Title: Special Populations: Clinical Trials and Elderly Cancer Patients
1Special PopulationsClinical Trials and Elderly
Cancer Patients
- Stuart M. Lichtman, MD, FACP
- Associate Attending
- Clinical Geriatrics Program
- Memorial Sloan-Kettering Cancer Center
2Special PopulationsClinical Trials and Elderly
Cancer Patients
- Stuart M. Lichtman, MD, FACP
- Associate Attending
- Clinical Geriatrics Program
- Memorial Sloan-Kettering Cancer Center
3Special PopulationsClinical Trials and Elderly
Cancer Patients
Older
- Stuart M. Lichtman, MD, FACP
- Associate Attending
- Clinical Geriatrics Program
- Memorial Sloan-Kettering Cancer Center
4Special Populations
- The older patients are special because they are
majority of patients you will be treating in the
future - Trials should be made as inclusive as possible to
accommodate these patients
5 US Population 65 and older
6Age Specific Cancer Incidence Rates
7Question
- What is the median age of diagnosis of colorectal
cancer (SEER)? - A. 55-60
- B. 60-65
- C. 65-70
- D. 70-75
- E. 75-80
8Incidence of 10 Major Cancers in Patients Over 65
years (73-95)
Modified from Yancik and Ries, Hematology
Oncology Clin NA 2000 1417
9Question
- What is the life expectancy of a 75 year old
woman in good health - A. 0-5
- B. 5-10
- C. 10-15
- D. 15-20
- E. 20-25
10Life Expectancy Woman
11Life Expectancy Woman
12Life Expectancy Woman
13The 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
14Geriatric 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
15Elderly 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
16NCI Sponsored Trials
Essentially no data for patients 80
J Clin Oncol 202109-2117, 2002
17Barriers 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
18Topics
- Pharmacology
- Design Issues
19Pharmacology
- Absorption
- Distribution
- Metabolism
- Excretion
20Absorption
- Factors that may affect absorption
- Controllable
- Concomitant medication, ie. H2 blockers, antacids
- Compliance-polypharmacy, financial
- Not Controllable
- Reduced gastric secretion, gastric emptying,
gastrointestinal motility - Diminished splanchnic blood flow
- Decreased absorption surface
21Polypharmacy
- Potential for drug interactions and toxicity
- Complementary and alternative medication need
evaluation - Evaluate for unnecessary medication (Beers List)
Extermann, et al. ASCO 2003 Boparai, Lichtman
2008 (unpublished)
22Metabolism 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
23Excretion
- Decline in glomerular filtration rate (GFR) is
one of the most predictable changes associated
with aging - Additional effect of comorbid conditions on renal
function
24Sample CrCl Calculations Cockcroft-Gault Female
25Sample CrCl Calculations Using Cockcroft-GaultFem
ale
26CrCl 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
27Pharmacology
- 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
28Pharmacodynamic
- Heterogeneity of Effect
- Tremendous variability in toxicity
- Increased susceptibility
- Myelosuppression
- Mucositis
- Cardiac toxicity
- Nervous system toxicity
29Design Issues
30Design Issues
- Patient Selection
- Endpoints
- Dose Limiting Toxicity
- Functional Assessment
31Which 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
Near Death
Hamerman D Toward an understanding of frailty.
Ann Intern Med 130945-50, 1999
32Which 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
Near Death
Hamerman D Toward an understanding of frailty.
Ann Intern Med 130945-50, 1999
33Patient Selection
- Which older patient?
- Comorbidity
- Endorgan dysfunction renal, hepatic
- Cardiac disease
- Neuropathy
- Prior malignancy, i.e. prior chemotherapy,
radiotherapy - Cognitive impairment require MMSE?
34Design Issues Endpoints
- Survival
- Is the patient going to die of or with cancer?
- Competing comorbidity
- Response
- Overall response
- Freedom from progression
- Time without symptoms
- Functional and clinical benefit, quality of life
35Toxicity Evaluation-CTC v2
36Toxicity Evaluation Functional
37Toxicity Evaluation-Frail
38Proposed 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
39Function
40Comorbidity 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?
41Functional Assessment as Endpoint
- Alterations in
- ADL
- IADL
- Geriatric syndromes
- Falls, delirium, incontinence, nutrition
- Maintain independence/avoid further dependence as
potential endpoint
42Comprehensive 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.
43Comprehensive 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
44Suggestions
- 1)Drugs, which will be primarily used by older
patients, should be studied in older patients. - 2)Dose modify in a phase I fashion using
progressive degrees of functional impairment and
increasing comorbidity. - 3)Include functional independence as a clinical
benefit of cancer treatment in older individuals.
45Suggestions
- 4)Consider studying long term functional and
medical consequences of cancer treatment in long
term older cancer survivors. - 5)Clinical trial design of adult cancer patients
should prospectively incorporate age analysis to
maximize clinical benefit of data generated - 6)Older patients should be encouraged to
participate in trials and study design should
take into account practical social support issues
(i.e. scheduling of treatments, required data).
46Thank You