Colonic Malignancies

Sarthak Moharir
Sarthak Moharirrdgmc Ujjain
COLON CANCER
Dr. Sarthak Moharir
PGY2
Department Of Radiation Oncology
• Introduction
• Relevant Anatomy
• Genetics
• Clinical Features
• Diagnostic Work-up
• Management
• Surveillence & Survivorship
INTRODUCTION
• 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
Colonic Malignancies
Colonic Malignancies
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
cancers.
MSI-H tumors include:
• Right sided pooly differentiated tumors
• right sided mucinous tumors
• Adenocarcinomas in any location with measurable intraepithelial lymphocytes.
FAMILIAL POLYPOSIS COLI
• Autosomal dominant
• Nearly 100% penetrance.
• 30% of patients have de novo mutations
and are without an ostensible family
history.
• Deletion on the 5q21 chromosome.
• 1% of all CRC incidence
• hundreds to thousands of colonic polyps
that develop in patients in their teens to
30s.
• 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
tumors
Colonic Malignancies
Colonic Malignancies
SCREENING
• 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.
Colonic Malignancies
TNM STAGING
• TNM-AJCC
• 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
Dysplasia/severe dysplasia)
T1 Invasion up to submucosa
T2 Invasion up to the muscularis propria
T3 Through the muscularis, into the subserosa/pericolic or
perirectal tissue
T4(a) Perforation the visceral peritoneum
T4(b) Invasion of other abdominal organs and structures
TNM STAGING
Nx Incomplete information
N0 pN0: when <12 nodes have been examined.
N0: No nodes positive for disease
N1(a)
N1(b)
N1(c)
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.
N2(a)
N2(b)
metastasis in four to six regional LNs.
>7 nodes
•Minimum 12 LNs analysed for accurate N staging of tumor
•Increase in number of LNs resected~ improved survival.
TNM STAGING
M0 No evidence of distant mets
M1 Distant metastasis+
external iliac, common iliac, para-aortic, supraclavicular, or other nonregional LNs
M1(a)
M1(b)
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.
Colonic Malignancies
PROGNOSTIC FACTORS
• HISTOLOGY
• HOST LYMPHOID REACTION
• SENTINEL NODE BIOPSY
• RESECTION MARGINS
• PNI/LVE
• TUMOR BORDER CONFIGURATION
• PERFORATION
• CATEGORY III FACTORS: DNA content (ploidy) proliferation indices.
• PRIMARY TUMOR LOCATION
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
infilteration+
HOST LYMPHOID REACTION: Associated with better response and increased
OS.
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.
PROGNOSTIC FACTORS
RESECTION MARGINS
• 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
of tumor.
• 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%
MICROSATELLITE INSTABILITY
• 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
IV specimens.
• Germline mutations in MMR genes MLH1, MSH2, MSH6, PMS2/EpCAM +ve in
individuals with lynch syndrome: 2-4% of all colonic malignancies.
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
life)
• Right sided EGFR+ tumors do not respond to Avastin based CTx. (41% in left sided tumors)
MMR Mutation:
• MMR deficient tumors relapse @11%. MMR proficient tumors relapse @26%, but it doesn’t
predict the responsiveness to CTx.
CLINICAL FEATURES
• Weight loss
• Altered bowel habits: Alternating constipation and diarrhoea
• SAIO Complete GI Obstruction
• Hematochezia Frank bleeding PR
• Acute Abdomen
• Jaundice
DIAGNOSTIC WORK-UP
• Complete physical exam + Review of systems
• Routines
• Serum CEA titers.
• Barium Enema
• Colonoscopy
• 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
TUMOR BOARD
MANAGEMENT
• 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
CTx/CT-RT.
• Adjuvant chemotherapy in Management of stage II is controversial.
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
contraindications absent.
ADJUVANT TREATMENT
According to stage
Stage I and low risk stage II (MSI-H): No adjuvant management required.
Low risk stage II:
• Clinical trial
• Observation
• Capecitabine/LV-5FU
• 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
• FLOX/FOLFOX/CapeOx/Capecitabine.
• QUASAR trial: 5FU/LV based Ctx improved OS from patients not receiving Adj.
Rx.
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
14 weeks
• Adj. Tx to be started as soon as medically feasible.
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
cycle
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
ADVERSE DRUG REACTIONS
• Myelosuppression, mucositis, diarroea, hand foot
syndrome: palmer-plantar erythrodysesthesia, CNS
toxicity, Cardiac toxicity, metallic taste in mouth on
bolus administration.
• Vitamin B6: for prevention of hand foot syndrome
5-FU
• Sensory neuropathy (reversible), diarrhoea,
myelosuppression, allergic reaction, facial flushing,
hepatotoxicity, BOOP
Oxaliplatin
• Myelosuppression, Diarrhoea, Alopecia, Deranged
LFT, Asthenia, fever.
Irinotecan
SECOND LINE THERAPY
Cetuximab/Panitumumab:
• 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.
Bevacizumab:
• 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
Surgery.
• RAS-wild type right colon tumors respond better to Bevacizumab.
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
Oxaliplatin 85mg/m2
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
PRINCIPLES OF RADIATION
THERAPY
RT to Tumor bed: Defined
by preoperative radiologic
imaging and/or surgical
clips.
Radiation doses should
be: 45–50.4 Gy in 25–28
fractions.
Parallel opposed
fields/multifields(coplanar)
to tumor bed+ 3-5cms
margin.
Boost in case of
close/positive margins.
Dose to small bowel
</=45Gy.
Dose to liver, large bowel,
stomach should be
evaluated via DVH
PRINCIPLES OF RADIATION
THERAPY
Concurrent CTx. With 5-
FU based regimens.
3DCRT is method of
choice. IMRT/IGRT
reserved for unique
clinical situations.
Neo-adjuvant Chemo-RT
with 5-FU based regimen
for downstaging
unresectable non-
metastatic T4 disease.
IORT as an additional
boost in T4 or recurrant
setting. Otherwise EBRT
boost of 10-20Gy or
brachytherapy may be
considered.
SBRT/SABR for
oligometastasis to
liver/lung.
Colonic Malignancies
PRINCIPLES OF RADIATION
THERAPY
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.
• Synchronous/Metachronous
• Oligometastasis can be considered for resection.
• Unresectable disease requires systemic therapy:
• Therapy after progression of metastatic disease depends upon previous
therapies.
• Mitomycin, MTx, Taxanes, Pemetrexed, Sunitinib, Sorafenib, Erlotenib,
Gemcitabine are contraindicated.
METASTATIC DISEASE
5 regimens recommended:
FOLFOX (mFOLFOX6)
FOLFIRI
CapeOx
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
observed.
• HIPEC+peritoneal debulking (Mitomycin C)
POST TREATMENT
SURVEILLENCE
Colonic Malignancies
Colonic Malignancies
Colonic Malignancies
Colonic Malignancies
THANK YOU
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Colonic Malignancies

  • 1. COLON CANCER Dr. Sarthak Moharir PGY2 Department Of Radiation Oncology
  • 2. • Introduction • Relevant Anatomy • Genetics • Clinical Features • Diagnostic Work-up • Management • Surveillence & Survivorship
  • 3. INTRODUCTION • 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 cancers. 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 history. • Deletion on the 5q21 chromosome. • 1% of all CRC incidence • hundreds to thousands of colonic polyps that develop in patients in their teens to 30s. • 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 tumors
  • 10. SCREENING • 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 • TNM-AJCC • 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 Dysplasia/severe dysplasia) T1 Invasion up to submucosa T2 Invasion up to the muscularis propria T3 Through the muscularis, into the subserosa/pericolic or perirectal tissue 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 N1(a) N1(b) N1(c) 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. N2(a) N2(b) metastasis in four to six regional LNs. >7 nodes •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 M1(a) M1(b) 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.
  • 16. PROGNOSTIC FACTORS • HISTOLOGY • HOST LYMPHOID REACTION • SENTINEL NODE BIOPSY • RESECTION MARGINS • PNI/LVE • TUMOR BORDER CONFIGURATION • PERFORATION • CATEGORY III FACTORS: DNA content (ploidy) proliferation indices. • PRIMARY TUMOR LOCATION
  • 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 infilteration+ HOST LYMPHOID REACTION: Associated with better response and increased OS.
  • 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 RESECTION MARGINS • 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 of tumor. • 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% MICROSATELLITE INSTABILITY • 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 IV specimens. • 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 life) • Right sided EGFR+ tumors do not respond to Avastin based CTx. (41% in left sided tumors) MMR Mutation: • 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 • Jaundice
  • 22. DIAGNOSTIC WORK-UP • Complete physical exam + Review of systems • Routines • Serum CEA titers. • Barium Enema • Colonoscopy • 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 TUMOR BOARD
  • 23. MANAGEMENT • 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 CTx/CT-RT. • 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 contraindications absent.
  • 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 • Observation • Capecitabine/LV-5FU • 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 • FLOX/FOLFOX/CapeOx/Capecitabine. • QUASAR trial: 5FU/LV based Ctx improved OS from patients not receiving Adj. Rx.
  • 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 14 weeks • 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 cycle 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 bolus administration. • Vitamin B6: for prevention of hand foot syndrome 5-FU • Sensory neuropathy (reversible), diarrhoea, myelosuppression, allergic reaction, facial flushing, hepatotoxicity, BOOP Oxaliplatin • Myelosuppression, Diarrhoea, Alopecia, Deranged LFT, Asthenia, fever. Irinotecan
  • 29. SECOND LINE THERAPY Cetuximab/Panitumumab: • 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. Bevacizumab: • 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 Surgery. • 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 Oxaliplatin 85mg/m2 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 THERAPY RT to Tumor bed: Defined by preoperative radiologic imaging and/or surgical clips. Radiation doses should be: 45–50.4 Gy in 25–28 fractions. Parallel opposed fields/multifields(coplanar) to tumor bed+ 3-5cms margin. Boost in case of close/positive margins. Dose to small bowel </=45Gy. Dose to liver, large bowel, stomach should be evaluated via DVH
  • 32. PRINCIPLES OF RADIATION THERAPY Concurrent CTx. With 5- FU based regimens. 3DCRT is method of choice. IMRT/IGRT reserved for unique clinical situations. Neo-adjuvant Chemo-RT with 5-FU based regimen for downstaging unresectable non- metastatic T4 disease. IORT as an additional boost in T4 or recurrant setting. Otherwise EBRT boost of 10-20Gy or brachytherapy may be considered. SBRT/SABR for oligometastasis to liver/lung.
  • 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. • Synchronous/Metachronous • Oligometastasis can be considered for resection. • Unresectable disease requires systemic therapy: • Therapy after progression of metastatic disease depends upon previous therapies. • Mitomycin, MTx, Taxanes, Pemetrexed, Sunitinib, Sorafenib, Erlotenib, Gemcitabine are contraindicated.
  • 36. METASTATIC DISEASE 5 regimens recommended: FOLFOX (mFOLFOX6) FOLFIRI CapeOx 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 observed. • HIPEC+peritoneal debulking (Mitomycin C)