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ASCO 2010 Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold. Overview of adjuvant clinical trials in stage II colon cancer - results, challenges, and confusion. - Al B. Benson, III, MD - PowerPoint PPT Presentation
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ASCO 2010
Biomarker-driven Treatment in Stage II Colon Cancer:
When to Hold and When to Fold
– Overview of adjuvant clinical trials in stage II colon cancer - results, challenges, and confusion. -Al B. Benson, III, MD
– Prognostic and predictive molecular biomarkers in stage II colon cancer current evidence and future perspective. -Sabine Tejpar, MD, PhD
– Biomarker-driven treatment decisions in stage II colon cancer – making sense of what we know. -Neal J. Meropol, MD
Overview of Adjuvant Clinical Trials in Stage II Colon Cancer -
Results, Challenges, and Confusion
Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer Centerof Northwestern University
Trends in Oncology Care
• Evidence-based practice/guidelines• Risk assessment
– Pathology– Markers
• Comparative Effectiveness Research (CER)
• Archie Chocrane identified three concepts related to the evaluation of a medical technology – efficacy, effectiveness, and efficiency:– Efficacy is the extent to which an intervention does more
good than harm under ideal circumstances (i.e., in circumstances designed to maximize the effect of the intervention and eliminate confounding factors). (“Can it work?”)
– Effectiveness is the extent to which an intervention does more good than harm when provided to real-world patients by physicians practicing in ordinary clinical settings. (“Does it work in practice?”)
– Efficiency measures the effect of an intervention in relation to the resources it consumes. (“Is it worth it?”)
Comparative Effectiveness
• Individual factors contribute to differences in clinical outcomes– Race or ethnic diversity– Co-morbidities– Drug-drug interactions– Tumor heterogeneity– Tumor genetics– Host genetics
Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer
Recurrence Risk• Bowel obstruction or perforation• T-Stage• # of nodes assessed• Tumor grade• Lymphatic/vascular invasion• Margin status
Treatment Benefit• None
According to current guidelines*:• Unlike in breast cancer, there are no molecular markers established in
clinical practice for stage II colon cancer• No markers in stage II colon cancer identify patients with
disproportionately high or low benefit from chemotherapy
* NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.
Category SEER SEER
TN Relative survival, 5-year (%)
SE TNM stage, 6th ed
TNM stage , 7th ed
Observed survival, 5-year (%)
SE
T1N0 97.4 0.6 I I 78.7 0.5
T2N0 96.8 0.6 I I 74.3 0.4
T3N0 87.5 0.4 IIA IIA 66.7 0.6
T4aN0 79.6 1.0 IIB IIB 60.6 0.8
T4bN0 58.4 1.3 IIB IIC 45.7 1.0
T1-2N1a 90.7 1.5 IIIA IIIA 73.7 1.2
T1-2N1b 83.0 2.0 IIIA IIIA 67.2 1.6
T1-2N2a 79.0 3.6 IIIC IIIA/IIIB 64.7 3.0
T3N1a 74.2 0.8 IIIB IIIB 58.2 0.6
T4aN1a 67.6 2.0 IIIB IIIB 52.2 1.5
Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t)
AJCC 7th edition
Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t)
Category SEER SEER
TN Relative survival, 5-year (%)
SE TNM stage, 6th ed
TNM stage , 7th ed
Observed survival, 5-year (%)
SE
T3N1b 65.3 0.8 IIIB IIIB 51.7 0.6
T1-2N2b 62.4 6.5 IIIC IIIB 51.8 5.3
T4aN1b 54.0 1.9 IIIB IIIB 42.1 1.5
T3N2a 53.4 1.0 IIIC IIIB 42.8 0.8
T4aN2a 40.9 2.1 IIIC IIIC 32.5 1.7
T3N2b 37.3 1.2 IIIC IIIC 30.4 0.9
T4bN1a 38.5 2.2 IIIB IIIC 30.6 1.8
T4bN1b 31.2 2.0 IIIB IIIC 25.4 1.6
T4bN2a 23.3 2.1 IIIC IIIC 18.3 1.6
T4aN2b 21.8 2.2 IIIC IIIC 17.5 1.7
T4bN2b 15.7 1.9 IIIC IIIC 12.9 1.5
AJCC 7th edition
Observed survival rates for 28,491 cases with adenocarcinoma of the colon
0 1 2 3 4 50
10
20
30
40
50
60
70
80
90
100
I IIA IIB IIC IIIA IIIB IIIC IV
AJCC 7th edition
Prognostic Factors in Colorectal CancerCOLLEGE OF AMERICAN PATHOLOGISTS CONSENSUS
Category I path-local extent of tumor = pT path-nodes = pN blood or lymphatic invasion post-op residual tumor = R (e.g., + margin) post-op CEA
Category IIA tumor grade radial margin status residual tumor s/p neoadjuvant tx
Estimates of 5 Year DFS (%) with Surgery Plus Adjuvant Therapy
Nodal T stage Low Grade High GradeStatus
S +AT S +AT
0 nodes T3 73 77 65 70 T4 60 66 51 57
T1-T2 62 75 53 681-4 nodes T3 49 65 38 56
T4 33 51 23 40
T1-T2 39 57 28 46> 5 nodes T3 24 43 15 32
T4 11 27 5 17
Adapted from Cill et al.. J Clin Oncol 22 :1801, 2004
Existing Tools for Selecting Stage II Patients for Treatment Are Inadequate
• Guidelines: presence of any existing risk marker categorizes patients into “higher risk” vs “standard risk” groups– No further discrimination for “standard risk” (the majority)– Not individualized or quantitative
• In the absence of established predictive markers, treatment decisions today are based on the expectation that higher risk stage II colon cancer patients derive larger absolute benefit with adjuvant chemotherapy
NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.
Clinical Background• The 5 year overall survival rate for patients with stage II colon
cancer is between 75% and 80%• Defining a specific high risk group of patients with stage II
disease that may benefit from adjuvant chemotherapy remains a challenge
• Retrospective analysis of molecular prognostic factors suggest that there may be subsets of patients with stage II disease who are at higher risk of recurrence
• Prognostic markers to identify these patients have not been validated in prospective trials
• Treatment options are evolving – Role of biologics in adjuvant therapy
INT 0089
67%65%75%LDLV/LEV
63%60%77%LEV
66%63%75%HDLV
67%63%77%LDLV
All Stages 5-yr OS
Stage III 5-yr OS
Stage II 5-yr OS
Proc ASCO 17:982, 1998
Multivariate Analysis for LN Negative Patients: INT-0089
Covariate OS CSSAge .0001 .0876Sex .0704 .4283T Stage .2252 .1659Tumor Type .5440 .2108Differentiation .0711 .1941# LN Removed .0005 .0071Adj Therapy .1701 .1823
CSS= cause-specific survival
Cohort Definition
3444 resected Stage II colon cancer patients
“Usual” Risk Stage II
3151
T3N0 tumor
No obstruction
No perforation
High Risk Stage II
293
T4N0 tumor
Obstruction
Perforation
International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT)
Investigators• Gruppo Interdisciplinare Valutazione Interventi Oncologia (GIVIO)
• National Cancer Institute Canada Clinical Trials Group (NCIC-CTG)
• Fondation Francaise de Cancerologie Digestive (FFCD)
• North Central Cancer Treatment Group (NCCTG)
• University of Siena
Survival by Receipt of Chemotherapy IMPACT B2 vs. SEER-Medicare
SEER-MedicareIMPACT
Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU
based Chemotherapy in Adjuvant Colon Cancer
DJ Sargent, S Marsoni, SN Thibodeau, R Labianca, SR Hamilton, V Torri, G Monges, C Ribic, A Grothey, S Gallinger
ASCO 2008
Pooled data (N=1027)Trial Treatment N % Stage
II% dMMR
784852 5FU/LEV 117 30% 14%
INT 0035 5FU/LEV 215 50% 18%
874651 5FU/LV 66 19% 12%
GIVIO 5FU/LV 183 52% 16%
FFCD 5FU/LV 154 66% 19%
NCIC 5FU/LV 292 61% 15%
Total 1027 52% 16%
DFS by MMR status, pooled data
0102030405060708090
100
0 1 2 3 4 5Years
% D
isea
se F
ree
0102030405060708090
100
0 1 2 3 4 5Years
% D
isea
se F
ree
HR: 0.79 (0.49-1.25)p=0.30
HR: 0.51 (0.29-0.89)p=0.009
Treated (N=512) Untreated (N=515)
dMMR 70%pMMR 67%
5 yr DFSdMMR 80%pMMR 56%
5 yr DFS
DFS in pMMR patients, Pooled data
0102030405060708090
100
0 1 2 3 4 5Years
% D
isea
se F
ree
0102030405060708090
100
0 1 2 3 4 5Years
% D
isea
se F
ree
HR: 0.84 (0.57-1.24)p=0.38
HR: 0.64 (0.48-0.84)p=0.001
Stage II (N=428) Stage III (N=434)
Untreated 72%Treated 77%
Untreated 41%Treated 58%
5 yr DFS 5 yr DFS
QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients
RFI
Treatment Surgery Chemo
Pro
port
ion
Eve
nt F
ree
0.0
0.2
0.4
0.6
0.8
1.0
Years
0 1 2 3 4 5
OS
Treatment Surgery Chemo
Pro
port
ion
Eve
nt F
ree
0.0
0.2
0.4
0.6
0.8
1.0
Years
0 1 2 3 4 5
DFS
Treatment Surgery Chemo
Pro
port
ion
Eve
nt F
ree
0.0
0.2
0.4
0.6
0.8
1.0
Years
0 1 2 3 4 5
Kerr et al., ASCO 2009, #4000
RFI (recurrence-free interval) DFS (disease-free survival)
OS (Overall Survival)
QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon
Cancer
Variable
Key
Category HR
P
value
Mismatch Repair (MMR) by IHC Deficient (13% of pts) 0.32 <.001
T Stage T4 (15% of pts) 1.83 0.005
Tumor Grade High (29% of pts) 0.62 0.026
# Nodes Examined <12 (62% of pts) 1.47 0.040
Lymphovascular Invasion Present (13% of pts) 1.40 0.175
RS per 25 units Continuous 1.61 0.008
Multivariate Analysis
Figueredo et al, JCO 22(16), 2004
Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit*
Dukes’ B Dukes’ C
No. of No. of Survival ARR Patients Survival ARR Patients
At 3 years 85% 2.5% 8,000 65% 5.2% 3,400
At 4 years 80% 3.3% 5,800 58% 6.0% 2,800
At 5 years 75% 4.0% 4,700 50% 6.6% 2,400
Abbreviation: ARR = absolute risk reduction•For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C.
Buyse, Piedbois, 2001
Recent Adjuvant Colon Cancer Trials
• X-ACT
• MOSAIC
• NSABP C-07
• C89803
• PETACC 3
• ACCORD-02
•NSABP C-08
•N0147
LV
OXA
RR
MOSAIC: Treatment arms
LV5FU2
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
Every 2 weeks, 6 months of treatment (12 cycles)
D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus
LV LV5-FU infusion* 5-FU infusion*
D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus
LV LV5-FU infusion* 5-FU infusion*LV LV5-FU infusion* 5-FU infusion*
D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus
LV LV5-FU infusion* 5-FU infusion*
D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus
LV LV5-FU infusion* 5-FU infusion*LV LV5-FU infusion* 5-FU infusion*
Disease-free Survival: Stage II and Stage III Patients
Data cut-off: June 2006
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
Months
Prob
abili
ty
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
Disease-free Survival: High-risk Stage II Patients
Disease-free survival (months)
FOLFOX4 n=286
LV5FU2 n=290
Prob
abili
ty
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; Data cut-off: June 2006
7.2%
Exploratory analysis
Stratification:
• Stage II vs. III
• Center
RANDOMIZATION
Day 1 Day 2
FA 200 mg/m2
5-FU bolus 400 mg/m2
5-FU CI 600 mg/m2
Day 1 Day 2
Irinotecan 180 mg/m2
LV5FU2
LV5FU2 as above
F
IF
Repeat q 2 weeks
for 12 Cycles
PETACC-3 (V307)
VanCutsem PASCO 2005 abstract #8
Efficacy Data for Treated Patients Randomly Assigned to the LV5FU2 Regimen
Parameter LV5FU2 Irinotecan + LV5FU2
Relapse-free survival (stage III), risk adjusted
3 year 62.9 67.9
5 year 57.3 62.8
HR 0.84
95% CI 0.73 to 0.96
P .009
Disease-free survival (stage II)
3 year 82.5 84.6
5 year 76.9 80.9
HR 0.81
95% CI 0.61 to 1.08
P .158
Parameter LV5FU2 Irinotecan + LV5FU2
Disease-free survival (stage II and III combined)
3 year 67.1 690.
5 year 61.0 63.8
HR 0.89
95% CI 0.79 to 1.00
P .045
Overall survival (stage III)
3 year 81.5 83.3
5 year 71.3 73.6
P .094
Overall survival (stage II)
3 year 93.5 95.1
5 year 88.8 90.0
P .344
Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp. 3117-3125
Copyright © American Society of Clinical Oncology
Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007
Fig 1. National Surgical Adjuvant Breast and Bowel Project Protocol C-07 Consolidated Standards of Reporting Trials diagram
Copyright © American Society of Clinical Oncology
Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007
Fig 3. Treatment hazard ratio and 95% CI for disease-free survival according to patient subsets defined by baseline prognostic factors significant in multivariate analysis
Copyright © American Society of Clinical Oncology
Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007
Fig 2. Kaplan-Meier estimates of disease-free survival by treatment
NSABP C-08
Stage ll + lll
mFF6+B
mFF6
Randomize
Strat: # Pos. N
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
020
4060
8010
0
Ev 3yDFSmFF6+B 291 77.4mFF6 312 75.5
HR 0.89P 0.15
NSABP C-08
DFS
%
Yrs
1 1.5 2 2.5 30.00
0.20
0.40
0.60
0.80
1.00
0.600000000000001
0.740000000000001
0.810.85000000000
00010.87000000000
0001
NSABP C-08 HR
0.0004
0.0040.02 0.05 0.08
Ev 3yDFSmFF6+B 40 87.4 mFF6 47 84.7
HR 0.82P 0.35
DFS Stage II
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
020
4060
80100
Δ 2.7
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
020
4060
80100
Ev 3yDFS mFF6+B 251 74.2mFF6 265 72.4
HR 0.90P 0.25
DFS Stage III
Δ 1.8
NSABP C-08
AVANT BO17920
Stage ll + lll
FF4+B
FF4
Randomize
Strat: # Pos. N
Xelox+B
12 ’04- 5 ‘07 N=3450
E5202 Trial Schema
Low-Risk PatientsMSS or MSI-L with
retention of 18q allelesMSI-H
Arm A:mFOLFOX6q2w × 12
Arm B:mFOLFOX6 + bevacizumab* q2w × 12
Arm C:Observation only
High-Risk PatientsMSS/18q LOH orMSI-L/18q LOH
areRANDOMIZED
MSI-L = low-level microsatellite instabilityMSI-H = high-level microsatellite instability*Bevacizumab continued for an additional 6 months
Stratify:Disease stage
(IIA or IIB)Microsatellite stability
(stable vs MSI)18q LOH