An Overview of Geriatric Oncology: From Research to Clinical Practice Melissa Loh, MBBCh BAO Wilmot Cancer Center University of Rochester Medical Center

Outline Epidemiology of aging Geriatric domains: comorbidities, geriatric syndromes, polypharmacy, cognition, social support Utility of geriatric assessment Prediction of chemotherapy toxicity Decision-making Interventions

Epidemiology of Aging

Epidemiology of Aging

Age Distribution in Specific Cancer Breast cancer Age Distribution <65 years ≥ 65 to <75 ≥ 75 years Age at diagnosis 59% 20% 21% Colorectal cancer Age Distribution <65 years ≥ 65 to <75 ≥ 75 years Age at diagnosis 39% 24% 37% Prostate cancer Age Distribution <65 years ≥ 65 to <75 ≥ 75 years Age at diagnosis 42% 36% 23% Lung cancer Age Distribution <65 years ≥ 65 to <75 ≥ 75 years Age at diagnosis 32% 31% 37%

Lack of Enrollment of Older Adults in Treatment Trials *From NCI Surveillance, Epidemiology, and End Results (SEER) Program for 2005 to 2009 **For Phase 2 & 3 Tx Trials 2001 to 2011 - NCI/DCTD Clinical Data Update System May 2012

Important Variables for Prognostication in Older Adults with Cancer

Impact of Comorbidities on Life Expectancy

Increasing Severity of Comorbidities with Aging Piccirillo et al. Crit Rev Oncol Hematol. 2008

Impact of Multimorbidity on Outcomes Increased risk of: Death Institutionalization Increased utilization of healthcare resources Decreased quality of life Higher rates of adverse effects of treatment or interventions Brendan Smialowski (NY Times) AGS Expert Panel on the Care of Older Adults with Multimorbidity. J Am Geriatr Soc 2012;60:1957-68 Ferrat et al. J Gerontol A Biol Sci Med Sci. 2015

A High Prevalence Geriatric Syndrome and Functional Impairment in Older Adults with Cancer Mohile et al. JNCI. 2009

Impact of Geriatric Syndromes on Survival in Patients with Colon Cancer Geriatric syndromes and mortality One syndrome HR=1.18 (0.99-1.41) Two syndromes HR=2.34 (1.74-3.15) Koroukian et al. J Gerontology Med Science, 2009

Polypharmacy Now, people age 65+ are 13% of US population, buy 33% of prescription drugs. By 2040, will be 25% of population, will buy 50% of prescription drugs

Risk Factors for Adverse Drug Events 6 or more concurrent chronic conditions 12 or more doses of drugs/day 9 or more medications Prior adverse drug reaction Low body weight or low BMI Age 85 or older Estimated CrCl < 50 mL/min

Common Drug-Drug Interactions Combination Risk ACE inhibitor + diuretic Hypotension, hyperkalemia ACE inhibitor + potassium Hyperkalemia Antiarrhythmic + diuretic Electrolyte imbalance, arrhythmias Benzodiazepine + antidepressant, antipsychotic, or benzodiazepine Confusion, sedation, falls Calcium channel blocker + diuretic or nitrate Hypotension Digitalis + antiarrhythmic Bradycardia, arrhythmia

Cognitive Disorders Cognitive disorders are frequently under-diagnosed 24% of geriatric cancer patients are screened positive for cognitive disorders Risks of treatment in patients with dementia Mohile SG, et al. Cancer 109: 802-10, 2007.

Decreased Survival in Patients with Cognitive Impairment Robb C, Boulware D, Overcash J, Extermann M. Patterns of care and survival in cancer patients with cognitive impairment. Critical Reviews in Oncology/Hematology 4: 218-24, 2010.

Psychological Status Prevalence up to 50% in patients with cancer Clinical depression predicts severe treatment related-toxicity and overall survival Depression diagnosed prior to and after diagnosis of cancer were associated with mortality Freyer G, et al. Ann Oncol. 2005 Pinquart M, et al. Psychol Med. 2010 Massie MJ. JNCI. 2004

Social Support Influence of marital status on breast cancer Unmarried women were more likely to be diagnosed with breast cancer stage II-IV versus stage I or in situ Unmarried women diagnosed with Stage I or II breast cancer were less likely to receive definitive treatment Unmarried women were at increased risk of death from breast cancer Osborne C, et al. Breast Cancer Res Treat. 2005

All Older Patients with Cancer are Not the Same

Oncology versus Geriatrics Oncology  stage the cancer Make predictions of life expectancy Expected side effects of cancer therapy Geriatrics  stage the “aging” Anticipate potential complications Better evaluate whether the benefits of therapy outweigh the risks in the context of physiologic age

Chronologic versus Physiologic Age When considering prognosis and treatment options in this population, decisions should be based more on “physiologic” age versus chronologic age. It is necessary for oncologists to be adept at efficiently and accurately estimating physiologic and functional capacity in older patients.

Conceptual Model of GA

Comprehensive Geriatric Assessment Functional status Activities of daily Living Instrumental activities of daily living Physical function Falls Comorbidities Medications Polypharmacy Inappropriate medications Psychological status Depression/Anxiety Cognitive impairment Dementia Delirium Nutrition Social support Vision/hearing Goals of Care Frailty

Developing a Cancer-Specific Geriatric Assessment (CSGA): A Feasibility Study Time to complete Mean 27 min (SD 10) Range 8-45 min No association of age with time to complete assessment (p = 0.13) No association of age with ability to complete without assistance (p=0.16) ABILITY TO COMPLETE UNASSISTED No: 22% Yes: 78% Hurria A et al. Cancer. 2005.

Utility of Comprehensive Geriatric Assessment in Older Adults with Cancer Risk Prediction Surgical Complications and Chemotherapy Toxicity Survival Cancer treatment modification Modification of treatment/ chemotherapy Modification of supportive care Intervention Geriatrics vs. Cancer-focused General Goals

Chemotherapy Toxicity Prediction Identify risk factors for chemotherapy toxicity in the geriatric oncology population incorporating CGA Develop a risk stratification schema for chemotherapy toxicity Hurria A, et al. J Clin Oncol. 2011.

Adverse Events

Incidence of Toxicity

CARG Toxicity Profile Risk factor for Grade III-V Toxicity OR (95% CI) Score Age ≥73 years 1.8 (1.2-2.8) 2 GI/GU Cancers 2.1 (1.4-3.2) 3 Standard dose chemotherapy 2.1 (1.3-3.5) Polychemotherapy 1.7 (1.1-2.6) Anemia (Male < 11, female <10) 2.3 (1.1-4.6) Cr Cl <34 ml/min (using Jeliffe equation/IBW) 2.5 (1.1-5.4) Falls in last 6 months 2.5 (1.4-4.3) Hearing impairment 1.7 (1.0-2.7) Limited ability to walk 1 block 1.7 (1.0-2.8) Requires assistance with medications 1.5 (0.7-3.2) 1 Decreased social activities 1.4 (0.9-2.0) Possible score 0-25

http://www.mycarg.org/Chemo_Toxicity_Calculator

Utility of Comprehensive Geriatric Assessment in Older Adults with Cancer Risk Prediction Surgical Complications and Chemotherapy Toxicity Survival Cancer treatment modification Modification of treatment/ chemotherapy Modification of supportive care Intervention Geriatrics vs. Cancer-focused General Goals

CGA Influences Clinical Care Caillet P et al. J Clin Oncol 2011.

CGA Influences Clinical Care Treatment modification occurred in 78 patients Intensification -> 10.2% Delay -> 9% Decrease -> 80.8% Factors independently associated with changing the treatment plan Functional impairment (ADL score) Malnutrition Trend towards association with depression and higher number of comorbidities

Cancer Treatment Modifications Based on CGA Oncologist assessment: Initial treatment plan CGA Oncologist and geriatrician: Final treatment plan French ASRO study N=217, mean age 83 years 40% treatment recommendation modifications On multivariate analysis: ADL dependence and Fried’s frailty markers associated with treatment modifications Farcet et al. PLOS One. 2016

Utility of Comprehensive Geriatric Assessment in Older Adults with Cancer Risk Prediction Surgical Complications and Chemotherapy Toxicity Survival Cancer treatment modification Modification of treatment/ chemotherapy Modification of supportive care Intervention Geriatrics vs. Cancer-focused General Goals

Geriatric-Assessment Guided Interventions Mohile et al, JNCCN, 2015

Delphi Participants

Interventions

Evaluates the impact of geriatrician-delivered CGA interventions on chemotherapy toxicity and tolerance for older people with cancer Observational study

Results More participants in the intervention group completed treatment as planned (33.8% vs 11.4%, OR 4.14, P=0.006) Fewer required treatment modifications (43.1% vs 68.6%, OR 0.34, P=0.006) Non-significant trend towards fewer discontinuing treatment early (40.0% vs 51.4%, OR 0.63, P=0.183) No difference in all-cause death rates at 6 months (20.0% control, 15.4% intervention, P.0.483). *Adjusted for age, comorbidity, metastatic disease and initial dose reductions

Toxicity Non-significant trend for a lower grade 3+ toxicity rate in the intervention cohort (43.8% vs 52.9%, P=0.292)

A Pilot Study of Geriatric Assessment Intervention for Older Cancer Patients Receiving Systemic Cancer Treatment Prospective, randomized pilot study evaluating the effect GA-driven interventions Primary Aim: To determine if providing information regarding GA and GA-guided interventions to oncologists reduces grade 3-5 toxicity in patients aged 70 and over receiving first or second-line treatment with chemotherapy

A Pilot Study of Geriatric Assessment Intervention for Older Cancer Patients Receiving Systemic Cancer Treatment Secondary Aims: To determine the effects of GA-guided interventions on functional measures, hospitalizations, and dose delays/early termination of treatment To determine if providing oncologists with the results of GA and GA-guided interventions influences overall survival To determine whether providing oncologists with the results of GA influences decision making

Eligibility Criteria Patients age 70 and older Solid tumor malignancies Recommended by primary oncologist to receive treatment with chemotherapy/chemoRT First or second line treatment Have decision-making capacity or an assigned HCP

Pilot Study Results Baseline Characteristics balanced between the two groups with the exception of IADL impairment: higher in the intervention group (p = 0.046) CARG-toxicity score: higher in intervention group (8% vs 27%, p=0.10)

Pilot Study Results 3 month follow-up: Overall 58% of patients experienced grade 3-5 toxicity within 3 months There was no significant difference between the control and intervention group (48.3 % vs 51.7%, p = 0.96) There were no significant differences in rates of: Hospitalization (38% vs 23%, p= 0.26) Dose reduction (42% vs 39%; p= 0.82) Dose delays (42% vs 35%; p= 0.61)

Pilot Study Results Consider meals-on-wheels – 33% Nutrition referral – 67% Consider PT/OT Referral – 33% Consider more aggressive antiemetic regimen – 50% Fall counseling handout – 44% Ride assistance programs – 50% Home safety evaluation – 39% Social work involvement – 80% Check vitamin D and repletion as indicated – 17% Identification of HCP– 30% Consider initial dose reduction – 72% Co-sign for consents – 10% Medication review – minimize psychoactive meds – 57% Delirium risk handout – 30% Pillbox – 19% PERS if alone – 0% Medication review – minimize high risk medications – 36% Energy conservation handout – 36% Exercise handout – 36% Consider depression pharmacological therapy – 17% VNS/home health aide referral – 42% Consider referral for psychotherapy/psychiatry – 17% Nutrition counseling (handout) – 50% Support Group Information – 71%

Pilot Study Results 3-month follow up Depression GA at 3 months demonstrated increased interval development of depression in the control group (36% vs 5%; p = 0.02)

Pilot Study Results 3-month follow up Function Resolution of baseline differences in IADL dependence (44% vs 42%; p=0.90)

Pilot Study Discussion Conclusions: Able to enroll older, advanced cancer patients to a clinical trial in a reasonable timeframe Patients not being referred to the geri-onc clinic have a good deal of geriatric-related issues Unfortunately, we weren’t able to see that the intervention algorithm improved the primary outcome – chemotherapy toxicity for patients Did see improvements with regards to function and depression

Study Co-Investigators A Geriatric Assessment Intervention for Patients Aged 70 and Over Receiving Chemotherapy for Advanced Cancer: Reducing Chemotherapy Toxicity in Older Adults -GAP-70+: Funded by NCI R01 Study Chair Supriya Mohile, MD, MS, University of Rochester Study Co-Investigators Garry Morrow PhD, MS University of Rochester Karen Mustian PhD, MPH, University of Rochester Ron Epstein, MD, University of Rochester Arti Hurria, MD, City of Hope William Dale, MD, PhD, University of Chicago

Primary Aim To determine if providing information regarding GA and GA-driven recommendations to oncologists reduces grade 3-5 chemotherapy toxicity in patients aged 70 and over with advanced solid tumor malignancy

Conceptual Model

Schema

Summary The population is aging Older adults often have other comorbidities, geriatric syndromes, functional and cognitive impairment, polypharmacy and reduced social support GA can help predict outcomes and decision-making More data is needed on impact of GA-driven interventions on outcomes

Acknowledgement New York Cancer Registrar’s Association Dr. Supriya Mohile Dr. Allison Magnuson