Document 2424

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
ƒ 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.
ƒ 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
ƒ 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
Case #1
Actual case e-mailed from an oncology fellow
ƒ “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?”
ƒ “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.”
ƒ “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”
ƒ Dose = AUC* (GFR + 25)
ƒ To estimate GFR, used 51Cr-EDTA
ƒ In practice, clinicians estimate creatinine clearance
(CrCl) and substitute for GFR
– Creatinine is filtered by glomeruli and secreted by
– 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
ƒ Cockcroft-Gault CrCl = 20 mL/min
ƒ MDRD GFR = 20 mL/min/1.73m2
Carboplatin Formula
ƒ Calvert
– Dose = AUC (GFR + 25)
ƒ For current patient:
– Dose = 5 (20 +25)
– 225 mg
ƒ Most sources recommend 25% dose reduction
with CrCl 10-50 mL/min
ƒ 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
ƒ 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?
ƒ What carboplatin dose?
ƒ 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
ƒ Actual creatinine
– CrCl = 86 mL/min
ƒ Adjusted creatinine to 0.8 mg/dL
– CrCl = 54 mL/min
Limiting Minimal Scr
ƒ 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
– 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
ƒ 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
ƒ 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”?
(~ 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
ƒ Curative intent
– Consider using minimal Scr = 0.7-0.8 mg/dL to avoid
– Decrease dose if excessive AEs are seen
ƒ Noncurative intent
– Consider a more conservative lower limit (eg, 1
– Titrate subsequent doses upward if tolerated
Pregnancy and Chemotherapy
Which Weight to Use?
ƒ 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
ƒ Average weight gain during pregnancy 12.5 kg
ƒ 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
ƒ Renal
– Size slightly increases
– GFR increases 50%
ƒ 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
ƒ 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
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
ƒ Second and third trimesters are safest
– Avoid chemo in first trimester
– Avoid after week 35
ƒ Fetal malformations = 1.3%
– Similar with or without chemo
NCCN Breast Cancer Guidelines ver 1.2007
Arguments Against WeightBased Chemotherapy Dosing
ƒ Multiple PK studies show no correlation between
clearance and weight
ƒ Fixed doses would be safer because of fewer
calculations and chance for dosing errors
ƒ Fixed dosage forms would be more economical
Arguments in Support of WeightBased Chemotherapy Dosing
ƒ 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?
ƒ 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
ƒ Source of original BSA-based dosing was from
scale up from preclinical (animal) studies
ƒ 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?
ƒ 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
ƒ 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
ƒ Clearance varies at least 4-fold
ƒ Relatively small sample sizes, especially for the
phase 1 studies with PK analysis
ƒ Multiple covariates, some known
ƒ Limited numbers of outliers in PK studies (phase
1) that can better characterize the effect of these
Docetaxel vs BSA
(Rudek, et al 2004)
We Need A Reality Check…
ƒ Potentially 10-fold variability
– Renal filtration
– Protein binding
ƒ Potentially 1000-fold variation
– Drug metabolism
– Receptor expression
– Transporter pumps
ƒ Weight or BSA: 2x variability
Which Agent Is the Cause?
Tyrosine Kinase Inhibitor (TKI)
Induced ADRs
Skin ulcerations
Hand/foot syndrome
Skin discolorations
Electrolyte abnormalities
Heart failure
Case #2
ƒ 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
Grade 1
Grade 2
Grade 3
Grade 4
transient  >20
mm Hg (diastolic)
>150/100 if
previously WNL;
no intervention
Recurrent or
persistent (≥24 hrs)
or symptomatic
Requiring more
than 1 drug or
more intensive
therapy than
 >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
Any Grade
Grade 3-4
Sorafenib (Nexavar,
BAY 43-9006)
Sunitinib (Sutent,
6% (Grade 3)
Package insert information
What Is the Cause?
ƒ Prospective evaluation of 20 patients receiving
sorafenib 400 mg PO bid
ƒ Monitored BP q3 weeks x 18 weeks
ƒ Measurements: VEGF, total catecholamines,
epinephrine, norepinephrine, endothelin I,
urotensin II, renin, and aldosterone
ƒ 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
Mean ± SEM values of SBP, DBP, and HR
mm Hg
Week 3 mm Hg
Week 18
mm Hg
130.6 ± 4.3
151.2 ± 4.8*
144.4 ± 3.7*
74.4 ± 2.1
82.3 ± 2.3*
80.9 ± 2.9*
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
Week 3
P value
108 ± 25
279 ± 128
CAIx, %
23 ± 4
29 ± 3*
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
ƒ 1 patient required an antihypertensive med –
ƒ 1 patient required dosage increase of current
antihypertensive (drug not stated)
How Should TKI HTN Be Treated
or Prevented?
ƒ 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
– Suggestion that green tea (EGCG) may decrease the vascular
thickening and fibrosis (realistic conc?)
ƒ ACE inhibitors should be avoided in Renal Cell Cancer
patients who only have one kidney
Nakano S. Hypertens Res. 2005;28:925; 2Francois H, et al. FASEB J. 2004;18:926-8.
Conclusions for TKI HTN
ƒ Significant increase in indices of vascular stiffness;
however, unknown if present due to established BP
ƒ Hypertensive effects directly at the level of the vasculature
– Vascular rarefaction and/or
– Endothelial dysfunction and/or
– Altered nitrous oxide metabolism
ƒ Optimal prevention or treatment not yet identified
Child-Pugh for Hepatic Damage
ƒ Leaky cells
– AST (aspartate aminotransferase)
– ALT (alanine aminotransferase)
– GGT (gamma-glutamyl transpeptidase)
ƒ 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
1 point
2 points
3 points
1 or 2
3 or 4
Bilirubin (mg/dL)
Albumin (G/dL)
Prothrombin time
Total Points:
For hepatically metabolized drugs
5-6: mild dysfunction
7-9: moderate dysfunction
~ 25% dose decrease
>9: severe dysfunction
~ 50% dose decrease (approx)
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)
ƒ 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
ƒ Total points
<10: Mild disease
10-20: Moderate disease
>20: Severe disease
Hepatic Clearance Factors
ƒ Age
– Effect of age on drug metabolism is usually modest
when corrected for body mass
– Predictable loss of renal function
ƒ 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
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
Which of the following drugs is contraindicated in patients with elevation
of bilirubin (2.5-5 x UNL)?
Chemotherapy administration in which pregnancy trimester carries the
highest risk of fetal/child malformations?
No difference within trimesters
Self-Assessment Questions
The Calvert formula is used for carboplatin dose calculation. Which
variable do you not need in this calculation?
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
ACPE Credit for HOPA 2007
1. Go to
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