2. INTRODUCTION
• 2nd
commonest cancer in men and ranks 3rd
in frequency
in women in the western countries
• 2nd
m/c cause of cancer mortality (after Ca Lung)
• Incidence : 35.8/100,000 (USA)
• Developing countries < 10/100,000
• India: incidence - 7/1,00,000
• Median age of diagnosis- 62 yrs
• Unfavorable prognosis if age <40 yrs
SOURCE: RRCR 2007
3. CLINICAL ANATOMY
• Large intestine- Colon and Rectum
• Intraperitoneal- Caecum, Transverse colon
• Retroperitoneal- Ascending colon, Descending colon,
both flexures, initial part and end of Sigmoid
• Significance
– May have compromised sx margins
– Tumor spread from these regions may involve retroperitoneal soft
tissue, kidneys, ureters and pancreas
• Cancer <12 cm anal verge – rectal cancer
• Cancer >12 cm anal verge – colon cancer
7. Adenoma carcinoma sequence
Peak incidence for discovery of benign colorectal
polyp is 50 yrs an development of colorectal
cancer is 60yrs:
s/o 10 yrs span for progression of adenomatous
polyp to cancer
8. CARCINOGENESIS: Adenoma to Carcinoma Pathway
APC
Loss/mutation
Ch. 5q
Normal
Epithelium
Early
Adenoma
Cancer
Hyper-
proliferation
Intermediate
Adenoma
Late
Adenoma
K-ras
Mutation
Ch. 12p (50%)
DCC loss
Ch. 18q
DPC4
Ch. 4
p53
Loss
Ch. 17p
Loss of DNA
methylation
9.
10. Colon Polyps
• The term polyp of the colon refers to a
protuberance into the lumen from the
normally flat colonic mucosa.
• Polyps are usually asymptomatic but may
ulcerate and bleed, cause tenesmus if in the
rectum, and, when very large, produce
intestinal obstruction.
13. Synchronous lesion
• An adenoma that is diagnosed at the same
time as an index colorectal neoplasm is called
a synchronous lesion.
• Thirty to 50 percent of colons with one
adenoma will contain at least one other
synchronous adenoma.
14. Metachronous lesion
• One that is diagnosed at least six months later
is considered metachronous lesion
15. Pathologic classification
• The histologic features and size of colonic
adenomas are the major determinants of their
malignant potential.
• The glandular architecture of adenomas is
characterized as tubular, villous, or a mixture
of the two.
16. Tubular adenomas
• Tubular adenomas account for more than 80
percent of colonic adenomas.
• They are characterized by a network of
branching adenomatous epithelium.
• To be classified as tubular, the adenoma
should have a tubular component of at least
75 percent
17. Villous adenomas
• Villous adenomas account for 5 to 15 percent of
adenomas.
• They are characterized by glands that are long and
extend straight down from the surface to the center
of the polyp.
• To be classified as villous, the adenoma should have
a villous component of at least 75 percent.
19. Polyp base
• Sessile - base is attached to the colon wall,
• Pedunculated if a mucosal stalk is interposed
between the polyp and the wall.
• Adenomas are most commonly found within raised
lesions, up to 27 to 36 percent are flat (having a
height less than one-half the diameter of the lesion)
and up to 1 percent are depressed
20. Dysplasia
• All adenomas are dysplastic.
• A new system that recognizes two grades of
dysplasia - HIGH and LOW.
• Similarly, the older terms "carcinoma in situ"
or "intramucosal adenocarcinoma" should
both be described as high-grade dysplasia
21. Risk factors for focal cancer within an
individual adenoma
• Villous histology,
• Increasing polyp size,
• High-grade dysplasia
22. Polyp size & advanced features
• The proportion of adenomas showing advanced
histologic features (high-grade dysplasia or >25
percent villous histology) increases from
•
– 1 % in small adenomas (<5 mm) to
– 7 to 12 % for medium-sized adenomas (5 to 10 mm)
– 20 % for large adenomas (>1 cm)
23. POLYPS WITH LARGER MASS HAVE
GREATER VOLUME OF
NEOPLASTIC CELLS ,HENCE A
HIGHER LIKELIYHOOD OF
HARBORING CANCER.
POLYP SIZE(mm)
<5
6-15
16-25
16-36
37-42
>42
NUMBER
5137
3581
1069
516
219
677
% WITH INVASIVE
CARCINOMA
0
2.2
18.6
42.8
63.9
78.9
24. Age & advanced features
• Older age is also associated with high-grade
dysplasia within an adenoma, independent of
size and histology
25. Advanced pathologic risk factors
• Adenomatous polyps >1 cm in diameter
• Adenomatous polyps with high-grade
dysplasia
• Adenomatous polyps with >25 percent villous
histology
• Adenomatous polyps with invasive cancer
26. Haggits and colleagues have proposed classification for
polyps containing cancer acc to depth of invasion as:
Level 0: Carcinoma does not invade the
muscularis mucosa (ca –in-situ)
Level 1: carcinoma invades head of
pedunculated polyp(invades through
muscularis mucosae)
Level 2:invasion into neck
Level 3:invasion into stalk
Level 4:invasion into base.(invades
submucosa)
By defination ,all sessile polyps with
invasive carcinoma are level 4.
27.
28. Depth of submucosal invasion in sessile
malignant polyps.
Sm1: invasion into upper third
Sm2: invasion into middle third
Sm3:invasion into lower third.
32. 1.Familial adenomatous polyposis (FAP)
Prototypical hereditary
polyposis syndrome.
Autosomal dominant.
Frequency about
1:10,000.
Account for about 1% of
all colorectal cancers.
33. The APC gene:
The adenomatous polyposis coli (APC) gene is a
tumour suppressor gene located on chromosome
5q21.
Mutation in APC gene is genetic basis attributed to
a truncating mutation in the germ-line APC gene.
The gene expression is 100% in patients with the
mutation.
GENETICS
34. The presentation and severity
of disease is related to the site
of the APC gene mutation.
Proximal APC mutations
(proximal to codon 1249)
produce a milder attenuated
phenotype with sparse
polyposis.
APC mutations between
codons 1250 and 1330 present
with tremendous degrees of
polyposis.
35. APC is universally expressed but mRNA is found in
particularly high levels in normal colonic mucosa
Weighs 300-KDa: found in cytoplasm
APC binds and down regulates cytoplasmic b-catenin,
preventing its translocation to nucleus.
Abnormal APC protein fails to do this, so that b-catenin is
free to enter the nucleus and form a complex which
results in specific transcription of cell cycle stimulating
DNA sequences, and hence proliferation.
The APC protein
36. Common expression of syndrome is:
Multiple colonic polyps(>100)
Polyps start after age 10–20, cancer in
100% at age 40.
All patients will develop cancer of colon
if left untreated.
38. Gastric polyp :mostly are fundic gland
hyperplasia and have limited malignant potential.
Duodenal polyp: adenomatous thus
premalignant.
Duodenal cancer and desmoid disease are major
sources of morbidity and mortality.
Increased risk of adenocarcinoma in the
periampullary region in 3–10% of patients
39. Interesting marker is
CHRPE( congenital
hypertrophy of retinal
pigment cells).
It is a patchy fundus
discoloration.
Detected by indirect
ophthalmoscopy in 75%
of patients.
41. Gardner syndrome (GS)
Characterized by
Colonic adenomatous polyposis
Osteomas: usually present in skull, mandible,
and tibia
–They are virtually always benign.
Soft tissue tumours like epidermoid cysts,
fibromas, desmoid tumors.
42. Desmoid tumors can
present in the
retroperitoneum and
abdominal wall of affected
patients
These tumors seldom
metastasize but are often
locally invasive, and direct
invasion of the mesenteric
vessels, ureters, or walls of
the small intestine can
result in death.
45. MYH POLYPOSIS
An autosomal recessive form of FAP.
Caused by mutation in the MutY homolog (MYH)
gene.
Individuals have fewer than 100 polyps
Colonic microadenomas and duodenal adenomas
are present.
Diagnosis is considered in families where
No APC mutation have been identified
The mode of inheritance is not clearly autosomal dominant
Polyp numbers are low.
46. Attenuated familial adenomatous polyposis
(AFAP).
Approximately 25% of FAP patients remain without
an identified APC mutation
Have lower polyp number(1-50)
Later age at diagnosis
Tendency to spare the rectum.
Lower extra colonic manifestations.
47. Diagnosis
Genetic testing:
DNA from an individual with FAP is analysed to
identify a mutation in APC, which is successful in
about 80% of cases.
Failure to detect an APC mutation does not
exclude a diagnosis of FAP, and may occur for a
variety of reasons including gene deletion AND
some missense mutation.
48. Surveillance
Colonoscopy every 12 months starting at around
age 10 to 12 and continuing until age 35 to 40 if
negative.
Flexible proctosigmoidoscopy at age 10-12 year;
repeat every 1-2 yr until age 35; after age 35 repeat
every 3 yr
Upper GI endoscopy every 1-3 yr starting when
polyps first identified
49. Familial Adenomatous Polyposis (FAP) SCREENING RECOMMENDATIONS
Colorectal cancer 100% Colonoscopy annually, beginning age
10-12 yr
Duodenal or periampullary
cancer
5%-10% Upper GI endoscopy every 1-3 yr,
beginning age 20-25 yr
Pancreatic cancer 2% Possible periodic abdominal
ultrasound
Thyroid cancer 2% Annual thyroid examination
Gastric cancer <1% Upper GI endoscopy as for duodenal
and periampullary
Central nervous system
cancer
<1% Annual physical examination
50. Management of large bowel
Once FAP has been diagnosed, the aim is to perform
prophylactic surgery
Patients with severe polyposis or those people who
are symptomatic, should have surgery as soon as
possible.
In those individuals with milder disease, it can usually
be delayed.
In these circumstances, annual colonoscopy is
recommended to monitor disease.
51. Choice of operation
The surgical options for the management of this
condition are
Proctocolectomy with end ileostomy (with or
without ileal pouch)
Colectomy with ileoanal anastamosis
Proctocolectomy with ileal pouch anal
anastamosis (IPAA).
52. Because ONLY few patients desire a
permanent ileostomy, proctocolectomy with
end ileostomy is rarely done.
In most cases, however, the choice is
between colectomy with IRA or
proctocolectomy with ileoanal pouch
(IPAA) .
Surgical treatment of patients with FAP is
directed at removal of all affected colonic
and rectal mucosa.
53. Restorative proctocolectomy with
IPAA has become the most
commonly recommended operation.
The procedure is usually
accompanied by a distal rectal
mucosectomy to ensure that all
premalignant colonic mucosa is
removed, and the IPAA is fashioned
between the ileal pouch and the
dentate line of the anal canal.
54. An alternative approach is total abdominal
colectomy with ileorectal anastomosis: has
certain advantages.
Technically a simpler operation to perform
Pelvic dissection is avoided.
Theoretically less risk for anastomotic leak from the relatively simple
ileorectal anastomosis
An additional argument : sulindac and celecoxib have been observed to
cause the regression of adenomatous polyps in some patients with FAP.
The disadvantages are that the rectum remains at
high risk for the formation of new precancerous
polyps 12-29% after 20-25 years
55. Patients with Gardner syndrome require
surgical treatment of
Cutaneous cysts
Symptomatic dental anomalies and osteomas
Biopsy and resection for malignancies, including
hepatoblastoma, thyroid carcinoma, osteocarcinoma, gastric
carcinoma, periampullary carcinoma, and biliary tract
carcinoma
Liver transplantation may be required in patients with
hepatoblastoma
56. Patients with Turcot syndrome
require
surgical intervention for diagnosis and
management of CNS lesions, gastric lesions
and hepatic lesions
57. Postop surveillance
After IRA, the retained rectum should be
examined using a flexible sigmoidoscope, every
6–12 months.
Polyps larger than 5 mm should be removed
If severe dysplasia or uncontrolled polyposis
develops, completion proctectomy with or
without ileoanal pouch formation is indicated.
In patients who have had IPAA, the pouch should
be examined by flexible endoscopy annually, and
a careful digital examination of the anorectal
transition zone should be performed.
58. Chemoprevention
Have reduced the number and size of colorectal
adenomas
THESE ARE
i. (NSAID) –sulindac
ii.The COX-2 inhibitor celecoxib
59. 2.Hereditary non-polyposis colon
cancer (HNPCC)
HNPCC is the most frequently occurring
hereditary colorectal cancer syndrome
Autosomal dominant.
It also known as Lynch I and II syndromes.
The Lynch I variants describe patients with
predominantly colorectal cancer at a young age
Lynch II: those with both colorectal and
extracolonic cancers.
60. Mutations in Mismatch
repair genes (MMR ) result
in the HNPCC syndrome
(including hMLH1,
hMSH2, hMSH3, hPMS1,
hPMS2, and hMSH6)
Mutations in hMSH2 or
hMLH1 account for more
than 90% of cases.
61. These mutations produce microsatellite
instability which result in errors in S phase
when DNA is newly synthesized and copied.
Patients with hMSH2 mutation tend to develop
extracolonic cancers, in particular endometrial
cancer, as compared with hMLH1 mutation
carriers
62. To facilitate the clinical diagnosis of HNPCC,
the International Collaborative Group on
HNPCC (ICG-HNPCC) proposed the
Amsterdam Criteria in 1990.
65. Revised Bethesda Guidelines (2002) for Testing Colorectal
Tumours for MSI
Criterion Comment
Colorectal cancer diagnosed in a patient less
than 50 years of age
Presence of synchronous, metachronous
colorectal cancer, or other HNPCC-associated
tumor, regardless of age
Stomach, ovarian, pancreas, ureter and renal
pelvis, biliary tract, and brain, sebaceous gland
adenomas and keratoacanthomas, and small
bowel
Colorectal cancer with MSI-high histology
diagnosed in a patient less than 60 years of age
Tumor infiltrating lymphocytes, Crohn's-like
lymphocytic reaction, mucinous/signet-ring
differentiation, or medullary growth pattern
Colorectal cancer diagnosed in at least on first-
degree relative with an HNPCC-related tumor
diagnosed under age 50
Colorectal cancer diagnosed in two or more first
or second-degree relatives with HNPCC-related
tumors, regardless of age.
66. The mainstay of the diagnosis of HNPCC is a
detailed family history.
20% of newly discovered cases of HNPCC are
caused by spontaneous germline mutations, so a
family history may not accurately reflect the
genetic nature of the syndrome.
Colorectal cancer, or an HNPCC-related cancer,
arising in a person younger than 50 years should
raise the suspicion of this syndrome.
67. Surveillance
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
Colorectal cancer 80% Colonoscopy, every 2 yr
beginning age 20 yr, annually
after age 40 yr or 10 years
younger than earliest case in
family
Endometrial cancer 40%-60% Pelvic exam, transvaginal
ultrasound, endometrial aspirate
every 1-2 yr, beginning age 25-
35 yr
Upper urinary tract cancer 4%-10% Ultrasound and urinalysis every
1-2 yr; start at age 30-35 yr
Gallbladder and biliary cancer 2%-18% No recommendation
Central nervous system cancer <5% No recommendation
Small bowel cancer <5% No recommendation
68. MANAGEMENT
When colon cancer is detected in a patient with HNPCC, an
abdominal colectomy and ileorectal anastomosis is the
procedure of choice.
If the patient is a woman with no further plans for
childbearing, prophylactic total abdominal hysterectomy
and bilateral salpingo-oophorectomy are recommended.
The rectum remains at risk for development of cancer, and
annual proctoscopic examinations are mandatory after
abdominal colectomy.
69. Other forms of cancer associated with HNPCC
are treated according to the same criteria as in
nonhereditary cases.
The role of prophylactic colectomy for patients
with HNPCC has been considered in some
instances, but this concept has not received
universal acceptance.
It is an interesting but well-documented fact
that the prognosis is better for cancer patients
with HNPCC than for non-HNPCC patients
with cancer of the same stage.
70. 3.Peutz-Jeghers syndrome.
Autosomal dominant syndrome
The combination of
hamartomatous polyps of the
intestinal tract
Germline defects in the tumor
suppressor serine/threonine
kinase 11 (STK11) gene are
implicated in this rare disease.
71. Symptoms include:
• GI bleeding
• Intussusception
• Rectal prolapse
• Nasal polyposis (chronic sinusitis) Pigmented macules on the lips
and digits
• Gynecomastia
The most common location of Peutz-Jeghers polyps is in
the uppergastrointestinal tract, specifically the upper
jejunum.
72. There is also an increased risk for extraintestinal
malignancies including
cancer of the breast, ovary ,Cervix, fallopian tubes
Thyroid
Lung
Gallbladder
bile ducts
pancreas
testicles.
73. PJS Diagnostic Criteria (WHO, 2010)
1.3 or more histologically confirmed PJ polyps, or
2. Any number of PJ polyps with a family history of
PJS,
3.Characteristic prominent mucocutaneous
pigmentation with a family history of PJS, or
4.Any number of PJ polyps and characteristic
prominent mucocutaneous pigmentation.
76. Peutz-Jeghers Syndrome surveillance
Upper GI endoscopy 2 yearly.
Small bowel radiography 2 yearly.
Colonoscopy every 2 yr.
Ultrasound.
Haemoglobin levels annually.
Gynaecologic examination, cervical
smear, and pelvic ultrasound annually.
77. Clinical breast exam and mammography at age
25 yr.
Clinical testicular exam and testicular
ultrasound in males with feminizing features.
Nasal endoscopy :to exclude the presence of
nasal polyps.
Potassium titanyl phosphate (KTP) laser has
been used to treat mucocutaneous melanosis of
the lips and hands in a patient with PJS
78. 4.Juvenile polyposis syndrome (JPS)
Most common hamartomatous syndrome
Inherited as an autosomal dominant trait.
A germ-line mutation in the SMAD-4 gene
(18q21) accounts for approximately 50% of
the reported cases of the syndrome.
The term "juvenile" refers to the type of
polyp, not the age of onset of polyps.
79. Characterized by predisposition for
hamartomatous polyps in the (GI) tract,
specifically in the stomach, small intestine,
colon, and rectum.
The average age of onset is approximately18
years.
Associated with congenital birth defects (15%-
20%) of patients including malrotation,
hydrocephalus, cardiac lesions, Meckel's
diverticulum, and mesenteric lymphangioma
80. Although the diagnostic criteria
for juvenile polyposis syndrome
aresomewhat controversial, the
most commonly used criteria
include
i. 3 or more juvenile polyps of the
colon,
ii. polyposis involvingthe entire
gastrointestinal tract,
iii.or any number of polyps in a
member of a family with a
known history of juvenile
polyps.
JUVENILE POLYP
81. In infancy, patients may present with acute or
chronic gastrointestinal bleeding,
intussusception, rectal prolapse, or a protein-
losing enteropathy.
In adulthood, patients commonly present with
either acute or chronic gastrointestinal blood
loss.
Polyps are located most frequently in the recto
sigmoid region.
82. Some individuals may only have four or five
polyps over their lifetimes, whereas others in
the same family may have over a hundred.
Most juvenile polyps are benign; however,
malignant transformation can occur.
Estimates of developing GI cancers in
families with JPS range from 9-50%.
84. 5.Cowden syndrome
Also known as multiple hamartoma-
neoplasia syndrome.
It is an autosomal dominant condition
Complete penetrance by the age 20.
Germ-line mutations in the PTEN tumor
suppressor gene located at 10q22.
Polyps arise more commonly from
85. 80% of patients present with benigntumor
of the hair shaft.
CNS is the second mostinvolved system,
with approx 40% having macrocephaly.
The majority of patients with Cowden's
disease suffer from benign thyroid or
breast disease- projected lifetime risk of
10% for thyroid cancer and of 30–50% for
breast cancer.
86. Annual physical exam with special
attention to thyroid
Mammography at age 30 or 5 yr
before earliest breast cancer case in
the family
87. 6.Hyperplastic polyposis syndrome
Hyperplastic polyps are found commonly in
the large bowel, predominantly in the rectum
and sigmoid.
Because of their small size, hyperplastic
polyps rarely cause symptoms.
However, large or multiple hyperplastic
polyps occasionally can be responsible for
gastrointestinal symptoms.
88. HPS is a rare condition
Characterized by numerous hyperplastic
polyps throughout the large bowel that give
the mucosa a "studded" look.
The endoscopic and radiologic appearance
of the mucosal abnormalities closely
resembles FAP, but hyperplastic polyposis is
not heritable and does not have any
extraintestinal manifestations.
89. 7.Cronkite-Canada syndrome
Characterized by diffuse hamartomatous
polyposis
The polyps are Ectodermal abnormalities such
as alopecia, onychodystrophy, and skin
hyperpigmentation.
The syndrome can be distinguished by the
diffuse distribution of polyps throughout the
entire gastrointestinal tract with exception of
the esophagus, which is spared.
90. Symptoms include diarrhea, weight loss, nausea,
vomiting, and anorexia, as well asparesthesias,
seizures, and tetany related to electrolyte
abnormalities.
Cancer occurs in the stomach, colon, and rectum, but
it remains controversial whether polyps in Cronkite-
Canada syndrome possess malignant potential.
As many as 15% of patients with Cronkite-Canada
syndrome have a malignant tumor at the time of
diagnosis
91. Five-year mortality rates as high as 55
percent have been reported with most
deaths due to gastrointestinal bleeding,
sepsis, and congestive heart failure.
Treatment has included nutritional
support, corticosteroids, acid suppression,
and antibiotics
92. 8.Bannayan-Riley-Ruvalcaba Syndrome
Rare autosomal dominant condition
Includes two other syndromes, both of which, like
Cowden's disease, are associated withgenetic
alterations in the PTEN gene on chromosome 10q23 ,
may be considered a variant of juvenile polyposis
coli.
No increased risk of colorectal carcinoma, other
gastrointestinal malignancies, or extraintestinal
malignancy has been documented in these patients.
93. It is characterized by
hamartomatouspolyps of the gastrointestinal tract
macrocephaly
mental retardation,
delayed psychomotor development
lipid storage myopathy,
Hashimoto's thyroiditis,
hyperpigmentationof the skin of the penis.
94. Research testing of PTEN gene
available
No known published
recommendations for screening
95. Gorlin syndrome (GS),
Also termed nevoid basal cell carcinoma syndrome
commonly presents with
Hamartomatous gastric polyps,
Palmar pits, Short metacarpals,
Odontogenic keratocysts,
96. Intracranial calcifications,
Skeletal malformations,
Neoplasia (basal cellcarcinoma, ovarian
carcinoma, medulloblastoma).
(GS) may present in infancy with congenital
hydrocephalus, cleft lip and palate, lung cysts,
rib and vertebral anomalies, and palmar pits.
97. Children with GS may present with symptoms
of medulloblastoma when younger than 5
years.
Dental anomalies and basal cell carcinoma can
appear in adolescents.
98. • Patients with GS may require surgical management
for the following:
• Craniofacial lesions (cleft lip and palate, jaw cysts,
other mandibular lesions)
• Abdominal masses (mesenteric cysts, lymphatic
cysts, ovarian fibromas)
• Diagnostic and therapeutic interventions for
potential neoplasia within the CNS
(medulloblastoma), skin (basal cell carcinoma), jaw
(fibrosarcoma), ovaries (fibrosarcoma), and
endometrium (adenocarcinoma)
•
99. PATHOLOGY: WHO Classification
• I. Epithelial
– Benign
– Malignant
• Adeno ca >95%
• Mucinous adenoca 17%
• Signet ring cell ca 2-4%
• SCC
• Adenosquamous
• Undiff/ Unclassified
• II. Neuroendocrinal – carcinoid
• III. Nonepithelial
– Leiomyoma/ lipoma/hemangioma
– Leiomyosarcoma
• IV. Hematopoietic/
lymphoid(DLBCL)
• V. Unclassified
• VI. Secondaries
• VII. Tumor like lesions
• VIII. Epithelial atypia in Ulcerative
colitis
100. Prevention
• Guidelines proposed by American College of
Gastroenterology (ACG):
• A diet that is low in fat and high in fruits, vegetables, and
fiber. There may be advantages with cruciferous vegetables
and unprocessed forms of cereal fiber.
• Maintenance of normal body weight through regular exercise
and caloric restriction.
• Avoidance of smoking and excessive alcohol use, especially
beer.
• Dietary supplementation with 3 g of Calcium Carbonate.
101.
102. SPREAD
Local
Multidirectional growth progression
Intramural- bowel wall penetration
Invasion into adjacent organs/ structures
Perineural invasion ~10 cm from primary lesion
•Lymphomatous
• Tumor grade
• LVI
–Normal lymphatic flow along major arteries to three echelons of LN
• Pericolic/ Intermediate /Principal LN
103. • Hematogenous
– Liver- primary site – 40%
– Lung- 2nd
m/c site
– 10-15% have e/o distant metastasis at diagnosis
• Peritoneal seeding/ implantation
– Intraluminal/ serosal sheding/ by surgical
manipulation
104. CLINICAL PRESENTATION
• Related to tumor size/ type/ location
• Ascending colon- large, exophytic/ bulky
– Pain abdomen
– Bleed PR
– Unexplained anemia/ fatigability or weight loss
• Descending colon- infiltrating/annular/obstructive
– Altered bowel habits
– Decreased stool calibre
– Frequent gas pains, bloating, fullness ,cramps
– Mass P/A
106. BARIUM ENEMA
– Complementary for colonoscopy
– Full column Ba enema misses 1/5th
-1/4th
of all colon ca and
2/5th
of all polypoidal lesions
– DOUBLE CONTRAST Ba enema detects almost all
colonic lesions~5mm
– C/I- Acute /severe IBD, suspected perforation, recent
bowel surgery
107. FLEXIBLE SIGMOIDOSCOPY
• Can examine about half of
the colon
• Less incidence perforations
– 1-2/1000 Colonoscopy
– 1/10,000 Sigmoidoscopy
• Misses proximal lesions,
usually used in conjunction
with FOBT or BE
• Sensitivity-90%
/Specificity- 99% (For areas
examined by scope)
108. COLONOSCOPY
• Essential procedure for the proper diagnosis/ t/t / and surveillance
of patients with nonfamilial colorectal polyps/ patients treated
with curative intent
• Detect the lesions and biopsy ± removal
• Rule out synchronous lesions/ anastomotic recurrence - aggressive
colonoscopy indicated in patients with a proven diagnosis
• Asymptomatic patients with well documented FOBT and
symptomatic patients should have a colonoscopy of entire colon
even with normal sigmoidoscopic findings and normal or
equivocal Ba enema
• Limitations- failure to reach / examine fully
– Splenic flexure (10%)
– Hepatic flexure (15%)
– Caecum (20%)
109.
110. • VIRTUAL COLONOSCOPY :Thin section
helical CT using air contrast and glucagon for
bowel sedation and has same efficacy to standard
colonoscopy in detecting lesions≥ 6mm.
• USG: minimal role of TAUSG
– Useful when augmented with retrograde instillation of
water into colon k/a HYDROCOLONIC
SONOGRAPHY
which permits detailed evaluation of bowel wall
permitting more precise preop staging
111. CECT ABDOMEN/ PELVIS
• More accurate for T4 than T2/3lesions
• Asses extraluminal extent of locally advanced dis.
• Limitation: can't detect
– Tumor infiltration of pericolic fat
– Focal tumor spread external to muscularis propria
– Pericolonic LN <1 cm
– Liver mets <1cm
• Overall accuracy staging primary – 70%
• Sensitivity LN detection- 45%
112. • FDG-PET
– To asses response to RT/CCT
– Detect occult areas of recurrent CRC patients considered
for re exploration
• MRI- not superior to CT
• TUMOR MARKER : CEA
– No role in diagnosis/ screening of ca colon
– Correlate with tumor burden and prognosis
– Monitoring tool for patients treated with curative intent
– Post op CEA level is more sensitive indicator of
recurrence
– Normal :
116. TREATMENT
• SURGERY- Primary
• RADIOTHERPY- Adjuvant
• CHEMOTHERAPY-Adjuvant and metastatic
• TARGETED / IMMUNOTHERAPY- Adjuvant
and metastatic
117. SURGERY
• SURGRY is the GOLD STANDARD and
principle therapy of primary and non metastatic ca
colon
– Curative
– Palliative
– Accurate disease staging
– Guides adjuvant treatment
• Likelihood of cure is greater when disease is
detected at early stage
118. SURGERY
• PRINCIPLE: Standard treatment
•WIDE RESECTION of the involved segment including
the lymphatic drainage areas+ mesocolon+enblock
resection of the neighbouring involved organs
•AIM
•To excise the primary lesion with adequate margin ~5 cm
of normal bowel proximal and distal to the tumor
•To reconstitute bowel continuity
•To avoid complications
•To inspect the other viscera for mets
119. • TYPES OF SURGICAL RESECTION
– Right Hemicolectomy
– Extended Right Hemicolectomy
– Left Hemicolectomy
– Segmental resection
– Total Abdominal Colectomy: UC, FAP Syndrome/ FH
• Sx approach determind by the lesion size and
location
• Location determines what region of bowel is
removed, and the extent of its resection is dictated
by its vascular and lymphatic supply
• Minimum of 12-15 LNs should be removed
120.
121.
122. Right Colectomy. A right colectomy is used to remove lesions
or disease in the right colon and is oncologically the most appropriate
operation for curative intent resection of proximal colon
carcinoma.
The ileocolic vessels, right colic vessels, and right
branches of the middle colic vessels are ligated and divided.
Approximately 10 cm of terminal ileum are usually included in
the resection.
A primary ileal-transverse colon anastomosis is
almost always possible.
123. • Extended Right Colectomy. An extended right
colectomy
• may be used for curative intent resection of
lesions located at the
• hepatic flexure or proximal transverse colon.
A standard right colectomy
• is extended to include ligation of the middle
colic vessels
• at their base. The right colon and proximal
transverse colon are resected.
124. • Transverse Colectomy. Lesions in the mid
and distal transverse
• colon may be resected by ligating the middle
colic vessels and resecting the transverse
colon, followed by a colocolonic
• anastomosis.
125. • Left Colectomy. For lesions or disease states
confined to the distal transverse colon, splenic
flexure, or descending colon, a left colectomy
is performed.
• The left branches of the middle colic vessels,
the left colic vessels, and the first branches of
the sigmoid vessels are ligated.
126. • Extended Left Colectomy. An extended left
colectomy is an option for removing lesions in
the distal transverse colon.
• In this operation, the left colectomy is
extended proximally to include the right
branches of the middle colic vessels.
127. • Sigmoid Colectomy. Lesions in the sigmoid
colon require
• ligation and division of the sigmoid branches
of the inferior mesenteric artery. In general,
the entire sigmoid colon should be resected to
the level of the peritoneal reflection and an
anastomosis created between the descending
colon and upper rectum.
• .
128. • Full mobilization of the splenic flexure is often
required to create a tension-free anastomosis.
129. • Total and Subtotal Colectomy. Total or
subtotal colectomy is occasionally required
for patients with fulminant colitis,
attenuatedFAP, or synchronous colon
carcinomas.
• In this procedure, the ileocolic vessels, right
colic vessels, middle colic vessels,and left colic
vessels are ligated and divided.
130. • The superior rectal vessels are preserved. If it
is desired to preserve the sigmoid, the distal
sigmoid vessels are left intact, and an
anastomosis is created between the ileum and
distal sigmoid colon (subtotal
• colectomy with ileosigmoid anastomosis).
• .
131. • If the sigmoid is to be resected, the sigmoidal
vessels are ligated and divided, and
• the ileum is anastomosed to the upper rectum
(total abdominal colectomy with ileorectal
anastomosis).
• If an anastomosis is contraindicated, an end
ileostomy is created, and the remaining
sigmoid or rectum is managed either as a
mucus fistula or a Hartmann’s pouch
132. • Total Proctocolectomy. In this procedure, the
entire colon, rectum, and anus are removed
and the ileum is brought to the skin as a
Brooke ileostomy
133. ADJUVANT THERAPY
BASIS
• Despite curative surgery half of these patients suffer
INCURABLE TUMOR RECURRENCE leading to
cancer related death
• Therefore there is a need of adjuvant therapy to
improve DFS and OS
• Establishment of adjuvant therapy as a standard
treatment in stage III colon cancer based on
improvement in overall survival
• In stage II colon cancer adjuvant treatment remains
controversial
134. Adjuvant Therapy for Colon Ca
• Stage I Colon: Surgery alone
• Stage II Colon: Adjuvant chemotherapy use is
controversial. Indicated beyond stage IIA. Considered
for the following:
– Obstructed or perforated colon cancer
– High-risk histology-LVI +/ extramural spread or PD
histo.
– Involvement of adjacent organs (T4 lesion)
– Inadequate LN sampling (<13 LNs retrieved)
– Elevated preop CEA
– High S-phase fraction
– Tumor not having high level of MSI
– 18q deletion
135. RADIATION• Rationale of adjuvant radiation
– Based on patterns of failure following potential curative
surgery
– Primary determinant of failure patterns in CRC is the
location of tumors in reference to peritoneal reflection
– T/t recommendation are based on the stage of disease and
tumor location in reference to peritoneal reflection. If tumor
is completely above the peritoneal reflection, its treated as
colon ca and if its below, then treated as rectal ca
• RT is an effective but a local modality
• Adjuvant RT role less well defined due to
difference in natural history of Ca colon
136. • All stages combined m/c failure site in ca colon is
abdominal (liver) rather than local
• When local failure, its extrapelvic and symptoms are
less debilitating as seen in ca rectum
• Overall incidence of local failure relatively low,
depends on stage and as high as 35% in stage III & IV
• Higher risk- Partially retroperitonealized regions
• Adjuvant RT use limited to
– Clinical presentations with the risk of local failure is sufficiently
high enough (10%)
– When an adequate dose can be delivered to the site at the
highest risk of failure
137. Failure pattern following curative surgery
Series Stage n LF
(%)
Abdominal
failure (%)
Distant
failure(%)
Gunderson et
al
All
T3-4 and /or
N1-2
91
72
22
17
4
6
7
7
Willet et al All
T3-4 and /or
N1-2
533
395
6
8
11
14
4
Minsky et al All
T3-4 and /or
N1-2
284
229
6
4
8
10
3
5
138. • Indications of RT
– Incomplete excision/ Residual disease
– Positive resection margins
– B2, B3, C2 tumors arising in the immobolized bowel with
close CRM(<1 cm)
– Fixed tumors i.e. caecal and sigmoidal ca
– Tumor a/w perforation/ obstruction/fistula/abscess
139. Technique• Bowel preparation
• Positioning
– NON SIGMOID CA- Lat. Decubitus position by two
parallel opposed fields
– SIGMOID CA- Prone position by 3-4 fields to exclude
small bowel and maximize homogeneity in treatment
volume
• Immobilization
• Target volume delineation
• Simulation- Conventional/CT
• Portal delineation and check films
• Marking on the body
140. • TUMOR BED / FIELD
• Involved segment of large bowel and, when present, the
adjacent organ or structures to which it was adherent or
invading
• If adherent to partially resected organ→ whole organ has
to be treated if within tolerance
• If adherent to structure (pelvic side wall, psoas,
diaphragm) → 3-5 cm margins beyond area of adherence
• Pelvic nodal groups at risk
• Tumor bed + immediate adjacent PA or pelvic LNs+ 3 cm
margin
– Dose- 45- 50 Gy/25#/ 4.5-5 weeks
• KIDNEY SHIELDING after 8#
149. • Critical normal (dose limiting) tissues
– Small intestine: max 45 Gy (30 Gy by WART)
– Liver : 2/3rd
of liver should get <30 Gy
– Kidneys: 2/3rd
of one kidney should get <20 Gy
– Spinal cord: max dose to spinal cord< 50 Gy
150. HISTORICAL
• WART
– To treat the volume at risk with a potentially curative
dose of radiation required for microscopic disease……
the whole abdomen need to receive 45 Gy
– Rationale- High incidence of local failure
– Dose- 30 Gy , then cone down to the primary tumor bed
– Combined results- In 3 series – 5FU- in field (abdominal)
failure rate: 12-50% and 3 yr survival ~50%
– SWOG 8572- T3N1-2M0→ WART+ CVI 5FU f/b a
monthly cycle of CVI 5FU. WART 30 Gy f/b boost of
1.6 Gy for 10#
• Median FU 5yr: DFS-58%, OS- 67%, Toxicity-17%
151. NEWER RT Techniques
– IOERT- Radiation boosting for dose intensification
–T4 tumors with uncertain margins/ invading
adjacent structures
–Preop EBRT + 5-FU based CCT followed by
resection with or without IOERT and postop
systemic therapy
• Advantage
– Visual contrast of target volume
– Homogenous treatment of controlled thickness of tissue
with tumor
– Protection of mobile uninvolved normal tissue
• Disadvantage
– Increase incidence of late normal tissue complications
• Dose- With 9-15 Mev electron, 10-20 Gy normalized at 90%
152. CHEMOTHERAPY
• Adjuvant: Aim is to destroy microscopic
metastatic disease and preventing death from
metastasis as substantially no. of patients treated
surgically with curative intent eventually died of
metastatic disease
• Metastatic setting/Palliative
153.
154. Historical data in favor of chemotherapyHistorical data in favor of chemotherapy
FU, semustine & VCR (MOF)
NSABP-C-01 randomized N(-), N(+) patients BCG
Sx alone
MOF – 5 yrs DFS 58%, OS – 67%
DFS(
%)
OS(%)
Stage II Sx alone 71 72
Sx→
5FU+Levamisole
79 72
Stage III Sx alone 44
Sx→
5FU+Levamisole
61 Death rate ↓ 33%
Rec. rate ↓40%
Sx→ Levamisole NS
NCI 1990
consensus
established
adjuvant CCT
as standard of
care of
patients with
node (+)
resected ca
colon
155. 5FU 370-400mg/m2
+ LCV 200mg/m2
D1-D5x4 weeklyx6 cycles
NCCTG/ NCI 3 yr survival
(%)
RFS(%) Gr 3 toxicity
5FU+LCV(Mayo)x 6 months 83.2 68.6 High
PVI 5FU 200mg/m2
/d x 12
weeks
87.9 80 Less
156. • QUASAR (Quick and Simple and Reliable)
– No difference in survival b/w HDLCV and LDLCV
– Worse survival with levamisole
– No difference in outcomes for dailyx5 and weekly schedules
– Once weekly regimen less toxic
INT-0089 Treatment duration
(weeks)
5 yr DFS(%) 5 yr OS(%)
5-FU +levamisole 52 56 63
5-FU + weekly HDLCV
(Roswell park )
32 59 65
5-FU +LDLCV on d1- 5
(Mayo clinic)
24 60 66
Mayo Clinic schedule of 5-
FU/LCV + levamisole.
24 60 67
157. • LV5FU2 vs Mayo clinic regimen
– LCV 2 hr infusion f/b 5FU bolus and then a 22 hr CVI of
5FU d1-2 x biweekly
– Superior response rate and PFS of LV5FU2
– DFS and OS similar yet toxicities are less with LV5FU2
• Oral fluoropyrimidines- Capecitabine and UFT
– In metastatic disease efficacy comparable with Mayo
schedule
158. MOSAIC Trial: LV5FU2 vs LV5FU2 + FOLFOX-4
LV5FU2 (n =
1,123) (%)
FOLFOX-4 (n =
1,123) (%)
3 yr DFS stage III 66 72
3 yr DFS stage II 84 87
OS NA NA
Grade 3-4 neutropenia 5 41
Neutropenic fever 0 1
Grade 3-4 diarrhea 0 1
Grade 3-4 vomiting 7 11
Neuropathy, any grade 0 92
Neuropathy, grade 3 0 12
Persistent neuropathy, grade 2-3, 1 year after t/t 0 5
159. Commonly Used Fluorouracil (5-FU) Regimens
Regimen Reference Schedule
Mayo clinic Poon et al., 1989 LV 20 mg/m2
, followed by bolus 5FU, 425 mg/m2
each daily d1-d5 repeated 4 weekly for 1st
2 cycles,
than q35d thereafter
Roswell Park Haller et al., 1998 LV 500 mg/m2
over 2 h; 5-FU 500 mg/m2
bolus 1
h into LV infusion. weekly x 6 wks, every 8 wks
Low-dose weekly
LV.,
Jager et al., 1996 LV 20 mg/m2
over 5-15 min, followed by bolus 5-
FU 500 mg/m2
; weekly x 6 wks, every 8 weeks
Protracted venous
infusion
Lokich et al., 1989 5-FU 300 mg/m2
/day by continuous infusion
AIO (weekly 24-h
infusion)
Kohne et al., 1998 LV 500 mg/m2
over 2 h, followed by 5-FU 2,600
mg/m2
over 24 h, weekly
LV5FU2 de Gramont et al.,
1997
LV 200 mg/m2
over 2 h days 1, 2, followed by
bolus 5-FU 400 mg/m2
/day 1 and 2, f/b 5-FU 600
mg/m2
over 22 h, day 1 and 2: every 14 days
Simplified LV5FU2 Adapted from Andre
et al., 1999
LV 400 mg/m2
over 2 h, followed by bolus 5-FU
400 mg/m2
, followed by 5-FU 2,400-3,000 mg/m2
over 46-48 h; cycles repeated every 14 days
160. Commonly Used Irinotecan/5-FU Combination Regimens
Regimen Study Schedule
IFL Saltz et al; 2000 Irinotecan 125 over 90 min, followed by LV 20 mg/m2
by brief
infusion, followed by bolus 5-FU 500 mg/m2
; weekly for 4
weeks , repeated every 6 weeks
FOLFIRI Douillard et al.,
2000
Irinotecan 180 mg/m2
over 2 h; LV 200 mg/m2
concurrently
with irinotecan (can be given in same line through Y
connector); followed by 5-FU bolus 400 mg/m2
, followed by 5-
FU 600 mg/m2
infusion over 22 h. Irinotecan given day 1 only.
All other meds given days 1 and 2. Cycle repeated every 14
days
FOLFIRI
(simplified)
Andre et al.,
1999
Irinotecan 180 mg/m2
over 2 h; LV 400 mg/m2
concurrently
with irinotecan (can be given in same line through Y
connector); followed by 5-FU bolus 400 mg/m2
, followed by 5-
FU 2,400-3,000 mg/m2
infusion over 46-48 h. Cycle repeated
every 14 days
FUFIRI Douillard et al.,
2000
Irinotecan 80 mg/m2
, then LV 500 mg/m2
, followed by 5-FU
2,300 mg/m2
; all drugs given weekly for 6 weeks, repeated
every 7 weeks
161. Selected Commonly Used Oxaliplatin/5-FU Combination
Regimens
Regimen Study Schedule
FOLFOX-4 de Gramont et
al., 2000
Oxaliplatin 85 mg/m2
over 2 h; LV 200 mg/m2
concurrently
with oxaliplatin (can be given in same line through Y
connector); followed by 5-FU bolus 400 mg/m2
, followed by 5-
FU 600 mg/m2
infusion over 22 h. Oxaliplatin given day 1 only.
All other meds given days 1 and 2. Cycle repeated every 14
days
FOLFOX-6 Tournigand et al.,
2004
Oxaliplatin 100 mg/m2
over 2 h; LV 400 mg/m2
concurrently
with oxaliplatin (can be given in same line through Y
connector); followed by 5-FU bolus 400 mg/m2
, followed by 5-
FU 2,400-3,000 mg/m2
infusion over 46-48 h. Cycle repeated
every 14 days
Modified
FOLFOX-6
(mFOLFOX-
6)
Widely used in
current phase III
trials, but not
published
Oxaliplatin 85 mg/m2
over 2 h; LV 400 mg/m2
concurrently
with oxaliplatin (can be given in same line through Y
connector); followed by 5-FU bolus 400 mg/m2
, followed by 5-
FU 2,400-3,000 mg/m2
infusion over 46-48 h. Cycle repeated
every 14 days
FUFOX Grothey et al.,
2002
Oxaliplatin 50 mg/m2
over 2 h, followed by LV 500 mg/m2
,
followed by 5-FU 2,000 mg/m2
over 24 h, weekly for 5 weeks,
repeated every 6 weeks.
163. 5-Fluorouracil + Leucovorin (Mayo Clinic Schedule) NCCTG
5-FU: 425 mg/m2 IV on d1 – 5
LCV : 20 mg/m2
IV on d1 – 5 before 5 - FU
Repeat cycle every 4 – 5 weeks for a total of 6 cycles
Oxaliplatin + 5-Fluorouracil + Leucovorin (FOLFOX4)
Oxaliplatin: 85 mg/m2
IV on day 1
5-Fluorouracil 400 mg/m2
IV bolus, followed by 600
mg/m2
IV continuous infusion for 22 hours on days
1 and 2
Leucovorin: 200 mg/m2
IV on days 1 and 2 as a 2-hour
infusion before
5-Fluorouracil
Repeat cycle every 2 weeks
Chemotherapy as adjuvant in CRC
165. • Unresectable disease- generally incurable
– Goal: Palliation- symptom control/ control of tumor
growth/ lengthen PFS and OS
– Palliative chemotherapy: indication if following
guidelines are met
• Favorable performance status
• Acceptable BM / renal / hepatic function
• Reasonable nutritional status
• Well motivated patients
166. Oxaliplatin + 5-Fluorouracil + Leucovorin (mFOLFOX7)
Oxaliplatin: 100 mg/m2
IV on day 1
5-Fluorouracil: 3000 mg/m2
IV continuous infusion on days 1 and 2 for 46 hours
Leucovorin: 400 mg/m2
IV on day 1 as a 2-hour infusion before 5-
fluorouracil
Repeat cycle every 2 weeks
Irinotecan + 5-Fluorouracil + Leucovorin (FOLFIRI Regimen)
Irinotecan: 180 mg/m2 IV on day 1
5-Fluorouracil: 400 mg/m2
IV bolus on day 1, followed by 2400 mg/m2 IV
continuous infusion for 46 hours
Leucovorin: 200 mg/m2
IV on day 1 as a 2-hour infusion prior to 5-
fluorouracil
on days 1 – 5 administered before 5 - Fluorouracil
Repeat cycle every 2 weeks
Capecitabine
Capecitabine: 1250 mg/m2
PO bid on days 1 – 14
Repeat cycle every 21 days for a total of 8 cycles. Dose may be decreased to 850-
1000 mg/m2
PO bid on days 1-14 to reduce the risk of toxicity without
Chemotherapy as adjuvant in CRC
167. Capecitabine + Oxaliplatin (XELOX)
Capecitabine: 1000 mg/m2
PO bid on days 1 - 14
Oxaliplatin: 130 mg/m2
IV on day 1
Repeat cycle every 21 days. May decrease dose of capecitabine
to 850 mg/m2
PO bid and dose of oxalioplatin to 100 mg/m2
IV to
reduce the risk of toxicity without compromising clinical efficacy
Capecitabine + Irinotecan (XELIRI)
Capecitabine: 1000 mg/m2
PO bid on days 1 - 14
Irinotecan: 250 mg/m2
IV on day 1
Repeat cycle every 21 days. May decrease dose of capecitabine
to 850 mg/m2
PO bid and dose of irinotecan to 200 mg/m2
IV to
reduce the risk of toxicity without compromising clinical efficacy
Chemotherapy as adjuvant in CRC
168. • Stage II: IMPACT metaanalysis
– Sx alone-81% / Adj. 5FU+ LCV – 83%
– Long term OS statistically insignificant
– Satge II patients with poor prognostic factors should be considered for
adjuvant chemotherapy
• Stage III:
– In the absence of medical or psychiatric C/I, patients with node(+)
colon ca should receive postop chemotherapy
– Daily X 5d Mayo schedule – more toxic, shouldn’t be used
– At the very least, a 5-FU based regimen be appropriate, and ~a half
year of therapy supported by the majority of trials
– Oral capecitabine or UFT/LCV acceptable alternatives if a
fluoropyrimidine-only approach is selected
– FOLFOX schedule is now the most widely used adjuvant t/t
– Modified FOLFOX -6 –NCI intergroup adjuvant trials, is routinely used
because of its greater convenience
– FOLFIRI shouldn’t be used in the adjuvant setting due to increased risk
of early death and no long-term benefit
169. Investigational adjuvant approaches
• Portal vein infusion (↑DFS by 10%)
• Intraperitoneal chemotherapy- stage III- 43% ↓mortality
• Edrecolomab- not used
• Vaccine- Canarypox virus encoded gene induce CEA specific T-cell
response in patients with advanced adenoca
• ASI
170.
171. Targeted therapy in advanced colon cancerTargeted therapy in advanced colon cancer
40% patients undergoing systemic CT for advanced
disease do not achieve tumor shrinkage
Molecular warfare focusing on dissection of molecular
pathways resulting in tumor growth and progression
172. Targeting the angiogenesis process
Tumor growth and metastasis is strongly linked with
angiogenesis process. The vascular network in the
tumor growth involves different complex pathways.
VEGF is the most potent and specific angiogenic
factor and its expression in CRC is correlated with
recurrence and prognosis. Two different strategies
devised to target VEGF are:
1) Developing MCA directed against VEGF
2) Developing intervention to VEGF pathway involving
small different molecules with tyrosine kinase
inhibition activity directed towards the VEGF
receptors
174. Bevacizumab
Approved for use in metastic colo rectal
carcinoma in cimbination with IV 5FU as first-
line
Dose: 5 mg/kg IV over 90 mins every 2 weeks
• Avastin 100 mg (4 ml) & 400 mg (16 mg)
• Toxicities: GI perforation, wound dehiscence,
hemorrhage, risk of arteriel TE events (MI,
stoke), hypertension, infusion-related toxicity,
proteinuria and nehprotic syndrome
175. The importance of EGFR in
metastatic colorectal cancer
EGFR is involved in the progression of mCRC
Patients with EGFR-expressing tumors have a
shorter survival
EGFR is expressed in 75 – 89% of mCRC
176. Cetuximab (C225)
Chimeric MCA to EGFR
Binds with high affinity to transmembrane domain
of EGFR and blocks binding of natural ligands
(EGF, TGF)
Inhibits EGFR function and downstream signal
transduction pathways, promoting apoptosis
Synergistic inhibition with chemotherapy and
radiation
.
177. Cetuximab
Approved for use in EGFR expressing
metastatic CRC in combination with
irinotecam in patients refractory to irinotecam
or as mono therapy in pts intolerant to
irinotecam
Dose: Loading dose of 400 mg/s.m., then 250
mg.s.m. IV weekly
Erbitux: 50 ml vials, 2 mg/ml
Infusion-related toxicity (40-50%), rash, ILD,
asthenia & fatigue, paronychia
178. Cetuximab in EGFR expressing metastatic
CRC: first line trials
Hoehler T. et al.
Proc ESMO 2004
Van Cutsem E. et al.
Proc ESMO 2004
Reference
21% resection of
livermetastases
remarks
21 %2%PD
24 %17%SD
55 %81% (74% conf.)
(61-88)
CR + PR
(95% CI)
3843Total patients
FUFOX +
cetuximab
FOLFOX +
cetuximab
180. PROGNOSITC FACTORS
• ADVERSE C/F
– Younger age < 40 yr
– Long symptomatology
– Obstruction/ perforation
– Ulcerative lesion
– BT
• ADVERSE PATHOLOGY
– High grade
– Colloid/ Signet ring cell
– LVI
– Perineural invasion
– Aneuploidy
– ↑↑ CEA/ collagen
– Cell surface antigens CA-19.9
– Local immune response
•Most important guide to prognosis is STAGE of the disease
i.e. depth of penetration and number of LNs involved
181. Rational post therapy surveillance
programme
• CEA every 3 month x 1st
3 yrs, than 6 monthly up
to 5 yrs (CEA detects 80% recurrence) and
• Complete physical examination on each FU
• CECT abdomen pelvis yearly x 1st
3 yrs
• Colonoscopy every 3 to 5 yrs
• FDG-PET- rising CEA in two consecutive tests in
absence of imageable disease by CT
183. ACS colorectal cancer screening guidelinesACS colorectal cancer screening guidelines*
Fecal occult blood test (FOBT)†
or fecal immunochemical test
(FIT) every year, or
Flexible sigmoidoscopy every 5 years, or
An FOBT†
or FIT every year plus flexible sigmoidoscopy every
5 years (of these first three options, the combination of FOBT or
FIT every year plus flexible sigmoidoscopy every 5 years is
preferable), or
Double-contrast barium enema every 5 years, or
Colonoscopy every 10 years
• * Beginning at age 50, men and women who are at average risk for developing
colorectal cancer should have one of the five screening options listed. Those at
increased risk for colorectal cancer should undergo screening earlier and at more
frequent intervals.
• † For FOBT or FIT, the take-home multiple sample method should be used.
• Source: “Can colorectal polyps and cancer be found early?” American Cancer
Society (www.cancer.org); 2005 Accessed Sept 2008.
186. Population Screening
• Simple
• Cheap
• Reliable
• Safe
• Acceptable
CRC fulfills many of these criteriaCRC fulfills many of these criteria
for effective screeningfor effective screening
Editor's Notes
Arterial supply- (A). Superior mesenteric A.- 1) Middle colic A. 2) Ileocolic A.- a) R colic A. b) Ileal A. c) Caecal
(B). Inferior mesenteric A- 1) L colic A. 2) 3-4 sigmoidal arteries 3) R colic A
Venous drainage- Parallel to arterial supply- Sup. and Inf. Mesenteric veins ultimately into Portal vein
Lymphatic drainage- Curative surgical resection and staging requires resection of LNs that drain the primary tumor site.
Lymphatic drainage follow arterial supply. From muscularis mucosa → submucosa efferents to intramuscular and subserosal plexus of the bowel to 1st tier of LNs → lying adjacent to large intestine (Epicolic LN)
Paracolic LN- lie on marginal atreries along mesenteric side of colon and frequently involved in metastasis
Intermediate LN- along major arterial branches of SMA and IMA in mesocolon
Principal LN- present around the origin of these vessels from the Aorta
Regional LNs
Caecum- Ant. & post. Colic/ileo/Rt colic
AC- Middle colic, ileocolic, Rt colic
HF- Middle and Rt colic
TC- Middle colic
SF- Lt and middle colic, inf. Mesenteric
DC- Lt. colic , sigmoid
Sigmoid- Inf. mesent, sup. rectal, sigmoid, sigmoid mesenteric
Multi step process influenced by numerous factors → takes years for a carcinoma to evolve
Hereditary syndrome- 10% of all CRC
Inheritance- Autosomal dominant
Alcohol- interfere with folate metabolism through acetaldehyde
Polyp removal leads to CRC prevention
Polyp is surrogate marker
Normal epithelium
↓ ← Loss/ Mutation of APC locus on Ch. 5q
Hyperproliferative epithelium
↓ ← Loss of DNA methylation
Early adenoma
↓ ← Mutation of ras oncogene on Ch.12p
Intermediate adenoma
↓ ← Loss of DCC gene on Ch. 18q
Late adenoma
↓ ← Loss of p53 gene on Ch. 17p
Carcinoma
Grading- Adeno ca only histologic type further classified by grades by BRODER (1920) based on percentage of differentiated cells found in the overall tumor specimen
(I)-Well diff. (II)-Moderately diff. (III)-Poorly diff. (IV)- Undifferentiated
DUKE (1932)- based on cytological characteristics or cells/ glandular formation and nuclear pleomorphism ranging from A (Well diff.) to D (Anaplastic)
Present day- Three grade system
Since the advent of treatment, management of primary colon malignancies has been exclusively – SURGERY and with - improvement in surgical skills, aggressiveness and patient preparation and support – resectability has increased to ~90% and mortality ~2-10%
Stage I / polyps- Surgical resection
Pedunculated lesion- Colonoscopic resection
Sessile lesions and Large polypoidal lesion- Segmental colonic resection
No further adjuvant after seeing the HPR
5 yr survival &gt;95%
Stage II- III- primary- surgical resection
Rationale- Significant risk of residual micrometastatic disease as there is inability of current diagnostic technique to identify patients with or without micrometastatis
Aim – To eradicate any residual micrometastatic disease
Conclusion- All though surgery is the corner stone of initial treatment of ca colon, but looking at these trials it can be definitively said that adjuvant treatment is needed.
Techniques of Irradiation
Design and delivery of radiation therapy – require knowledge of
1.Natural history of the disease
2.Patterns of failure
3.Anatomy
4.Identification of surrounding structures
5.Radiobiologi principles
6.Use of proper equipments
7.Implemantaion of methods to decease t/t related toxicities
Idealized t/t field- individualized-actual design of field depends on
1.Preop assessment of tumor volume
2.Operative / pathological studies
3.Position of clips marking the tumor bed
4.Sites of adherence to adjacent organs / structures
Treatment field design in colon cancer is based on patterns of failure data. As is true in the treatment of rectal carcinoma, great care must be taken in the design of postoperative treatment of adenocarcinoma of the colon. Field arrangement will vary depending on the site of the primary disease as well as areas judged to be at high risk for local recurrence (62). Patient positioning (supine, prone, decubitus) should be considered in planning. Small bowel is often a dose-limiting structure in this therapy, and it is often advantageous to position patients in the right or left decubitus position for at least a portion of their treatment, allowing displacement of the small bowel away from the treatment field. Immobilization devices may improve reproducibility. A small-bowel series defines small-bowel volume within the treatment field. It may be useful to compare films in both the decubitus and supine positions to determine the actual amount of small bowel displacement. CT-based planning may facilitate defining the tumor bed, determining beam orientation, as well as estimating the volume of small bowel included within the treatment fields. As in other abdominal malignancies, a portion of one kidney may be irradiated. Unilateral renal irradiation results in minimal long-term clinical sequelae, assuming baseline function in the contralateral kidney is normal (174).
The total radiation dose used in the adjuvant treatment of colon carcinoma depends on the amount of suspected residual disease and tolerance constraints of surrounding normal tissue. Generally, an initial dose of 45 Gy in 25 fractions of 1.8 Gy per fraction is delivered through larger fields to the primary tumor and at-risk tissues. Reduced fields may be treated to 50 Gy if only a small portion of small bowel is included. For patient with T4 tumors, the general goal is to treat the tumor bed to a total dose of 54 to 60 Gy. Any treatment beyond 50 Gy mandates exclusion of all small bowel from the field. Spinal cord dose should be limited to 45 Gy. In addition, at least two thirds of one functional kidney should receive no more than 18 to 20 Gy and at least two thirds of the total liver volume should not receive more than 30 Gy. In a Mayo Clinic analysis, small bowel obstruction rates were lower when more than two treatment fields were used, and attempts should be made to implement multifield techniques, which may be aided by CT-based planning (150).
Generally, the primary tumor site should be covered with a 4- to 5-cm margin proximally and distally with 3- to 4-cm margin medially and laterally to cover areas of potential residual disease. The nodal basins in the mesentery beyond surgical margins are usually not treated as satisfactory margin clearance is obtained in these sites. An exception to this may be right colon tumors where both small bowel and right colon are supplied by ileocolic vessels, limiting the extent of resection. In some instances, treatment of the para-aortic nodes may be indicated, particularly with extensive retroperitoneal involvement by tumor. Treatment of proximal mesenteric nodes may be appropriate if nodes adjacent to the surgical or resection margin are involved
Idealized radiation treatment field for caecum and proximal ascending colon
Idealized radiation treatment field for mid ascending colon
Idealized radiation treatment field for the distal descending colon. The ipsilateral common and external iliac LN at the distal end of the tumor as well as para aortic LNs at the level of proximal tumor bed should be included
Idealized radiation treatment field for middle sigmoid colon adherent to left pelvic sidewall or proximal sigmoid. As with other sites in the colon, placement of fields varies depending on the exact site of the tumor volume or the tumor bed
Idealized radiation treatment field for distal colon and hepatic flexure
Idealized radiation treatment field for splenic flexure and proximal descending colon
Idealized radiation treatment field for the middle descending colon
Idealized treatment field for the sigmoid colon adherent to the bladder. A 3 or 4 fields technique is recommended. At the time of simulation, 30-50 ml contrast agent should be instilled in to the bladder via foley as well as 10-15 ml air to help define its anterior extent. The entire bladder and pelvis, including external and internal and iliac LNs, should be included in the radiation field. For patients with distal sigmoid primary tumors, a 3 or 4 fields technique similar to the one shown here is used except the bladder doesn’t need to be included in the field.
The use of intraoperative irradiation as a supplement to EBRT in certain T4 tumors (i.e., those with uncertain margins) may also be appropriate. For patients with tumors adherent to or invading adjacent structures, the preferred treatment sequence would be preoperative EBRT plus 5-FU based chemotherapy followed by resection with or without IOERT and postoperative systemic therapy, based on excellent results in preliminary IOERT reports from both U.S. and European institutions . A similar approach would be reasonable for patients with locally recurrent cancers or with regional nodal relapse
Aim is to destroy microscopic metastatic disease and preventing death from metastasis as substantially no. of patients treated surgically with curative intent eventually died of metastatic disease
NSABP-03 : MOF regimen eliminated due to toxicity and leukemiogenesis
NCCTG/NCI: Grade III neutropenia/ diarrhea/ Stomatitis/ alopecia less in 3 month PVI
12 weeks t/t similar survival but with less toxicity
Results of the MOSAIC Trial: Biweekly Infusional Fluorouracil (5-FU)/Leucovorin (LV5FU2) versus LV5FU2 plus Oxaliplatin (FOLFOX-4) in Patients with Stage II and III Colon Cancer
LV5FU2 (n = 1,123) FOLFOX-4 (n = 1,123) Hazard Ratio (95% Confidence Interval) 3-year disease-free survival stage III patients (60% of total) 66% 72% .76 (0.02–0.92) 3-year disease-free survival, stage II patients (40% of total) 84% 87% .82 (0.57–1.17) Overall survival Not available Not available — Grade 3-4 neutropenia 5% 41% — — Grade 3-4 diarrhea 0% 1% — Grade 3-4 vomiting 7% 11% — Neuropathy, any grade 0% 92% — Neuropathy, grade 3 0% 12% — Persistent neuropathy, grade 2-3, 1 year after treatment 0% 5%