Dosing

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.  

Body surface area is one way of measuring how large a person is. Body surface area correlates with the capacity of the kidneys and liver, which are the most organs for dealing with poisons.  When you are running up at high doses of a drug with a narrow therapeutic range, body surface area is a better thing to look at than weight.

Chemotherapy drug doses are usually formulated in theory for mg/m2 of body surface area.  Doctors don’t usually know a person’s surface area but height and weight are easy to measure so they use them. A typical adult man of 70 kg might have a surface area of 19,000 sq centimeters while an adult woman of 60 kg might have a surface area of 16,000 sq centimeters.

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) can only help but oncologists have to work with what they have.  Different patients have variations in response to a drug, even if the patients have 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.

Flat Dosing

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).

The idea behind BSA was that elimination of the drug was by the kidneys and liver and their capacity scaled with body surface area.  So, it was thought, the capacity of the body to stand up to the negative effects of harsh chemotherapy drugs would scale with BSA.  That system was started over 50 years ago.   By the 21st Century people started questioning the conventional wisdom and analysis showed little justification for BSA.  A study from 2007 stateduse of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking.”   In many cases, flat-fixed dosing does not produce substantial differences in bloodstream concentrations from one individual to the next.  That doesn’t mean it’s optimal, though.

Dose Banding

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.  Dose banding refers to how much of the chemo agent is put into individual vials that are stored at hospitals and clinics and, in some cases, are given to individual patients for home care.

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. It allows doses to be modified in response to toxicity.   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).

Dose banding is about reducing cost and increasing efficiency in the administration of chemotherapy agents.

Logarithmic Dose Banding (LDB) is a system started in the UK in which the bands are space logarithmically rather than evenly.  This allows the average patient to get closer to the optional dose for his or her size, even within a dose banding system.

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)  Genotyping and phenotyping strategies for dosing may be the best approach but are hard to do, expensive, and rarely used.

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).

Dosing for Obese Patients

Obesity presents a challenge for the oncologist in determining how much medicine to give.  It is not a matter of scaling up directly according the body mass, as an obese person’s extra weight is disproportionately adipose tissue.  Allegations that obese patients are underdosed – especially in adjuvant therapy – have made headlines.  The BSA method of dosing is not always the same, either.  If the actual body weight is used in the BSA calculation, many doctors feel the dose is too high, which is why they used an ideal body weight.  But this smaller dose may not be big enough to effectively treat the bigger people, who can, all other things being equal, better handle side effects.

The Associated Press reported 40 percent of obese patients get less than 85 percent of an optimal dose.  Of course, it is hard to say for sure what the optimal dose is for heavier people.  There are no clinical trials for questions like this and the estimates must come from

 

References:

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

Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H., & Skipper, H. E. (1966). Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemotherapy Reports, 50(4), 219–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4957125

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

Ibrahim, N. (2011). Chemotherapy dosing in obese patients: The real evidence. European Journal of Oncology Pharmacy, 5(1), 22–23.

Kaestner, S. A., & Sewelly, G. J. (2006). Chemotherapy Dosing Part I: Scientific Basis for Current Practice and Use of Body Surface Area. J. Clinical Oncology, 19, 23–37. https://doi.org/10.1016/j.clon.2006.10.010

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

Pinkel, D. (1958). The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Research, 18(3), 853–856.