Dosing of cytotoxic chemotherapy in adult oncology patients : evidence to inform clinical practice.

The administration of cytotoxic chemotherapy is one of the key strategies for the treatment of early and advanced cancer. In Australia, there are over 300,000 hospitalisations per year for the administration of cytotoxic chemotherapy, equating to approximately a third of all cancer related hospitals admissions. As a consequence of the variability in drug exposure and the narrow therapeutic window of cytotoxic chemotherapy, clinicians have adopted various approaches to individualise chemotherapy dosing in an attempt to maximise clinical outcome and minimise toxicity. In this thesis, a series of studies have been undertaken to examine and inform the dosing of cytotoxic chemotherapy in clinical practice. These studies focused on existing clinical practices where evidence to support the practice was lacking. The use of body surface area (BSA) as a means of individualising doses of cytotoxic chemotherapy is the most common dosing method in clinical practice. One of the historical justifications for the BSA approach is the postulated relationship between renal function and BSA. The first paper evaluated the relationship between BSA and glomerular filtration rate (GFR) measured by radiolabelled technetium-99m diethyl triamine penta-acetic acid (Tc99mDTPA) clearance. In 122 adult oncology patients planned for chemotherapy, the correlation between BSA and GFR was r = 0.24 (95% confidence interval: 0.06 -OAO). These results do not support BSA dosing based on a purported relationship with renal function. While BSA is the predominant means for dose individualisation for cytotoxic chemotherapy, there are other instances when BSA is not utilised. Carboplatin is one such example, which is dosed based on a target area under the plasma concentration-time curve (AUC) with two formulae (Calvert and Chatelut) used in practice. The Chatelut formula had been validated in a very small patient cohort, while the Calvert formula has been utilised for 2 decades in clinical practice. Anecdotal clinical experience observed that Significantly different doses are calculated depending on which formula is used and also the method of estimating renal function, for example, Tc99mDTPA or the Cockcroft and Gault (CG) formula. The second paper evaluated i) a comparison of the doses of carboplatin calculated using the Chatelut formula compared with the Calvert formula and ii) a comparison of doses calculated using the Calvert formula when modified with non-isotopic estimations of GFR. When the Chatelut formula was compared the Calvert formula in 122 oncology patients, it was found to statistically over-estimate doses for males (% diff = +22%, P<0.001) and under-estimate doses for females (% diff = -6%, P<0.05). When non-isotopic estimates of GFR where substituted into the Calvert formula there were statistically significant reductions in the dose calculated (CG formula: -8% mean difference, P<0.05; Jelliffe formula: -14% mean difference, P