background and controversies in dosing and adjustment of chemotherapy agents dana cole, bscpharm,...
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Background and Controversies in Dosing and Adjustment of Chemotherapy Agents
Dana Cole, BScPharm, PharmDOncology Drug Information
SpecialistBC Cancer Agency
Partners in Cancer Care Conference
November 30, 2002
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Outline
How Doses are Established BSA Dose Intensity Dose Scheduling
How Doses are Adjusted Hematologic toxicity Hepatic dysfunction Renal dysfunction Other toxicities
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BCCA Protocol Summary for Palliative Therapy for Advanced Breast Cancer using Cyclophosphamide, Methotrexate and Fluorouracil
BRAVCMF
ELIGIBILITY:Palliative treatment for advanced breast cancer.
TESTS: Baseline: CBC & diff, bilirubin, creatinineBefore each treatment: CBC & diffIf clinically indicated: bilirubin, creatinine
TREATMENT:
Drug Dose BCCA Administration Guidelinecyclophosphamide 600 mg/m2 IV in 100-250 mL NS or D5W over 20-60 minmethotrexate 40 mg/m2 IV pushfluorouracil (5-FU) 600 mg/m2 IV push
Repeat every 21 days x 6-8 cycles.
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Body Surface Area - History
Pinkel in 1958 examined literature
found conventional doses in animals and humans for 5 cytotoxic drugs
correlation between animal/human dose and BSA
recommended BSA be used in future for dosing
No pharmacokinetic or efficacy studies
Retrospective look at handful of cases
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Body Surface Area - History
In 1966, established as means of estimating dose to be used in Phase I trials from animal data
Phase II and III trials adopted this convention
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Body Surface Area (m2)
DuBois & DuBois 1916BSA = 0.20247 x Ht (m) 0.725 x Wt (kg) 0.425 Boyd 1935BSA = 0.0003207 x Ht (cm) 0.3 x Wt (g) 0.7285-(0.0188 x log(g)
Gehan & George 1970BSA = 0.0235 x Ht (cm) 0.42246 x Wt (kg) 0.51456
Haycock et al. 1978BSA = 0.024265 x Ht (cm) 0.3964 x Wt (kg) 0.5378
Mosteller 1987
BSA = Ht (cm) x Wt (kg) 3600
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Advantages of Mosteller Formula
Easy to remember
No error if Wt and Ht are accidentally interchanged
Validated against other formulas, <5% difference if >10kg body weight
children - use Wt
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Disadvantages of BSA
Risk of arithmetic error (small)
Increases time
Increases drug wastage
False sense of accuracy (precise but NOT accurate)
Suggested that level of inaccuracy may equal magnitude of benefit of adjuvant chemo in a breast cancer patient
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Interpatient Variability
Activity of CYP 3A4 varies 50-fold add in interactions…
Dihydropyrimidine Dehydrogenase (DPD) activity varies 8-fold trial of 5FU treated patients - 80% had
ineffective plasma concentrations
Biliary excretion affected by multidrug resistance efflux pumps
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Conservative estimate
Drug elimination varies at least 4-fold between individuals.
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Good Correlation with BSA
Gemcitabine Clearance and Vd sensitive to BSA
Docetaxel Variability in Cl correlates to BSA
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Poor Correlation with BSA
Etoposide Carboplatin Ifosphamide Paclitaxel Epirubicin Busulfan 5FU Methotrexate (oral)
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Gurney H. Br J Cancer 2002;86:1297-1302
Suggested Guidelines for Dose Calculation
Do not use BSA solely. Consider other parameters. Avoid extremes in BSA. Round liberally. Know how drug is eliminated. Check for drug interactions. Consider factors affecting tissue sensitivity. Know that 40% of time BSA calc dose is incorrect. Measure a biological endpoint. Always have doses checked.
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Gurney H. Br J Cancer 2002;86:1297-1302.
An Alternative Dosing Scheme
1. Determine standard dose 2. Modify pretreatment
known differences in metabolism or elimination
3. Adjust next dose according to presence or absence of toxicity.
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Assessing for Interactions – Active Metabolites
Cyclophosphamide Doxorubicin Epirubicin Irinotecan Methotrexate Tamoxifen
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Role for Therapeutic Drug
Monitoring??
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Potential Problems with TDM
Drugs often in combination Cost of assays Inconvenience, personnel Skills required for interpretation Errors in sampling, etc Sample every cycle or just first? Blood samples may not reflect action in
tissues
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The Case of Carboplatin
Cleared 70% by glomerular filtration
Linear correlation: Cl and GFR
AUC correlates with thrombocytopenic nadir
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Calvert et alJ Clin Oncol 1989;7:1748-56
Derived formula based on renal function Constant used to represent nonrenal Cl Used 51CrEDTA clearance Better correlation to AUC than with BSA
dosing
Dose (mg) = target AUC x (GFR + 25)
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Challenges in Applying Calvert Formula in Practice
51CrEDTA assessments not usually done
Cockcroft-Gault and Jeliffe equations underestimate GFR, resulting in potential underdosing
In patients without “normal” renal function, nonrenal Cl may be higher
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The Future...
Genotyping
Phenotyping
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Determining How Often to Give a Dose
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Hematological Considerations for Dose Scheduling
Lifespan Platelet - 7-10 days Red blood cell - 120 days Neutrophils - 6-12 hours
Time from Stem Cell to Mature Neutrophil ~7-10 days
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Deciding on Treatment Intervals
As short as possible Recovery of bone marrow
Supplies mature cells for 8-10 days Onset 9-10th days Lowest (nadir) 14-18th days Recovery by day 21-28.
Usual schedule is q21-28 days.
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Dose Intensity
Dose Intensity: Amount of drug delivered per unit of time
Relative Dose Intensity: Amount relative to an arbitrarily chosen standard
Positive relationship between dose intensity and tumour response
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CMF for Adjuvant Breast Cancer
Bonadonna et al N Engl J Med 1995;332:901-6
386 women with node + breast cancer
CMF vs placebo (20 yr F/U)
Overall Survival ≥ 85% dose - 55% alive at 20 years 65-84% dose – only 35% alive at 20 years
<65% of dose was same as giving placebo!
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Dose Intensity of CMF
Wood et al. N Engl J Med 1994;330:1253-9.
1572 women with node + breast cancer 3 dose regimens of CMF
Standard (6 cycles) 50% higher dose for 4 cycles (equal total dose) 50% less total dose over 6 cycles
Significantly longer DFS in standard or high dose No survival advantage of higher dose (plateau
effect?)
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Dose Adjustment Based on Prognostics?
Muss HB, et al. N Engl J Med 1994;330:1260-6.
Analyzed 442 women from the Wood trial for HER2-neu status
Longer DFS and Overall Survival in high dose group if HER2 positive.
Illustrates added importance of dose intensity if higher risk
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Adjusting for Toxicity
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Organ Systems & Effect of Chemotherapy
Rapidly Dividing
Gut Mucosa
Bone Marrow
Ovaries
Testes
Hair Follicles
Slowly Dividing
Lung
Liver
Kidney
Endocrine Glands
Vascular Endothelium
Very Slow/ No Division
Muscle
Bone
Cartilage
Nerve
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Pharmacokinetic Determinants of Toxicity
Genetics Diet Other
medications Smoking Alcohol
consumption Age
Renal Function Hepatic function Pleural Effusion Obesity Amputations Performance
Status
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Pharmacodynamic Determinants of Toxicity
Prior Therapy Age Performance Status Genetics Other medications Comorbidities
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Adjustments for Toxicity
Due to pharmacokinetics? Adjustment reasonable as similar drug levels
achieved
Due to pharmacodynamics? Adjustment may only lessen response
Often significant dose reduction will have small effect on toxicity and great effect on efficacy
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The Challenge: True Hepatic Function Tests
Metabolic Capacity
Microsomal function
Functional hepatic perfusion
Galactose elimination capacity
Max removal of indocyanine green
Aminopyrine demethylation Caffeine Cl Antipyrine Cl Erythromycin breath test
Galactose Cl Sorbitol Cl Indocyanine green Cl Sulfobromophthalein Cl
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What We Currently Measure
Bilirubin marker of impaired excretion, not metabolism
AST/ALT hepatocellular damage only, mets
Alk Phos bone disease, mets
INR/Albumin measures of synthetic ability may be better estimate of metabolic function need to have significant decrease before
affected
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Significant Renal Clearance
carboplatin cisplatin ifosfamide fludarabine
methotrexate etoposide topotecan bleomycin hydroxyurea
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Challenges in Renal Dosage Adjustments
Serum creatinine vs Creatinine Clearance SCr 135 - 185 = 30-65 mL/min
protocol states 66% literature 50 or 75%
SCr >185 = <30-50 mL/min protocol states alternative drug literature alternative drug or 50%
Significant Variability amongst protocols
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Guidelines to Consider
% Excreted Renally
75-100%
50-74%
<50%
CrCl Breakpoints
60/30/15 mL/min
50/20/10 mL/min
<15 mL/min
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Take Home Points
Consider other factors in addition to BSA
Dose Intensity is importance to long term efficacy
Significant variability in adjustments for renal dysfunction.
Consider INR/albumin in addition to bilirubin to evaluate hepatic dysfunction.