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
COLORECTAL CANCER UPDATEScreening
Flat Polyps
Soetinko et al. JAMA. 2008;299(9):1027-1035
COLORECTAL CANCER UPDATEScreening
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
RR (%) PFS (mos) OS (mos)
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
RR (%) PFS (mos) OS (mos)
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. ?
?
Molecular re-classification of metastatic colorectal cancer
.
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.
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
COLORECTAL CANCER UPDATESurgical Management
Total Mesorectal Excision• nerve preservation
• sharp dissection
• complete hemostasis
• intact mesorectal envelope.
COLORECTAL CANCER UPDATESurgical Management
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)
Molecular re-classification of metastatic colorectal cancer
.
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
• Target enrollment, 3450
FOLFOX4 + Bevacizumab
XELOX + Bevacizumab
US NIH Clinical Trials Database (www.clinicaltrials.gov); accessed 8/21/06.
?????????????
N0147: Adjuvant Cetuximab
RANDOMIZE
FOLFOX4 ± Cetuximab
• Patients with resected stage III colon cancer
• Target enrollment, 2300
(FOLFOX then FOLFIRI) ± Cetuximab
FOLFIRI ± Cetuximab
US NIH Clinical Trials Database (www.clinicaltrials.gov); accessed 8/3/06.
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...........