How much chemotherapy agent should be administered to a patient?
How big should the dose be?
Cancer patients are at high risk for developing drug toxicity due to the low therapeutic index of the chemo agents (Miller, 2002). Determining the dose of a chemo drug for any patient is particularly challenging.
As with any drug, bigger people should get bigger doses, all other things being equal. That is where dosing calculations start from, and for decades the “body surface area” of the patient has been an important factor in calculating doses. Everybody knew BSA had limitations, but it was fairly straightforward and based on the intuition that BSA is mathematically correlated to blood volume and therefore somewhat related to clearance rate. Clinical relevance of this dosing method was questioned about a decade ago; it neglects other patient-related factors that might affect drug pharmacokinetics and pharmacodynamics such as liver function, and glomerular filtration rate. (The early BSA advocates assumed that kidney removal rate was roughly proportional to surface area, and that turned out not to be true.) Therefore, flat-fixed dosing, BMI, dose banding methods have been proposed among other methods as alternatives to BSA to decrease the inter-patient variability in response to treatment.
better understanding of drug pharmacokinetics (PK) and pharmacodynamics (PD). Individual variations in response to drug and in developing toxicity was noted, even between two patients with the same BSA and hence same dose of anti-cancer agent. Doctors and scientists looked for a better way – alternatives that accounted for factors affecting drug exposure and clearance such as liver and kidney function (Beumer, Chu, & Salamone, 2012).
Body Surface Area method and its limitations
Measures related to body size such as body surface area, height and weight are used to calculate the required doses, as they theoretically are a way of tailored dosing according to body size and ability to clear the drug.
If doctors knew the pharmacokinetic details for each drug and patient combination, it would be straightforward to calculate its effective dose and avoid the risk of toxicity. However, failure of BSA to correlate with the PK measures of anti-cancer agents led scientists to propose other methods that better normalize the inter-patient variability. Flat fixed dose, dose banding, phenol-typing, ideal body weight (IBW) and Modified IBW are all alternatives that account for various physical and physiological factors affecting drug PK.
Most drugs the field of medicine uses are administered as a flat fixed dose. Little variation is employed, other perhaps than a standard reduction in size when the patients are children. That’s okay because most of drugs in medicine have a wide therapeutic index and less inter-patient pharmacokinetic (PK) variability than oncology drugs do. The appeal of a flat fixed dose regimen in oncology are ease in calculation and reduced of the risk of error in over/under-dosing by clinicians, with much easier procedure in manufacturing drugs in pharmacies. Some practitioners also assume better patient compliance in taking fixed doses rather than for example taking two large and one small tablet per day (Felici, Verweij, & Sparreboom, 2002)
In dose banding, patients are classified according to their BSA into predefined ranges: “BSA bands”. A fixed dose is given to patients in each band. The major advantage of this system is that pharmacies can better plan for drug formulation – ,once the doctor prescribes chemotherapy the patient can start immediately with no waiting time, no complicated calculation of the dose and hence less risk of PK inter-patient variability arising from errors in calculations or tailored dose reconstruction. A study performed by Chatelut et al showed that plasma drug concentration is not substantially different in dose-banding compared to BSA-based doses (Chatelut et al., 2012).
Phenotyping of enzymes involved in the drug metabolism is proved to correlate with drug PK (clearance and toxicity), so it can be a tool in developing an optimal dose for each patient. This takes some time and lab work, but variability in enzyme activity for the patient is measured. The dose is calculated accordingly. Some examples in the literature include CYP3A4 activity in docetaxel chemotherapy and DPD in 5-flourouracil (Felici et al., 2002).
Clinicians tend to prescribe lower doses for obese patients for fear of toxicity in patients who may be overall less healthy than non-obese patients. This practice increases the risk of under-dosing; under-dosing is almost as big a concern as the risk of toxicity in overdosing (Field et al., 2008). This is one more reason other body size measures have been proposed for dosing calculations. Oncologists have proposed use of measurements that might and correlate better with drug metabolism such as lean body mass (LBM), body mass index (BMI), ideal body weight (IBW) and adjusted ideal body weight (AIBW)(Hempel & Boos, 2007). Hard scientific justification for employing these parameters is still lacking (Felici et al., 2002).
Beumer, J. H., Chu, E., & Salamone, S. J. (2012). Body-surface area-based chemotherapy dosing: Appropriate in the 21st century? Journal of Clinical Oncology, 30(31), 3896–3897. https://doi.org/10.1200/JCO.2012.44.2863
Chatelut, E., White-Koning, M. L., Mathijssen, R. H., Puisset, F., Baker, S. D., & Sparreboom, a. (2012). Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents. British Journal of Cancer, 107(7), 1100–6. https://doi.org/10.1038/bjc.2012.357
Felici, A., Verweij, J., & Sparreboom, A. (2002). Dosing strategies for anticancer drugs: the good, the bad and body-surface area. European Journal of Cancer 38. Retrieved from http://moscow.sci-hub.bz/9476b26911bba2fad36408b86b7870ae/felici2002.pdf
Field, K. M., Kosmider, S., Jefford, M., Michael, M., Jennens, R., Green, M., & Gibbs, P. (2008). Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. Journal of Oncology Practice / American Society of Clinical Oncology, 4, 108–113. https://doi.org/10.1200/JOP.0832001
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Hempel, G., & Boos, J. (2007). Flat-Fixed Dosing Versus Body Surface Area Based Dosing of Anticancer Drugs: There Is a Difference. The Oncologist, 12(8), 924–926. https://doi.org/10.1634/theoncologist.12-8-924
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Miller, A. A. (2002). Body Surface Area in Dosing Anticancer Agents: Scratch the Surface! JNCI Journal of the National Cancer Institute, 94(24), 1822–1831. https://doi.org/10.1093/jnci/94.24.1822
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