevention with
surrogate markers
Learning Objectives
• Discuss current recommendations regarding
colon cancer screening and their evidence base.
• Discuss the initial management and work-up of a
patient with a biopsy showing colon cancer.
• Discuss treatment options and follow-up for
both advanced and local disease.
So you want the answers?
• Colonoscopy liberally: Sx, anemia, over
50; (or over 40 if positive FH)
• If they have cancer refer to a surgeon and
an oncologist.
• Do what they suggest you do?
Can we go home now ?
General
• 2002: 148,000 new cases
– 107,000 colonic, 41,000 rectal.
– 57,000 death
• Mainly (90%) adenocarcinomas.
• 90% in people over 50 years
Risk factors for colon ca
• 75 to 80% of colon cancer is in people with no
•
•
risk factors (“sporadic”)
Intermediate risk: personal history of colorectal
polyps or FH of first degree relative w/ colon
cancer or adenomatous polyps.
High-risk: Familial hereditary cancer syndromes
(e.g. Familial adenomatous polyposis, Heredity
nonpolyposis colorectal cancer) or inflammatory
bowel disease.
How do you “prevent” colon
ca?
Prevention
• Fecal Occult Blood testing
• Aspirin
• NSAID’s reduce adenomas in patients w/
high risk familial syndromes
• Calcium: 1200 mg/d prevents recurrent
adenomas in patients w/ adenoma hx
(RCT)
• No evidence for benefit from high-fiber
diets.
People w/ symptoms
• All patients (except menstruating women) with
•
iron-deficiency anemia are candidates for
colonoscopy. Look for a microcytic anemia and
a low Ferritin.
Symptoms of colon cancer include:
–
–
–
–
–
new abdominal pain/abdominal symptoms
change in bowel habits,
blood in the stool
Weight loss
Anemia sx: fatigue
What are the screening
modalities?
Screening Modalities
• Guaic-cards
• Sigmoidoscopy
• Colonoscopy
• Double-contrast barium enema
• Virtual colonoscopy using CT/MRI
• DNA stool tests
FOBT
• 3 consecutive stool samples. Rehydration
•
increases sensitivity, decreases specificity. Pts
should follow special diet.
1993 Minnesota RCT showed that “about a
1000 people would need to be screened
annually over 10 years to prevent one death
from colorectal cancer.” 38% will end up
getting colonoscoped over 13 yrs.
• Am Fam Physician 2002;66:297-302
• No evidence for benefit from a sample
collected during PE.
Double contrast BE
• Winawer et. al. compared DCBE w/
colonoscopy in patients w/ a history of
adenoma. Compared to colonoscopy,
DCBE has a sensitivity of:
– 32% for adenomas less than ½ cm
– 53% for adenomas between 0.6 and 1 cm
– 48% for adenomas over 1 cm.
• Specificity was 85% (i.e. 15% false
pos)
• N Engl J Med 2000:342:1766-72.
Sigmoidoscopy
• Images about ½ of the colon & requires
no anesthesia.
• Obviously less sensitive than colonoscopy,
but perforation rate is 1/10,000 as
compared with 2/1000 with the
colonoscope.
• Typically polyps are not biopsied so that
about ¼ of pts will need a colonoscopy.
Evidence Basis
• FOBT: 3 large RCT’s
• DCBE: not even controlled trials
• Flex sig: controlled studies
• Colonoscopy: “indirect evidence” from the
FOBT & flex sig trials.
• JAMA 2003:289:1288-1296
Surgery
• Resect tumor, mesentery and regional
•
•
mesentery (best 12 lymph nodes).
Thoroughly explore abdomen for metastatic
disease.
There does not seem to be good evidence
concerning primary vs secondary closure of the
colon.
Surgery
• Resect tumor, mesentery and regional
•
•
mesentery (best 12 lymph nodes).
Thoroughly explore abdomen for metastatic
disease.
There does not seem to be good evidence
concerning primary vs secondary closure of the
colon.
Chemotherapy
• No demonstrated benefit for patients w/ stage I
•
•
or II disease.
Stage III: 5-FU and leucovorin; typically 5 days
every 4 weeks for six cycles.
Radiotherapy is used for rectal cancers.
Chemotherapy
• No demonstrated benefit for patients w/ stage I
•
•
or II disease.
Stage III: 5-FU and leucovorin; typically 5 days
every 4 weeks for six cycles.
Radiotherapy is used for rectal cancers.
Metastatic disease
• Resection of up to 3 liver lesions improves
survival.
• Mainstay of therapy is usually
chemotherapy: 5-FU +/- leucovorin.
• Newer drugs include irinotetin.
Chemotherapeutic agents: older
• 5-FU:
– Pyrimidine antagonist; interferes w/
thymidlyate synthesis
– Mucositis, alopecia, myelosuppression,
diarrhea/vomiting.
• Irinotecan (Camptosar):
– Inhibits topoisomerase I which is needed for
DNA synthesis.
– Diarrhea, often serious, is major side effect.
Newer agents
• Oxaliplatin (Eloxatin):
– inhibits DNA sythesis by causing crosslinkages.
– Significant neurotoxicity.
– May show promise for both initial and rescue
therapy.
Newer agents
• Cetuximab (Erbitux):
– Monoclonal Antibody to EGFR (epithelial growth factor
receptor)
– Most common side effect: acne-like rash
• Bevacizumab (Avastin)
– Monoclonal ab to Vascular endothelial growth factor
– 2% risk of GI bleed.
– Can prolong survival
Recurrence
• Usually within 3 to 5 years of surgery.
• Typically in liver, site of original tumor,
abdomen & lung.
• Evidence on surveillance strategies not
great.
• Meta-analysis found that “intensive
surveillance strategies” reduced RR of
death by 20% (absolute risk reduction
7%).
– NEJM 2004:350:2375-82
Surveillance strategies
• History/PE/routine lab tests: Risk of
recurrence greatest in those w/FH & those
diagnosed at age 50 or younger.
• Chest X-ray
• CEA
• CT abdomen (or) US of the liver
• Colonoscopy currently preferred method
How often colonoscopy?
• ESMO: Colonoscopy q5 yrs.
• NCCN: 1 yr after primary (6 mo if
obstructing); q1yr if abnormal, q3yr if
neg.
• ASCO: Colonoscopy q 3-5 yrs.
• Figueroa: Yearly if polyps or high risk, q 35 yrs if normal.
• Berman: q 3-5 yrs.
– NEJM 2004:350:2375-82
Have a nice weekend!