1. Why Do We Need Separate Clinical Trials for Older Adults?
Arti Hurria, MD
Director, Cancer and Aging Research Program
Associate Professor
City of Hope

2. US Population Age > 65 (millions)
Year
U.S Census Bureau, 2010 2

3. 60% of cancer occurs in people > age 65
Cancer and Aging
60% of cancer occurs in people > age 65
100,000 Population
Rates per
Age Groups
CDC, Morbidity and Mortality Weekly Report, 2013

4. Majority of Cancer Deaths Occur in Older Adults
Cancer and Mortality
Majority of Cancer Deaths Occur in Older Adults
Howlader et al., SEER Cancer Statistics Review

5. Life Expectancy is Increasing
Age
Year
National Vital Statistics Report 5

6. Projected Rise in Cancer Incidence from 2010 to 2030
67% in patients 65+
Cancer Incidence (million)
11% in patients <65
Year
Smith et al, J Clin Oncol, 2009

7. The Population is Aging
The Number of Older Adults With Cancer is on the Rise
Are we prepared?

8. No Change in Overall Age Distribution in NCI Trials
Age Distribution in Phase 2 and Phase 3
NCI Cooperative Group Clinical Treatment Trial
NCI/DCTD Clinical Data Update System, 2012

9. Older Adults Under-represented on Cancer Registration Trials
N= enrolled into 55 registered trials of new cancer drugs or new indications of FDA approved marketed cancer drugs
Graph excludes those on hormonal therapy trials. If hormonal therapy trials are included, the percentages of enrolled are: 36% (≥65), 20% (≥70), 9% (≥75)
Talarico et al. JCO 2004

10. 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

11. Advances in evidence based knowledge in Geriatric Oncology
U13: Background
Foundation for research planning in Cancer & Aging
Geriatric Oncology Education Retreat
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 11

12. Planning for the Next 10 Years: U13 Grant
“Geriatric Oncology Research to Improve Clinical Care”
Collaboration
NIA, NCI, The Cancer & Aging Research Group
Mission:
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

13. U13 Oversight Board Arti Hurria, MD (PI)
Supriya Mohile, MD, MS (co-PI)
William Dale, MD, PhD (co-PI)
Basil Eldadah, MD*
Margaret Mooney, MD*
Harvey Cohen, MD (Geriatric Oncology)
Martine Extermann, MD (Geriatric Oncology)
Betty Ferrell, PhD (Nursing Research)
Hyman Muss, MD (Geriatric Oncology)
Richard Schilsky, MD (Oncology)
Kenneth Schmader, MD (Geriatrics)
CARG
NIA
Alliance
NCI
AACR
SIOG
ASCO
AGS
*Prior Oversight Board Members: Susan Nayfield and Edward Trimble

14. Goals of U13 Grant
To identify the present level of evidence & areas of high research priority in Geri Onc
To identify strengths in research methodology, from the fields of Geriatrics and Oncology
To foster collaboration between multidisciplinary scholarly teams
To foster and promote the research of existing and new investigators in Geriatric Oncology
To disseminate findings from this conference grant program with easily adaptable recommendations
Research
Methodology
Training
&
Education

15. How to Fill the Gaps Conference Structure Gaps in Knowledge
What Is Known
Gaps in Knowledge
How to Fill the Gaps

16. Conference Series Topics
3 Successive Conferences:
Year 1:
Biological, Clinical,
and Psychological
Correlates
at the interface of
Aging and Cancer Research
Year 3:
Design and
Implementation of
Therapeutic Clincial
Trials for Older
and/ Frail Adults
with Cancer
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
Dissemination
Dissemination:
ASCO Symposium
AGS Symposium
White papers
Web: Slide sets with audio

17. Conference 1: Biological, Clinical, & Psychosocial Correlates at the Interface of Aging and Cancer Research
Goals:
Factors to consider in geriatric oncology research:
clinical assessment
biological factors
psychosocial factors
Identify and create opportunities for multidisciplinary research
Disseminate

18. Key Publications from the U13
JNCI, 2012
Nat Rev Clin Oncol, 2012
J Natl Compr Canc Netw, 2012

19. Conference 2: Design and Implementation of Therapeutic Clinical Trials for Older and/or Frail Adults with Cancer
Goals:
Identify gaps in knowledge of cancer therapy in older adults
Study design of therapeutic clinical trials
Methods to optimize patient accrual
Propose opportunities for multidisciplinary studies
Disseminate

20. Two Major Deficiencies
Need to:
accrue older adults to existing clinical trials
develop specific trials for the “oncologically frail” older adults

21. Standard Clinical Trial Design: Is More Better?
Arm A
Drug X
Phase III Trial
Randomize
Arm B
Drug X + Y
Patients age ≥ 65 not enrolled onto the study due to:
Doctors’ concerns regarding toxicity
Patient may not be “fit” for the study
Kemeny et al., JCO 2003

22. 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
Age < 65
Age ≥ 65
Offered Trial
51%
34%
Accepted Participation
56%
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

23. The patient is not the barrier.
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
The patient is not the barrier.
Kemeny et al., JCO 2003

24. 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?

25. Chronological Age ≠ Functional Age
Functional Age vs.
Chronological Age
To weigh the risks and benefits

26. The Extra Challenge: The Ultimately Efficient Clinic
Vitals Taken
Patient in Gown
Sitting on Exam Table

27. What is old? 65

28. 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

29. Can Geriatric Assessment Predict Chemo Toxicity? (CARG)
Eligibility criteria
- Age 65 or older
- Diagnosis of cancer
- To start a new chemotherapy regimen
Timepoint 1:
Timepoint 2:
Pre-chemo
Geriatric Assessment
Post-chemo
Geriatric Assessment
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

30. Predictors of Toxicity
Age ≥ 72 years
GI/GU Cancer
Standard Dose
Polychemotherapy
Hemoglobin (male: <11, female: <10)
Creatinine Clearance (Jelliffe-ideal wt <34)
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)
Age
Tumor/ Treatment Variables
Labs
Moderate activities (moving a table, pushing a vacuum cleaner, bowling, or playing golf
Hearing (fair or worse)
Geriatric Assessment Variables 30

31. Prevalence of Toxicity by Score
Model Performance:
Prevalence of Toxicity by Score
High (83%)
Medium (52%)
Low (30%)
Grade 3-5 Toxicities
Total Risk Score

32. Geriatric Assessment is Feasible in Oncology Trials
Geriatric Assessment for Older Adults with Cancer on Cooperative Group Trials
CALGB (PI: Hurria)
Eligibility Criteria
- Age 65 or older
- Diagnosis of cancer
- To start treatment on a cooperative group clinical trial
Pre-chemo
Geriatric assessment
Feasibility data
Treatment and follow-up per protocol
Geriatric Assessment is Feasible in Oncology Trials
Hurria et al, JCO 2011

33. 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

34. Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) Score
Prospective multicentric study
518 patients age ≥ 70 yrs
Predictors of Toxicity
Points 1 2
Heme
Diastolic Blood Pressure
≤ 72
> 72
IADL
26-29
10-25
Lactate Dehydrogenase
0-459
>459
Chemotherapy Toxicity
0-0.44
>0.57
Non-Heme
ECOG PS
1-2
3-4
Mini Mental Health Status 30
<30
Mini Nutritional Assessment
28-30
<28
Extermann et al, Cancer 2012

35. CRASH Model
% Risk
Score
Extermann et al, Cancer 2012

36. Metastatic Colorectal Cancer: Randomized Study
N=62 FU-Based Chemotherapy Alone
Mean Age: 80.3
Phase III Study:
Age ≥ 75
Metastatic Colorectal Cancer
1st line
Randomize
N=61 FU-Based Chemotherapy + Irinotecan
Mean Age: 80.5
All underwent a Geriatric Assessment
Aparicio et al., J Clin Oncol, 2013

37. Predictors of Toxicity & Dose Modification
Grade 3-4 Toxicity
OR (95% CI)
P-Value
Irinotecan Arm
5.03 ( )
.006
Mini-Mental State Examination (MMSE) ≤ 27/30
3.84 ( )
.019
Impaired Autonomy
(IADL)
4.67 ( )
.011
Cognitive & physical function should be considered when making treatment decisions.
Aparicio et al., J Clin Oncol, 2013

38. The Past: Risk Factors for Chemotherapy Toxicity
Aaldriks
Aparicio
Extermann
Freyer
Hurria
Age X
ECOG PS/ KPS
Vital Signs (blood pressure)
Labs
Cancer Type
Chemotherapy
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

39. The Present: Geriatric Assessment Items Predictive of Chemotherapy Toxicity
Risk Factors
Aaldriks
Aparicio
Extermann
Freyer
Hurria
Daily Activities
(ADL & IADLs) X
Hearing
(Fair or Deaf)
Nutrition
Cognition
Psychological Status
Social Activities
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

40. Chronological Age 80
Functional Age Functional Age 70

41. 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

42. Thank you!
Geriatrics
Geriatric Oncology
Oncology