Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD...
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Transcript of Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD...
Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal
CancerRichard M. Goldberg, MD
The Klotz Family Professor and Physician in Chief The James Cancer Hospital
Ohio State University Comprehensive Cancer CenterColumbus, OH
Today’s Topics: Considerations When Treating Older Patients
• Demographics: Who do we see in the office?• Patient and Tumor Biology-
– Different in older people? – Does that matter?
• Do adjuvant therapy strategies need to be adjusted for age and frailty?
• How do you make the best choices?
Colorectal Cancer:A disease of the elderly
• Median age at diagnosis of CRC = 70– 76% > age 65– 40% > age 75– 12% age > 85
• 40% of CRCs are Stage III at diagnosis
Howlander, SEER Cancer Statistics Review, 2011
Additional Expected Years of Life By Age/Gender
60 70 800
5
10
15
20
25
30
womenmen
Kohne, Folprecht, Goldberg et al, Oncologist , 13:390, 2008
Expectancy
• 75 yo11-13 yrs
• 85 yo 6-7 yrs
Stage 2: 67% of recurrences occur
by 3 years
Stage 3: 75% of recurrences occur by 3
years
Colon Cancer Stage II vs Stage IIIPatterns of Recurrence
Sargent et al, JCO 2005
US Cancer Trial EnrollmentDEMOGRAPHICS ENROLLMENT
Cooperative Group Trials %
SEER Incident Cases %
Enrollment Fraction
OR enrollment
95% CI
RACE White
85.6% 83% 1.7% 1
Black 9% 11% 1.3% 0.71, 0.68-0.74
Hispanic 3% 4% 1.3% 0.72, 0.68-0.77
AGE 30-64
68% 38% 3% 1
65-74 24% 31% 1.3% 0.43, 0.42-0.44
≥75 8% 31% 0.5% 0.15, 0.15-0.16
Murthy et al, JAMA 2004; 291: 2720
* Years 2000-2002
Today’s Topics: Considerations When Treating Older Patients
• Demographics: Who do we see in the office?• Patient and Tumor Biology-
– Different in older people? – Does that matter?
• Do Adjuvant therapy strategies need to be adjusted for age and frailty?
• How do you make the best choices?
Biology: Are There Really Distinctions?
• Patients differ in their:– Physiology– Pharmacology– Psycho/sociology– Pathology & stage of disease– Preferences
• Tumors may differ: in drug responsiveness • Do physicians see older patients as different?
– Do no harm versus treating aggressively
Older/Frail Patients Differ
• Physiology/Pharmacology (PK/PD differences)– Adherence (capecitabine)– GI tract physiology: Mucosal atrophy, decline in
digestive enzymes, decreased motility etc – Body composition (more fat, less water)– Chronic heart, liver, or renal compromise
• Reduced drug clearance
– Diminished hematologic reserve– Polypharmacy and drug interactions
Older/Frail Patients Differ
• Psycho/sociology– Living alone versus with support
• Preferences: Different goals– Quality versus length of life– Independence– Acute chemotherapy toxicity versus long term
benefit
Today’s Topics: Considerations When Treating Older Patients
• Demographics: Who do we see in the office?• Patient and Tumor Biology-
– Different in older people? – Does that matter?
• Do adjuvant therapy strategies need to be adjusted for age and frailty?
• How do you make the best choices?
Patient’s Tumor Biology Differs: But Does That Matter?
• Sensitivity versus resistance relates to driver mutations
• Oncogenic drivers of CRC– Microsatellite Instability High Tumors (MSI-H)
• Lynch Syndrome-more common in younger patients• CpG island methylator phenotype (CIMP)-more
common in older patients
– Loss of heterozygosity (LOH) aka chromosomal instability-more common in younger patients
The CpG island methylator phenotype and chromosomal instability are inversely correlated
in sporadic colorectal cancer.
Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, Compton C, Mayer RJ,
Goldberg R, Bertagnolli MM,Boland CR
Gastroenterology. 132:127-38, 2007.
CpG Island Methylator Phenotype (CIMP)
•Gene silencing by promoter region methylation•Frequent loss of expression of MLH1, MINT1, MINT2, MINT31, p6INK4, p14ARF
Stage III Colorectal Cancer
Goel, et al. Gastroenterology 2006
55%CpG Island Methylator Phenotype
45%Chromosomal
Instability
19%Microsatellite
Instability
Aneuploidy,WidespreadLOH
Epigeneticsilencing ofmultiple tumorsuppressors
MLH1 promotermethylation,DNA mismatchrepair defect
Linear Age by CIMP Association
904 cases from the Nurses Health& Health Professionals Follow-upStudies who developed CRC
Nosho et al;Comprehensive biostatisticalanalysis of CpG Island methylator phenotype in colorectal cancer using a large population-basedSample PLoSOne 3:e3698, 2008
Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in
Adjuvant Colon Cancer
Sargent, Marsoni, Thibodeau, Labianca, Hamilton, Torri, Monges, Ribic, Grothey, Gallinger
DFS By MMR Status
0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Years
% D
ise
as
e F
ree
0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Years
% 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 DFS
dMMR 80%pMMR 56%
5 yr DFS
OS By Treatment, Stage II MSI-H Patients
0 1 2 3 4 5 6 7 80
10
20
30
40
50
60
70
80
90
100
Years
% A
live
HR: 3.15 (1.07-9.29)p=0.03
N = 55N = 47
Untreated 93%Treated 75%
5 yr OS
P-value = 0.014 for treatment by MMR status interaction
CALGB 89803: 5-FU/ LV +/- Irinotecan
• 723/1264 tumors evaluated for MSI– Patients with samples no different from overall
population – 96 (13%) MSI-H by DNA microsatellite analysis– PFS (p=0.04) advantage and OS trend (p=0.17) for
IFL over FL treated MSI-H patients– No PFS or OS advantage for MSS patients
Bertagnolli et al, J Clin Oncol 27:1814-21, 2009
IFL vs FL in MSI-H Tumors
The Cancer Genome Atlas NetworkNature 487: 330-337, 2012
Genomics:Comprehensive Molecular Characterization of
Human Colon and Rectal Cancer
Raju Kucherlapati
Methods and Key Findings• Methods: Whole genome sequencing of 276 colorectal
tumors– Exome sequence, DNA copy number, promotor methylation,
messenger and micro RNA expression• Key Findings
– 16% hypermutated; 75% MSI-H– Colon and rectal cancers share similar patterns of genomic
alteration– 24 genes significantly mutated:
• Expected: APC, TP53, SMAD4, PIK3CA, KRAS• Unexpected: ARID1A, SOX9, FAM123B, ERBB2
– Potential new targets: ERBB2, IGF2
Genomics: Cancer Genome Atlas
Relating This to the Elderly CRC Patient
• No subset analysis of mutational status by age was done
• This will be done in future studies and may provide insights
• Pooled analyses will be needed for adequate power
Does Tumor Biology Matter?
• 67% of Stage III patients who relapse do so within 3 years
• Universal MSI testing via IHC • No 5-FU in MSI-H stage II patients (good
prognosis, poor outcome)• ? 5-FU in MSI-H stage III patients• Future exploitation of tumor biology is to be
determined
Today’s Topics: Considerations When Treating Older Patients
• Demographics: Who do we see in the office?• Patient and Tumor Biology-
– Different in older people? – Does that matter?
• Do adjuvant therapy strategies need to be adjusted for age and frailty?
• How do you make the best choices?
Evidence Bases
• Pooled analyses• Subset analyses• Population based analyses
Pooled Analysis: Methods
• Pooled analysis of all mature studies comparing IV 5-FU + Leucovorin (LV) or Levamisole (Lev) to observation
• Includes 3,351 individual patient’s data
• All eligible randomized patients included
• Stage II and III patients included
Sargent, Goldberg, Jacobson et al, NEJM 345: 1091-7: 2001
020
40
60
80
10
0
0 2 4 6 8
Rx
No Rx
Age<=70
Years from Randomization
020
40
60
80
10
0
0 2 4 6 8
Rx
No Rx
Age>70
Years from Randomization
Time to Recurrence
020
40
60
80
10
0
0 2 4 6 8
Rx
No Rx
Age<=70
Years from Randomization
020
40
60
80
10
0
0 2 4 6 8
Rx
No Rx
Age>70
Years from Randomization
Overall Survival
Outcomes
• 5-year overall survival– Surgery alone 64%– With 5-FU 71%
• 506 patients over 70 had similar benefits• More neutropenia but no other grade > 3
toxicities were more common in the elderly
35
Fluoropyrimidines ± Oxaliplatin Stage III
HR for DFS
P value DFS Delta (%)
HR for OS P value OS Delta (%)
MOSAIC (1)
0.78CI, 0.65-0.93
At 5 year
0.005 7.5%58.9% vs 66.4%
At 5 year
0.80CI, 0.65-0.97
At 6 year
0.023 4.2%68.7% vs 72.9%
At 6 year
NSABP C-07(2)
0.78CI, 0.68-0.90
At 5 year
0.0007 6.6 %
57.8% vs 64.4%At 5 year
0.85CI, 0.72-1.00
At 5 year
0.052 2.7%73.8% vs 76.5%
At 5 year
XELOX(3)
0.80CI, 0.69-0.93
At 3 year
0.0045 4.4%66.5% vs 70.9%
At 3 year
0.87CI, 0.72-1.05
At 5 year
0.1486 3.4%ND
(57 months FU)
1 André T, J Clin Oncol. 20092 Yothers G, J Clin Oncol 20113 Haller D, J Clin Oncol 2011
Subset Analyses:
Adjuvant therapy with fluorouracil and oxaliplatin in Stage II and elderly patients (between ages 70 and 75 years) with colon cancer : subgroup analysis of
the MOSAIC trial.
C. Tournigand, T. Andre , F Bonnetain, et al. for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the
Adjuvant Treatment of Colon Cancer (MOSAIC)
J Clin Oncol, 30: 3353-60, 2012
MOSAIC Phase III Trial Schema
RANDOMIZ ATION
LV5FU2 every 2 weeks x 12LV5FU2 every 2 weeks x 12
FOLFOX4 every 2 weeks x 12FOLFOX4 every 2 weeks x 12
N=1100
155 elderly
N=1100
160 elderly
• 40% Stage II
• 60% Stage III
5-FU In Stage III Patients
• 1990 NCI consensus recommends adjuvant Rx in Stage III CRC regardless of age
• 6 year OS: – Surgery alone 50%– LV/5-FU 68.7%– FOLFOX 72.9%
• Incremental 6 year OS with oxaliplatin: 4%
*MOSAIC, NEJM 2006
OS
0 6 12 18 24 30 36 42 48 54 60 66 720.0
0.2
0.4
0.6
0.8
1.0
FOLFOX4>70LV5FU2>70FOLFOX4<70LV5FU2<70
months
pro
bab
ilit
y
OS in patients ≥ 70 years
OS benefit similar to younger patients until 4 yrsFOLFOX
RFS in patients ≥ 70 yearsRFS ³ 70 years
0 6 12 18 24 30 36 42 48 54 60 66 720.0
0.2
0.4
0.6
0.8
1.0
FOLFOX4LV5FU2
HR 0.68 [0.44-1.06]
months
prob
abili
ty
RFS benefit (deaths of other causes excluded in the definition)FOLFOX
OS after relapse ≥ 70 yearsOS post relapse of colon cancer > 70 years
0 6 12 18 24 30 36 42 48 54 60 66 720.0
0.2
0.4
0.6
0.8
1.0
FOLFOX 10.36 monthsLV5FU2 19.86 months
months
prob
abili
ty
P= 0.14 HR 1.440 CI (0.8979-2.443)
Shorter OS post relapse due to less intensive management of relapseFOLFOX
Oxaliplatin Increases Adverse Effects
5FU/LV FOLFOX
All Grades Severe or Life-
threatening
All Grades Severe or Life-
threatening
Paresthesia 16% <1% 92% 12%
Npenia 40% 4% 79% 41%
Vomiting 24% 1% 47% 6%
Diarrhea 48% 7% 56% 11%
The lack of survival benefit in OS in elderly pts : - is not due to imbalance in comorbidities - might be due to deaths of subsequent disease (cancer) and -less intensive management of relapse
FOLFOX can still be used for the DFS/RFS advantage.
Reduced duration of chemotherapy could improve the tolerability in elderly patients : -IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Colon Cancer Prospective Pooled Analysis
CONCLUSIONS
NSABP C-07
5-FU/LV
FLOX
RANDOMIZE
• Primary end point: DFS
n=1207
n=1200
• Stage II/III colon carcinoma
• ECOG 0-2• No prior chemotherapy• Normal hepatic and renal
function
Yothers G, O’Connell MJ, Allegra CJ et al, J Clin Oncol 29:3768-72, 2011
Overall survival (A) and disease-free survival (B) in the National Surgical Adjuvant Breast and Bowel Project C-07 trial.
Yothers G et al. JCO 2011;29:3768-3774
©2011 by American Society of Clinical Oncology
Overall survival (A) and disease-free survival (B) by age in years (< 70, 70+) in the National Surgical Adjuvant Breast and Bowel Project C-07 trial.
Yothers G et al. JCO 2011;29:3768-3774
©2011 by American Society of Clinical Oncology
N016968 (Roche Trial)
5-FU/LV
N= 942
XELOX
N=944
RANDOMIZE
• Primary end point: DFS
n=1207
n=1200
• Stage II/III colon carcinoma
• ECOG 0-2• No prior chemotherapy• Normal hepatic and renal
function
Haller DG, Tabernero J, Maroun J et al, J Clin Oncol 29:1465-71, 2011
(A) Disease-free survival (DFS), intention-to-treat population; (B) relapse-free survival (RFS), intention-to-treat population; (C) overall survival (OS), intention-to-treat population.
Haller D G et al. JCO 2011;29:1465-1471
©2011 by American Society of Clinical Oncology
NO16968 subgroup analysis of RFS by age
3-year RFSHazard ratio
(95% CI)XELOX 5-FU/LV
Overall
n=1886 72% 67% 0.78 (0.67,0.92)
<70 vs. ≥70 years
<70 years, n=1477 73% 69% 0.78 (0.65,0.93)
≥70 years, n=409 69% 61% 0.83 (0.60,1.15)
NO16968 subgroup analysis of OS by age
5-year OSHazard ratio
(95% CI)XELOX 5-FU/LV
<65 vs. ≥65 years
<65 years, n=1142 80% 77% 0.87 (0.67,1.13)
≥65 years, n=744 73% 70% 0.90 (0.68,1.19)
<70 vs. ≥70 years
<70 years, n=1477 80% 76% 0.86 (0.69,1.08)
≥70 years, n=409 69% 67% 0.94 (0.66,1.34)
Adjuvant Chemotherapy For Stage III Colon Cancer In The Oldest Old: Results Beyond Clinical Guidelines.
Abraham A, Habermann EB, Rothenberger DA, Kwaan M, Weinberg AD, Parsons HM, Gupta P, Al-Refaie WB.
Cancer, 119:395-403, 2012
27,805 Stage III Colon Cancer Patients from the California Cancer Registry
• 32% were 75-85 years old• 13% were >85 years old
• 51% received chemotherapy– 38% of the 75-85 year old persons
• 5-year survival: 55% with vs 43% without adjuvant Rx
– 11% > 85 year old persons• 5-year survival: 43% with vs 38% without adjuvant Rx
• Survival benefits of adjuvant Rx are comparable regardless of age
Effect Of Adjuvant Chemotherapy On Survival Of Patients With Stage III Colon Cancer Diagnosed
After Age 75 Years.
Sanoff H, Carpenter W, Sturmer T, Goldberg RM et alJ Clin Oncol 30: 2624-34, 2012
EFFECTIVENESS DATA SOURCES
Data Source
Key Elements Includes
SEER-Medicare
-Registries cover ~26% of US population -Linked by pt identifier to claims-Restricted to Medicare beneficiaries
- Tumor stage, grade, pt demo- Claims used for treatment, toxicity
NY-Medicare
-All incident cases in NY state-Restricted to 65. younger are in medicaid.
-Tumor stage, grade, pt demo-Claims used for treatment, toxicity.
NY-Medicaid
-All incident cases in NY state-Restricted to <65 older are in Medicare
-Tumor stage, grade, pt demo-Claims used for treatment, toxicity.
CanCORS -Incident cases approached for enrollment in prospective cohort-Multiple diverse practice settings- Intentionally oversampled minorities
-Treatment and tumor from medical records-Pts provided demographic, function by survey
NCCN -21 NCI cancer centers-Since 2005 “outcomes” database for CRC and breast cancer for pts at 8 sites
- Trained registrars at each site collect tumor, treatment information
5,489 Patients >75 years old with Stage III Colon cancer
• Oxaliplatin treatment associated with a 3% OS benefit
• Greater number of outpatient AEs in patients older than 75 getting FOLFOX
• No more ER visits, hospitalizations, or deaths in the older versus younger patients
Sanoff HK, Carpenter WR, Freburger J, Li L, Chen K, Zullig LL, Goldberg RM, Schymura MJ, Schrag D.Cancer, 118:4309-20, 2012
How Do We Make the Best Choices?
• Reflect on the biology• Apply the data from subset, pooled, and
population based analyses• Do patient centered care:
– Support them– Look at them– Talk to them– Watch them– And adjust the treatment plan as you go