Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD...
-
Upload
joshua-walton -
Category
Documents
-
view
214 -
download
2
Transcript of Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD...
![Page 1: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/1.jpg)
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
![Page 2: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/2.jpg)
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?
![Page 3: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/3.jpg)
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
![Page 4: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/4.jpg)
![Page 5: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/5.jpg)
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
![Page 6: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/6.jpg)
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
![Page 7: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/7.jpg)
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
![Page 8: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/8.jpg)
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?
![Page 9: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/9.jpg)
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
![Page 10: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/10.jpg)
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
![Page 11: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/11.jpg)
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
![Page 12: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/12.jpg)
![Page 13: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/13.jpg)
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?
![Page 14: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/14.jpg)
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
![Page 15: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/15.jpg)
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.
![Page 16: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/16.jpg)
CpG Island Methylator Phenotype (CIMP)
•Gene silencing by promoter region methylation•Frequent loss of expression of MLH1, MINT1, MINT2, MINT31, p6INK4, p14ARF
![Page 17: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/17.jpg)
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
![Page 18: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/18.jpg)
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
![Page 19: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/19.jpg)
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
![Page 20: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/20.jpg)
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
![Page 21: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/21.jpg)
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
![Page 22: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/22.jpg)
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
![Page 23: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/23.jpg)
IFL vs FL in MSI-H Tumors
![Page 24: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/24.jpg)
The Cancer Genome Atlas NetworkNature 487: 330-337, 2012
Genomics:Comprehensive Molecular Characterization of
Human Colon and Rectal Cancer
Raju Kucherlapati
![Page 25: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/25.jpg)
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
![Page 26: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/26.jpg)
Genomics: Cancer Genome Atlas
![Page 27: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/27.jpg)
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
![Page 28: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/28.jpg)
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
![Page 29: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/29.jpg)
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?
![Page 30: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/30.jpg)
Evidence Bases
• Pooled analyses• Subset analyses• Population based analyses
![Page 31: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/31.jpg)
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
![Page 32: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/32.jpg)
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
![Page 33: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/33.jpg)
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
![Page 34: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/34.jpg)
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
![Page 35: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/35.jpg)
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
![Page 36: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/36.jpg)
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
![Page 37: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/37.jpg)
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
![Page 38: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/38.jpg)
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
![Page 39: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/39.jpg)
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
![Page 40: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/40.jpg)
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
![Page 41: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/41.jpg)
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
![Page 42: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/42.jpg)
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%
![Page 43: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/43.jpg)
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
![Page 44: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/44.jpg)
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
![Page 45: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/45.jpg)
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
![Page 46: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/46.jpg)
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
![Page 47: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/47.jpg)
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
![Page 48: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/48.jpg)
(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
![Page 49: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/49.jpg)
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)
![Page 50: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/50.jpg)
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)
![Page 51: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/51.jpg)
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
![Page 52: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/52.jpg)
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
![Page 53: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/53.jpg)
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
![Page 54: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/54.jpg)
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
![Page 55: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/55.jpg)
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
![Page 56: Adjuvant Therapy For The Elderly and/or Frail Patient With Colorectal Cancer Richard M. Goldberg, MD The Klotz Family Professor and Physician in Chief.](https://reader035.fdocuments.us/reader035/viewer/2022070413/5697bfa51a28abf838c9799c/html5/thumbnails/56.jpg)
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