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