biomarker-driven treatment decisions in stage ii colon cancer - making sense of what we know
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Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know. Neal J. Meropol, M.D. Chief, Division of Hematology and Oncology University Hospitals Case Medical Center Associate Director for Clinical Research Case Comprehensive Cancer Center - PowerPoint PPT PresentationTRANSCRIPT
Biomarker-driven treatment decisions in stage II colon cancer -
making sense of what we know
June 7, 2010
Neal J. Meropol, M.D.Chief, Division of Hematology and Oncology
University Hospitals Case Medical CenterAssociate Director for Clinical Research
Case Comprehensive Cancer CenterCase Western Reserve University
Cleveland, Ohio
QUASARSurvival – Stage II (92% of patients enrolled, N=2963)
QUASAR Collaborative Group, Lancet, 2007
RR=0.84P=0.05
Sargent, D. et al. J Clin Oncol; 2009
N = ~70005% benefit at 8
years
ACCENT pooled analysis: benefit of adjuvant therapy in stage II colon cancer
The Data
• Not all patients with stage II colon cancer have the same risk
• In unselected patients– 5-FU improves survival by a few percent– Oxaliplatin does not improve survival– Capecitabine as effective as 5-FU
• Clinical risk factors include– T4, obstruction, lymphovascular invasion,
lymph node retrieval
Risk stratificationis critical to decision making
in stage II colon cancer
• Predictive: explains variability in response to treatment
• Prognostic: explains variability irrespective of treatment
Variability exists in the host (germline) and tumor (somatic)
A Common Assumption
The risk reduction associated with adjuvant therapy is consistent across
the spectrum of risk
Risk
Relapse
No Rx
Adj Rx
The use of adjuvant therapy for stage II colon cancer requires a
decision on the part of physicians and patients
What makes a good decision?
• Adequate understanding of alternatives• Adequate understanding of potential risks
and benefits• Freedom from coercion• “Rational” weighing of risks and benefits
– consonant with individual values and preferences
– “rational” does not imply that we would make the same decision
• Results in satisfaction
How do patients weigh decisions?
• Side effects- Intensity- Duration
• Cost• Inconvenience
• Delay recurrence
• Reduce recurrence
What are the key issues?
• Potential benefit• Potential harm
–Short-term–Long-term
• Patient preferences
Should baseline risk make a difference?
Only if risk reduction is proportionate to absolute risk level
Decision making considerations
Relative vs. Absolute Risk Reduction
100
50
75
25
Surv
ival
%
Time
5%RRR = 25%ARR = 5%
“I can improve your chances by 5%”“I can reduce your risk by 25%”
“I have to treat 100 people like you to save 5”
Patients are not MathematiciansWeinfurt et al. Cancer 2003
The following question involves a hypothetical situation in which your doctor is describing a new treatment. Imagine that your doctor says this new
treatment controls cancer in 40% of cases like yours. How do you interpret what the doctor is
saying?
14% The doctor is 40% confident that the treatment will control my cancer.
72% For every 100 patients like me, the treatment will work for 40 patients.
3% The new treatment will reduce my disease by 40%.4% I am not sure what this information means.3% Other5% Don’t know/unsure
What is Rational?
Or
What is the minimum absolute benefit that you would require to
feel comfortable offering (or receiving) adjuvant therapy?
Weinfurt, K. P. J Clin Oncol; 25:223-227 2007
Prospect Theory: People Care More About Outcomes Close to Their
Reference Point
Weinfurt, K. P. J Clin Oncol; 25:223-227 2007
Prospect Theory: People Care More About Loss Than Gain
Shifting Reference
Point
People weight probabilities differently depending on where they fall on the probability curve
• The “Russian Roulette” experiment (Zeckhauser; Kahneman and Tversky)– You’d pay more to remove 1 bullet if the chamber
is full, than if it only has 3 or 4 bullets to begin– You’d pay more to remove the final bullet, than to
remove 1 bullet from a chamber with 3 or 4 bullets
Do patients with stage II colon cancer weight absolute benefits of adjuvant therapy differently based upon their
baseline underlying risk of recurrence?
Age may be an appropriate consideration
%AC85%52%35%
Earle et al. J Surg Oncol, 2009
Should age matter?ACCENT: No benefit for combinations on
survival in elderly (stage II/III)
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2
Hazard Ratio
Age < 70
Age >= 70
Oxaliplatin
Oral
Irinotecan
Overall
McCleary et al. ASCO 2009
Molecular Risk Stratification• Mismatch repair is ready for clinical use
– MSI vs. IHC– Prognostic and ?predictive– Implications for hereditary predisposition
• Oncotype DX is a validated platform – Establishes prognosis– Relative benefit of 5-FU is consistent
across risk spectrum– Does not address benefit of oxaliplatin– Peer-reviewed publication is awaited
• ?Other molecular risk classifiers
Classifier discovery and validation
Discovery Validation
• assay technology• patient population
characterized• samples representative• training and validation sets
• Prospective randomized trial is gold standard
• Retrospective randomized trial may be acceptable if:– a priori hypothesis and
statistical design– samples available from
vast majority of patients– adequate follow up and
annotation
Adapted from D. Sargent, ISGIO 9/07
QUASAR Recurrence Score
• There a significant relationship between the risk of recurrence and the pre-specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone
• The relative risk reduction with 5-FU is consistent across Recurrence Score risk levels
STROMALFAP
INHBABGN
CELL CYCLEKi-67
C-MYCMYBL2
REFERENCEATP5EGPX1PGK1UBB
VDAC2
GADD45B
RECURRENCE SCORECalculated from Tumor
Gene Expression
Kerr et al. ASCO 2009
QUASAR : Clinical/Pathological Covariates and Recurrence
Variable Categories HR HR
95% CI P value
Mismatch Repair (MMR) 13% Deficient vs. 87% Proficient 0.32 (0.15,0.69) <.001
T Stage 15% T4 vs. 85% T3 1.83 (1.23,2.75) 0.005
Tumor Grade 29% High vs. 71% Low 0.62 (0.40,0.96) 0.026
Number of Nodes Examined 62% <12 vs. 38% ≥12 1.47 (1.01,2.14) 0.040
Lympho-Vascular Invasion 13% Present vs. 87% Absent 1.40 (0.88,2.23) 0.175
Recurrence Score continuous per 25 units 1.61 (1.13,2.29) 0.008
Pre-specified Multivariate Analysis, Surgery Alone Patients (n=605)
Kerr et al. ASCO 2009
QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following
Surgery
Ris
k of
Rec
urre
nce
at 3
yea
rs
0%
5%
10%
15%
20%
25%
30%
35%
Recurrence Score0 10 20 30 40 50 60 70
| | ||| | | | | | | | | || | |||| ||||||||||| |||||||||||||||||||||||| |||| |||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||| || ||| | | ||| |||| ||| |||| | || | |||||| |
Kerr et al. ASCO 2009
Recurrence Score, T Stage, and MMR Deficiency are Independent Predictors of Recurrence in Stage II Colon Cancer
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
0 10 20 30 40 50 60 70
Recurrence Score
Ris
k of
recu
rren
ce a
t 3 y
ears
MMR deficient (11%)
T4 stage (13%)
T3 and MMR proficient (76%)
Kerr et al. ASCO 2009
E5202: Stage II Colon Cancer
Accrual Goal: 3438
Arm A:FOLFOX
Arm B:FOLFOX + Bevacizumab
Tumor block risk
assessment based on biology
(18q/MSI)
High-risk (MSS and 18q LOH)
Low-risk (MSI + or no
loss 18q)Observation
Surgery
NCCN Recommendations 2010
• Ask the patient how much they’d like to know• Discuss risks and benefits• Consider clinical features that confer risk• Consider comorbidities and life expectancy• If considering fluoropyrimidine alone, MMR
testing recommended
Proposed Stage II Algorithm Today
MMR
Clinical Risk
No Adjuvant
Deficient Intact
Not HighHigh
No AdjuvantOr
Adjuvant
Adjuvant
*all decisions require discussion with patient
Proposed Stage II Algorithm Soon
MMR
Clinical & Molecular
Risk
No Adjuvant
Deficient
Intact
Very small benefit from adjuvant
therapy?<3%
No AdjuvantOr
Adjuvant
No Adjuvant
*all decisions require discussion with patient
More than very small benefit from adjuvant therapy
?3+%
What we need• Models that integrate clinical and molecular risk
assessment• Improved methods of communicating risk (and
risk reduction) to patients• Formal modeling of impact of molecular vs.
clinical tools on adjuvant therapy use, recurrence, survival, QOL, and cost
• Decision tools that go beyond simple calculations of 3 or 5 year clinical endpoints, and integrate comorbidities and life expectancy, i.e. will I gain or lose QALYs by taking adjuvant therapy?
What we needR
ecur
renc
e R
isk
Life Expectancy
Low
HighLow High
DON’T TREAT
TREAT
?
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