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.

How are doses determined?  Largely by trial and error.  Dose size is one of the questions animal trials and clinical trials set out to answer.  Experiments with small animals identify the lethal dose, which scaled for body size as a first estimate of the lethal dose for humans.  LD10 is the dose that kills 10 percent of animals (LD means “lethal dose”). The first dose used in human clinical trials is by convention 10 percent of LD10.  Patient response is measured as dosing is increased to get an idea of how high a dose a human can be given before side effects become intolerable.  One goal of clinical trials is to establish a maximum tolerated dose (MTD) of a medicine.  In treatment, oncologists have traditionally administered close to the MTD to patients, regardless of whether they thought, based on clinical experience, that dose would eliminate the cancer.  This is partly why side effects were so bad from chemotherapy.    Alternative dosing philosophies such as adaptive chemotherapy, variable dose regimens, and metronomic chemotherapy are used more often today than in the past.

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 (BSA) 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 organs that detoxify and eliminate poisons.  To figure correct dosing 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, and dose banding methods have been proposed among other methods as alternatives to BSA.

Better understanding of drug pharmacokinetics (PK) and pharmacodynamics (PD) can help but oncologists have to work with what they have. Patients vary 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 to tailor doses according to body size and ability to clear the drug.

If doctors could know the pharmacokinetic and pharmacodynamic details for each drug and patient combination, it would be straightforward to calculate its effective dose and avoid the risk of toxicity. Because BSA does not correlate with the pharmacokinetics, scientists have developed other methods. Flat fixed dose, dose banding, phenol-typing, ideal body weight (IBW) and modified IBW are alternatives that account for various physical and physiological factors affecting pharmacokinetics.

BSA is used for most old-style cytotoxic drugs, but things are different for targeted therapies.  Monoclonal antibody doses are more often set by the patient’s body weight, while fixed doses are used for many oral chemotherapy medicines.

Flat Dosing

Most drugs doctors prescribe are administered in fixed doses. The most common variation is a reduction in dose when the patients are children. This system works because most drugs for other maladies have a wide therapeutic index and less interpatient pharmacokinetic variability than oncology drugs do. Some practitioners also believe patient adherence is better when fixed doses are prescribed 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 withstand 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 stated “use 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 spaced 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 proven 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 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).

The Calvert Formula

A calculation called the Calvert formula is used to determine doses for the alkylating agent Carboplatin. To employ this formula, doctors must estimate the patient’s glomerular filtration rate (GFR) in the kidneys – a measure of how fast the patient’s body removes the chemotherapy agent in tbe blood to the urine.  The concentration-time profile of the agent in the bloodstream is quantified as the the area under the plasma concentration/time curve (AUC).

The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]

An on-line calculator is available at https://reference.medscape.com/calculator/carboplatin-auc-dose-calvert

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 with the body mass, as an obese person’s extra weight is disproportionately adipose tissue.   The epidemic of obesity means many cancer patients are overweight.  Heavy people have higher rates of cancer incidence and cancer-related mortality than the rest of the population. This has made the problem of chemotherapy dosing for obese patients more important.

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.

For Underweight Patients

This doesn’t get as much attention as consideration of obese patients does, but given the narrow therapeutic window of cytotoxic drugs, it can be an important consideration.  Underweight patients are common in cancer settings, especially as advanced cancer often results in weight loss.  Sarcopenia and cancer-associated cachexia can weaken the body, making side effects less tolerable.  Doctors must take this into consideration when setting doses.

Consolidation therapy

Consolidation therapy is a course of relatively heavy dosing given after induction therapy and a remission of the cancer.  Also called intensification therapy, the purpose is to consolidate the gains of treatment and reduce the chances of tumor growth.

Medication Errors

Administering the wrong dose is a well-known hazard in medicine.  Mistakes in size of dose, frequency of dose, or giving the drug at the wrong time can have adverse effects.  This is particularly of concern when chemotherapy is administered as oncology drugs, especially cytotoxic ones, typically have narrow therapeutic windows.  Further, chemotherapy is frequently given to elderly patients with comorbidities and the regimens are more complex than for other types of drugs.  Anti-cancer drugs are among the most common causes of medication errors.

Monitoring patients

The kidneys and liver eliminate drugs, through elimination and metabolism, so patients identified as having damage to those organs get special attention and consideration as far as dosing – lower doses may be administered.

An interesting new development is electronic patient-reported outcome (PROs or ePROs) systems. This is a way to connect patients to the medical team when the patient is away from the clinic and to give feedback from the patient and his or her subjective experience of treatment to the medical team. The idea is that the patient answers questions or enters data through an internet intake system. The patient uses a computer or mobile (cell) phone; different systems can have different interfaces. The data the patient enters is customized for his or her situation, but usually involves severity of side effects, adherence to medicine regimen, and overall quality of life. The PRO system can prompt the patient to respond (by email or text or automated phone call) or the patient and monitoring team may agree that the patient will put in data on specific days or dates. The data enters a computer system and periodically the nurse reviews it.

A benefit of such a system is that is can increase adherence. Patients may be more likely to follow doctor’s orders if they are used to reporting in.

These systems offer potential to help increase the quality of healthcare at many stages – during neoadjuvant chemotherapy before planned surgery, in a long-term maintenance chemotherapy program, or even when the patient is participating in a clinical trial.

See also: drug-drug interactions

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712269/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897534/