anatomy,epidemiology,risk factors,clinical features,staging and management

1. COLON CANCER
BY;Dr MOHAMED SALAT GONJOBE,
RESIDENT,MMED CLINICAL ONCOLOGY

2. Outline
 1.Introduction
 2.case
 3.Anatomy
 4. Epidemiology
 5. Risk Factors
 6. Clinical Features
 7. Screening
 8. Pathology
 9. Pathway of Spread
 10. Staging
 11.Diagnostic Work Up
 12.Treatment

3. Introduction
Colorectal cancer is the cancer which affect caecum, colon, and
rectum
 Colorectal cancer is the third leading cause of cancer deaths in
both males and females
 Colorectal cancer account of more than 50% of GI malignancy
 Adenocarcinoma comprises the vast majority 98% of colorectal
cancers. Other rare rectal cancers, including carcinoid 0.4%
,lymphoma 1.3% and sarcoma 0.3%.Squamous cell carcinoma
may develop in the transition area from the rectum to the anal

5. ANATOMY
 The colon is 150 cm long and is subdivided into the
cecum, ascending, transverse, descending, and sigmoid
colon. The ileocecal valve forms the junctionbetween the
small and large bowel and demarcates the cecum from
the ascending colon.
 The transverse and sigmoid colons have a mesentery
and are entirely intraperitoneal. The ascending and
descending colons are partially extraperitoneal.
 The superior mesenteric artery supplies the colon
between the ileocecal valve and the splenic flexure.
 The inferior mesenteric artery supplies the colon distal to
the splenic flexure.

6. BLOOD SUPPLY
 • SMA -
Ileocolic artery (absent in up to 20% of people), terminal
ileum and proximal ascending colon
Right colic artery - ascending colon
Middle colic artery - transverse colon
 • IMA –
Left colic artery - descending colon
Sigmoidal branches - sigmoid colon
Superior rectal artery - proximal rectum
Communicate via the marginal artery of Drummond,
complete in only 15 to 20% of people

7. CONT

8. CONT,
 Veins
 Veins of the colon parallel their corresponding arteries (except IMV)
and
bear the same terminology
 Inferior mesenteric vein ascends in the retroperitoneal plane over the
psoas muscle, posterior to the pancreas to join the splenic vein.
 Nerve Supply
 Sympathetic (inhibitory) and parasympathetic (stimulatory) nerves,
which
parallel the course of the arteries.
 Sympathetic nerves arise from T6–T12 and L1–L3.
 Vagus nerve ->parasympathetic innervation to the right and transverse
colon;
 Parasympathetic nerves to the left colon arise from sacral nerves S2–
S4 to form the nervi erigentes.

9. CONT,
 The colonic wall comprises 4 layers, including
the:
 – Mucosa
 – submucosa
 – muscularis propria (inner circular layer and
outer longitudinal layer,comprising 3 narrow
bands tenia Coli)
 and serosa

11. Lymphatic drainage
 Ascending colon and two third transverse colon from
percolic node drain into superior mesenteric group
 One third of transverse colon and descending colon
drain into inferior mesenteric group
 Upper two third of rectum drained by superior rectal
nodes to the inferior mesenteric nodes
 lower one third of rectum drained by superior rectal
nodes to the inferior mesenteric nodes and internal iliac
nodes

13. Epidemiology

14. Epidemiology….

15. Risk factors
 Age
 Diet
 Polyps
 Personal Medical History
 Family Medical History
 Genetic factors
 Inflammatory bowel disease
 Irradiation

16. Risk factor cont,
 Colorectal cancer is more likely to occur as
people get older. The disease is more common
in people over the age of 50.
 However, colorectal cancer can occur at
younger ages, in rare cases, in the teens.

17. Diet.
 Colorectal cancer seems to be associated with
diets that are high in fat and calories and low in
fiber. diet low in indigestible fibers , high in
animal fat
 Fruit, Vegetables, and Fiber--Association
between higher intake of vegetables and lower
cancer risk
 Folate--Higher intake of folate associated with
lower colon cancer risk

18. Cont,
 Calcium--Avoidance of low intakes of calcium
may minimize risk of colon cancer
 Fat, Carbohydrates, and Proteins--Excess
energy intake leading to obesity increases the
risk of colon cancer
 Possible association of red meat with increased
risk

19. Lifestyle Factors- BMI & Physical
Activity
 Higher BMI is associated with an increased risk
of colon cancer
 Approximately twofold higher risk in individuals
who are overweight or obese Individuals who
are more physically active have a decreased
risk of colon cancer

20. Cont,
 Race and Ethnicity
 Higher rates and mortalities among blacks than whites
 Socioeconomic status
Possible association between low SES and colorectal
cancer mortality
 Alcohol
Somewhat controversial, but appears that high alcohol
intake increases risk
 Tobacco
Most studies indicate excess risk in smokers

21. Cont,
 Inflammatory bowel disease:
 - Ulcerative colitis:
Patient with extensive colitis for long duration are at
high risk of developing colorectal cancer
 - Crhon,s disease :
is also associated with increased risk of cancer
 Irradiation & immunosuppresion:
– Irradiation is well known carcinogenic,
– patient on immunosuppression drugs or disease are
at increased risk of developing colorectal cancer

22. Genetics
APC gene
 “Gatekeeper”- controls polyp formation
 Involved with FAP in an autosomal dominant
manner
 APC mutations found in >70% of all colon
cancers/polyps
K-RAS
Proto-oncogene
Only one allele
G protein involved in intracellular gtp signal transduction

23. MYH gene
Base excision repair gene
mutation causes autosomal recessive form of FAP
DCC
Tumor-suppressor
Present in more than 70% of colorectal carcinomas
P53
Tumor-suppressor gene
Crucial for initiating apoptosis
75% of colorectal cancers

24. PRE INVASIVE LESIONS
 Adenomatous polyps
 Seen in 25% of the population older than 50 years
The risk of carcinoma in a polyp larger than 2 cm is 35 to 50%.
 Familial juvenile polyposis
 Autosomal dominant
May degenerate into adenomas and, eventually, carcinoma.
 Familial Adenomatous Polyposis
 Autosomal dominant
Mutation in the APC gene, located on chromosome 5q.
Lifetime risk approaches 100% by age 50 years.
 FAP may be associated with congenital hypertrophy of the retinal
pigmented epithelium,desmoid tumors, epidermoid cysts, mandibular
osteomas (Gardner's syndrome), and central nervous system tumors
(Turcot's syndrome

25. Cont,
 Attenuated FAP
AFAP is a recently recognized variant of FAP associated with mutations at
the 3' or 5' end of the APC gene.
Carcinoma develops in more than 50% of these patients
 Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome)
Extremely rare (1 to 3%).
Autosomal dominant
Average age: 40 to 45 years
70% of affected individuals will develop colorectal cancer.
Diagnosis of HNPCC is made based majorly upon family history.

26. Risk of colorectal cancer

27. Pathogenesis…
 It has been proposed that a specific mutation is required
at each stage of progression along the adenoma–
carcinoma sequence
 Mutations in the Adenomatous Polyposis Coli (APC)
gene are typically the critical initiating event in cases of
Familial adenomatous polyposis, resulting in
translocation of beta catenin to the nucleus where it
activates MYC and CyclinD both of which stimulates cell
proliferation.

28. Pathogenesis…
 This is followed by point mutations in the KRAS
oncogene and loss of heterozygosity (LOH) of
chromosome 18q, where tumor suppressor
genes including deleted in colon cancer (DCC)
and the human homolog of Cables lie.
 TP53 mutations are a late event, occurring
during the transition from the advanced
adenoma to invasive carcinoma.

29. Colon: Normal  Adenoma 
Carcinoma
Colon Cancer: Common type - 80%
Carcinogenesis)

30. PATHWAY OF SPREAD
 Local
 Multidirectional growth progression
 Intramural- bowel wall penetration
 Invasion into adjacent organs/ structures
 Perineural invasion ~10 cm from primary lesion
 Lymphomatous
 LVI
 Normal lymphatic flow along major arteries to three
echelons of LN
 Pericolic/ Intermediate /Principal LN

31.  Hematogenous
 Liver- primary site – 40%
 Lung- 2nd most common site
 Brain
 Bones
 10-15% have episode of distant metastasis at
diagnosis
 Peritoneal seeding/ implantation
Intraluminal/ serosal sheding/ by surgical
manipulation

32. Clinical features

33. Diagnostic workup
 Complete history
 Physical examination /DRE-size, location, distance from
the verge, mobile versus fixed, and sphincter function.
 Pelvic exam should be performed in women.
 Routine investigations-CBC/LFT/RFT
 Confirmatory- Biopsy
 Gold standard- Colonoscopy+ Biopsy

34. Staging workup
 CXR or Chest CT
 Barium enema Colonoscopy- To evaluate extent of
tumour
 Virtual colonoscopy: 91% sensitive, 17% false positive
rate
 Air contrast barium enema: 50% sensitive for large
(>1 cm) adenomas, 39% for polyps
 CT abdomen- pelvis-The sensitivity of CT scan is 50%
to 80%accurate, with a 30% to 80% specificity .65% to
75% accurate for tumor staging and 55% to 65%
accurate in mesorectal lymph node staging.

35. Cont,
 The ability of CT scans for detecting distant
metastasis, including pelvic and para-aortic
lymph nodes, is higher than for detecting
perirectal nodal involvement (75% to 87% vs.
45%).
 MRI-Liver MRI is considered the test of choice
in assessment of hepatic metastases in patients
with CRC.

36. WHO Histological classification
 Adenocarcinoma in situ / severe dysplasia
 Adenocarcinoma >95%
 Mucinous (colloid) adenocarcinoma (>50%
mucinous)
 Signet ring cell carcinoma (>50% signet ring
cells)
 Squamous cell (epidermoid) carcinoma
 Adenosquamous carcinoma
 Neuroendocrine
 Small-cell (oat cell) carcinoma
 Medullary carcinoma
 Undifferentiated Carcinoma

37. TNM staging
Ah Young Kim; Imaging Diagnosis of Colorectal Cancer, June 14, 2010

39. Screening

40. Familial risk

41. Mgt of ca colorectal

42. Treatment options overview

43. Surgery
 SURGERY is the GOLD STANDARD and
principle therapy of primary and non
metastatic CA Colon
• Curative
• Palliative
• Accurate disease staging
• Guides adjuvant treatment

44.  •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

45. • TYPES OF SURGICAL RESECTION
• Sx approach is dictated 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.
• Right Hemicolectomy
• Extended Right Hemicolectomy
• Left Hemicolectomy
• Segmental resection
• Total Abdominal Colectomy: UC, FAP Syndrome

47. CHEMOTHERAPY
 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
• Adjuvant Chemotherapy
 • The benefit of adjuvant chemotherapy has been clearly demonstrated in
stage III patients, whereas benefit in stage II patients is more controversial.
 Prospective randomized trials have shown that the addition of 5-
flourouracil (5-FU) and leucovorin (LV) improves survival for resected stage
III patients.

48. Bottom Line General
Approach:
 Stage I: segmental colectomy, no role for
adjuvant therapy.
 Stage IIA (T3N0): segmental colectomy,
consider 6 months adjuvant fluoropyrimidine in
patients with high-risk (at least one of the high-
risk features) T3N0 disease.
 Stage IIB/C (T4N0): segmental colectomy,
consider 6 months of adjuvant fluoropyrimidine
or modified FOLFOX6 in high-risk patients

49.  Stage III: segmental colectomy followed by 6
months of adjuvant chemotherapy with a
fluoropyrimidine or modified FOLFOX6.
-Stage III colon cancer in patients > 70 years
old: There is no clear benefit of adjuvant
FOLFOX
chemotherapy However, it is reasonable to
consider FOLFOX
 Stage IV: chemotherapy in this population/best
supportive care.

50. Adjuvant FOLFOX4 in Stage II-III
COLON CANCER –MOSAIC
STUDY

53. MOSAIC STUDY,6yr OAS by
treatment arm

54. MOSAIC STUDY,6yr OAS by
treatment arm and by stage

57. Stage III colon ca
 Current standard of care for stage III colon
cancer patients: 6 months of oxaliplatin-based
adjuvant therapy with FOLFOX or CAPOX
(XELOX)
 Oxaliplatin is associated with cumulative dose-
dependent neurotoxicity.
 Debilitating for many patients, both short- and
long-term – Nerve damage (e.g. numbness,
tingling, pain) can persist long after
discontinuation of therapy, sometimes
permanently

58.  Dose reductions and early discontinuation of
therapy are common.
 Shorter duration treatment without loss of
efficacy would be of benefit to patients and
health care resources.

59. Prospective Pooled Analysis of Six Phase III
Trials Investigating Duration of Adjuvant
Oxaliplatin-based therapy (3 vs 6 months) for
Patients with Stage III Colon Cancer:
The IDEA (International Duration Evaluation of
Adjuvant Chemotherapy) Collaboration
Qian Shi, Alberto F. Sobrero, et al
12 countries – SCOT (UK, Denmark,
Spain, Australia, Sweden, New Zealand),
TOSCA (Italy), Alliance/SWOG 80702 (US,
Canada), IDEA France,
ACHIEVE (Japan), HORG (Greece)
12,834 patients with
stage III disease-
analysis

61. Characteristics of the Study
Patients

66. Benefit of post-op RT
No clear evidence of benefit with RT.
However, RT may be useful in the setting of
 Incomplete excision/ Residual disease
 Positive resection margins
 Fixed tumors i.e. caecal and sigmoidal ca
 Tumor a/w perforation/ obstruction/fistula/abscess
If RT is included in treatment regimen, field should include margin around
tumor bed based on pre-op imaging and/or surgical clips.
……Dose 45–50.4 Gy in 25–28 fx.
However, there is a paucity of high-quality evidence addressing the
role of adjuvant RT (with or without concurrent chemotherapy) in
patients with resected locally advanced colon cancer.

68. Techniques of Irradiation
 • Generally, an initial dose of 45 Gy in 25 fractions at 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.
 Critical normal (dose limiting) tissues
 Small intestine: max 45 Gy (30 Gy by WART)
 Liver : 2/3rd of liver should not get >30 Gy
 Kidneys: 2/3rd of one kidney should not get >20 Gy
 Spinal cord: max dose to spinal cord< 45 Gy

69. NEWER RT Techniques
 IORT- 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 IORT 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

70. METASTATIC COLORECTAL
CANCER

71. Bottom Line General Approach:
Potentially resectable patients
 In select patients, segmental resection of obstructing or bleeding colorectal primary lesions
may be considered.
 Palliative radiotherapy or stereotactic body radiation therapy (SBRT) may be considered.
 Liver-only metastasis or solitary/lobe-confined pulmonary mets may be considered for
resection.
 Potentially resectable patients may be treated with neoadjuvant chemotherapy until optimal
Resectability. It is preferable to consider oxaliplatin-based chemotherapy prior to liver
metastasectomy as irinotecan can cause steatohepatitis, which can interfere with surgery.
 However, irinotecan is NOT a contraindication to surgery and can be used if the patient is
ineligible for oxaliplatin-based treatment. A limited number of cycles of chemotherapy should
be delivered to minimize the consequences to the liver and adverse effects.
The criteria for liver resection are: -
 at least 2 adjacent lobes (caudate lobe excluded) free of tumour,
 biliary drainage intact, arterial inflow,
 non-thrombosed portal vein,
 20% or more liver functional reserve.

73.  patient were randomized to either
chemotherapy alone or primary tumour
resection followed by modified FOLFOX6
(mFOLFOX6) plus bevacizumab or CapeOX
plus bevacizumab

75. results
 median OS was25.9 months (95% CI 19.9 – 31.5) with
PTR plus CTX and 26.7(21.9 – 32.5) with CTX alone
(hazard ratio 1.10 [0.76 – 1.59], one-sided p = 0.69).
Median PFS was 10.4 (8.6-13.4) with PTR plus CTX and
12.1 (9.4 – 13.2) with CTX alone (hazard ratio 1.08 [0.77
– 1.50]). There were three treatment related deaths
following PTR due to postoperative complications.
 Conclusions: PTR followed by CTX has no survival
benefit over CTX alone. PTR is not recommended for
CRC patients with asymptomatic primary tumor and
synchronous unresectable metastases

77. Unresectable patients
 Upon diagnosis of metastatic disease, patients’ tumours should
be tested for activating mutations in Ras (Kras and Nras).
 Patients with known Ras mutations should NOT be treated
with the EGFR inhibitors, Panitumumab or Cetuximab.
 Patients with RAS wild-type left-sided colorectal cancer
should be treated with chemotherapy (FOLFOX or FOLFIRI)
in combination with an EGFR inhibitor (cetuximab or
panitumumab) in the first line setting.
 In patients with RAS wild-type right-sided colorectal
cancer, first line EGFR inhibitors should NOT be used. The
combination of a VEGF inhibitor with standard chemotherapy
remains the standard for these patients.

78. Other standard first-line palliative chemotherapy options (eg. for
patients who cannot receive combination chemo) are:
 Capecitabine
 Irinotecan
 5-FU
 CAPOX
 Patients who have progressed on all standard chemotherapy
may receive fourth-line regorafenib or TAS-102.

79. Targeted therapeutic
agents in CRC

83. results
 The median duration of survival for the group treated with
FOLFOX4 and bevacizumab was 12.9 months compared with 10.8
months for the group treated with FOLFOX4 alone (corresponding
hazard ratio for death = 0.75; P = .0011), and 10.2 months for those
treated with bevacizumab alone. The median PFS for the group
treated with FOLFOX4 in combination with bevacizumab was 7.3
months, compared with 4.7 months for the group treated with
FOLFOX4 alone (corresponding hazard ratio for progression =
0.61; P < .0001), and 2.7 months for those treated with
bevacizumab alone. The corresponding overall response rates were
22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with
bevacizumab v FOLFOX4 comparison).
 CONCLUSION The addition of bevacizumab to oxaliplatin,
fluorouracil, and leucovorin improves survival duration for patients
with previously treated metastatic colorectal cancer

85. results
 Median PFS was significantly longer in the
treatment group than in the control group (9
months vs 8 months, p=0·036). Furthermore,
more patients in the treatment group had a
decrease in tumour size than those in the
control group (46·9% vs 38·7%, p=0·005)

87. Anti-VEGF( protein
that helps tumor for
angiogenesis
 Bevacizumab
(avastin)
 Ramucirumab
(cyramza)
 Ziv-aflibercept
(zaltrap)
EGFR INHIBITORS:
 Cetuximab (erbitux)
 Panitumumab(vectib
ix)
Kinase inhibitor:
 Regorafenib
only for refractory dx
to all other regimens

88. FOLLOW-UP/Surveillance
 ……HP- side effects of chemo and radiation therapy. Q3-
6mo for 1st 2yrs then Q6mo for 3-5yrs
 CEA every 3 months x 2 years, then every 6 months x5
years: to assess disease response.
 ……Consider CT scan if high risk of recurrence
approximately every 4–6 months. Recurrence commonly
occurs within 2 years after initial therapy. However, late
failures even beyond 5 years have been noted after
local excision.
 ……Colonoscopy in 1 year, then every 2–3 years if negative

90. References
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