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Why Do We Need Separate
Clinical Trials for Older Adults?
Arti Hurria, MD
Director, Cancer and Aging Research Program
Associate Professor
City of Hope
US Population Age > 65 (millions)
Year
U.S Census Bureau, 2010
Cancer and Aging
Rates per
100,000 Population
60% of cancer occurs in people > age 65
Age Groups
CDC, Morbidity and Mortality Weekly Report, 2013
Cancer and Mortality
31%
69%
Age < 65
Age ≥ 65
Majority of Cancer Deaths Occur in Older Adults
Howlader et al., SEER Cancer Statistics Review 1975-2010
Life Expectancy is Increasing
Age
Year
National Vital Statistics Report
Projected Rise in Cancer Incidence
from 2010 to 2030
Cancer Incidence
(million)
67% in patients 65+
11% in patients <65
Year
Smith et al, J Clin Oncol, 2009
The Population is Aging
The Number of Older Adults With Cancer
is on the Rise
Are we prepared?
No Change in Overall Age Distribution
in NCI Trials
Age Distribution in Phase 2 and Phase 3
NCI Cooperative Group Clinical Treatment Trial
≥ 65 and ≤ 74 years
< 65 years
≥ 75 years
80%
70%
60%
50%
40%
30%
20%
10%
0%
2001
2002
2003
2004
2005
2006 2007 2008 2009 2010 2011
NCI/DCTD Clinical Data Update System, 2012
Older Adults Under-represented on
Cancer Registration Trials
60%
% with Cancer
% Enrolled
50%
40%
30%
20%
10%
0%
≥ 65
≥ 70
Age Groups
≥ 75
Talarico et al. JCO 2004
The Questions We Face in Daily Practice are
Not Addressed in Clinical Trials
Who will die of disease vs. with disease?
Who is vulnerable to cancer therapy toxicity?
How should I adjust the therapy based on:
- their functional status
- their comorbid illnesses
- their social situation
U13: Background
 Foundation for research planning in Cancer & Aging
- 1997 Geriatric Oncology Education Retreat
- 2001 NIA/NCI workshop “Exploring the Role of Cancer
Centers for Integrating Aging and Cancer Research”
Advances in evidence based knowledge in Geriatric Oncology
 Training and mentoring is essential to move the field
forward
- ASCO/ Hartford combined fellowship in Geriatric Oncology
- The Cancer & Aging Research Group
Planning for the Next 10 Years: U13 Grant
“Geriatric Oncology Research to Improve Clinical Care”
 Collaboration
NIA, NCI, The Cancer & Aging Research Group
 Mission:
1.
2.
3.
Review the present level of evidence
Identify areas of highest research priority
Develop research approaches to improve clinical care for older
adults with cancer
Within the next 10 years
U13 Oversight Board
Arti Hurria, MD (PI)
Supriya Mohile, MD, MS (co-PI)
William Dale, MD, PhD (co-PI)
CARG
NIA
Basil Eldadah, MD*
Alliance Margaret Mooney, MD*
NCI
AACR
Harvey Cohen, MD (Geriatric Oncology)
Martine Extermann, MD (Geriatric Oncology)
SIOG
Betty Ferrell, PhD (Nursing Research)
Hyman Muss, MD (Geriatric Oncology)
ASCO
Richard Schilsky, MD (Oncology)
Kenneth Schmader, MD (Geriatrics)
AGS
*Prior Oversight Board Members: Susan Nayfield and Edward Trimble
Goals of U13 Grant
Research
Methodology
Training
&
Education
1.
To identify the present level of evidence &
areas of high research priority in Geri Onc
2.
To identify strengths in research methodology,
from the fields of Geriatrics and Oncology
3.
To foster collaboration between multidisciplinary
scholarly teams
4. To foster and promote the research of existing and
new investigators in Geriatric Oncology
5.
To disseminate findings from this conference grant
program with easily adaptable recommendations
Conference Structure
What Is Known
Gaps in Knowledge
How to Fill the Gaps
Conference Series Topics
3 Successive Conferences:
Year 3:
Design and
Implementation of
Therapeutic Clincial
Trials for Older
and/ Frail Adults
with Cancer
Year 1:
Biological, Clinical,
and Psychological
Correlates
at the interface of
Aging and Cancer
Research
Year 4:
Design and
Implementation of
Intervention Studies
to maintain or
improve the Quality
of Survival of Older
and/or Frail Adults
with Cancer
Dissemination
Dissemination:
ASCO Symposium
AGS Symposium
White papers
Web: Slide sets with audio
Dissemination
Dissemination
Conference 1:
Biological, Clinical, & Psychosocial Correlates at the
Interface of Aging and Cancer Research
Goals:
1. Factors to consider in geriatric oncology research:
– clinical assessment
– biological factors
– psychosocial factors
2. Identify and create opportunities for multidisciplinary
research
3. Disseminate
Key Publications from the U13
JNCI, 2012
Nat Rev Clin Oncol, 2012
J Natl Compr Canc Netw, 2012
Conference 2:
Design and Implementation of Therapeutic Clinical
Trials for Older and/or Frail Adults with Cancer
Goals:
1. Identify gaps in knowledge of cancer therapy in
older adults
2. Study design of therapeutic clinical trials
3. Methods to optimize patient accrual
4. Propose opportunities for multidisciplinary studies
5. Disseminate
Two Major Deficiencies
Need to:
 accrue older adults to existing clinical trials
 develop specific trials for the “oncologically
frail” older adults
Phase III
Trial
Randomize
Standard Clinical Trial Design:
Is More Better?
Arm A
Drug X
Arm B
Drug X + Y
 Patients age ≥ 65 not enrolled onto the study due to:
1) Doctors’ concerns regarding toxicity
2) Patient may not be “fit” for the study
Kemeny et al., JCO 2003
Barriers to Participation of Older Women
with Breast Cancer in Clinical Trials
 CALGB Retrospective Case-Control study
 77 patients age ≥ 65 vs. 77 patients age < 65 with breast cancer
 Matched based on physician and stage
Offered Trial
Accepted Participation
Age < 65
51%
56%
Age ≥ 65
34%
50%
 Age was:
 The only risk factor for if a patient was offered a clinical trial
 Not a predictor of whether a patient would agree to enroll in a trial
Kemeny et al., JCO 2003
Barriers to Participation of Older Women
with Breast Cancer in Clinical Trials
Reasons Older Adults Eligible for Clinical Trials
Were Not Offered Participation (N=33)
%
MD thought treatment was too toxic
33
Not the best treatment option available
27
MD unaware a trial was available
21
MD thought patient was not eligible
18
MD concerned with patient’s comorbid conditions
18
The patient is not the barrier.
Kemeny et al., JCO 2003
Factors to Consider in Clinical Trial Design
 Incorporation of geriatric principles: Start low, go slow
 Include endpoints of relevance for older adults:
 Ability to live independently
 Impact of therapy on function or cognition
 Need for family caregiver
 Is biology of cancer different across the age spectrum?
 If so, separate trials are needed
Can incorporation of geriatric principles in oncology trials help?
Chronological Age ≠ Functional Age
To weigh the risks
and benefits
Functional Age vs.
Chronological Age
The Extra Challenge:
The Ultimately Efficient Clinic
 Vitals Taken
 Patient in Gown
 Sitting on Exam Table
What is old?
65
Understanding the Grey
Factors other than chronological age that predict
morbidity & mortality in older adults
 Functional status
 Comorbid medical conditions
 Cognition
 Nutritional status
 Psychological state
 Social support
 Medications (polypharmacy)
Geriatric
Assessment
Can Geriatric Assessment
Predict Chemo Toxicity? (CARG)
Eligibility criteria
Timepoint 1:
- Age 65 or older
Pre-chemo
Post-chemo
Geriatric
Assessment
Geriatric
Assessment
- Diagnosis of
cancer
- To start a new
chemotherapy
regimen
Timepoint 2:
Chemotherapy:
toxicity grading at
each visit
 Sample size: 500 patients (Chemo alone)
 7 participating institutions (Cancer and Aging Research Group)
Hurria et al, JCO 2011
Predictors of Toxicity
Age ≥ 72 years
GI/GU Cancer
Standard Dose
Polychemotherapy
Hemoglobin (male: <11, female: <10)
Creatinine Clearance (Jelliffe-ideal wt <34)
Age
Tumor/
Treatment
Variables
Labs
Fall(s) in last 6 months
Hearing impairment (fair or worse)
Limited in walking 1 block (MOS)
Assistance required in medication intake (IADL)
Decreased social activity (MOS)
Geriatric
Assessment
Variables
Model Performance:
Prevalence of Toxicity by Score
Grade 3-5 Toxicities
High
(83%)
Medium
(52%)
Low
(30%)
Total Risk Score
Geriatric Assessment for Older Adults with
Cancer on Cooperative Group Trials
CALGB 360401 (PI: Hurria)
Eligibility Criteria
Pre-chemo
- Age 65 or older
Geriatric
assessment
- Diagnosis of cancer
- To start treatment on
a cooperative
group clinical trial
Treatment and
follow-up per
protocol
Feasibility
data
Geriatric Assessment is
Feasible in Oncology Trials
Hurria et al, JCO 2011
Geriatric Assessment is Feasible
in Oncology Trials
92% Length is “Just Right”
95% Easy to comprehend
96% Not upsetting
87% Completed patient
questionnaire w/o assistance
94% Completed healthcare
provider portion
94%
Chemotherapy Risk Assessment Scale for
High-Age Patients (CRASH) Score
 Prospective multicentric study
 518 patients age ≥ 70 yrs
Heme
Predictors of Toxicity
0
1
Diastolic Blood Pressure
≤ 72
> 72
IADL
26-29
10-25
Lactate Dehydrogenase
0-459
Chemotherapy Toxicity
Non-Heme
Points
2
>459
0-0.44
0.45-0.57
>0.57
ECOG PS
0
1-2
3-4
Mini Mental Health Status
30
<30
28-30
<28
Mini Nutritional Assessment
Chemotherapy Toxicity
0-0.44
0.45-0.57
>0.57
Extermann et al, Cancer 2012
% Risk
CRASH Model
Score
Extermann et al, Cancer 2012
Metastatic Colorectal Cancer:
Randomized Study
Age ≥ 75
Metastatic
Colorectal Cancer
1st line
Randomize
Phase III Study:
N=62
FU-Based Chemotherapy
Alone
Mean Age: 80.3
N=61
FU-Based Chemotherapy +
Irinotecan
Mean Age: 80.5
All underwent a Geriatric Assessment
Aparicio et al., J Clin Oncol, 2013
Predictors of Toxicity & Dose Modification
Grade 3-4 Toxicity
OR (95% CI)
P-Value
Irinotecan Arm
5.03 (1.61-15.77)
.006
Mini-Mental State Examination
(MMSE) ≤ 27/30
3.84 (1.24-11.84)
.019
Impaired Autonomy
(IADL)
4.67 (1.42-15.32)
.011
Cognitive & physical function should be considered
when making treatment decisions.
Aparicio et al., J Clin Oncol, 2013
The Past:
Risk Factors for Chemotherapy Toxicity
Risk Factors
Aaldriks Aparicio Extermann Freyer Hurria
Age
X
ECOG PS/ KPS
X
Vital Signs
(blood pressure)
X
X
Labs
Cancer Type
X
X
X
X
Chemotherapy
X
X
X
Freyer et al., Annals of Oncology, 2005
Hurria et al., J Clin Oncol, 2011
Extermann et al., Cancer, 2012
Aaldriks et al., Breast, 2013
Aparicio et al., J Clin Oncol, 2013
The Present:
Geriatric Assessment Items
Predictive of Chemotherapy Toxicity
Risk Factors
Aaldriks Aparicio
Daily Activities
(ADL & IADLs)
X
Extermann
Freyer
Hurria
X
X
X
Hearing
(Fair or Deaf)
X
Nutrition
X
Cognition
X
Psychological
Status
X
X
X
X
X
Social Activities
Freyer et al., Annals of Oncology, 2005
Hurria et al., J Clin Oncol, 2011
Extermann et al., Cancer, 2012
X
Aaldriks et al., Breast, 2013
Aparicio et al., J Clin Oncol, 2013
Chronological Age 80
Functional Age 90
Functional Age 70
Conclusions
 Cancer is a disease associated with aging
 Older adults are under-represented on cancer
clinical trials
 There is a need to:
 Develop clinical trials for older adults
 Improve recruitment of older adults to
existing trials
 Incorporate geriatric principles in oncology
trial design
Thank you!
Geriatrics
Geriatric
Oncology
Oncology