HOPA 2007 Friday, June 15 HOPA 3rd Annual Conference Colorado Convention Center Denver, Colorado June 14-16, 2007 What to Do With the Complicated Oncology Patient? Jon D. Herrington, PharmD, BCPS, BCOP Department of Pharmacy Scott & White Memorial Hospital Assistant Professor of Medicine Texas A&M University Temple, Texas Paul R. Hutson, PharmD Associate Professor of Pharmacy University of Wisconsin School of Pharmacy Paul P. Carbone Cancer Center Madison, Wisconsin Disclosure Jon D. Herrington, PharmD, BCPS, BCOP, has received fees for non-CE services from Amgen. His spouse is employed by Pfizer and has received salary and stock/stock options. Paul R. Hutson, PharmD, MS, has received consulting fees from Baxter Health Care and Projections Research. He also has stock ownership in Amgen, Genentech, and Proctor & Gamble. Learning Objectives Explain the values and rationale for setting minimum serum concentrations in estimating creatinine clearance values Discuss the merits and drawbacks of modifying chemotherapy dosing weight in obese patients Identify drugs for which dose modification in patients with impaired renal or hepatic disease is well established Estimate and titrate chemotherapy doses in patients with impaired renal or hepatic disease receiving drugs for which dosing in impaired organ function is NOT well established Develop dose modification plans for chemotherapy administered to pregnant women Develop a therapy plan for patients with preexisting or incident hypertension who receive treatment cycles with tyrosine kinase inhibitors Case #1 Actual case e-mailed from an oncology fellow “Jon, I have a lady coming in for chemo on Wed (4/11), small cell lung cancer. Her name is XXXXX, if you care to peruse her chart in your free time. She is 77 and has extensive stage (which I just discovered 2 minutes ago after looking at her MRI and seeing she has 25 brain mets). We really thought she was limited. ANYWAY, she has CAD and CKD stage 3 secondary to an atrophic kidney, and still smokes, and has COPD and rheumatoid arthritis on prednisone and silly us, we are going to give her chemo! So.. my question is, would you start with a lower dose of both carbo (AUC 5?) and would you also lower the dose of etoposide?” “Her last set of labs were as follows: K: 5.9, BUN 45, Creat 2.4, uric acid 8.0, LDH 265, BUT her liver enzymes are normal! I started her on allopurinol 100 mg on 4/4.” “She is being directly admitted 4/11. What do you think? Thanks! I am on vacation but will be back Wed & checking e-mail. MS” Calvert Dose = AUC* (GFR + 25) To estimate GFR, used 51Cr-EDTA In practice, clinicians estimate creatinine clearance (CrCl) and substitute for GFR – Creatinine is filtered by glomeruli and secreted by tubules – CrCl theoretically overestimates GFR Calvert AH, et al. J Clin Oncol. 1989;7:1748-56. Patient Demographics Caucasian woman Age 77 Height 157 cm = 62 in Weight 58 kg = 128 lbs Creatinine = 2.1 mg/dL BUN = 66 mg/dL Albumin = 3.1 g/dL Cockcroft-Gault CrCl = 20 mL/min MDRD GFR = 20 mL/min/1.73m2 Carboplatin Formula Calvert – Dose = AUC (GFR + 25) For current patient: – Dose = 5 (20 +25) – 225 mg Etoposide Most sources recommend 25% dose reduction with CrCl 10-50 mL/min Remember: elderly vs frailty – – – – Patients 65-74: mean # comorbidities = 6 Decreased liver and renal function Diminished bone marrow reserve Impaired physical condition and nutritional intake Would recommend 50% reduction – If well tolerated, increase with next cycle Janssen-Heijnen ML, et al. Lung Cancer. 1998;21:105-13. What If This Patient Had “Normal” Renal Function? What carboplatin dose? Patient demographics – 77 yo woman who has lost 8% of body weight over the last 6 months – Height 157 cm = 62 in – Weight 58 kg = 128 lbs – Creatinine = 0.5 mg/dL – Albumin = 3.1 g/dL Cockcroft and Gault (140 - age) * kg * (0.85 for women) serum creatinine * 72 Weight and creatinine – Smaller Cr = higher CrCl – Larger weight = higher CrCl Actual creatinine – CrCl = 86 mL/min Adjusted creatinine to 0.8 mg/dL – CrCl = 54 mL/min Limiting Minimal Scr Many clinicians believe it necessary to set a minimum Scr of 1 mg/dL when estimating GFR with Cockcroft-Gault in elderly with low Scr (<1 mg/dL) – Concern is with elderly subjects with a low muscle mass for age (low creatinine output) – No limit needed for MDRD or (U*V)/Scr – Setting Scr at 1 mg/dL will underestimate GFR and avoid excessive doses Minimal Scr in the Elderly Resolution of the issue – Use urine collection or MDRD – Drugs most commonly affected are the aminoglycosides; get levels after first dose – Do a study and see if a minimal Scr is required … Use of Minimal Scr in Adults N = 957 adults treated with gentamicin – Age range 16-97 – Two-point gentamicin levels drawn • Vd and K determined • “True” clearance determined – Various “adjustments” evaluated • Use of minimum of LBW or TBW vs ABW • Use of minimal Scr of 0.06mM (0.68 mg/dL) Kirkpatrick CMJ, et al. Br J Clin Pharmacol. 1999;47:637-43. At What Point is a Serum Creatinine “Too Low”? r² (~ 0.7 mg/dL) Kirkpatrick CMJ, et al. Br J Clin Pharmacol. 1999;47:637-43. These data suggest that a minimum Scr of 0.7 mg/dL should be used with the Cockcroft-Gault equation in adults Limits to Serum Creatinine Curative intent – Consider using minimal Scr = 0.7-0.8 mg/dL to avoid underdosing – Decrease dose if excessive AEs are seen Noncurative intent – Consider a more conservative lower limit (eg, 1 mg/dL) – Titrate subsequent doses upward if tolerated Pregnancy and Chemotherapy Which Weight to Use? Example – – – – – Weight 132 lbs = 60 kg Height 64 in = 163 cm BSA = 1.64 m2 Weight gain of 12.5 kg = 72.5 kg BSA = 1.78 m2 What Physiologic Changes Occur? Average weight gain during pregnancy 12.5 kg Weight gain (besides baby) – Maternal stores 3.3 kg – Extravascular fluid 1.5 kg – Blood 1.5 kg – Uterus 0.8 kg – Other 1.8 kg Renal – Size slightly increases – GFR increases 50% Liver – No liver morphology changes detected – LFTs can be different, however significance unknown Cummingham FG, et al. Williams Obstetrics. 22nd ed. McGraw-Hill, Inc. 2005. Breast Cancer and Pregnancy Largest prospective series in 54 pregnant breast cancer patients receiving FAC Body weight measured before each cycle; actual BSA used Median gestational age at chemotherapy start = 23 wks (range 11-34 wks) Median gestational age at delivery = 37 wks (range of 29-42 wks) Median birth weight was 2890 g (range of 1389-3977 g) Serious neonatal outcomes different than general population – 1/40 developed subarachnoid hemorrhage – 1/40 Down’s syndrome – 1/40 club foot Postneonatal outcomes – 38/39 considered “normal development” Hahn KM, et al. Cancer. 2006;107:1219-26; Personal communication, Johnson PH 4/2007. Pregnancy and Chemotherapy Second and third trimesters are safest – Avoid chemo in first trimester – Avoid after week 35 Fetal malformations = 1.3% – Similar with or without chemo NCCN Breast Cancer Guidelines ver 1.2007 Arguments Against WeightBased Chemotherapy Dosing Multiple PK studies show no correlation between clearance and weight Fixed doses would be safer because of fewer calculations and chance for dosing errors Fixed dosage forms would be more economical Arguments in Support of WeightBased Chemotherapy Dosing Accommodates differences in body size – Should we assume that we can give the same dose we would to an adult to a 2 year old? Decreases the intrapatient variability of exposure to chemotherapy (Cmax, AUC) – There is poor correlation of dose with AUC and with effect (response or toxicity) – Dose/WGT is only one of multiple factors that must be identified that affects response Allometric Scaling Source of original BSA-based dosing was from scale up from preclinical (animal) studies Theoretical justification of allometric scaling is based upon fractal branching – Provides normalization of blood flow and BMR over many orders of magnitude in body size West GB, et al. Science. 1997;276:122-26. Poor Correlations with BSA? Poor correlations of BSA (or WGT0.75) with CL (and AUC) suggest confounding covariates – Detoxifying enzyme induction or inhibition – Efflux pump induction or inhibition – Renal dysfunction Poor correlations of BSA (or WGT0.75) with CL do not refute what we intuitively and practically know Why Don’t We Find A Stronger Relationship Between Size and Clearance? Clearance varies at least 4-fold Relatively small sample sizes, especially for the phase 1 studies with PK analysis Multiple covariates, some known Limited numbers of outliers in PK studies (phase 1) that can better characterize the effect of these covariates Docetaxel vs BSA (Rudek, et al 2004) We Need A Reality Check… Potentially 10-fold variability – Renal filtration – Protein binding Potentially 1000-fold variation – Drug metabolism – Receptor expression – Transporter pumps Weight or BSA: 2x variability Which Agent Is the Cause? Tyrosine Kinase Inhibitor (TKI) Induced ADRs Skin ulcerations Hand/foot syndrome Skin discolorations Diarrhea Electrolyte abnormalities Heart failure Hypertension Case #2 A 48-yo man presents with newly diagnosed metastatic renal cell carcinoma, clear cell type Performance status of 1 with no concurrent comorbidities besides nephrectomy Patient was initiated on sunitinib 50 mg PO daily x 4 wks, then off x 2 wks Patient is seen on week 4 of starting therapy Patient has complained of Grade 1 diarrhea with no other significant side effects Stable vital signs except for an increase in blood pressure – Baseline – 135/85 – Week 4 – 155/100 Should the blood pressure increase be medically managed at this time? TKI-Induced Hypertension Hypertension Grade 1 Grade 2 Grade 3 Grade 4 Asymptomatic, transient ⁭ >20 mm Hg (diastolic) or >150/100 if previously WNL; no intervention Recurrent or persistent (≥24 hrs) or symptomatic Requiring more than 1 drug or more intensive therapy than previously Lifethreatening (hypertensive crisis) ⁭ >20 mm Hg (diastolic) or >150/100 if previously WNL; monotherapy may be indicated Common Terminology Criteria for Adverse Events v3.0 (CTCAE) How Common Is Hypertension? TKI Any Grade Grade 3-4 Sorafenib (Nexavar, BAY 43-9006) 17% 3% Sunitinib (Sutent, SU11248) 28% 6% (Grade 3) Package insert information What Is the Cause? Prospective evaluation of 20 patients receiving sorafenib 400 mg PO bid Monitored BP q3 weeks x 18 weeks Measurements: VEGF, total catecholamines, epinephrine, norepinephrine, endothelin I, urotensin II, renin, and aldosterone Analyzed indices of vascular stiffness, including central aortic augmentation index (CAIx) and aortic pulse wave velocity (APWV) Veronese ML, et al. J Clin Oncol. 2006;24:1363-9. Alterations in Blood Pressure and Pulse Mean ± SEM values of SBP, DBP, and HR Measure Baseline mm Hg Week 3 mm Hg Week 18 mm Hg SBP 130.6 ± 4.3 151.2 ± 4.8* 144.4 ± 3.7* DBP 74.4 ± 2.1 82.3 ± 2.3* 80.9 ± 2.9* HR 81.1 ± 3.7 80.8 ± 4.1 81.2 ± 3.9 * P < .001 Veronese ML, et al. J Clin Oncol. 2006;24:1363-9. Significant Findings Mean ± SEM values Measure Baseline Week 3 P value 108 ± 25 279 ± 128 .045 CAIx, % 23 ± 4 29 ± 3* <.05 APWV, m/sec 8.9 ± 0.5 9.7 ± 0.7* < .03 VEGF pg/mL (normal 31-86) *Drawn after mean of 34 days; central aortic augmentation index (CAIx), aortic pulse wave velocity (APWV). Veronese ML, et al. J Clin Oncol. 2006;24:1363-9. Other Findings 1 patient required an antihypertensive med – hydrochlorothiazide 1 patient required dosage increase of current antihypertensive (drug not stated) How Should TKI HTN Be Treated or Prevented? Evidence in spontaneously and iatrogenic hypertensive rats suggests a mixed effect of TK inhibition – Spironolactone may attenuate vascular hyperplasia and fibrosis associated with EGFR/ERK activity1 – Other models suggest that TKIs may attenuate vascular fibrosis2 – Suggestion that green tea (EGCG) may decrease the vascular thickening and fibrosis (realistic conc?) ACE inhibitors should be avoided in Renal Cell Cancer patients who only have one kidney 1 Nakano S. Hypertens Res. 2005;28:925; 2Francois H, et al. FASEB J. 2004;18:926-8. Conclusions for TKI HTN Significant increase in indices of vascular stiffness; however, unknown if present due to established BP increase Hypertensive effects directly at the level of the vasculature – Vascular rarefaction and/or – Endothelial dysfunction and/or – Altered nitrous oxide metabolism Optimal prevention or treatment not yet identified Child-Pugh for Hepatic Damage Leaky cells – AST (aspartate aminotransferase) – ALT (alanine aminotransferase) – GGT (gamma-glutamyl transpeptidase) Cirrhosis – Ascites • Increased portal vein pressure from scarring • Decreased oncotic pressure from decreased albumin – Encephalopathy • CNS mental status changes arising from the accumulation of toxins not cleared by the liver Child-Pugh Classification Marker 1 point 2 points 3 points None 1 or 2 3 or 4 Absent Slight Moderate Bilirubin (mg/dL) 1-2 2-3 >3 Albumin (G/dL) >3.5 2.8-3.5 <2.8 Prothrombin time (seconds>control) 1-4 4-10 >10 Encephalopathy Ascites Total Points: For hepatically metabolized drugs 5-6: mild dysfunction 7-9: moderate dysfunction ~ 25% dose decrease >9: severe dysfunction ~ 50% dose decrease (approx) MELD Model for End-Stage Liver Disease MELD score = 3.8 Ln (bili [mg/dL]) + 11.2 Ln (INR) + 9.6 Ln (Scr [mg/dL]) + 6.4 (if cholestatic or alcoholic) Pt with alcoholic cirrhosis, bili 2.3, INR 1.8, Scr 1.9 MELD = (3.8*0.833) + (11.2*0.588) + (9.6*0.642) + 6.4 = 22.3 Total points <10: Mild disease 10-20: Moderate disease >20: Severe disease Hepatic Clearance Factors Age – Effect of age on drug metabolism is usually modest when corrected for body mass – Predictable loss of renal function Diet – More complex diets maintain P450 activity • Drug metabolism decreases in elemental diets – Charred meats and cruciferous vegetables will induce CYP1A2 What To Do With the Complicated Oncology Patient? Guidelines Determine goal of therapy Minimize unnecessary risk to the patient Utilize current literature Monitor patient response, and titrate accordingly Self-Assessment Questions 1. Which of the following serum creatinines should be used as the lower limit when using the Cockcroft-Gault equation to estimate the creatinine clearance in adults? A. 0.5 mg/dL B. 0.7 mg/dL C. 1 mg/dL D. No constraint 2. Which preexisting condition would be a relative contraindication for the use of an angiotensin converting enzyme inhibitor for treating hypertension in a patient treated with sorafenib for renal cell carcinoma? A. Existing use of hydrochlorothiazide B. Unilateral nephrectomy C. Angina D. None of the above are relative contraindications for ACE-I use Self-Assessment Questions 3. Which of the following drugs is contraindicated in patients with elevation of bilirubin (2.5-5 x UNL)? A. B. C. D. 4. Paclitaxel Doxorubicin Docetaxel Sunitinib Chemotherapy administration in which pregnancy trimester carries the highest risk of fetal/child malformations? A. B. C. D. First Second Third No difference within trimesters Self-Assessment Questions 5. The Calvert formula is used for carboplatin dose calculation. Which variable do you not need in this calculation? A. B. C. D. 6. Glomerular filtration rate Target AUC BSA (m2) All of the above are needed The use of body surface area (BSA) for the calculation of chemotherapy doses is an accurate means of producing predictable concentrations in your patient A. B. True False ACPE Credit for HOPA 2007 is ONLINE ONLY 1. Go to www.hoparx.org/MyHOPACredit.aspx 2. Set up your HOPA Credit Profile 3. The HOPA 2007 code is on the back of your Pocket Agenda 4. Click on the Claim Credit button and enter the code 5. Select the 2007 sessions you want to claim (at the end of each day and/or the end of the meeting) 6. Complete a conference evaluation before you generate a Certificate of CE Credit (at the end of the meeting) 7. The certificate will be e-mailed to you automatically 8. You have 4 weeks to claim credit for HOPA 2007 (until July 16, 2007, midnight Pacific time) HOPA 2007 Friday, June 15 2:45 – Refreshment Break Meeting Rooms Foyer 3:00 – Workshops 1-4 (Repeated) Meeting Rooms 102-113 4:00 – Networking Time 6:00 – Poster Session & Reception Four Seasons Ballroom 4 & Foyer