Background and Controversies in Dosing and Adjustment of Chemotherapy Agents

1. 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

2. Outline • How Doses are Established • BSA • Dose Intensity • Dose Scheduling • How Doses are Adjusted • Hematologic toxicity • Hepatic dysfunction • Renal dysfunction • Other toxicities

3. 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.

4. 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

5. 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

6. Body Surface Area (m2) • DuBois & DuBois 1916 BSA = 0.20247 x Ht (m) 0.725 x Wt (kg) 0.425 • Boyd 1935 BSA = 0.0003207 x Ht (cm) 0.3 x Wt (g) 0.7285-(0.0188 x log(g) • Gehan & George 1970 BSA = 0.0235 x Ht (cm) 0.42246 x Wt (kg) 0.51456 • Haycock et al. 1978 BSA = 0.024265 x Ht (cm) 0.3964 x Wt (kg) 0.5378 • Mosteller 1987 BSA = Ht (cm) x Wt (kg) 3600

7. 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

8. 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

9. 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

10. Drug elimination varies at least 4-fold between individuals. Conservative estimate

11. Good Correlation with BSA • Gemcitabine • Clearance and Vd sensitive to BSA • Docetaxel • Variability in Cl correlates to BSA

12. Poor Correlation with BSA • Etoposide • Carboplatin • Ifosphamide • Paclitaxel • Epirubicin • Busulfan • 5FU • Methotrexate (oral)

13. 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

14. 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. Gurney H. Br J Cancer 2002;86:1297-1302.

15. Assessing for Interactions – Active Metabolites • Cyclophosphamide • Doxorubicin • Epirubicin • Irinotecan • Methotrexate • Tamoxifen

16. Role for Therapeutic Drug Monitoring ??

17. 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

18. The Case of Carboplatin • Cleared 70% by glomerular filtration • Linear correlation: Cl and GFR • AUC correlates with thrombocytopenic nadir

19. 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)

20. 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

21. The Future... • Genotyping • Phenotyping

22. Determining How Often to Give a Dose

23. 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

24. 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.

25. 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

26. 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!

27. 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?)

28. 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

29. Adjusting for Toxicity

31. 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

32. Genetics Diet Other medications Smoking Alcohol consumption Age Renal Function Hepatic function Pleural Effusion Obesity Amputations Performance Status Pharmacokinetic Determinants of Toxicity

33. Pharmacodynamic Determinants of Toxicity • Prior Therapy • Age • Performance Status • Genetics • Other medications • Comorbidities

34. 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

37. 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 The Challenge: True Hepatic Function Tests

38. 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

39. carboplatin cisplatin ifosfamide fludarabine methotrexate etoposide topotecan bleomycin hydroxyurea Significant Renal Clearance

40. 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

41. % Excreted Renally 75-100% 50-74% <50% CrCl Breakpoints 60/30/15 mL/min 50/20/10 mL/min <15 mL/min Guidelines to Consider

42. 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.