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

Outline

How Doses are Established BSA Dose Intensity Dose Scheduling

How Doses are Adjusted Hematologic toxicity Hepatic dysfunction Renal dysfunction Other toxicities

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.

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

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

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

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

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

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

Conservative estimate

Drug elimination varies at least 4-fold between individuals.

Good Correlation with BSA

Gemcitabine Clearance and Vd sensitive to BSA

Docetaxel Variability in Cl correlates to BSA

Poor Correlation with BSA

Etoposide Carboplatin Ifosphamide Paclitaxel Epirubicin Busulfan 5FU Methotrexate (oral)

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.

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.

Assessing for Interactions – Active Metabolites

Cyclophosphamide Doxorubicin Epirubicin Irinotecan Methotrexate Tamoxifen

Role for Therapeutic Drug

Monitoring??

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

The Case of Carboplatin

Cleared 70% by glomerular filtration

Linear correlation: Cl and GFR

AUC correlates with thrombocytopenic nadir

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)

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

The Future...

Genotyping

Phenotyping

Determining How Often to Give a Dose

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

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.

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

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!

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?)

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

Adjusting for Toxicity

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

Pharmacokinetic Determinants of Toxicity

Genetics Diet Other

medications Smoking Alcohol

consumption Age

Renal Function Hepatic function Pleural Effusion Obesity Amputations Performance

Status

Pharmacodynamic Determinants of Toxicity

Prior Therapy Age Performance Status Genetics Other medications Comorbidities

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

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

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

Significant Renal Clearance

carboplatin cisplatin ifosfamide fludarabine

methotrexate etoposide topotecan bleomycin hydroxyurea

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

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

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.