A Report from ASCO 2007 Adjuvant Colorectal Cancer John L. Marshall, MD Chief, Division of Hematology/Oncology Associate Director of Clinical Research Director, Developmental Therapeutics and GI Oncology Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC
42
Embed
A Report from ASCO 2007 Adjuvant Colorectal Cancer John L. Marshall, MD Chief, Division of Hematology/Oncology Associate Director of Clinical Research.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
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:
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
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.
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.