Aging, Frailty, and Medical Therapy for Colorectal Cancer: Who Should Be Treated and How?
description
Transcript of Aging, Frailty, and Medical Therapy for Colorectal Cancer: Who Should Be Treated and How?
Aging, Frailty, and Medical Therapy for Colorectal Cancer: Who Should Be Treated and How?
Martine Extermann M.D., Ph.D.Moffit Cancer Center
Daniel Sargent Ph.D.Mayo Clinic Cancer Center
Richard M. Goldberg M.D.University of North Carolina
Lineberger Comprehensive Cancer Center
Elderly and/ or frail patients with colorectal cancer - a clinician's approach
Richard M. GoldbergUniversity of North Carolina
Lineberger Comprehensive Cancer Center
Disclosures: Consulting and/or Research Support
• Abbott • Amgen• Astra Zeneca• BMS• Enzon• Genentech
• GHI• ImClone• Myriad• NCI• Poniard• sanofi-aventis
Statistics
• 2/3 of pts with mCRC are >65 years old• 40% > 75 years old
Edwards , Cancer 94: 2766-92, 2002And http:seer.cancer.gov
<20 20-34 35-44 45-54 55-64 65-74 75-84 >8505
1015202530
% of cases by age
Additional Expected Years of Life By Age/Gender
60 70 800
5
10
15
20
25
30
womenmen
Kohne, Oncologist , 13:390, 2008
2
3.7 43.3
2.41.9 1.7
1.3 1.2 1.10.6 0.7 0.5 0.5 0.2 0.3
4.7
109.4
7.7
5.6
4.5
3.3 3.1
1.9 1.5 1.3 1.1 0.8 0.8 0.6 0.30
2
4
6
8
10
12
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8
Year
Rec
urre
nce
Rat
e
Stage 2Stage 3
Stage 2: 67% of recurrences occur
by 3 years
Stage 3: 75% of recurrences occur by 3
years
Colon Cancer Stage II vs Stage IIIRecurrence Rate by 6 mo intervals
Sargent, JCO 2005
STEPP analysis – Oxaliplatin-based therapyage cutoff validation for observed lack of added treatment effect
Age 68.5
3 Ye
ar D
FS
39 44 48 51 54 55 58 60 62 64 66 68 70 73 74
020
4060
8010
0
(n=547) (n=509) (n=584) (n=606) (n=556) (n=544) (n=523) (n=633) (n=512) (n=518) (n=513) (n=503) (n=543) (n=502) (n=338)(n=547) (n=509) (n=584) (n=606) (n=556) (n=544) (n=523) (n=633) (n=512) (n=518) (n=513) (n=503) (n=543) (n=502) (n=338)
Subpopulations by Median Age
ControlExperimental
p-value = 0.318 Age 70
A Five Part Talk
• Surgery• Radiation• A few relevant chemotherapy/biologic reports• Comparative effectiveness research• Clinical approaches
Percent of Patients Who Died Related to Colorectal Cancer Surgery
• 6457 Dutch patients• 4.4 % overall mortality, 10% and 13% if >80
Damhuis, Int J Colorect Dis, 11:45-48,1996
<50 50-9 60-9 70-9 80-9 >900%
2%
4%
6%
8%
10%
12%
14%
Colorectal Cancer Surgery in England:Laparoscopic surgery may be better
• 29,000 patients > 75 years old operated from 1996-2007 at National Health Service Hospitals
• Hospital Episodes Database• Emergency procedures excluded• 865 laparoscopic procedures
– 12% in 2007– Postoperative mortality 3.1% – 5.4% for open colectomy, p=0.003– Range between hospitals 0-14.1%
Faiz, Colorectal Dis, epub April 19,2010
Liver Resection In >70 Year Old Patients
• 1624/7764 (21%) Patients operated on at LiverMetSurvey Registry Centers in Europe were >70– 70-74: 999 (13%)– 74-80: 468 (6%)– >80: 157 (2%)
• 6% were over 70 in 1990, 26% in 2007
Adam, Br J Surg 97:366-76, 2010
Liver Resection In >70 Year Old Patients
• 1624/7764 (21%) Patients operated on at LiverMetSurvey Registry Centers in Europe were >70– 70-74: 999 (13%)– 74-80: 468 (6%)– >80: 157 (2%)
• 6% were over 70 in 1990, 26% in 2007
Adam, Br J Surg 97:366-76, 2010
<2035-44
55-6475-84
0102030
% of cases by age
Outcomes: > 70 versus <70 years old
• 60 day perioperative mortality p< 0.001– 3.8% versus 1.6%
• 60 day perioperative morbidity– 32% versus 29%
• 3-Year overall survival 57% vs 60% p <0.001• Median overall survival
– 43 months versus 47 months
5-Year Overall Survival<70 Years old > 70 years old P-value
> 3 lesions 24% 12% <0.001
Unilateral 58% 73% 0.001
Synchronous 57% 42% <0.001
Perioperative Ctx 44% 34% <0.001
Liver Resection In >70 Year Old Patients
• Preoperative Chemotherapy– No survival difference between those who did or
did not have preoperative chemotherapy– Morbidity was higher 38% vs 32% p=0.03
• Postoperative chemotherapy– An independent predictor of survival HR 1.79,
p <0.001
Radiation for Rectal Cancer
• Meta-analysis of 22 randomized trials of surgery +/- RT – Preop: 6350 patients in 14 trials– Postop: 2157 patients in 8 trials
Colorectal Cancer Collaborative Group, Lancet 356:968-74, 2000.
Rectal Cancer Meta-AnalysisOverall survival
Ro resection Local recurrence
Dead, Rectal Ca
Dead, other
Surgery 62% 86% 50% 4%
Surgery + RT 63% 45% 8%
Preop 85% 46% lower
Postop 37% lower
P-value 0.06 NS 0.002 0.003 0.0001
Age and Death Rates:Rectal Cancer and “Other”
Age Dead of Rectal CA Dead of Other Cause
Surgery Surgery + RT Surgery Surgery + RT
<55 48% 31% 5% 6%
55-64 40% 38% 6% 9%
65-74 43% 32% 13% 21%
>75 40% 32% 26% 34%
Dutch TME Trial Elderly Analysis
• All patients received a total mesorectal excision
• All patients given RT received 5 fractions of 500 cGy preoperatively
• 1356 patients– 17% older than age 75
Rutten, Eur J Cancer, 43: 2295-3000, 2007
TME Study Statistics< 75 >75 P-value
Overall Survival 70% 43% <0.0001
Spared Sphincter 66% 60% <0.001
1-month death rate 2.5% 7.8% <0.0001
6-month death rate 3.3% 14% <0.0001
Outcomes By Age and Study Arm< 75 >75
Surgery Surgery + RT
P-value Surgery Surgery + RT
P-value
Overall Survival 72% 72% 0.3 43% 48% 0.27
Local Failure 11% 5.2% 0.001 14% 5.4% 0.02
DFS 70% 81% 0.44 66% 81% 0.03
Conclusions
• Older patients benefit from RT + surgery more than younger patients
• Older patients have a significantly higher complication and early death rate
• Patients should be in optimal shape before surgery
• If life expectancy exceeds 1 year combined modality therapy is best in the older patient
Bevacizumab Pooled Analysis
• Three 1st line and one 2nd line trial with 5-FU, irinotecan and oxaliplatin
• 1,142/3007 (38%) > 65 years old• 24% > 70 years old
Age\PFS + Bev - Bev P-value< 65 9.5 mos 6.7 <0.0001> 65 9.3 6.9 <0.0001> 70 9.2 6.4 <0.0001
Cassidy, J Cancer Res Clin Oncol 136:737-43, 2010
Overall Survival With and Without Bevacizumab
Age\ Median OS + Bev - Bev P-value
< 65 19.9 mos 16.5 <0.0001
>65 17.9 15 <0.015
>70 17.4 14.1 =0.005
Toxicity As a Function of Age
Sources of Additional Data
• Limited numbers of patients >75 are accrued to Phase II or III studies
• These patients are carefully selected• There is only so much data out there• We need other sources of information
Comparative Effectiveness Research
Health Care Quality
• IOM:– The degree to which health services for individuals
and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge.
– Underuse, overuse, misuse
Outcomes – Comparative Effectiveness
• Comparative effectiveness research (CER) is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care.
• The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.
(IOM, 2009)
Federal Funding Mechanisms
• AHRQ:– Agency for Health Research and Quality Quality
• improvement and patient safety.• Outcomes and effectiveness of care.• Clinical practice and technology assessment.• Health care organization and delivery systems. • Primary care (including preventive services).• Health care costs and sources of payment.
AHRQ Cancer Comparative Effectiveness
• Medicare Modernization Act: – “…conduct research to improve the quality, effectiveness, and efficiency of
Medicare, Medicaid, and State Children Health Insurance (SCHIP) programs.”
• Increasing emphasis on patient-level attributes (rather than “the average patient”) that may modify the balance of benefits or harms can lead to more personalized medicine, reducing the pressure to try alternatives found to be ineffective in similar subgroups.
• DEcIDE : Decisions about effectiveness research : – Expeditiously develop valid scientific evidence about the outcomes,
comparative clinical effectiveness, safety, and appropriateness of health care items and services
AHRQ Cancer DEcIDE Comparative Effectiveness
• Clinical trials– Relatively homogeneous population
• Younger, healthier, more likely Caucasian– Randomization to control for unmeasured (and
unmeasurable) heterogeneity
• CER– Examinations prioritizing the context of heterogeneity
• Better representativeness• Examination of subpopulations
ExamplesStage II/III Colorectal cancer Chemotherapy
Trials– NEJM, 2004– JCO, 2007
vs.
SEER:
II III IVMean Age 71.4 69.0 67.7
Race White 83.7% 81.2% 79.3% Black 9.0% 10.6% 13.5% Other/Unk 7.4% 8.3% 7.2%
Gender Female 52% 52% 51% Male 48% 48% 49%
*Source: SEER, 2004-2005 data.
Stage at Diagnosis
Generalizable, results by sub-population
NCDB study: n=86,000; hospitals=560(Jessup et al, JAMA, 2005)
CER and Outcomes Research
• CER has value, maximizing our understanding with observational data– Fast– Inexpensive– Can be very large databases
• CER will not replace clinical trials• Larger future of outcomes research: Moving
from studies of “what” to understanding “why”
CER and Outcomes Research:Emerging Directions
• Application of advanced methods using secondary data, including the development of new methods– AHRQ-sponsored White papers:
• “Registries for Evaluating Patient Outcomes”– July 2009 DEcIDE RFTO (~$500,000 x 1 year):
• “Methods to Study the Heterogeneity of Treatment Effects in Comparative Effectiveness Research”
– Fall 2009: 10 x $10 million awards• Clinical and Health Outcomes Initiative in Comparative
Effectiveness
CER and Outcomes Research:Emerging Directions
• Development and application of advanced data– Developing new data sources
• Retrospective studies• Prospective studies
– Fall 2009: $48 million• New Registries for CER
• Data needs:– Sample size, generalizability of claims-based studies– Richness, depth of measures of survey / interview-based
studies– Clinical detail, follow-up of registries
Why new data and models?A prevailing model of cancer, comorbidity, and outcomes:
• Current models are linear, simply specified, and fairly simple• Randomization controls for many relevant factors• Intent-to-treat is dominant
Source: Geraci, JM, et al. (2005). “Comorbid Disease and Cancer: The Need for More Relevant Conceptual Models in Health Services Research.” Journal of Clinical Oncology. 23(30):7399-404.
Why new data and models?
• Because its just not that simple• We are increasingly interested in other outcomes,
including Patient Reported Outcomes (PROS)• With observational data, you can’t randomize-out
confounders and effect modifiers– Before we can make assumptions with them, we need to study
them• Need new data that allow rich characterization of factors
at multiple levels, with a substantial sample size for generalizability of findings and sub-population analysis
What Data Sources Might We Use to Evaluate Effectiveness?
1. SEER-Medicare
2. NYSCR/CCR-Medicaid
3. CanCORS
4. NCCN
– SEER • For purposes of anchoring comparison for overall mortality
Conclusions
• Elderly colorectal cancer patients are underrepresented in clinical trials
• Surgery (including hepatic resections) and RT for rectal cancers can be done safely and effectively but leads to higher early death rates
• CER can help answer some of the questions in this subpopulation