Cytotoxic agents in the elderly

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Cytotoxic agentsin the elderly
Matti S. Aapro Genolier Switzerland

• based on Stuart M. Lichtmans
• presentation at SIOG Nov 06

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Should one ban chemotherapy after age 80?
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COMPREHENSIVE GERIATRIC ASSESSMENT

• CGA adds information to
• Eastern Cooperative Oncology Group performance
  status
• in elderly cancer patients
• Repetto L, Fratino L, Audisio RA, et al. J Clin
  Oncol 2002 20 494-502

Use of Comprehensive Geriatric Assessment in
older cancer patients. Recommendations from the
Task Force on CGA of the International Society of
Geriatric Oncology (SIOG) Extermann M. et al
Critical Rev Oncol Hematol Sept 2005
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What does a CGA bring?

• Br Ca adj chemotherapy
• reduces relative death risk by 15.3
• Beta-blockers
• reduce MI relative mortality by 22
• ( 1.8 absolute )
• CGA might reduce mortality by 14

M. Extermann, H. Cohen, 2000
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Assessing the Older Patient for Cancer Treatment

• Fitness does not mean you can all do the same
  exercise, does it?

Shown by Audisio, SIOG 2003
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SIOG Taskforce Evaluation of chemotherapy
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Adverse Drug Events and Aging
JAMA 2006
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CHEMOTHERAPY AND THE ELDERLY

• What are the true limitations?
• Drug distribution and absorption
• Drug interactions
• Renal function
• Liver function
• Marrow reserves
• Neurologic

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Pharmacology

• Absorption
• Concomitant medication, ie. Ca, H2 blockers,
  antacids
• Compliance
• Distribution
• albumin reduced (etoposide, taxanes highly
  protein bound)
• anemia
• Metabolism
• Excretion

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Potential for drug interactions and toxicity
Extermann, et al. ASCO 2003
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Chemotherapy and P450 Metabolism
declines by 32 after the age of 70 years
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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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Renal Excretion

• Drugs completely excreted through the kidneys
• Methotrexate
• Carboplatin
• Drugs partially excreted through the kidneys
• Epipodophyllotoxins
• Fludarabine
• Capecitabine
• Pemetrexed
• Drugs producing active or toxic metabolites
  excreted through the kidneys
• Cytarabine (high doses)

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Sample CrCl Calculations Using Cockcroft-GaultFem
ale
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Taskforce Goals of Analysis

• Most evaluations and reviews state that fit
  older patients without significant comorbidity
  and without significant functional impairment
  should be treated the same as younger patients.

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Taskforce Goals of Analysis

• Should there be changes in therapy based on age
  alone?
• Dose, schedule, supportive care
• How should impairments change therapy?
• Function
• Comorbidity
• Endorgan dysfunction
• Consensus conclusions

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Limitations of Review

• What is elderly (lt65 lt70 PS2)
• Few elderly specific trials
• Elderly make up small proportion of patients on
  trials
• Selection bias-fit elderly
• Age analysis often not done
• No data on patients gt80 years

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Fluoropyrimidines

• Data has focused on toxicity
• Prospective PK studies not done
• Pharmacogenetic influence (DPD, TS)
• Most studies increased toxicity in older
  patients, poor PS and women (DPD?)
• Sargent (2001)slight increase in leucopenia
• Differences in studies due to
• Other drugs (i.e. methotrexate, leucovorin)
• Fluoropyrimidine schedule (bolus, infusion)

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FluoropyrimidinesCapecitabine

• Toxicity
• Differences in renal function
• Folate (?)-US vs. Europe
• Issues in the elderly
• Elderly by virtue of age alone do not have
  different PK than non-elderly
• Moderate to severe renal dysfunction can result
  in excess drug exposure
• What dose?
• 1000 mg/m2 or 1250 mg/m2 bid
• Compliance
• Drug interactions, i.e. coumadin

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Platinum compoundsOxaliplatin

• Oxaliplatin
• Prospective PK not done
• Toxicity analyses (Goldberg, 2006)
• Hematologic toxicity increased (neutropenia,
  thrombocytopenia)
• No change in neuropathy

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Platinum compoundsCarboplatin/Cisplatin

• Carboplatin
• Toxicity related to renal insufficiency
• Combination therapy
• Cisplatin
• Clinical trial patients usually show no
  difference in toxicity
• Patient selection
• PS, comorbidity, creatinine clearance
  determinations

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Taxanes

• Paclitaxel
• Difference in PK with increased AUC by age
• No significant toxicity difference
• Docetaxel
• Minimal to no difference in PK by age
• PD effect

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April 20, 2006
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(No Transcript)
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ConclusionsDrug Administration

• Age alone is rare issue in dose modification
• Correction of reversible comorbidity-use CGA to
  uncover issues
• Euvolemic state
• Evaluation of endorgan function, particularly
  renal function
• Adjust doses based on known PK of drug, i.e.
  renal or hepatic metabolism