CARCINOMA COLON AND IT’S

MANAGEMENTDr. Manoj Kumar B.

Moderator: Dr. R. Kapoor30.10.08

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)

• Globally 800,000 new CRCs occur each year, accounting for 10% of all incident cancers with 450,000 deaths/year

• About 75-80% present with localized disease

• 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

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

Ascending Colon 4%

Transverse Colon 8%

Descending Colon 14%

Sigmoid Colon 35.7%

Rectum 39%

CLINICAL RISK FACTORS• Age > 40yrs

• Male sex

• Genetic syndromes- PJS/FAP/Gardener’s/Turcot /Oldfield’s

• F/H- Lynch-I : Familial CRC syndrome

Lynch-II : Hereditary adenocarcinomatosis synd.

• Other– Prior h/o CRC /Malignant colorectal polyps

– Inflammatory bowel disease

– High BMI / Low physical activity

– Red meat / processed food/ ? Low fiber diet

– Excessive alcohol consumption/ low folate intake

– Prolonged cigarette smoking

– Pelvic irradiation

CARCINOGENESIS: Adenoma to Carcinoma Pathway

APCLoss/mutation

Ch. 5q

NormalEpithelium

EarlyAdenoma

CancerHyper-

proliferationIntermediate

AdenomaLate

Adenoma

K-rasMutation

Ch. 12p (50%)

DCC lossCh. 18qDPC4 Ch. 4

p53Loss

Ch. 17p

Loss of DNA methylation

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

SPREAD

LocalMultidirectional growth progressionIntramural- bowel wall penetrationInvasion into adjacent organs/ structuresPerineural 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

• 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

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

DIAGNOSIS• Complete history

• Physical examination /DRE

• Routine investigations

• Confirmatory- Biopsy

• Staging workup– CXR

– Barium enema

– Colonoscopy

– USG

– CECT abdomen- pelvis

– Virtual colonoscopy

– MRI

– PET

• Gold standard- Colonoscopy+ Biopsy

•Others•FOBT•Stool cytology •CEA•IHC markers- keratin•Molecular markers- oncogenes•DNA flow cytometry •Immunoscintigraphy

•Screening investigations

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

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)

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%)

• 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

CECT ABDOMEN/ PELVIS • More accurate for T4 than T2/3 lesions

• 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%

• 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 :

AJCC/ UICC STAGING

TREATMENT

• SURGERY- Primary

• RADIOTHERPY- Adjuvant

• CHEMOTHERAPY-Adjuvant and metastatic

• TARGETED / IMMUNOTHERAPY- Adjuvant and metastatic

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

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

• 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

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

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

• Stage III Colon– FOLFOX (5-FU + leucovorin + oxaliplatin)

– Improved both overall survival and disease-free survival (MOSAIC Trial)

• Adjuvant XRT is reserved for selected T4 lesions that involve penetration to fixed structures

Stage Mean 5 yr survival rate (%)

T1N0 97

T2N0 90

T3N0 78

T2N+ 74

T4N0 63

T3N+ 48

T4N+ 38

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

• 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

Failure pattern following curative surgery

Series Stage n LF (%)

Abdominal failure (%)

Distant failure(%)

Gunderson et al

All T3-4 and /or N1-2

9172

22

17

46

77

Willet et al All T3-4 and /or N1-2

533395

6

8

11

14

4

Minsky et al All T3-4 and /or N1-2

284229

64

810

35

• 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

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

• 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#

Caecum and proximal ascending colon

Mid ascending colon

Distal descending colon

Middle sigmoid colon adherent to left pelvic sidewall or proximal sigmoid

Distal ascending colon and hepatic flexure

Splenic flexure and proximal descending colon

Middle descending colon

Palliative - Sigmoid colon adherent to the UB

• 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

Group Stage N Surgery Sx+RT Surgery Sx+RT

Adjuvant T3N0(B2) 163 10 9 70 72

T4N0(B2) 83 31 7 63 79

T3N1-2 (C2)

100 35 30 44 47

T4N1-2 (C3)

49 53 28 37 53

Perforation/fistula

T4N0 21 48 6 43 91

Residual disease

All 47 37

5 yr Local/Regional failure (%) DFS (%)

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%

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%

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

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

INT-0035 NCI 1990

consensus established adjuvant CCT as standard of care of patients with node (+) resected ca colon

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

• 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

• 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

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

Commonly Used Fluorouracil (5-FU) RegimensRegimen 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

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

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/m2over 24 h, weekly for 5 weeks, repeated every 6 weeks.

Single Agents: 5FU/Leucovorin (Mayo, Roswell, DeGramont)

Capecitabine Oxaliplatin

IrinotecanCombinations:

Oxaliplatin + 5FU (FOLFOX) Irinotecan/5FU/Leuco (IFL, Saltz)

Irinotecan + 5FU (FOLFIRI)Capecitabine + Oxaliplatin (Capox)Capecitabine + Irinotecan (Capiri)

Chemotherapy in CRC

5-Fluorouracil + Leucovorin (Mayo Clinic Schedule) NCCTG5-FU: 425 mg/m2 IV on d1 – 5LCV : 20 mg/m2 IV on d1 – 5 before 5 - FURepeat cycle every 4 – 5 weeks for a total of 6 cycles

Oxaliplatin + 5-Fluorouracil + Leucovorin (FOLFOX4)Oxaliplatin: 85 mg/m2 IV on day 15-Fluorouracil 400 mg/m2 IV bolus, followed by 600 mg/m2 IV continuous infusion for 22 hours on days 1 and 2Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour infusion before

5-FluorouracilRepeat cycle every 2 weeks

Chemotherapy as adjuvant in CRC

Stage IV/ Metastatic Ca Colon

• Selectively resectable group– Options: Regional strategies

• Organ-specific infusional therapy• Isolated or continuous perfusion therapy• Radiofrequency ablation • Cryotherapy• Surgical debulking• Radiation

– Surgical metastsectomy

• 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

Oxaliplatin + 5-Fluorouracil + Leucovorin (mFOLFOX7)Oxaliplatin: 100 mg/m2 IV on day 15-Fluorouracil: 3000 mg/m2 IV continuous infusion on days 1 and 2 for 46 hoursLeucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion before 5-fluorouracilRepeat cycle every 2 weeks

Irinotecan + 5-Fluorouracil + Leucovorin (FOLFIRI Regimen)Irinotecan: 180 mg/m2 IV on day 15-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV

continuous infusion for 46 hoursLeucovorin: 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

CapecitabineCapecitabine: 1250 mg/m2 PO bid on days 1 – 14Repeat 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

Capecitabine + Oxaliplatin (XELOX)Capecitabine: 1000 mg/m2 PO bid on days 1 - 14Oxaliplatin: 130 mg/m2 IV on day 1Repeat 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 - 14Irinotecan: 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

• 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

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

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

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 VEGF2) Developing intervention to VEGF pathway involving

small different molecules with tyrosine kinase inhibition activity directed towards the VEGF receptors

Bevacizumab

Anti – VEGF monoclonal antibody

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

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*FOLFOX+B vs FOLFOX: P < 0.0001

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

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

O‘Dwyer PJ, Benson AB III. Semin Oncol. 2002;29(suppl 14):10.

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

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

FOLFIRI5-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 + Cetuximab5-FU bolus 400 mg/m2, infusion 2400 mg/m2 + Irinotecan 180 mg/m2 +Leucovorin 400 mg/m2 every 2 wksCetuximab 400 mg/m2 initial dose, then 250 mg/m2 wkly(n = 608)Van Cutsem E, et al. ASCO 2007. Abstract 4000.

CRYSTAL Trial FOLFIRI ± CRYSTAL Trial FOLFIRI ± CetuximabCetuximab

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

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

RISING CEA

COLONOSCOPY

FDG-PET

NORMAL NORMAL

CXR CXR CECT

ACS colorectal cancer screening guidelinesACS colorectal cancer screening guidelines*Fecal occult blood test (FOBT) † or fecal immunochemical test

(FIT) every year, orFlexible sigmoidoscopy every 5 years, orAn 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, orColonoscopy 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.

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Population Screening

• Simple

• Cheap

• Reliable

• Safe

• Acceptable

CRC fulfills many of these criteria CRC fulfills many of these criteria for effective screeningfor effective screening