1. COLORECTAL CARCINOMA-
ANATOMY TO MANAGEMENT
By
Dr. Ayush Garg

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

3. ANATOMY
• Embryology
• Starts the fourth week of gestation
• Derived from the endoderm
• Three segments: foregut, midgut, and hindgut
• Midgut and Hindgut contribute to the colon, rectum, and anus
• Hindgut - distal transverse colon, descending colon, rectum, and
proximal anus all blood supply from IMA

5. Colon/Rectum and Peritoneum
• Colon/Rectum covered by
serosa
• Cecum
• Transverse
• Sigmoid
• Anterior descending
• Anterior ascending
• Rectosigmoid
• Upper third and anterior wall of
middle third of rectum
• Colon/Rectum without serosa
• Posterior ascending
• Posterior descending
• Lower third of rectum (rectal
ampulla)

6. Arterial 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. 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.

8. Colon Cancer- Lymph Nodes
All sites
Colic
Epicolic
Mesocolic
Para/pericolic
Nodule in fat/mesentery/
mesocolic fat

9. Regional nodes for
each segment of colon
Colon Cancer CS Lymph Nodes
Cecum
Ascending
Hepatic
flexure
Transverse
Splenic
flexure
Descending
Sigmoid

10. Rectal Cancer- Lymph Nodes
Rectosigmoid
Rectal
Perirectal
Para/pericolic
Nodule in pericolic fat/
mesentery/mesocolic fat
Rectum
Rectal
Perirectal
Nodule in perirectal fat

11. Rectum
• Rectum -12 to 15 cm in length
• Valves of Houston - three distinct submucosal folds
• Posteriorly -presacral fascia,
• Anteriorly - Denonvilliers' fascia
• Lateral ligaments support the lower rectum
• The rectum is classically divided into three parts: the upper third, the
middle third, and the lower third. Each part is practically assumed to be 5
cm in length.

13. Rectum Arterial Supply
• Superior rectal artery <- inferior mesenteric artery (upper rectum)
• Middle rectal artery <- internal iliac
• Inferior rectal artery <- internal pudendal <- internal iliac artery.
• Rich collaterals

14. Veins and Lymphatics
Venous
• Superior rectal vein -> inferior mesenteric -> portal system
• Middle rectal vein -> internal iliac vein
• Inferior rectal vein -> internal pudendal vein -> internal iliac vein
• Submucosal plexus deep to the columns of Morgagni forms the hemorrhoidal
plexus and drains into all three veins.
Rectum Lymphatic Drainage
• Parallels the vascular supply
• Upper and middle rectum -> inferior mesenteric nodes
• Lower rectum -> inferior mesenteric and internal iliac nodes Anal canal
• Proximal to the dentate line -> inferior mesenteric and internal iliac nodes
• Distal -> inguinal nodes, inferior mesenteric and internal iliac nodes

15. Rectum Nerve Supply
• Sympathetic - L1–L3 -> preaortic plexus -> hypogastric plexus combine with ->
• Parasympathetic (nervi erigentes) S2–S4 to form the pelvic plexus.
• Sympathetic and parasympathetic fibers then supply the anorectum and adjacent
urogenital organs.

16. EPIDEMIOLOGY
MALE FEMALE

17. BOTH

18. RISK FACTORS
Sporadic
(65%–85%)
Familial
(10%–30%)
Hereditary
nonpolyposis colorectal
cancer (HNPCC) (5%)
Familial adenomatous
polyposis (FAP) (1%)
Rare CRC
syndromes
(<0.1%)

19. Familial Risk
Approximate
lifetime
CRC risk
(%)
Affected family members
0
20
40
60
80
100
None One 1° One 1°
and two
2°
One 1°
age
<45
Two 1° HNPCC
mutation
2%
6% 8% 10%
17%
70%
Aarnio M et al. Int J Cancer 64:430, 1995
Houlston RS et al. Br Med J 301:366, 1990
St John DJ et al. Ann Intern Med 118:785, 1993
20
100
80
60
40

20. Risk of Colorectal Cancer
0 20 40 60 80 100
General population
Personal history of
colorectal neoplasia
Inflammatory
bowel disease
HNPCC mutation
FAP
5%
15%–20%
15%–40%
70%–80%
>95%
Lifetime risk (%)

21. Genetics
APC gene
• Present in 80% of sporadic cases
• Tumor-suppressor gene
• Ad
K-RAS
• Proto-oncogene
• Only one allele
• G protein involved in intracellular gtp signal transduction.

22. MYH gene
• Base excision repair gene
• AR
DCC
• Tumor-suppressor
• Present in more than 70% of colorectal carcinomas
P53
• Tumor-suppressor gene
• Crucial for initiating apoptosis
• 75% of colorectal cancers

23. • 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
Other Factors

24. • 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
• 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

25. • 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
Lifestyle Factors- BMI & Physical Activity

26. 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).
PRE INVASIVE LESIONS

27. 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.
• Risk of synchronous or metachronous colorectal carcinoma is 40%.
• Associated with extracolonic malignancies, including endometrial, which is
most common, ovarian, pancreas, stomach, small bowel, biliary, and
urinary tract carcinomas.
• Diagnosis of HNPCC is made based upon family history.

28. CLINICAL FEATURES

29. SCREENING
• Neoplastic polyps, including tubular adenomas, villous adenomas,
and tubulovillous adenomas, are precursors of colon cancers.
• Most CRC arise from pre-existing polyps.
• The cumulative lifetime risk of developing CRC in the United States is
about 6%.
• The goal of screening is to detect preinvasive polyps or early invasive
cancer.

30. • The American Cancer Society (ACS) and the United States Preventative
Services Task Force recommend screening in average-risk individuals
starting at age 50.
• The ACS advocates for tests that detect adenomatous polyps and cancer as
follows:
• 1. Flexible sigmoidoscopy every 5 years.
• 2. Double contrast barium enema every 5 years.
• 3. Computed tomography (CT) colonography every 5 years.
• 4. Colonoscopy every 10 years.
• 5. Guaiac-based fecal occult blood, fecal immunohistochemical, and stool
DNA tests may be performed for CRC, but not polyp, detection.

31. • In high-risk patients (patients with adenomatous polyps, history of
CRC, first-degree relative diagnosed with CRC or adenomas,
inflammatory bowel disease, or high risk due to family history or
genetic testing), more-intensive surveillance is recommended.
• Individuals with FAP initiate annual sigmoidoscopy or colonoscopy
beginning at age 10 to 12 years until age 35 to 40 years if negative.
• Patients with HNPCC initiate annual screening at age 20 to 25 years or
10 years prior to earliest familial CRC diagnosis.
• Patients with inflammatory bowel disease should initiate screening
with colonoscopy 8 to 10 years after initial diagnosis.

33. PATHWAY OF 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

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

35. PATHOLOGY
• 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

36. Microscopic Anatomy of Large Intestine
• Villi are absent
• Contains numerous goblet cells
• Intestinal crypts – simple tubular glands
• Lined with simple columnar epithelial tissue
• Epithelium changes at anal canal
• Becomes stratified squamous epithelium

37. Mucosa of the Large Intestine

38. 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

39. STAGING

40. Stage 0 Colorectal Cancer
• Known as “cancer in situ,” meaning
the cancer is located in the mucosa
(moist tissue lining the colon or
rectum)
• Removal of the polyp
(polypectomy) is the usual
treatment

41. Stage I Colorectal Cancer
• Tumor invades submucosa.
• Treatment is surgery to remove the
tumor and some surrounding lymph
nodes

42. Stage II Colorectal Cancer
• The cancer invades muscularis
propria of the colon or rectum
but has not spread to the lymph
nodes
• Stage II colon cancer is treated
with surgery and, in some cases,
chemotherapy after surgery
• Stage II rectal cancer is treated
with surgery, radiation therapy,
and chemotherapy

43. Stage III Colorectal Cancer
• The cancer has spread to the
regional lymph nodes (lymph
nodes near the colon and
rectum)
• Stage III colon cancer is treated
with surgery and chemotherapy
• Stage III rectal cancer is treated
with surgery, radiation therapy,
and chemotherapy

44. Stage IV Colorectal Cancer
• The cancer has spread outside of
the colon or rectum to other areas
of the body
• Stage IV cancer is treated with
chemotherapy. Surgery to remove
the colon or rectal tumor may or
may not be done
• Additional surgery to remove
metastases may also be done in
carefully selected patients

46. Stage at Diagnosis
Localized
(confined to
primary
site)
39%
Regional
(spread to
regional
lymphnodes)
37%
Distant
(cancer has
metastasize
d)
19%
Unknown
(unstaged)
5%

47. Sites of Metastasis
• Liver
• Lung
• Brain
• Bone

48. DIAGNOSTIC WORK UP
• 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/KFT
• Confirmatory- Biopsy
• Gold standard- Colonoscopy+ Biopsy

49. • Staging workup
• CXR or Chest CT
• Barium enema
• Colonoscopy- To evaluate extent of tumour
• USG Whole Abdomen
• CECT 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.

50. • 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.
• PET-CT Scan has emerging role.

51. • For rectal malignancies
• Endoscopic Ultrasound (EUS)
• Transrectal EUS techniques have been more helpful in efforts to clinically
stage rectal cancers.
• EUS is 80% to 95% accurate in tumor staging and 70% to 75% accurate in
mesorectal lymph node staging.
• MRI
• MRI techniques have high accuracy in defining the extent of rectal cancer
extension into the mesorectum and in determining the location and stage of
tumor.
• Another advantage of MRI is that it can detect involved lymph nodes on the
basis of characteristics other than size.

52. • Others
• Stool cytology
• CEA
• IHC markers- keratin
• Molecular markers- Oncogenes
• DNA flow cytometry
• Immunoscintigraphy
• Screening investigations

53. 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

54. TREATMENT OPTIONS
SURGERY RADIOTHERAPY CHEMOTHERAPY TARGETED

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

56. • 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

57. • TYPES OF SURGICAL RESECTION
• Right Hemicolectomy
• Extended Right Hemicolectomy
• Left Hemicolectomy
• Segmental resection
• Total Abdominal Colectomy: UC, FAP Syndrome/ FH
• Sx approach 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.

58. 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
• 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.

59. RADIOTHERAPY
• 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

60. 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

61. 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 Post
Op 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%

62. 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

63. • Stage III Colon
• FOLFOX (5-FU + leucovorin + oxaliplatin)
• Improved both overall survival and disease-free survival (MOSAIC
Trial)
• Adjuvant Chemo-RT is reserved for selected T4 lesions that involve
penetration to fixed structures
• 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

64. TREATMENT ALGORITHM RECTUM
• Stage I
• Lower one-third rectal cancers → APR
• Upper/middle one-third rectal cancers → low anterior resection (LAR)
• Highly-selected T1 tumors with good prognostic factors: local excision
alone
• Good prognostic factors: tumor size <3 cm, circumferential resection line
<1/3, maximum distance from anal verge <8 cm, well-differentiated,
surgical margin >3 mm, LVSI (−), PNI (−)
• T1 tumors with good prognostic factors (+), surveillance after surgery

65. • Stage II–III (resectable)- Preoperative 5-FU/RT + transabdominal surgery
+ adjuvant CT
• Stage III (unresectable and T4)- 5-FU/RT (then surgery if possible) + CT
• Stage IV- CT or surgery or RT or combinations of them

66. SURGERY

67. Surgical Procedure of Primary Site:
Rectosigmoid
• Wedge or segmental resection, partial proctosigmoidectomy
• Partial proctosigmoidectomy plus resection of contiguous organs
• Pull through with sphincter preservation
• Total proctectomy
• Total colectomy
• Total colectomy with ileostomy
• Ileorectal reconstruction
• Total colectomy with other pouch

68. Surgical Procedure of Primary Site: Rectum
• Wedge or segmental resection, partial proctectomy
• Pull through with sphincter preservation
• Total proctectomy
• Total proctocolectomy, NOS
• Proctectomy or proctocolectomy with resection in continuity with
other organs; pelvic exenteration
• LAR
• APR

69. RT PLANNING- Localization, Immobilization, and
Simulation
Immobilization and patient position
• Prone with arms above the head.
• Consider belly board to displace small bowel.
• Simulate and treat with full bladder to displace small bowel.
Contrast agents and markers
• Oral contrast to delineate the small bowel.
• Barium enema to delineate the tumor (caution with respect to tumor
displacement).
• IV contrast to delineate the tumor and LN.
• Anal marker to delineate the anus.

70. CONVENTIONAL RT FIELD
• Anterior–posterior fields
• Superior: between levels L5
and S1
• Inferior: preoperative, tumor +
3 cm; LAR, below obturator
foramen or tumor + 3 cm;
APR, includes perineal scar
• Lateral: bony pelvis+2 cm

71. Lateral fields
Superior–inferior: same as
anterior–posterior fields
Anterior: T3 tumors, posterior to
pubic symphysis; T4 tumors,
anterior to pubic symphysis
Posterior: includes sacrum

72. • Boost field → tumor/tumor bed + 2–3 cm. Sacral concavity should be
included in lateral fields.
• Dose
• 1.8 Gy/day, total dose: 45 Gy four field-box technique, 5.4 Gy boost may
be given.

73. Conformal RT Volumes
• CTV: tumor/tumor bed + perirectal tissue,
presacral region and internal iliac LNs.
• A craniocaudal 2 cm margin is added to
the tumor.
• 1-2 cm of the bladder and
prostate/vagina are included (particularly
in T4 cases).
• Anterior wall of the promontorium and
sacrum is within the CTV.
• PTV: CTV + 1–1.5 cm

74. Beam weighing typically 2:1:1 for PA and laterals
• High energy for PA field
• 6 MV photons used.
• IORT: consider for close/+ microscopic margins, especially for T4 or
recurrent CA.
• Brachytherapy: consider for macroscopic residual after pre-op
chemoRT and resection.

75. RT IN RECTUM
• Preoperative RT
• Advantages:
• Large and advanced tumors may be
downsized during radiation and the chances
of resection may also increase.
• Tumor cells that may be implanted into the
surgical region are eradicated.
• Tumor cells that may enter circulation are
eradicated and distant metastatic risk
decreases.
• Tumor cells are more oxic before surgery
and sensitive to radiation.
• Disadvantages:
• Overtreatment of early or metastatic tumors
• Delayed surgery and risk of stage
advancement
• Postoperative perineal complications may
increase
• Postoperative RT
• Advantages:
• There is no overtreatment with radiation
due to pathological confirmation of exact
stage.
• RT field is accurately designed since
tumoral extension is known.
• Disadvantages:
• RT efficacy may decrease due to hypoxic
medium after surgery.
• Postoperative adhesions may increase
intestinal side effects of RT.
• Field size increases after APR due to the
inclusion of the perineal scar in the RT
portal.

76. Neoadjuvant Radiotherapy
• It has emerged as the standard of care.
• It is associated with-
1. Tumour downstaging
2. Improved Resectability and Tolerance
3. Sphincter Preservation in Distal Rectum tumour
4. Improvement in Locoregional control & Overall survival

77. • Swedish Rectal Cancer Trial (Pahlman et al. 1997; Folkesson et al. 2005):
• 1,168 patients with resectable rectal CA randomized to
• Pre-op RT (25 Gy/5 fx) and surgery vs surgery alone (non-TME surgery).
• Pre-op RT improved 5-year Local Recurrence (11% vs. 27%) and 5-year
OS (58% vs. 48%).
• Thirteen-year OS was 38% vs 30% & LR 9% vs 26%.
• A higher rate of small bowel obstruction was seen in Pre Op RT arm.

78. • French Trial, Lyon 90-01
• RT was given as 39Gy @ 3Gy/#
• Arm I- RT followed by Sx within 2 weeks.
• Arm II- RT followed by Sx within 6-8 weeks.
• LC and OS was same of 33 months.
• Pathologic downstaging in Arm I vs Arm II was 10% vs 26% favouring
longer interval before surgery.
• Two meta analysis of 12,000 patients of 14 trials each-
• They reported that Neoadjuvant Radiation Treatment was associated
with-
• Significantly fewer local recurrences
• Improved specific survival
• OS benefit
• Death from rectal cancer

79. Neoadjuvant Chemoradiation
• French FFCD 9203 (Gerard 2006): 733 patients with T3-4N0 resectable AdenoCa
rectum randomized to pre-op RT (1.8/45 Gy) vs. pre-op concurrent Chemo RT +
bolus 5FU(350mg/m2) and LV d1-5 weeks 1 and 5.
• All patients had adjuvant 4 cycles of 5FU-LV chemo.
• No difference in 5 year OS.
• Pre-op chemoRT increased pCR (3.6 →11.4%) ,Local Relapse decreased (8.1% vs
16.5%), but also grade 3–4 toxicity increased (2.7% → 14.6%).
• No difference in sphincter saving surgery (52%), EFS, or OS (67%).

80. • EORTC 22921 (Bosset et al. 2006; JCO 2007): 1,011 patients with
resectable rectal CA randomized to -
Pre-op RT,
Pre-op chemoRT,
Pre-op RT + post-op chemo, or
Pre-op chemoRT + post-op chemo.
• RT consisted of 45 Gy and chemo consisted of 5-FU and LV (pre-op
chemo × 2 cycles, post-op chemo × 4cycles).
• Increased tumor down staging (14% vs. 5.3%; p = .0001) and lower rates
of LR (9% vs. 17%) but no difference in 5-year OS (65% in both arms).
• This information suggests that although there are lower rates of
recurrence, there is no evidence that combined treatment offers a survival
benefit compared to radiation alone in the neoadjuvant setting.
• There is, however, a higher incidence of acute toxicity associated with
ChemoRT.

81. Pre Op vs Post Op Chemo RT
• German Rectal Cancer Study Group (Sauer et al. 2004): 823 patients with
T3/4 or N+ rectal CA randomized to pre-op vs. post-op chemoRT. Both
arms had 50.4 Gy with concurrent 5-FU; post-op arm had additional 5.4 Gy
boost.
• Increased rate of sphincter saving procedures (39% vs. 19%); and
decreased grade 3–4 acute and late toxicity and late anastomotic
strictures.
• Overall, no difference in overall survival between pre- and post-operative
chemoRT (76% vs 74%, p = 0.80) but local relapse rates were 6% in the
pre-op chemoRT arm vs 13% in the post-op arm, p = 0.01

82. 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
compromising clinical efficacy
Chemotherapy as adjuvant in CRC

83. 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

84. 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

86. Targeted therapy in advanced colon cancer
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

87. Anti – VEGF monoclonal
antibody

88. Vascular Endothelial Growth
Factor (VEGF)
• Bevacizumab
• Humanized monoclonal antibody
targeting VEGF
• Overall Response=none
• Complications:
• Bleeding, Thrombosis,
Hypertension, Proteinuria
• Wound dehiscence
• Bowel perforation
• Ziv-aflibercept (VEGF-trap)
• Recombinant fusion protein
• Complications: as above
• Regorafenib (multikinase inhibitor)
VEGFR/Raf/Kit/PDGFR
Agents bind or trap VEGF, reducing
tumor angiogenesis

89. Bevacizumab
 Approved for use in metastatic CRC in combination with IV 5FU as first-
line
 Dose: 5 mg/kg IV over 90 mins every 2 weeks
• Toxicities:
1. GI Perforation
2. Wound Dehiscence
3. Hemorrhage
4. Risk of Arteriel TE Events (MI, Stoke)
5. Hypertension
6. Infusion-related Toxicity
7. Proteinuria
8. Nehprotic Syndrome

90. E3200: Response Rates
0.7%
3.0%9.2%21.8%OR*
01.9%CR
29.1%
3.0%
230
Bevacizumab
45.0%51.7%SD
8.5%19.9%PR
271271
FOLFOX4FOLFOX4 +
bevacizumab
Giantonio BJ, et al. ASCO 2005
*FOLFOX+B vs FOLFOX: P < 0.0001

91. 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
Siddiqui and Piperdi. Ann
Surg Oncol. 17:1168
2010

92. Cetuximab
 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
 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/m2., then 250 mg/m2 IV weekly
 Infusion-related toxicity (40-50%), rash, ILD, asthenia & fatigue,
paronychia

93. 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

94. FOLFIRI
5-FU bolus 400 mg/m2, infusion 2400
mg/m2 +
Irinotecan 180 mg/m2 +
Leucovorin 400 mg/m2
every 2 wks
(n = 609)
Patients with previously
untreated EGFR-
expressing metastatic
colorectal cancer,
stratified by geographical
region, ECOG PS
(N = 1217)
FOLFIRI + Cetuximab
5-FU bolus 400 mg/m2, infusion 2400
mg/m2 +
Irinotecan 180 mg/m2 +
Leucovorin 400 mg/m2
every 2 wks
Cetuximab 400 mg/m2 initial dose,
then 250 mg/m2 wkly
(n = 608)
Van Cutsem E, et al. ASCO 2007. Abstract 4000.
CRYSTAL Trial FOLFIRI ± Cetuximab

95. EGFR Monoclonal Antibodies
• Cetuximab
• Overall Response = 10%
• Complications:
• Diarrhea
• Skin toxicity
• Infusion reactions
• Hypomagnesemia
• Interstitial lung disease
KRAS-wild type patients only!
 Panitumumab
– Overall Response = 10%
– Complications:
 Diarrhea
 Skin toxicity
 Hypomagnesemia

96. FOLLOW UP
• 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 Follow Up
• CECT whole abdomen 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

97. RISING CEA
COLONOSCOPY
FDG-PET
NORMAL
CXR CECT

98. TAKE HOME MESSAGE
• Incidence and death rates are declining
• Eat right, exercise and avoid smoking
• Highest risk observed in persons who are both physically inactive and
have high BMIs
• Screening saves lives
• Most people get screened because their doctor told them to
• Advances in treatment have led to improved survival
• Advances in molecular profiling of cancers has led to personalized
treatments

99. THANK YOU