• CRC incidence and mortality rates are the greatest in developed Western nations.
• migrants from low-incident areas to high-incident areas assume the incidence of the
host country within one generation
• 1,200,000 new CRC cases are believed to occur, which accounts for approximately
10% of all incident cancers.
• sporadic CRC increases dramatically above the age of 45 to 50 years for all groups.
• Classically, colon cancer was believed to be a disease of the left or distal colon.
• Incidence of right colon malignancies increasing:
(1) Increased longevity
(2) Response to luminal procarcinogens and carcinogens
(3) Genetic factors
6. HNPCC: LYNCH SYNDROME
• Defective mismatch repair
• Hereditary nonpolyposis CRC (HNPCC) accounts for about 3% of all CRCs.
• Autosomal Dominant and ~80% penetrance
• Up to 100 colonic polyps.
• HNPCC Type I: Indolent course, long term conversion to malignancy.
• HNPCC Type II: Extracolonic tumors.
• The lifetime risk of CRC: 80%, 50%-60% for endometrial cancer, 1%-13% for all other
MSI-H tumors include:
• Right sided pooly differentiated tumors
• right sided mucinous tumors
• Adenocarcinomas in any location with measurable intraepithelial lymphocytes.
7. FAMILIAL POLYPOSIS COLI
• Autosomal dominant
• Nearly 100% penetrance.
• 30% of patients have de novo mutations
and are without an ostensible family
• Deletion on the 5q21 chromosome.
• 1% of all CRC incidence
• hundreds to thousands of colonic polyps
that develop in patients in their teens to
• 100% of patients progress to CRC.
• Extracolonic manifestations: Congenital
hypertrophy of the retinal pigment
epithelium, mandibular osteomas,
supernumerary teeth, epidermal cysts,
adrenal cortical adenomas, desmoid
• Most CRC arise from pre-existing polyps.
• Neoplastic polyps, including tubular adenomas, villous adenomas, and tubulovillous
adenomas, are precursors of colon cancers.
• American Cancer Society Task Force recommend screening in average-risk individuals
starting at age 50.
• 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.
In high-risk patients, more intensive surveillence is required.
12. TNM STAGING
• Clinical Vs. Pathological Staging.
• V&L Substaging
• Y-prefix : Indicating neoadjuvant Rx.
Tx incomplete information
Tis confined to the glandular
basement membrane or lamina propria. (high grade
T1 Invasion up to submucosa
T2 Invasion up to the muscularis propria
T3 Through the muscularis, into the subserosa/pericolic or
T4(a) Perforation the visceral peritoneum
T4(b) Invasion of other abdominal organs and structures
13. TNM STAGING
Nx Incomplete information
N0 pN0: when <12 nodes have been examined.
N0: No nodes positive for disease
Metastasis in one regional LN.
two or three nearby LNs
Tumor cells found in areas of fat near LNs, but not in the LNs themselves.
metastasis in four to six regional LNs.
•Minimum 12 LNs analysed for accurate N staging of tumor
•Increase in number of LNs resected~ improved survival.
14. TNM STAGING
M0 No evidence of distant mets
M1 Distant metastasis+
external iliac, common iliac, para-aortic, supraclavicular, or other nonregional LNs
One distant organ or set of distant LNs
more than one distant organ or sets of LNs or to the peritoneum
Colonic malignancies are usually staged after surgical exploration of
abdomen and examination of histopathological specimen.
17. PROGNOSTIC FACTORS
HISTOLOGY: Most common is AdenoCa. Also: SCC, Melanoma, Small cell,
carcinoid, sarcoma, etc.
Major histologic subtypes:
• SIGNET RING: Adverse prognosis
• MUCINOUS: Adverse prognosis when associated with obstruction.
• SMALL CELL: Extrapulmonary oat cell i.e. high grade neuroendocrine tumors.
• MEDULLARY: Absence of glands, distinctive growth pattern. Lymphocytic
HOST LYMPHOID REACTION: Associated with better response and increased
18. PROGNOSTIC FACTORS
SENTINEL NODE BIOPSY
• Described by Saha et al.
• the goal of the sentinel node in colon cancer is to focus the pathologic
analysis on fewer nodes so a more extensive study can be performed.
• H&E or IHC
• Dissection is performed regardless of the biopsy outcome.
• Accuracy rates >80% and upstaging in 15.4% of patients according to
a recent prospective trial.
• Sentinel LN mapping detected aberrant lymphatic drainage in 22%,
which in turn led to a change in operation.
• Further large-scale trials are required to establish its role in the staging
of patients with CRC.
19. PROGNOSTIC FACTORS
• R0/R1/R2 Resections are defined based on the CRM (circumferential radial margin).
• The cut retroperitoneal or perineal soft tissue margin closest to the deepest penetration
• Positive if tumor is present microscopically (R1) or macroscopically (R2) on a cut radial
or lateral aspect of the surgical specimen.
• CRM+ resections have 38% chance of relapse, CRM- resections roughly 10%
• Importance: Adjuvant CTx in stage II disease.
• Tumors with MSI are either MSI-H or MSI-L
• MSI-H tumors less likely to metastasize: Frequency of MSI-H in stage II disease> stage
• Germline mutations in MMR genes MLH1, MSH2, MSH6, PMS2/EpCAM +ve in
individuals with lynch syndrome: 2-4% of all colonic malignancies.
20. PROGNOSTIC FACTORS
Bowel obstruction and perforation:
• Poorer prognosis, for DFS.
• SITE OF OBSTRUCTION: Right colon obstruction has worse prognosis
• 5 year survival: 31% with perforation, 59% otherwise.
Primary Tumor Location:
• Right-sided colon cancers carry a worse prognosis than left-sided ones.
• Multiple contradictory studies show variable results. 9counding factor: Right sided in later in
• Right sided EGFR+ tumors do not respond to Avastin based CTx. (41% in left sided tumors)
• MMR deficient tumors relapse @11%. MMR proficient tumors relapse @26%, but it doesn’t
predict the responsiveness to CTx.
21. CLINICAL FEATURES
• Weight loss
• Altered bowel habits: Alternating constipation and diarrhoea
• SAIO Complete GI Obstruction
• Hematochezia Frank bleeding PR
• Acute Abdomen
22. DIAGNOSTIC WORK-UP
• Complete physical exam + Review of systems
• Serum CEA titers.
• Barium Enema
• Histopathology of suspected malignant lesion.
• CT Scan (disease status+metastatic work-up)
• CXR/USG W/A
• MMR mutation, MSI status
• PET Scan if considering Metastatectomy (M1)
• BRAF/RAS mutations in stage IV disease
• Medical, Surgical and Radiation.
• SURGERY: MAINSTAY
• Resection with curative intent possible in nearly 75% patients.
• Adjuvant treatment required according to stage.
• Stage III patients require multimodality treatment with adjuvant
• Adjuvant chemotherapy in Management of stage II is controversial.
24. SURGICAL MANAGEMENT
• For invasive carcinomas of the colon, stages I
through III, the surgical approach will be dictated
by the size and location of lesions in the colon.
The location will determine what region of bowel
is removed, and the extent of its resection is
dictated by its vascular and lymphatic supply.
• Minimally invasive surgery may be considered if
25. ADJUVANT TREATMENT
According to stage
Stage I and low risk stage II (MSI-H): No adjuvant management required.
Low risk stage II:
• Clinical trial
• Oxaliplatin is not indicated (MOSIAC trial: FOLFOX<<5FU/LV)
High risk stage II: T4, unfavourable histology, MSI-L, LVI, PNI, margins
indeterminate, inadequate nodal dissection
• LV/5FU based chemotherapy
• QUASAR trial: 5FU/LV based Ctx improved OS from patients not receiving Adj.
26. ADJUVANT TREATMENT
• IRINOTECAN containing regimens not recommended in adjuvant first
line setting. (CALGB 89803)
• Bevacizumab also not indicated in upfront adjuvant setting (NSABP-
08/ AVANT ph-3)
• Cituximab: increased toxicity with no improvement of OS/DFS
(NCCTG Intergroup ph-3)
• These agents best reserved for M1 disease, or progression on
5FU/LV based Tx.
• End-point of adjuvant therapy: DFS 2-3 years post op.
• Each 4-week of delay in starting adjuvant treatment reduces OR by
• Adj. Tx to be started as soon as medically feasible.
27. ADJUVANT TREATMENT
• mFOLFOX6 is the preffered regimen: repeated 2 weekly
D1 Oxaliplatin 85mg/m2 over 2 hours
D1 LV 400mg/m2 over 2 hours
D1 5FU 400mg/m2 IV bolus
followed by 5FU1200mg/m2/day for 2 days continous infusion
• FLOX: 8 week cycles
5FU 500mg/m2 IV weekly
LV 500mg/m2 IV weekly on days 1,8,15,22,29,36: i.e. 6 weekly of each 8 week
Plus Oxaliolatin 85mg/m2 IV on days 1, 15, 29 of each 8 week cycle x 3 cycles
• CapeOx: 3 weekly
Oxaliplatin 130mg/m2 over 2 hours plus
Day 1-14: Capecitabine 1000mg/m2 BD
28. ADVERSE DRUG REACTIONS
• Myelosuppression, mucositis, diarroea, hand foot
syndrome: palmer-plantar erythrodysesthesia, CNS
toxicity, Cardiac toxicity, metallic taste in mouth on
• Vitamin B6: for prevention of hand foot syndrome
• Sensory neuropathy (reversible), diarrhoea,
myelosuppression, allergic reaction, facial flushing,
• Myelosuppression, Diarrhoea, Alopecia, Deranged
LFT, Asthenia, fever.
29. SECOND LINE THERAPY
• EGFR-expressing mCRC in combination with irinotecan in irinotecan-refractory
disease or as monotherapy in irinotecan-intolerance.
• Cetuximab CI: in KRAS mutated tumors.
• RAS wild type left colonic tumors: respond better to Cetuximab.
• VEGF receptor antibody.
• 1st line therapy in mCRC, in combination with 5FU/LV.
• Second line in case of progression.
• MS: 17.9 vs. 14.6 months.
• Interferes with wound healing. 5-6 weeks between Avastin based NACT and
• RAS-wild type right colon tumors respond better to Bevacizumab.
30. SECOND LINE THERAPY
• FOLFIRI: 2 weekly x 4 cycles.
Day1: Irinotecan 180mg/m2 over 30-90 minutes
Day1: LV 400mg/m2
Day1: 5-FU 400mg/m2 IV bolus
Day1&2: 1200mg/m2 (2400mg total)
• FOLFOXIRI: 2 weekly x 4 cycles.
Irinotecan 165mg/m2 over 1 hour
LV 200mg/m2 concurrently over 120 min.
5FU 3200mg/m2 over 48 hours.
FOLFIRI+ Cetuximab: only for pan-RAS wild type tumors when 5FU/LV has been
used as 1st line therapy.
Cetuximab 400mg/m2 loading followed by 250mg/m2 weekly on D1 followed by FOLFIRI
31. PRINCIPLES OF RADIATION
RT to Tumor bed: Defined
by preoperative radiologic
imaging and/or surgical
Radiation doses should
be: 45–50.4 Gy in 25–28
to tumor bed+ 3-5cms
Boost in case of
Dose to small bowel
Dose to liver, large bowel,
stomach should be
evaluated via DVH
32. PRINCIPLES OF RADIATION
Concurrent CTx. With 5-
FU based regimens.
3DCRT is method of
reserved for unique
with 5-FU based regimen
metastatic T4 disease.
IORT as an additional
boost in T4 or recurrant
setting. Otherwise EBRT
boost of 10-20Gy or
brachytherapy may be
35. METASTATIC DISEASE
• Importance of RAS/BRAF/VEGF mutation studies.
• 50-60% patients develop metastatic lesions.
• 80-90% patients have unresectable disease.
• Mostly in the liver. Lung also common.
• Oligometastasis can be considered for resection.
• Unresectable disease requires systemic therapy:
• Therapy after progression of metastatic disease depends upon previous
• Mitomycin, MTx, Taxanes, Pemetrexed, Sunitinib, Sorafenib, Erlotenib,
Gemcitabine are contraindicated.
36. METASTATIC DISEASE
5 regimens recommended:
Infusional 5FU/LV or Capecitabine
FOLFOXIRI +/- targeted therapy.
However, single agent Capecitabine is useless in 5FU resistant mCRC.
• Intensive initial therapy followed by maintainence untill progression is
• HIPEC+peritoneal debulking (Mitomycin C)