COLORECTAL CANCER Charles Lopez, M.D., Ph.D. Associate Professor of Medicine Hematology and Medical Oncology May 2009

COLORECTAL CANCER

Charles Lopez, M.D., Ph.D.

Associate Professor of Medicine

Hematology and Medical Oncology

May 2009

Outline

• Background.

• Metastatic colorectal cancer.– Chemotherapeutic and biologic agents– Ongoing trials updates

• Adjuvant colorectal cancer.– Current practice and ongoing trials

2007 Estimated US Cancer Cases*

ONS=Other nervous system.Source: American Cancer Society, 2007.

Men766,860

Women678,060 26% Breast

15% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

4% Thyroid

3% Ovary

3% Kidney

3% Leukemia

21% All Other Sites

Prostate 29%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Non-Hodgkin4% lymphoma

Melanoma of skin 4%

Kidney 4%

Leukemia 3%

Oral cavity 3%

Pancreas 2%

All Other Sites 19%

COLORECTAL CANCER UPDATE

* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to 2002.Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0 Statistical Research and Applications Branch, NCI, 2005. http://srab.cancer.gov/devcan

Lifetime Probability of Developing Cancer

WomenAll sites 1 in 2

Prostate 1 in 6

Lung 1 in 13

Colon and rectum 1 in 17

Urinary bladder 1 in 28

Lymphoma 1 in 46

Melanoma 1 in 52

Kidney 1 in 64

Leukemia 1 in 67

Oral Cavity 1 in 73

Stomach 1 in 82

All sites 1 in 3

Breast 1 in 8

Lung & bronchus 1 in 17

Colon & rectum 1 in 18

Uterine corpus 1 in 38

Lymphoma 1 in 55

Ovary 1 in 68

Melanoma 1 in 77

Pancreas 1 in 79

Urinary bladder 1 in 88

Uterine cervix 1 in 135

Men

COLORECTAL CANCER UPDATEEpidemiology

Gastrointestinal Cancers in the United States

American Cancer Society. Cancer Facts and Figures 2006. Atlanta: American Cancer Society; 2006.

Anus2%

Other digestive organs

2%

Small intestine2%

Gallbladder3%

Esophagus6%

Stomach8%

Pancreas13%

Colon41%

Rectum16%

Liver 7%

Colorectal Cancer• Major public health problem in the US and

worldwide• Worldwide, nearly 1,000,000 cases diagnosed

each year• In the US, 130,000-140,000 cases diagnosed

each year. • In the US with 50,000-60,000 deaths each year < 40% of CRC diagnoses are localized disease

CRC = colorectal cancer.Colorectal Cancer Facts & Figures. 2005. American Cancer Society.

Staging

I T1N0M0 A I T2N0M0 B1

IIA T3N0M0 B2 IIB T4N0M0 B3 IIIA T1-2N1M0 C1 IIIB T3-4N1M0 C2/C3 IIIC TanyN2M0 C1/C2/C3 IV TanyNanyM1 D

TNM Stage

TNM Class

MAC

(Modified Astler-Coller and New TNM Staging)

N2 denotes 4 or more regional lymph nodes (Need to sample at least 12 nodes).

COLORECTAL CANCER UPDATEEpidemiology

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 17 Regs Limited-Use, Nov 2006 Sub (1973-2004 varying), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2007, based on the November 2006 submission.

Stage I

Stage II

Stage III

Stage IV

Genetic susceptibility

FAP (risk approaches 100% by age 50)HNPCC (lifetime risk approaches 80%)

Family history Adenoma (first degree) RR 1.72;11% lifetime riskCRC (first degree) RR 2.62; 16% lifetime risk

Medical history Inflammatory bowel disease (pancolitis 8 years or left-sided colitis 15 years) (10-20% risk)

Characteristics Age (91% of cases occur after age 50)Male sex (35% in men)Race/ethnicity (15% in African Americans)Obesity and diet (red meat, alcohol consumption)Smoking

Risk Factors for Colorectal Cancer

FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colon cancer syndrome; CRC = colorectal cancer.

Anderson FW, et al. J Natl Cancer Inst. 2002;94:1126-1133; Colorectal Cancer Facts & Figures. American Cancer Society; 2005; Levin B, et al. NCCN. v.1.2005; Lynch HT, et al. Cancer. 1995;76;2427-2433; Petersen GM, et al. Cancer. 1999;86(suppl):2540-2550; Winawer SJ, et al. Gastroenterology. 2003;124:544-560.

Associations for Risk of Colorectal Cancer

Dietary Factors:Dietary FiberDietary FatRed MeatAlcohol FolateCalcium and vitamin D

Non-Dietary Factors:Body Mass IndexPhysical ActivityHormone replacementSmokingAspirin

• HPFS, middle age men: BMI 25 kg/m2;Physical activity 15 MET-hours/week;Daily folate containing MVI;Alcohol < 15 g/day;Non-smoker;Red meat 2 servings/week (e.g.-- 3.1% of all men)– Eliminate 71% of all colorectal cancer!

(95% CI, 33-92%)

Colon Cancer: Multi-step Model of Carcinogenesis = biologic heterogeneity

• Cancers arise in polyps

• Develop over years• Multiple molecular events• Activation of oncogenes

and loss of tumor suppressor genes

Beart R. Clinical Oncology. Abeloff M, et al. Ed.Beart R. Clinical Oncology. Abeloff M, et al. Ed. 1998 Churchill Livingstone 1998 Churchill Livingstone

Evolution of a lethal cancer

Jones S. et.al. PNAS 2008;105:4283-4288

©2008 by National Academy of Sciences

By Denise Grady

An easily overlooked type of abnormality in the colon is the most likely type to turn cancerous, and is more common in this country than previously thought, researchers are reporting.

lity in the colon is the most likely type to turn cancerous, and is more common in this country than previously thought, researchers are reporting.

New York Times, March 5, 2008

COLORECTAL CANCER UPDATEScreening

Easily Overlooked Lesions Tied to Colon Cancer

Flat Polyps

Soetinko et al. JAMA. 2008;299(9):1027-1035


Flat Polyps

Soetinko et al. JAMA. 2008;299(9):1027-1035


2000Irinotecan +

5-FU/LV (1st line)

2002Oxaliplatin + 5-FU/LV

(2nd line)

Development of Systemic Treatments for Metastatic Colorectal Cancer

19575-FU introduced

5-FU dominates treatment for mCRC

1996Irinotecan (2nd line)

1950 1960 1970 1980 1990 2000 2010

Investigations of 5-FU combination and schedules

2004 Oxaliplatin + 5-FU/LV

(1st line)

Targeted Therapies

2004Cetuximab

+ irinotecan (or alone)Bevacizumab + 5-FU-based

chemotherapy

5-FU = 5-fluorouracil; LV = leucovorin; mCRC = metastatic colorectal cancer.

Holen KD, Saltz LB. Lancet Oncol. 2001; 2:290-297; Venook A. The Oncologist. 2005;10:250-261.

Targeted regimens

Cytotoxic regimens

2006Panitumumab

Therapeutic Regimens for the Treatment of MCRC

*Both first- and second-line exposure to therapy.

MCRC = metastatic CRC; OS = overall survival.Avastin® (bevacizumab) PI. December 2004.Camptosar® (irinotecan) PI. July 2005.Eloxatin™ (oxaliplatin) PI. April 2005.Erbitux™ (cetuximab) PI. June 2004.Xeloda® (capecitabine) PI. April 2003.Vectibix (panitumumab) PI. 2006.

Med

ian

OS

* (m

o)

0

6

12

18

24

~4-6

~12-14

~15-20

~15-17

~11-12

1980s 2000s1990s1960s5-FU

5-FU biomodulation

Irinotecan

Oxaliplatin

Cetuximab

Bevacizumab

Panitumumab

Colorectal cancer:Evolution of 1st line therapy for metastatic

disease.

5-Fluorouracil; 5-FU

5-FU/LV Foundation.

U.S. Europe

bolus infusional

Mayomonthly

RoswellPark weekly

de Gramontbi-weekly

First line: de Gramont vs Mayo 5-FU/LV

RR (%) PFS (wks) OS (mos)

500 pts randomized

5FU: 425mgs/m2 x5d, q 4wksLV: 20 mgs/m2 x5d, q 4wks

5FU: 400 mgs/m2(bolus) d1,2 q 2wksLV: 200 mgs/m2 d1,2 q 2wks5FU: 600 mgs/m2(22hrs) d1,2 q 2wks

40-

20-

33%

14%

8-

4-

27.622

p=0.0004 p=0.0012

14.1

13.1

p=0.06715-

13-

de Gramont et.al. JCO 15:808 (97).

NH2

NH2

NH3C

O

O

C

O

Diaminocyclohexane(DACH) carrier ligand

CNH3

Cl

Cl

NH3

Pt

NH3

O

O

C

CISPLATINOXALATE

hydrolysable

ligand

trans-l-diaminocyclohexane

oxalatoplatinum

OXALIPLATIN, Eloxatin®CARBOPLATIN

Pt

Pt

O

O

Chemical Structure of Platinum Analogues

•Active in NCI CRC cell lines

•DNA adducts, cross-links

•Hold if CrCL<20cc/min

RR (%) PFS (mos) OS (mos)

420 pts randomized

Oxaliplatin 85 mg/m2 d1, q 2wksLV: 200 mg/m2; 5FU 400mg/m2 IVB5FU 600 mg/m2 (22 hr CIV);d1,2q2wk

5FU: 400 mgs/m2(bolus) d1,2 q 2wksLV: 200 mgs/m2 d1,2 q 2wks5FU: 600 mgs/m2(22hrs) d1,2 q 2wks

50-

20-

51%

22%

10-

5-

9.0

6.2

p<0.0001 p=0.00116.2

14.7

p=0.1218-

14-

deGramont et.al. JCO 18:2938 (2000).

*

First line: FOLFOX vs infusional LV/5-FU

*=primary endpoint

#

#

Irinotecan (CPT-11, Camptosar®)

Irinotecan hydrochloride

N NC

O

O N

N O

O

O

C 2H

O C 2H

C 3H

H C 3H

•Topoisomerase I inhibitor an enzyme that relieves torsional strain in DNA

•Hepatic metabolism. Majority excreted in bile requiring dose adjustment

•Converted by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent than the parent drug

First line: FOLFIRI vs infusional LV/5-FU


385 pts randomized

CPT-11 180 mg/m2+ deGramont q 2wksor

CPT-11 80 mg/m2+HDLVB/5FU24CI qwk

deGramont q 2wksor

500 LVB/5FU 2600mg/m2 24 CIV qwk

40-

20-

35%

22%

8-

4-

6.74.4

p<0.005 p=0.001

17.4

14.1

p=0.03118-

14-

Douillard et.al. Lancet 355:1041 (2000).

5-FU/LV Foundation.

U.S. Europe

bolus infusional

Mayomonthly

RoswellPark weekly

de Gramontbi-weekly

FOLFIRI FOLFOX

5-FU/LV Foundation.

U.S. Europe

bolus infusional

Mayomonthly

RoswellPark weekly

de Gramontbi-weekly

FOLFIRI FOLFOXIFL

First line: IFL vs Mayo 5-FU/LV


457 pts randomized

5FU: 425mgs/m2 x5d, q 4wksLV: 20 mgs/m2 x5d, q 4wks

CPT11: 125 mgs/m2LV: 20 mgs/m25FU: 500 mgs/m2; q wk 4/6

40-

20-

39%

21%

8-

4-

7.0

4.3

p<0.001p=0.004 14.8

12.6

p=0.0415-

13-

Saltz et.al. NEJM 343:905 (2000).• 3rd arm: CPT-11 alone arm=LV/5FU

5-FU/LV Foundation.

U.S. Europe

bolus infusional

Mayomonthly

RoswellPark weekly

de Gramontbi-weekly

FOLFIRI FOLFOXIFL

???

RRAANNDDOOMMIIZZAATTIIOONN

CPT-11:CPT-11: 200 mg/m200 mg/m22 d1 q 3 wks d1 q 3 wksOxaliplatin:Oxaliplatin: 85 mg/m 85 mg/m22 d1 q 3 wks d1 q 3 wks

CPT-11:CPT-11: 125 mg/m125 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks5FU:5FU: 500 mg/m500 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks

LV:LV: 20 mg/m 20 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks

Oxaliplatin:Oxaliplatin: 85 mg/m 85 mg/m22 d1 q 2 wks d1 q 2 wks5-FU:5-FU: 400 IV/600 CI mg/m400 IV/600 CI mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks

LV:LV: 200 mg/m200 mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks

Metastatic Metastatic Disease Disease Bolus Saltz Regimen*Bolus Saltz Regimen*

*Saltz *Saltz et alet al. . J Clin Oncol J Clin Oncol 14:2959, 1996. 14:2959, 1996.

Infusional FOLFOX-4 Regimen†Infusional FOLFOX-4 Regimen†

††André André et alet al. J Clin Oncol 17:3560, 1999. . J Clin Oncol 17:3560, 1999.

Wasserman Regimen‡Wasserman Regimen‡

‡‡Wasserman Wasserman et alet al. J Clin Oncol 17:1751, 1999.. J Clin Oncol 17:1751, 1999.

N=264N=264

N=267N=267

N=264N=264

Goldberg J Clin Oncol 22:23, 2004

First-Line Oxaliplatin in the US: N9741

Mayo

trash

IFL

FOLFOX4

IROX

Europe vs USA?

Feb 2004: FOLFOX FDA approvedas first-line chemotherapy in U.S.

U.S.Euro

N9741: Efficacy

IFL FOLFOX4 IROX

MS (mo) 14.8 19.5 17.4

TTP (mo) 6.9 8.7 6.5

ORR (%) 31 45 35

(p=0.001)

(p=0.0014)

(p=0.002)

Goldberg J Clin Oncol 22:23, 2004

(p=0.04)

FOLFOX: Second-line approval in US 8/02; First line approval 2/04

CPT-11:CPT-11: 200 mg/m200 mg/m22 d1 q 3 wks d1 q 3 wks

Oxaliplatin:Oxaliplatin: 85 mg/m 85 mg/m22 d1 q 3 wks d1 q 3 wks

N=264 N=267 N=264

R

FOLFIRI FOLFOX6 progression

FOLFOX6 FOLFIRI progression

progression

progression

FOLFIRI versus FOLFOX

Regimens: oxaliplatin* (100 mg/m2) or irinotecan† (180 mg/m2) IV + LV 200 mg/m2 over 2 hours d 1, 5-FU 2,400-3,000 mg/m2 over 46 hours

Primary end point: TTPSecondary end points: ORR, safety

Tournigand et al. J Clin Oncol. 2004

N=113

N=113

FOLFIRI verses FOLFOX6

Arm A Arm B

FOLFIRI FOLFOX FOLFOX FOLFIRI P

N=109 N=81 N=111 N=69 Value

ORR % 56* 15† 54* 4† .68

Median TTP (mo) 14.4 11.5 .65

Median Overall 20.4 21.5 .9Survival (mo

Tournigand C et al. JCO 2004

Results

(Similar results: Colucci G, et al. J Clin Oncol. 2005;23:4866-4875).

Molecular re-classification of metastatic colorectal cancer

.

N

DIA HRN

I.

II. ?

?


.

N

DIA HRN

I.

II.Preliminary data: gene signature predicts diffuse

metastatic disease

Incorporation of Targeted Agents in the Standard Management of Metastatic Colorectal Cancer

Agents Targeting the VEGF Pathway

VEGFR-2VEGFR-1PPP

P

Endothelial cell

Small-molecule VEGFR inhibitors

(TKIs)Ribozymes

Anti-VEGFR antibodies

Soluble VEGF

receptors

Anti-VEGF antibodies VEGF

PPP

P

–VEGF stimulates new blood vessel formation in normal tissues and tumors

–VEGF blockade normalizes tumor vasculature and improves drug delivery.

Phase III Trial of Avastin + IFL as First-Line Therapy for MCRC (AVF2107g): OS

Error bars represent 95% CIs.Avastin® (bevacizumab) PI. December 2004.Data on file (SR2), Genentech, Inc. 2005.Hurwitz et al. N Engl J Med. 2004;350:2335.

100

OS

(%

)

Months

Median survival: 15.6 mo (w/o Avastin) vs 20.3 mo (w/Avastin)HR=0.66, P<0.001

1-year survival:74% vs 63%

2-year survival:45% vs 30%

20

00

80

40

60

6 12 18 24 30

Placebo + IFL (n=411)Avastin + IFL (n=402)

EGFR as a Therapeutic Target

The EGF Receptor: (HER1 or c-Erb-1)

EGF = epidermal growth factor; TGF- = transforming growth factor-alpha; EGFR = epidermal growth factor receptor.

EGF TGF-

EGFR EGFRHER2/3/4

EGFR

EGFR a member of a subfamily of type I receptor tyrosine kinases

(including HER2, HER3 and HER4)

Properties of ERBITUX (Cetuximab) IgG1 MAb (chimerized) Binds specifically to EGFR

and its heterodimers Binds to EGFR with high affinity

(Kd = 2.0 x 10–10 M): 1 log higher than the natural ligand

Following the recommended doseregimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), the mean half-life was 114 hours (range 75-188 hours)

ERBITUX Package Insert, June 2004; Data on file. ImClone Systems Incorporated and Bristol-Myers Squibb Company; 2004.

MAb = monoclonal antibody; EGFR = epidermal growth factor receptor.

Please see Important Safety Information including WARNING regarding infusion reactions on slides 39 to 52.

Cetuximab activity in irinotecan refractory mCRC (Bond Trial): Objective Response Rates

All Patients

Irinotecan-Refractory and Oxaliplatin Failure Patients

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

ORR

8%

0%

• N=463• Patients

third-line mCRC

Panitumamab +BSC vs BSC

NCIC-CO.17

mCRC failing (<6 months)

oxaliplatin and CPT11 regimens

with 5FU. No prior

anti-EGFR Rx. Bev permitted.

Primary endpoint=OS

Cetuximab+BSC

N=287

BSC

N=285

NOTE: No crossover allowed

Median duration of f/u = 14.6 months

Jonker et. al, NEJM 357:2040-08 (2007)

OS

6.1 mo

4.6 mo

1 yr

21%

16%

p = 0.005

HR = .77

Cetuximab

plus bsc

Bsc alone

Primary endpoint

7% cross-over from bsc-->cet

Post trial rx: 27.5% (cet) verses 23.2% (bsc)

Jonker et. al, NEJM 357:2040-08 (2007)

EPIC

mCRC failing

Oxaliplatin+/-bev

N=1298

CPT-11

+ cetuximab

CPT-11* Primary Endpoint = OS

50% crossover

Irinotecan: 350 mg/m2 q3weeks

Cetux: 400mg/m2 load then 250mg/m2

*OS

10.7 mo

9.99 mo

(p = ns)

PFS

3.98 mo

2.56 mo

(p < 0.0001)

RR

16.4%

4.1%

Sobrero et.al. AACR April 2007

What about in a “real world” setting?

CRYSTAL

Untreated

mCRC

N=1217

FOLFIRI

+ Cetuximab

FOLFIRI

Primary Endpoint = PFS

PFS RR

8.9 mo

(34% 1yr)

8.0 mo

(23% 1yr)

p=0.036

46.9%

38.7%

p=0.005

Van Cutsem E, et al. ASCO 2007. Abstract 4000.

What about upfront?

Metastatic colorectal cancer....

?

CALGB/SWOG80405 Trial: First Line Met CRC.

FOLFOX

FOLFIRI

Bev

C225

Bev/C225

“Dea

lers

Cho

ice”

Ran

dom

ize

Su r

g eo n

s in

v olv

ed e

n ti r

e w

a y

Study PIs: Charles Blanke, M.D./Alan Venook, M.D.

Target accrual 2300

PACCE: Panitumumab Advanced CRC Evaluation Study

RANDOMIZE

Panitumumab + oxaliplatin- or irinotecan-based chemotherapy + bevacizumab

(q2 wk) • First-line mCRC

• No CNS metastases

• No CV risk factors

Oxaliplatin- or irinotecan-based chemotherapy + bevacizumab

(q2 wk)

US NIH Clinical Trials Database (www.clinicaltrials.gov); accessed 8/3/06

Primary endpoint=PFSN >1000

Interim (12-week) response-rate analysis first 500 patients:

response rates similar between treatment groups.

http://www.clinicaltrials.gov/

Cairo 2

mCRC

Capox + bev + cetux

Capox + bev

PFS tox

N=368

N=368

9.6 mo

10.7 mo

p=0.018

82%

72%

p=0.0013

Punt et. al ASCO 2008

Cairo 2

mCRC

Capox + bev + cetux

Capox + bev

PFS

N=368

N=368

9.6 mo

10.7 mo

p=0.018

Punt et. al ASCO 2008

PFSWT-KRAS

PFSMT-KRAS

10.5 mo

10.5 mo

8.6 mo

12.5 mo

p<0.05p=ns

CRYSTAL

Untreated

mCRC

N=1217

FOLFIRI

+ Cetuximab

FOLFIRI

10Endpoint = PFS

PFS

8.9 mo

(34% 1yr)

8.0 mo

(23% 1yr)

p=0.036

Van Cutsem E, et al. ASCO 2008.

PFS

WT-KRAS

9.9 mo

(43% 1yr)

8.6 mo

(25% 1yr)

p=0.017

PFS

MT-KRAS

p=0.75HR=0.85 HR=0.68 HR=1/07

No change in PFS or RR in FOLFIRI w/o cetuximab

Suggests KRAS a predictive marker (vs prognostic)

OPUS trial: randomized phase II FOLFOX +/- cetuximab similar results that only

WT-KRAS benefits from cetuximab (Bokemeyer et. al. ASCO 2008)

Metastatic colorectal cancer....

??????

The EGF Receptor: (HER1 or c-Erb-1)

EGF = epidermal growth factor; TGF- = transforming growth factor-alpha; EGFR = epidermal growth factor receptor.

EGF TGF-

EGFR EGFRHER2/3/4

EGFR

EGFR a member of a subfamily of type I receptor tyrosine kinases

(including HER2, HER3 and HER4)

CALGB/SWOG80405 Trial: First Line Met CRC.

FOLFOX

FOLFIRI

Bev

C225

Bev/C225

“Dea

lers

Cho

ice”

Ran

dom

ize

Su r

g eo n

s in

v olv

ed e

n ti r

e w

a y

Study PIs: Charles Blanke, M.D./Alan Venook, M.D.

Target accrual 2300

ONLY WT KRAS

ADJUVANT THERAPY

I T1N0M0 A I T2N0M0 B1

IIA T3N0M0 B2 IIB T4N0M0 B3 IIIA T1-2N1M0 C1 IIIB T3-4N1M0 C2/C3 IIIC TanyN2M0 C1/C2/C3 IV TanyNanyM1 D

TNM Stage

TNM Class

MAC

?

(Modified Astler-Coller and New TNM Staging)

?

N2 denotes 4 or more regional lymph nodes (Need to sample at least 12 nodes).

Zollinger, Atlas of Surgical Operations, 1993

COLORECTAL CANCER UPDATESurgical Management


Total Mesorectal Excision• nerve preservation

• sharp dissection

• complete hemostasis

• intact mesorectal envelope.


Revised, node-positive TNM classification for Stage III CRC (n=50,042)

59.8%59.8%

42.0%42.0%

27.3%27.3%

00

1010

2020

3030

4040

5050

6060

7070

IIIAIIIA IIIBIIIB IIICIIIC

Node-positive subgroupsNode-positive subgroups

Observed 5-year Observed 5-year survival (%)survival (%)

p<0.0001p<0.0001

IIIA: T1/2, N1IIIA: T1/2, N1 IIIB: T3/4, N1IIIB: T3/4, N1 IIIC: Any T, N2IIIC: Any T, N2

Greene Greene et alet al (2002) (2002)

Adjuvant Therapy for Stage II Colon Cancer:

• ASCO Guidelines : 8/15/04 JCO– “Pts with high risk features..might be considered candidates for adjuvant

therapy..” BUT,– “Direct evidence does not support adjuvant chemotherapy..even for high

risk stage II..”

• http://www.mayoclinic.com/calcs/colon/index-ccacalc.cfm

• Estimate that Stage II trials will need >8000 patients to provide direct evidence for benefit.• Need: better risk stratification to identify patient subgroups that will benefit (e.g. do-able trials).

Adjuvant Therapy for Stage II Colon Cancer

• Indirect evidence makes it reasonable to offer for patients with high risk features who are willing to accept toxicity for theoretical benefit.– High risk features:

• < 12 LN sampled• Obstruction at presentation• Perforation at tumor site• High grade tumor• LVI

• Should encourage participation in randomized trials.

MOSAIC: Treatment arms

R

LV5FU2(n=1123)

FOLFOX4(n=1123)

Primary: – 3-yr Disease Free Survival (DFS): a

surrogate for 5-yr Survival Secondary:

– Safety – Overall Survival (OS)

Endpoints

Resected Stage II/III CRC

N=2246

40% Stage II

60% Stage III

NEJM 350(23):2343, 2004

MOSAICStage III

1.0

0.9

0.8

0.7

0.6

0.50 10 20 30 40 50

24% risk reduction for stage III patients in the FOLFOX4 arm

DFS (months)

4-year DFS

FOLFOX4 (n=672) 70%LV5FU2 (n=675) 61%

p=0.002

Pro

bab

ilit

y

Improved 6 year overall survival for Stage III

(hazard ratio of 0.80, confidence interval [0.65, 0.97], p=0.023).

Phase III MOSAIC Trial (ITT): Clinical Efficacy

Disease-freesurvival (DFS) FOLFOX

LV/5-FU2

Overall 76% 69%p=0.0008

risk reduction 24%

Stage III 70% 61% p=0.002

Stage II 86.6% 83.9% p-value not significant

de Gramont A, et al. Proc Am Soc Clin Oncol. 2003 Abstr 1015; Andre et.al NEJM 6/04

Irinotecan Negative in Adjuvant Setting

Clinical Trial Patients Outcome

CALGB C89803

(IFL vs FL)

Stage III

(n=1264)

More neutropenia, death

PETACC-3(FOLFIRI vs deGramont)

Stage II/III

(n=3278)

More neutropenia, diarrhea

ACCORD02(LV5FU2+/-CPT11

High-risk Stage III

(n=400)

More neutropenia,

nausea

Saltz et.al ASCO Ab 3500 (2004)

Van Cutsem et.al ASCO Ab 8 (2005)

Ychou et.al. Ab 3502 ASCO (2005)


.

N

DIA HRN

I.

II. ?

?

Potentially resectable

mCRC

No extrahepatic disease

≤4 lesions

No prior Rx

Primary endpoint

– 40% increase in PFS

(NOT designed to validate

Pre vs post-op chemo)

EORTC 40983

Nordlinger, ASCO 2007

FOLFOX x6

Surgery

FOLFOX x6

N=182

Surgery

N=182

3 yr PFS

35.4%

28.1%

P=0.058

All pts Eligilble pts

36.2%

28.1%

P=0.041

EORTC 40983

• More postoperative complications in FOLFOX group 25% vs. 16% (p=0.04). (e.g. liver failure, biliary fistula).

• No difference in postoperative mortality

Nordlinger, ASCO 2007

Adjuvant colorectal cancer

1. FOLFOX for stage III (MOSAIC). -NSABPC07 (bolus 5FU+/- ox) confirms MOSAIC. FLOX with

unfavorable toxicity profile?

2. No direct evidence for stage II pts. But, indirect evidence makes reasonable to discuss if high risk features

• < 12 LN sampled• Obstruction at presentation• Perforation at tumor site• High grade tumor• LVI

Some ongoing adjuvant trials

Stage II CRC: E5202 Intergroup Trial

Stage IIStage IIpatientspatients

MSSMSSLOH 18qLOH 18q

MSI+MSI+normal 18qnormal 18q

RRFOLFOXFOLFOX

FOLFOX +FOLFOX +bevacizumabbevacizumab

No therapyNo therapy

Accrual goal: 3,125

NSABP C-08: mFOLFOX6 + Bevacizumab

RANDOMIZE

mFOLFOX6 + Bevacizumab

q14 d for 12 courses• Patients with resected stage II/III colon cancer

• Target enrollment, 2632

mFOLFOX6q14 d for 12 courses

Trial opened Sept 2004.

Bevacizumabq14 d for 6 mo(in absence of

PD)

US NIH Clinical Trials Database (www.clinicaltrials.gov); accessed 8/3/06.

ASCO 2008 Safety Update: increased grade III toxicity, p=0.006


AVANT Trial: FOLFOX vs FOLFOX/BEV vs XELOX/BEV

RANDOMIZE

FOLFOX4

• Patients with stage II/III colon cancer


FOLFOX4 + Bevacizumab

XELOX + Bevacizumab


?????????????


N0147: Adjuvant Cetuximab

RANDOMIZE

FOLFOX4 ± Cetuximab

• Patients with resected stage III colon cancer


(FOLFOX then FOLFIRI) ± Cetuximab

FOLFIRI ± Cetuximab


For WT-KRAS ONLY!!!!!!!!


Reality Check......

• Cost: Shrag, NEJM, 7/2004– Average patient with 1st line FOLFOX+ bevacizumab (8 months)

followed by CPT-11 + cetuximab (4 months)=$161,000 USD X 50,000 Stage IV cases/year

– > $5 BILLION USD /year (JUST for stage IV..if used for adjuvant..> $20 BILLION USD/year!!!!

– How do we save $$$?• Lower cost• Limit therapy (per group)• Individualize treatments to those most likely to benefit (per

patient)• Limit duration of therapy

Colon Cancer: Multi-step Model of Carcinogenesis = biologic heterogeneity

• Cancers arise in polyps

• Develop over years• Multiple molecular events• Activation of oncogenes

and loss of tumor suppressor genes

Beart R. Clinical Oncology. Abeloff M, et al. Ed.Beart R. Clinical Oncology. Abeloff M, et al. Ed. 1998 Churchill Livingstone 1998 Churchill Livingstone

The Genomic Landscapes of Human Breast and CRC Cancers

Wood et al. Science 2007;318:1108-13.

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes.

To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11

colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples.

Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the

genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains"

and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and

bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications

for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

Current

patients

A

B

All patients receive standard treatment (A)

Clinical trials survival benefit from A

Future

patients Molecular analysis of tumor

AA

BB

CC

DD

Choice of treatmentdependent upon molecular profile of tumor andpatient genotype

A New Paradigm for Colorectal Cancer A New Paradigm for Colorectal Cancer Clinical TrialsClinical Trials

A New Paradigm for Colorectal Cancer A New Paradigm for Colorectal Cancer Clinical TrialsClinical Trials

Stay tuned for upcoming exciting info...........

Documents

COLORECTAL CANCER Charles Lopez, M.D., Ph.D. Associate Professor of Medicine Hematology and Medical Oncology May 2009