Special Populations: Clinical Trials and Elderly Cancer Patients

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Special PopulationsClinical Trials and Elderly
Cancer Patients

• Stuart M. Lichtman, MD, FACP
• Associate Attending
• Clinical Geriatrics Program
• Memorial Sloan-Kettering Cancer Center

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Special PopulationsClinical Trials and Elderly
Cancer Patients

• Stuart M. Lichtman, MD, FACP
• Associate Attending
• Clinical Geriatrics Program
• Memorial Sloan-Kettering Cancer Center

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Special PopulationsClinical Trials and Elderly
Cancer Patients
Older

• Stuart M. Lichtman, MD, FACP
• Associate Attending
• Clinical Geriatrics Program
• Memorial Sloan-Kettering Cancer Center

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Special Populations

• The older patients are special because they are
  majority of patients you will be treating in the
  future

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US Population 65 and older
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Age Specific Cancer Incidence Rates
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Cancer Mortality and Mortality Rates
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Questions
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Incidence of 10 Major Cancers in Patients Over 65
years (73-95)
Modified from Yancik and Ries, Hematology
Oncology Clin NA 2000 1417
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Life Expectancy Woman
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Life Expectancy Woman
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Life Expectancy Woman
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The facts

• 60 of cancer is in people greater than 65 years
  of age
• 70 of cancer mortality is in people greater than
  65 years of age

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Therefore

• More older patients
• Living longer
• Living healthier
• More indications for anticancer therapy
• Many more patients in need of getting more therapy

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Geriatric Oncology

• How is cancer treatment studied?
• Primarily middle aged patients minimal inclusion
  of older patients
• Minimal comorbidity patients with other medical
  problems excluded
• Caucasian
• Cancer center based little community involvement

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Publications in Geriatric Oncology
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Elderly and Registration Trials
Talarico, L. et al. J Clin Oncol 224626-4631
2004
Fig 1. Proportion of elderly patients enrolled
onto registration trials compared with the
proportion of elderly patients in the US cancer
population
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Elderly and Registration Trials
Talarico, L. et al. J Clin Oncol 224626-4631
2004
Fig 2. Proportion of elderly patients (gt 65
years) enrolled onto registration trials compared
with the proportion of elderly patients in the US
cancer population
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NCI Sponsored Trials
Essentially no data for patients 80
J Clin Oncol 202109-2117, 2002
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Barriers to Participation

• Fewer trials available
• Focus on aggressive therapy
• Trial eligibility limits participation, ie.
  comorbidity, previous malignancy
• Limited expectation of benefit
• Physician reluctance to recruit older patients
  and recommend protocols (CALGB)
• Complicated trials requiring large expenditure of
  time for patients and caregivers

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Topics

• Pharmacology
• Design Issues

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Pharmacology

• Absorption
• Distribution
• Metabolism
• Excretion

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Metabolism and P450

• Drug interactions extremely important issue in
  elderly
• Increases risk of hospitalization and dependency
• Polypharmacy Emphasizes the importance of
  minimizing concomitant medications
• Role of different isoenzymes genetic influences
• Role of nonP450 medications

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Excretion

• Decline in glomerular filtration rate (GFR) is
  one of the most predictable changes associated
  with aging
• Additional effect of comorbid conditions on renal
  function

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Sample CrCl Calculations Cockcroft-Gault Female
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Sample CrCl Calculations Using Cockcroft-GaultFem
ale
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CrCl Which formula?

• Serum creatinine not an accurate measure of renal
  function
• Cockcroft-Gault
• Jelliffe
• Levey MDRD or aMDRD
• Wright
• Clinical Consequences
• May alter clinical trial eligibility or exclude
  patient from standard therapy
• Misperception of drug safety, I.e. cisplatin

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Renal Function on Trials
McHayleh , et al. ASCO 2007
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Renal Function on Trials
McHayleh , et al. ASCO 2007
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Pharmacology

• Pharmacokinetics
• Modest changes in PK changes based on age alone
• Changes (variability) are result of
• Comorbidity
• Endorgan dysfunction
• Physical factors fat, anemia, albumin, etc.
• Physiologic changes with aging
• Polypharmacy
• Gender, ethnicity, genotype

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Pharmacodynamic

• Heterogeneity of Effect
• Tremendous variability in toxicity
• Increased susceptibility
• Myelosuppression
• Mucositis
• Cardiac toxicity
• Nervous system toxicity

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Design Issues
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Design Issues

• Patient Selection
• Endpoints
• Dose Limiting Toxicity
• Functional Assessment

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Patient Selection

• Which older patient?
• Comorbidity
• Endorgan dysfunction renal, hepatic
• Cardiac disease
• Neuropathy
• Prior malignancy, i.e. prior chemotherapy,
  radiotherapy
• Cognitive impairment require MMSE?

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Which Older Patient? Stages of Aging
Primary/Healthy

• No activity limitations
• Reduced functional reserve

Intermediate/ Vulnerable

• Functional reserve critically reduced
• Functional limitations
• Some recovery possible

Secondary or frailty

• No recovery of functional reserve
• Severe limitations

• No functional reserve

Near Death
Hamerman D Toward an understanding of frailty.
Ann Intern Med 130945-50, 1999
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Which Older Patient? Stages of Aging
Primary/Healthy

• No activity limitations
• Reduced functional reserve

Intermediate/ Vulnerable

• Functional reserve critically reduced
• Functional limitations
• Some recovery possible

Secondary or frailty

• No recovery of functional reserve
• Severe limitations

• No functional reserve

Near Death
Hamerman D Toward an understanding of frailty.
Ann Intern Med 130945-50, 1999
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Comorbidity and Function

• Comorbidity evaluation
• Prevalent in elderly
• Can predict survival
• Various scales Charlson, Cumulative Illness
  Rating Scale-Geriatric (CIRS-G)
• Function
• Can predict survival
• ADL, IADL
• Physical function gait speed, get-up-and-go,
  etc.
• Dependency
• Should we or can we evaluate the frail patient?

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Design Issues Endpoints

• Survival
• Is the patient going to die of or with cancer?
• Response
• Overall response
• Freedom from progression
• Time without symptoms
• Functional and clinical benefit, quality of life

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Toxicity Evaluation-CTC v2
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Toxicity Evaluation Functional
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Toxicity Evaluation-Frail
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Proposed Toxicity Assessment

• Peripheral sensory neuropathy
• Oxaliplatin, vinca alkaloids, paclitaxel
• Sequelae of neuropathy in older patients
• Falls, social isolation (not driving), chronic
  impairment
• Incorporate other measures
• Hand grip
• Get up and go gait speed

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Function
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Functional Assessment as Endpoint

• Alterations in
• ADL
• IADL
• Geriatric syndromes
• Falls, delirium, incontinence, nutrition
• Maintain independence/avoid further dependence as
  potential endpoint

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Comprehensive Geriatric Assessment Is Highly
Sensitive to Common Problems in Elderly

• Findings among 200 patients age ??70
• dependent in ADL 18
• dependent in IADL 72
• serious comorbidity 36 on Charlson scale 94
  on CIRS-G scale
• memory disorder 22
• poor nutrition 19
• polypharmacy 41
• Conclusion CGA indicated in all patients age ?70

Balducci L, et al. Oncologist. 20005224237.
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Comprehensive Geriatric Assessment Is Highly
Sensitive to Common Problems in Elderly

• Which assessment should be done and included?
• CGA
• Limited VES-13
• Validating limited assessment
• Hurria, et al. Cancer 2005
• CALGB and MSKCC

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Suggestions

• 1)Drugs, which will be primarily used by older
  patients, should be studied in older patients.
  These studies should involve PK and oral
  medication should include measurements of
  compliance.
• 2)Randomized phase II trials of new agents in
  groups of patients divided by age.
• 3)Dose modify in a phase I fashion using
  progressive degrees of functional impairment and
  increasing comorbidity.
• 4)Include functional independence as a clinical
  benefit of cancer treatment in older individuals.

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Suggestions

• 5)Consider studying long term functional and
  medical consequences of cancer treatment in long
  term older cancer survivors.
• 6)Journal editors should encourage the inclusion
  of age related analyses in the reporting of
  clinical trials to provide meaningful information
  for clinicians caring for older patients.
• 7)Clinical trial design of adult cancer patients
  should prospectively incorporate age analysis to
  maximize clinical benefit of data generated

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Thank You