化疗与体表面积

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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
children - use Wt

Disadvantages of BSA


Risk of arithmetic error (small)
Increases time Increases drug wastage False sense of accuracy

(precise but NOT accurate)
Assessing for Interactions – Active Metabolites



Cyclophosphamide Doxorubicin Epirubicin Irinotecan Methotrexate Tamoxifen
Role for Therapeutic Drug Monitoring ??


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
51
CrEDTA 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
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
Know how drug is eliminated.
Check for drug interactions. Consider factors affecting tissue sensitivity.


Know that 40% of time BSA calc dose is incorrect.

known differences in metabolism or elimination
3. Adjust next dose according to presence or absence of toxicity.
Gurney H. Br J Cancer 2002;86:1297-1302.

AUC correlates with thrombocytopenic nadir
Calvert et al

J Clin Oncol 1989;7:1748-56
Derived formula based on renal function Constant used to represent nonrenal Cl
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

Gemcitabine Clearance and Vd sensitive to BSA
Docetaxel Variability in Cl correlates to BSA

Poor Correlation with BSA

Etoposide
Carboplatin Ifosphamide Paclitaxel Epirubicin
Background and Controversies in Dosing and Adjustment of Chemotherapy Agents
Dana Cole, BScPharm, PharmD Oncology Drug Information Specialist BC Cancer Agency Partners in Cancer Care Conference November 30, 2002
Potential Problems with TDM

Drugs often in combination
Cost of assays Inconvenience, personnel Skills required for interpretation Errors in sampling, etc
Outline

How Doses are Established


BSA Dose Intensity Dose Scheduling

How Doses are Adjusted


Hematologic toxicity Hepatic dysfunction Renal dysfunction Other toxicities

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

பைடு நூலகம்
Busulfan
5FU
Methotrexate (oral)
Suggested Guidelines for Dose Calculation

Do not use BSA solely. Consider other parameters. Avoid extremes in BSA. Round liberally.

2 (m )
DuBois & DuBois 1916
0.725
BSA = 0.20247 x Ht (m)

x Wt (kg)
0.425
Boyd 1935
0.3
BSA = 0.0003207 x Ht (cm)

x Wt (g)
0.7285-(0.0188 x log(g)
Gehan & George 1970
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

Biliary excretion affected by multidrug resistance efflux pumps
Conservative estimate
Drug elimination varies at least 4-fold between individuals.
Good Correlation with BSA
recommended BSA be used in future for dosing


No pharmacokinetic or efficacy studies
Retrospective look at handful of cases
Body Surface Area - History


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

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
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, creatinine Before each treatment: CBC & diff If clinically indicated: bilirubin, creatinine TREATMENT: Drug Dose BCCA Administration Guideline cyclophosphamide 600 mg/m2 IV in 100-250 mL NS or D5W over 20-60 min methotrexate 40 mg/m2 IV push fluorouracil (5-FU) 600 mg/m2 IV push Repeat every 21 days x 6-8 cycles.

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
0.42246
BSA = 0.0235 x Ht (cm)

x Wt (kg)
0.51456
Haycock et al. 1978
0.3964
BSA = 0.024265 x Ht (cm)

x Wt (kg)
0.5378
Mosteller 1987
BSA =
Ht (cm) x Wt (kg) 3600

Recovery by day 21-28.

Usual schedule is q21-28 days.
Dose Intensity

Dose Intensity: Amount of drug delivered per unit of time

add in interactions…

Dihydropyrimidine Dehydrogenase (DPD) activity varies 8-fold

trial of 5FU treated patients - 80% had ineffective plasma concentrations
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