Integrating Research and Clinical Practice

1. Integrating Research and Clinical Practice Jim Koeller, M.S. Professor University of Texas at Austin & the Health Science Center, San Antonio, USA

2. 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

3. 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?

4. 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

5. 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

6. 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?

7. 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

8. 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

9. 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

10. 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

11. 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

12. ExamplesPharmacy-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

13. ExamplesPharmacy-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

14. 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

15. ExamplePharmacy-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

16. ExamplePharmacy-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

17. Example • Pharmacoeconomics • The UK has the National Institute for Health and Clinical Excellence (NICE) which evaluates the cost-effectiveness 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

18. Turning Clinical Practice Into ResearchorPathways 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!

19. QUESTIONS ?