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 2

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

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 1975-2010

Life Expectancy is Increasing Age Year National Vital Statistics Report 5

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

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 NCI/DCTD Clinical Data Update System, 2012

Older Adults Under-represented on Cancer Registration Trials N=28.766 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

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

Advances in evidence based knowledge in Geriatric Oncology 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 11

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

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

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

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

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

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

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: 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

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

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

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

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

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

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 - 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

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

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

Geriatric Assessment is Feasible in Oncology Trials Geriatric Assessment for Older Adults with Cancer on Cooperative Group Trials CALGB 360401 (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

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

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 0.45-0.57 >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

CRASH Model % Risk Score Extermann et al, Cancer 2012

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

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 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

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

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