Transcript Document

Integrating Research and
Clinical Practice
Jim Koeller, M.S.
Professor
University of Texas at Austin & the Health
Science Center, San Antonio, USA
Learning Objectives
• Describe how research impacts clinical
practice
• List 3 different types of clinical research
• Describe 2 research areas that can be
applied to clinical practice
• Give 2 examples of research that can be
directly applied to daily practice
• Describe 2 ways to take clinical practice
and create a project or publication
Your ‘Scope’ of Clinical Practice
• What are your daily functions as an ‘oncology
pharmacist’?
• Do you directly participate in a patient
environment, or is it more indirect?
– Are you involved in direct patient care?
– Are you involved in chemotherapy/drug
preparation?
– Are you involved more in dispensing
functions?
• Do you participate in any type of drug research?
How Does Research Impact
Clinical Practice?
• Evidence-based clinical practice should
become a standard of care
– Having clinical decisions driven by clinical
trials data
– What types of studies provide ‘adequate’
data to base daily treatment on?
• Guidelines driven care (evidence-based)
– In the UK it may be NICE
– In the US it may be NCCN
Types of Research
• Phase I - Initial human testing focusing on
dosing (MTD) and toxicity
• Phase II - human testing focusing on efficacy
(response rates) and toxicity (randomized &
blinded)
• Phase III - Larger, comparative, randomized,
blinded testing looking at efficacy in general
use (many times compared to placebo)
– Disease/Progression-free survival; overall
survival
Basing Oncology Practice on
Research
• Oncology clinical practice changes quickly
• New ‘data’ is available all the time that
changes how to utilize anti-cancer agents and
approaches to disease treatment
• To stay on the ‘cutting edge’ of clinical
practice, one my stay abreast of the latest
clinical research data
• What types of research can be applied to your
practice setting?
Basing Oncology Pharmacy
Practice on Research
• Drug preparation and administration
– Stability
– Compatibility
• Appropriate drug use
– Keeping abreast of new drugs (regimens) and
new indications
– Increasing number of oral anti-cancer agents
• Drug toxicity/management
• Supportive care
• Pharmacoeconomics
• Pharmacogenomics
Examples
• Vascular Endothial Growth Factor (VEGF)
inhibitor-induced hypertension
– Monoclonal AB’s ~ Bevacizumab
» Overall - up to 68% (gr 3/4 ~ 8 - 18%)
– TKI’s ~ sunitinib, sorafenib
» Overall - up to 43% (gr 3/4 ~ 2 - 20 %)
– Can apply JNC VII guidelines
» 1st line ~ thiazide diuretics
» 2nd line ~ ACE-I or ARB’s
– First-line if renal dysfunction/proteinuria
VEGF-Induced Hypertension
(Pharmacy Applying the Research Data)
• Create monitoring guidelines
– BP monitoring Q 2 wk, then wkly if HTN
– Urine protein monitoring (same as BP)
» Monitor for 3 months after tx stops
• Create Guidelines for Treatment
– Grade 1 ~ continue bev, continue monitoring
– Grade 2 ~ stop bev, start drug tx, want
<160/100
– Grade 3 ~ stop until HTN under control,
combination therapy may be necessary
Examples
• Epidermal Growth Factor Receptor (EGFR)
inhibitor/TKI- induced rash
– Monoclonal AB’s ~ 40 - 85% (mild to moderate)
» Cetuximab, panitumumab
– TKI’s ~ 8 - 16% (mild to moderate)
» Erlotinib, Gefitinib, Imatinib
• See class effects: (epidermis affected)
– Acneiform - acne-like rash most common
– Also see dry skin, fissures, nail alterations
• Rash appears to correlate with efficacy
EGFR/TKI- Induced Rash
(Pharmacy Applying the Research Data)
• Pharmacy-Directed Treatment Guidelines
– Grade 1 ~ Topical hydrocortisone 1.0/2.5%
» Clindamycin 1.0/2.0%
» Metronidazole 1%
» Salicylic acid
– Grade 2 ~ Above topical’s +
» Oral minocycline/doxycycline 100mg qd/bid
– Grade 3 ~ Add wet compresses
» Higher dose oral tetracycline
» Steroid dose pack
Examples
Pharmacy-Directed Pharmacogenomic monitoring
• Tamoxifen and CYP2D6 Inhibitors
– Tamoxifen is metabolized into its active for by CYP2D6
– Inhibitors of CYP2D6 can decrease the conversion of
tamoxifen to its active form
– Woman who have a reduced-function CYP2D6
polymorphism and are poor metabolizers have lower levels
of the active form (< 10% population)
• Examples of CYP2D6 inhibitors
– Selective serotonin reuptake inhibitors (SSRI’s)
» Fluoxetine, paroxetine, sertraline (moderate inhibitors)
» Can cause a 50 - 80% decrease in AUC levels of
substrate drug
» Weaker inhibitors ~ Venlafaxine, citalopram,
fluvoxamine
– Other moderate inhibitors: fluconazole, bupropion
Examples
Pharmacy-Directed Pharmacogenomic monitoring
• Current retrospective data suggests a 2 fold increase
in relapse
• Until controlled confirmatory studies can be done, it
would be prudent to carefully monitor the drug
therapy of women taking tamoxifen
• In the future may need to test women on tamoxifen
for the CYP2D6 polymorphism, however some way
we should be testing all women who are to be treated
with tamoxifen now…
– May help identify women who should be on an
alternative hormonal agent
• An approved AmpliChip to test for CYP2D6 is
available now in US
Example
• Biomarker Monitoring:
– KRAS gene monitoring in colorectal cancer
– In mutant KRAS tumors the protein is ‘turned on’
rendering cetuximab/panitumumab inhibition much
less effective
– 40% of pts have the mutant gene ~ will not
respond to expensive therapy
– But for the 60% with the wild-type gene, a higher
response and overall survival is seen
» OS ~ 9.4 mo. vs. 4.8 mo.
– Pharmacy can help create the guidelines for the
biomarker monitoring and drug management
Example
Pharmacy-Directed Pharmacogenomic Monitoring
• UGT1A1 monitoring in Irinotecan-treated patients
– UGT1A1 necessary to convert irinotecan to SN
38 metabolite
– UGT1A1 polymorphism is rare familial or an
autosomal dominant (Gilbert’s syndrome )
alteration ~ +/- 10 - 17%
» More common in hispanic/african-americans
• Genotype predictor of Irinotecan toxicity which is
dose-related (diarrhea)
– <150mg/m2 - RR 1.8; 150 - 250mg/m2 - RR 3.2
>250 mg/m2 - RR 28
Example
Pharmacy-Directed Pharmacogenomic Monitoring
• Pharmacy Guidelines for UGT1A1 monitoring
– <150mg/m2 ~ normal dose/no testing
– 150 - 250mg/m2 ~ If 3-fold increase risk of
toxicity is enough to change regimen ~ then
test
– >250mg/m2 ~ test/give 75% normal dose
Example
• Pharmacoeconomics
– The UK has the National Institute for Health and Clinical
Excellence (NICE) which evaluates the costeffectiveness of cancer agents…
» It issues Final Appraisal Determinations (FAD’s)
» QALY, not to exceed 30,000 pounds, is considered std.
– Determines if a therapy is worth the expense of the
National Health Service (NHS)
– This spring lenalidomide (Revlimid) plus dex was
approved by NICE for use as third-line treatment in
multiple myeloma (deemed cost-effective)
– Also this spring, lapatinib (breast cancer) and
sutent (GI, in addition to previous renal) were
denied
Turning Clinical Practice Into Research
or
Pathways to Publication
• Making research out of everyday practice….
• May be best to start with something that isn’t so
intimidating!
– Letter to the Editor
– Case Reports
• Start with an observation seen as part of you daily
practice
– Unusual toxicity
– Drug-drug interaction
• Do a literature search - see if the observation has been
reported before, if it has, you now have a series to
report!
QUESTIONS ?