A Report from ASCO 2007
Adjuvant Colorectal Cancer
John L. Marshall, MDChief, Division of Hematology/OncologyAssociate Director of Clinical Research
Director, Developmental Therapeutics and GI OncologyLombardi Comprehensive Cancer Center
Georgetown University Medical CenterWashington, DC
Abstract 4007
Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of
6-Years
Aimery de Gramont, Corrado Boni, Matilde Navarro,
Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and
MOSAIC investigators
MOSAIC: Study Design
• Primary end-point: disease-free survival• Secondary end-points: safety, overall survival
N = 2246
Enrollment: Oct 1998–Jan 2001 (146 centres; 20 countries)
• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%
• Age 18–75 years
• KPS ≥60
• No prior chemotherapy
R
LV5FU2
FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)(N = 1,123)
(N = 1,123)
LV5FU2: Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days
FOLFOX4: LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1
MOSAIC: Cut-off Dates for Efficacy Analyses
2003 3-year DFS: primary endpoint
2006 5-year DFS: final update
(No further updates on relapses)
2007 Overall Survival: 6-year, final analysis
André, et al. N Engl J Med 2004;350:2343–2351.
Primary End-Point: Disease-Free Survival
• DFS allows for a quicker determination regarding the efficacy of a new treatment
• Clinical trials can be completed more quickly• Drug development time can be shortened• Better therapy can be made available to patients more
quickly• DFS can be considered as an endpoint of its own merit
in decreasing the high cost, quality-of life impact, and debilitating consequence of recurrent disease
Sargent, et al. J Clin Oncol 2005;23:8664–8670.
3-Year DFS vs. 5-Year OS
Sargent, et al. J Clin Oncol 2005;23:8664–8670.
0.5
0.55
0.6
0.65
0.7
0.75
0.8
0.5 0.55 0.6 0.65 0.7 0.75 0.8
r = 0.88
3-Y
ear
DF
S
5-Year OS
3-years
(April 2003)
5-years
(June 2006)
FOLFOX4 LV5FU2 FOLFOX4 LV5FU2
Median follow-up, mos. 37.9 37.8 73.5 73.4
Events (%) 21.1 26.1 27.1 32.1
DFS (%) 78.2 72.9 73.3 67.4
HR
[95% CI]
0.77
[0.65–0.91]
0.80
[0.68–0.93]
P-value 0.002 0.003
Andre, et al. N Engl J Med 2004;350:2343–2351.
MOSAIC: Disease-Free Survival
Events = Relapse + Second Primary Colon Cancer + Death by any cause
MOSIAC: Disease-Free Survival (ITT)
Data cut-off: June 2006
Disease-Free Survival (months)
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54
Events
FOLFOX4 304/1123 (27.1%)
LV5FU2 360/1123 (32.1%)
HR [95% CI]: 0.80 [0.68–0.93]
5.9%
P = 0.003
MOSIAC: Disease-Free SurvivalStage II and Stage III Patients
Data cut-off: June 2006Months
HR [95% CI] P-value
Stage II 0.84 [0.62–1.14] 0.258
Stage III 0.78 [0.65–0.93] 0.005
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 72
3.8%
7.5%
P = 0.258
P = 0.005
MOSIAC: Disease-Free Survival High-Risk Stage II Patients
Disease-Free Survival (months)
FOLFOX4 (N = 286)
LV5FU2 (N = 290)
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 72
3-year 5-year
FOLFOX4 85.4% 82.1%
LV5FU2 80.4% 74.9%
HR [95% CI]: 0.74 [0.52–1.06]
High-Risk Stage II – defined as at least one of the following:
• T4• Tumor perforation• Bowel obstruction• Poorly differentiated tumor• Venous invasion • <10 lymph nodes examined
7.2%
Exploratory analysisData cut-off: June 2006
MOSIAC: Long-Term Safety
FOLFOX
5.3%
LV5FU2
5.7%
0
10
20
30
40
50
60
During Tx 6 months 1-year 2-year 3-year 4-year
Grade 1
Grade 2
Grade 3
Data cut-off: January 2007
Second CancerPeripheral Sensory Neuropathy
Evaluable Patients
(N = 811)
Grade 0 84.3%
Grade 1 12.0%
Grade 2 2.8%
Grade 3 0.7%
De Gramont A, et al. ASCO 2007. Abstract #4007.
MOSIAC: Overall Survival(ITT)
Data cut-off: January 2007
Overall Survival (months)
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
Events
FOLFOX4 243/1123 (21.6%)
LV5FU2 279/1123 (24.8%)
HR [95% CI]: 0.85 [0.72–1.01]
2.6%
P = 0.057
De Gramont A, et al. ASCO 2007. Abstract #4007.
MOSIAC: Overall SurvivalStage II and Stage III
Data cut-off: January 2007
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Overall Survival (months)
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
HR [95% CI]
Stage II 1.00 [0.71–1.42]
Stage III 0.80 [0.66–0.98]
0.1%
4.4%
P = 0.996
P = 0.029
De Gramont A, et al. ASCO 2007. Abstract #4007.
MOSIAC: Conclusions
For FOLFOX4 vs. LV5FU2:• The DFS benefit at 3-years was maintained at 5-years• Trend showing improved DFS in “high-risk” stage II
patients• Significant OS benefit in stage III patients • No increase in the rate of secondary cancers• Continued recovery from sensory neuropathy
De Gramont A, et al. ASCO 2007. Abstract #4007.
Abstract 4022
Tissue Biomarkers (BIOM) in Colon Cancer (COC): The Translational Study on the Randomized Phase III Trial
Comparing Infused Irinotecan/5-fluorouracil (5-FU)/Folinic Acid (FA) to 5-FU/FA in Stage II-III COC
Patients (Pts) (PETACC 3 - EORTC 40993 -SAKK 60-00)
A.D. Roth1, S. Tejpar2, P. Yan3, R. Fiocca4, D. Dietrich5, G. Bodoky6, R. Labianca7, D. Cunningham8, E. Van Cutsem2, F. Bosman3
1Oncosurgery, Geneva University Hospital, Geneva, Switzerland, 2Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium, 3Dpt of Pathology, Lausanne University, Lausanne, Switzerland, 4Dpt of Surgical and Morphological Sciences, University of Genova,
Genova, Italy, 5Swiss Group of Clinical Cancer Research, Bern, Switzerland, 6Oncology, St Lazlo Hospital, Budapest, Hungary, 7Unit of Medical Oncology, Ospedali Riuniti, Bergamo, Italy,
8Medical Oncology, The Royal Marsden Hospital, Sutton, United Kingdom.
Methods (1)
• FFPE tissue blocks prospectively collected and cut in 5-20µ sections
• Immunohistochemistry (IHC)– P53: mouse mAb clone D07, ABC Basic DAB Detection
(Ventana medical system)– SMAD4: mouse mAb clone B8 (IgG1, Santa Cruz
Biotechnology). Novocastra polymer detection kit– Thymidylate Synthetase (TS): Monoclonal antibody TS
106/4H4B1 (IgG1, Zymed). DAKO EnVision detection system– Telomerase (HTERT): Monoclonal antibody NCL-hTERT (IgG2,
Novocastra). DAKO EnVision detection system
Roth AD, et al. ASCO 2007. Abstract #4022.
Methods (2)
• DNA was extracted with phenol/chloroform from normal (Nor) and tumoral (Tu) tissues after microdissection of FFPE sections
• Molecular analysis:– Microsatellite Instability (MSI): assessed on 10 markers
• (BAT-25, BAT-26, D5S346, D2S123, D17S250, BAT-40, TGF-ß RII, D18S58, D18S69, D17S787)
– 18q and 8p LOH: multiple SNPs typing by pyrosequencing on Nor/Tu DNA
– KRAS exon 2 and BRAF exon 15: Allele specific real time PCR on Tu DNA
– UGT1A1 7/7 genotype: PCR and fragment sizing on Nor DNA
Roth AD, et al. ASCO 2007. Abstract #4022.
Analysis Success Rate
• 1,530 patient slides analyzed by IHC • DNA successfully extracted from 1,201 patient slides (91.2%)
Roth AD, et al. ASCO 2007. Abstract #4022.
Number of Samples with Results
Marker SamplesSuccess Rate
(%)Telomerase 826 54%
TS 1,269 83%
SMAD4 1,443 94%
P53 1,447 95%
MSI 1,327 94%
KRAS 1,379 98%
BRAF 1,386 99%
LOH in 18q
- at least one snip OK1,220 87%
UGT1A1 1,335 95%
Biomarker Alteration Observed (Mutation, Expression, or Deletion)
Alterations Rate Observed
Alteration Rate Reported (literature)
P53 overexpression* 37% 25-76%
SMAD4 loss** 15% 13-63%
TS*** 48% No consistent data available
HTERT 48% No data available
MSI 15% 10-17%
18q 65% 70%
KRAS 37% 32-40%
BRAF 8% 10%
UGT1A1 (7/7 genotype) 12% 10-15%
* Intense expression, More than 45% cells positive ** Any loss*** Positive = more than 25% cell positive Roth AD, et al. ASCO 2007. Abstract #4022.
SMAD4: Preliminary Results (Stage III)
At Risk: 145 95 57 2817 663 449 38
0 500 1000 1500
0.4
0.5
0.6
0.7
0.8
0.9
1.0
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Day
Pro
port
ion
Dis
ease
-Fre
e
No ExpressionExpression Present
Roth AD, et al. ASCO 2007. Abstract #4022.
Cutpoint% Patients
≤ Cutpoint
Estimated 3-Year DFSLog-Rank
P-value≤ Cutpoint > Cutpoint
0 15% 53% 68% < 0.001
MSI: Preliminary Results (Stage III)
At Risk:
753 595 396 33104 89 61 3
0 500 1000 1500
0.5
0.6
0.7
0.8
0.9
1.0/
/
/
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Day
Pro
port
ion
Dis
ease
-Fre
e
Stable/LowHigh
% Patients
High
Estimated 3-Year DFSLog-Rank
P-valueStable/Low High
12% 65% 74% < 0.04Roth AD, et al. ASCO 2007. Abstract #4022.
Abstract 4008
Time-dependent Patterns of Failure and Treatment Benefit from Adjuvant Therapy for Resectable Colon Cancer: Lessons from the
20,800 Patient ACCENT Dataset
D Sargent, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group
Total: 18 trials; 20,898 pts
3,517 QUASAR867 GIVIO
905 GERCOR718 NSABP C02
3,547 INT 0089773 NSABP C01
1,078 SWOG 9415259 FFCD
878 N914653359 NCIC
915 N894651239 Siena
2,176 NSABP C05408 N874651
2,151 NSABP C04926 INT 0035
1,081 NSABP C03247 N784852
N TrialN Trial
Active ControlNo Treatment Control
ACCENT Dataset Trials Included
Sargent D, et al. ASCO 2007. Abstract #4008.
Three Questions Facing Adjuvant Colon Cancer Trialists
• Nature and duration of treatment benefit on overall survival (OS), disease-free survival (DFS)
• Long-term recurrence rates
• Adequacy of statistical assumptions, using DFS endpoint
Sargent D, et al. ASCO 2007. Abstract #4008.
Hazard Rates for OS and DFS
Disease-Free Survival
Follow-up Time (Years)
Haz
ard
Rat
e
0 2 4 6 8
0.0
0.00
020.
0004
0.00
06 Surgery Alone Arms5-FU Based Rx Arms
Overall Survival
Follow-up Time (Years)
Haz
ard
Rat
e
0 2 4 6 8
0.0
0.00
020.
0004
0.00
06 Surgery Alone Arms5-FU Based Rx Arms
Sargent D, et al. ASCO 2007. Abstract #4008.
0
1
2
3
4
5
6
7
8
9
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Year
Rec
urre
nce
Rat
e (%
) • After 5 years, recurrence rates < 1.5% / year
• After 8 years, recurrence rates < 0.5% / year
Recurrence Rate by Time from Randomization (All Patients)
Sargent D, et al. ASCO 2007. Abstract #4008.
Adequacy of Statistical ModelsConclusions
• Similar exercises demonstrated < 2% power loss due to non-constant risk of event
• Real world impact of DFS endpoint on trial design, for range of treatment effects observed in ACCENT, is minimal
• Continued use of standard approaches for sample size determination remains appropriate
Sargent D, et al. ASCO 2007. Abstract #4008.
Abstract 4009
Survival Following Recurrence in Patients with Adjuvant Colon Cancer: Findings from the ACCENT Dataset
MJ O’Connell, for the ACCENT Collaborative Group
Total: 17 trials; 17,381 pts
3,517 QUASAR867 GIVIO
905 GERCOR718 NSABP C02
3,547 INT 0089773 NSABP C01
1,078 SWOG 9415259 FFCD
878 N914653359 NCIC
915 N894651239 Siena
2,176 NSABP C05408 N874651
2,151 NSABP C04926 INT 0035
1,081 NSABP C03 247 N784852
N TrialN Trial
Active ControlNo Treatment Control
ACCENT Dataset Trials Included
O’Connell M, et al. ASCO 2007. Abstract #4009.
Prognostic Factors Examined
• Time from randomization on surgical adjuvant protocol to tumor recurrence (<1, 1-2, 2-3, 3-4, >4 years)
• Initial stage of colon cancer (II, III)
• 5-FU-based adjuvant therapy vs. surgery alone
• Era patient entered onto surgical adjuvant protocol (1978-1985, 1986-1992, 1993-1999)
O’Connell M, et al. ASCO 2007. Abstract #4009.
O’Connell M, et al. ASCO 2007. Abstract #4009.
Time from Recurrence to Deathby Year of Recurrence
100
Time (Years)
Year 0- 1 (N = 1,846)
Year 1-2 (N = 1,854)
Year 2-3 (N = 924)
Year 3-4 (N = 516)
Year 4+ (N = 582)
Total (N = 5,722)
0
20
40
60
80
0 1 2 3 4 5 6 7 8
% A
live
P < 0.0001
O’Connell M, et al. ASCO 2007. Abstract #4009.
Time from Recurrence to Death byYear of Recurrence for Stage II Patients
P = 0.1368
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8Time (Year)
% A
live
Year 0-1 (N = 311)
Year 1-2 (N = 351)
Year 2-3 (N = 198)
Year 3-4 (N = 118)
Year 4+ (N = 175)
Total (N = 1,153)
O’Connell M, et al. ASCO 2007. Abstract #4009.
Time from Recurrence to Death byYear of Recurrence for Stage III Patients
P < 0.0001
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Time (Year)
% A
live
Year 0-1 (N = 1,533)
Year 1-2 (N = 1,499)
Year 2-3 (N = 724)
Year 3-4 (N = 394)
Year 4+ (N = 400)
Total (N = 4,550)
P < 0.0001
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Time (Years)
% A
live
Stage II (N = 1,153)
Stage III (N = 4,550)
Total (N = 5,703)
O’Connell M, et al. ASCO 2007. Abstract #4009.
Time from Recurrence to Death by Stage
Time (Years)
P < 0.0001
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
% A
live
1978-1985 (N = 628)
1986-1992 (N = 3,904)
1993-1999 (N = 1,190)
Total (N = 5,722)
O’Connell M, et al. ASCO 2007. Abstract #4009.
Time from Recurrence to Death by Era
O’Connell M, et al. ASCO 2007. Abstract #4009.
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Time (Years)
% A
live
Surgery Alone (N = 916)
Adjuvant Treatment (N = 754)
Total (N = 1,670)
P < 0.0005
Time from Recurrence to Death byAdjuvant Treatment vs. Surgery Alone
Conclusions
• Time from initial surgery and stage of the primary colon cancer were important prognostic variables in patients with recurrent colon cancer
• Patients who have recurrent tumor following 5-FU-based adjuvant therapy had worse prognosis than those without adjuvant chemotherapy
• Survival following recurrence improved from 1978-1999
O’Connell M, et al. ASCO 2007. Abstract #4009.
Abstract 4019
The Impact of Dietary Patterns on Cancer Recurrence and Survival in
Patients with Stage III Colon Cancer: Findings from CALGB 89803
Jeffrey A. Meyerhardt1, Donna Niedzwiecki2, Donna Hollis2, Leonard B. Saltz3, Walter Willett4, Robert J. Mayer1,
Charles S. Fuchs1
1Dana-Farber Cancer Institute, Boston, MA; 2CALGB Statistical Center, Durham,
NC; 3Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Harvard School of Public Health, Boston, MA
Pearson Correlation Coefficients for the Relationship Between Food Intake and Factors Representing Dietary Patterns
*values < 0.15 are not shown (---). † Vegetables other than yellow, cruciferous, or leafy-green vegetables. ‡ Potato, corn chips, crackers, or popcorn.
Food grouping Prudent WesternVegetables † 0.72 ---Leafy vegetables 0.71 ---Yellow vegetables 0.67 ---Cruciferous vegetables 0.65 ---Legumes 0.56 ---Fruit 0.55 --Light salad dressing 0.48 ---Tomatoes 0.46 0.36 Garlic 0.39 ---Fish 0.46 ---Poultry 0.37 ---Fruit Juice 0.35 ---Whole grains 0.32 --Low fat mayonnaise 0.31 --Wine 0.19 ---Tea 0.16 ---Diet beverages --- --High-fat dairy --- 0.67 Low-fat dairy --- 0.64
Food grouping Prudent WesternRefined grains --- 0.60Condiments --- 0.51Red meat --- 0.53Sweets and desserts --- 0.53Margarine --- 0.50Processed meat --- 0.45Potatoes 0.17 0.45Regular mayonnaise --- 0.35Butter --- 0.33French fries -0.16 0.37Eggs --- 0.30Snacks ‡ --- 0.36Nuts --- 0.30Coffee --- 0.29Sugar beverages - 0.15 0.29Beer --- 0.22Cream soup or chowder 0.16 0.25Pizza --- 0.26Regular salad dressing 0.19 0.19Liquor --- ---
Meyerhardt J, et al. ASCO 2007. Abstract #4019.
Impact of Western Pattern Diet on Colon Cancer Recurrence and Mortality
Meyerhardt J, et al. ASCO 2007. Abstract #4019.
Quintile of Western Pattern Diet
1 2 3 4 5 P-value
Cancer recurrence or death-any cause (DFS)
# of events / # at risk 71/201 57/202 73/202 68/202 83/202
Multivariate adjusted hazard ratio Ref 1.2 2.03 2.16 3.91 <0.0001
(0.76-1.89) (1.30-3.16) (1.32-3.52) (2.21-6.89)
Cancer recurrence (Recurrence-Free Survival)
# of events / # at risk 68/201 51/202 68/202 61/202 76/202
Multivariate adjusted hazard ratio Ref 1.07 1.84 1.77 3.14 <0.0001
(0.66-1.73) (1.16-2.90) (1.06-2.95) (1.73-5.69)
Overall Mortality
# of events / # at risk 57/201 35/202 51/202 53/202 55/202
Multivariate adjusted hazard ratio Ref 0.96 2.09 2.84 3.75 <0.0001
(0.54-1.71) (1.22-3.57) (1.56-5.05) (1.90-7.41)
Adjusted for gender, age, depth of invasion through bowel wall (T1-2 vs. T3-4), number of positive lymph noses (1-3 vs. 4 or more), presence of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 vs. 1-2), treatment arm, weight change between 1st and 2nd questionnaire, time-varying body mass index, time-varying physical activity level, and time-varying total calories.
Impact of Prudent Pattern Diet on Colon Cancer Recurrence and Mortality
Meyerhardt J, et al. ASCO 2007. Abstract #4019.
Quintile of Prudent Pattern Diet
1 2 3 4 5 P-value
Cancer recurrence or death-any cause (DFS)
# of events / # at risk 79/201 79/202 71/202 53/202 70/202
Multivariate adjusted hazard ratio Ref 1.13 0.96 0.7 1.26 0.79
(0.71-1.67) (0.63-1.46) (0.44-1.11) (0.80-1.97)
Cancer recurrence (Recurrence-Free Survival)
# of events / # at risk 73/201 68/202 67/202 52/202 64/202
Multivariate adjusted hazard ratio Ref 1.05 0.96 0.76 1.2 0.76
(0.70-1.60) (0.62-1.49) (0.47-1.22) (0.75-1.94)
Overall Mortality
# of events / # at risk 63/201 58/202 44/202 34/202 52/202
Multivariate adjusted hazard ratio Ref 1.14 0.75 0.59 1.14 0.75
(0.73-1.78) (0.44-1.29) (0.33-1.65) (0.81-2.45)
Adjusted for gender, age, depth of invasion through bowel wall (T1-2 vs. T3-4), number of positive lymph noses (1-3 vs. 4 or more), presence of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 vs. 1-2), treatment arm, weight change between 1st and 2nd questionnaire, time-varying body mass index, time-varying physical activity level, and time-varying total calories.
Adjuvant Colorectal Cancer
Closing Comments
John L. Marshall, MD