The Washington Manual of Oncology, 3 Ed.

Principles of Systemic Cancer Therapy: Cytotoxic Chemotherapy

Leigh M. Boehmer • Sara K. Butler • Janelle Mann

 I. INTRODUCTION

1. General. Antineoplastic agents have a narrow therapeutic index and, as such, small changes in dose may result in unacceptable toxicity. Pretreatment characteristics including age, performance status, concurrent medications, renal and hepatic function, interpatient pharmacokinetic and pharmacodynamic variability, cachexia, obesity, and other comorbidities impact the efficacy and toxicity profile of many agents administered. In addition, many antineoplastic agents are extensively metabolized by cytochrome P-450 enzymes, resulting in the potential for drug–drug interactions and subsequent alterations in antineoplastic drug concentrations. The sequence of drug administration may also increase or decrease the antitumor effect or impact the severity of toxicities seen with these agents. Finally, calculation and manipulation of the actual dose to be administered is based on a variety of factors, including the patient’s body size and commercially available antineoplastic vial size, as well as previous response and treatment intent. With that in mind, many factors should be considered when determining a patient’s antineoplastic dose.
2. CALCULATION OF DOSE
3. General. The dose of antineoplastic agents may be based on a flat dose (e.g., imatinib), on body weight (e.g., conditioning regimens for hematopoietic stem cell transplantation), or, more commonly, a standardized reference body surface area (BSA) in order to provide consistent exposure of drug across various body types. Utilization of BSA is thought to be ideal because of its known relationship between body size and physiologic functions, including blood volume, cardiac output, glomerular filtration rate (GFR), and liver blood flow. The motivation for calculating the dose on the basis of BSA is to reduce interpatient variability of systemic antineoplastic exposure and to limit the toxicity exerted by the drug.
4. Formulas
5. Dubois and Dubois. This formula is the most widely utilized, originally derived in 1916 by making molds of nine nonobese individuals who varied in age, size, and shape. By trial and error, this formula was created by using height and weight alone to approximate BSA. However, caution should be used when applying this formula to infants and young adults. It is considered the gold standard for BSA calculations and the basis for many other nomograms.

BSA (m²) = W^0.425 × H^0.725 × 0.007184

W = weight (kg) H = height (cm)

2. Gehan and George. In 1970, the DuBois and DuBois formula was validated by Gehan and George by directly measuring the skin surface area of 401 individuals, including a large number of children. However, it was found that the BSA was overestimated by 15% in approximately 15% of the cases. In an effort to simplify the task of calculating the surface area, the authors provided tables and charts to estimate BSA from height and weight.
3. Mosteller. By modifying the equation proposed by Gehan and George, Mosteller et al. provided an equation that is easy to remember with a slight loss of accuracy of only 2%. Although the initial validation was only based on evaluations of adolescent and adult subjects, a subsequent study utilizing infants and children found it to be equally applicable.
4. Calvert. Early studies of carboplatin noted that a patient’s pretreatment renal function impacts the severity of thrombocytopenia observed. Approximately 70% of the drug is excreted unchanged via the urine within 24 hours, and pharmacokinetics suggests that the toxicity and efficacy of carboplatin is dictated primarily by pretreatment GFR. On the basis of these observations, Calvert et al. validated a simplified formula utilizing a targeted area under the curve (AUC) for carboplatin dose calculation and accounting for GFR in an effort to minimize the toxicity.

Carboplatin dose (mg) = target AUC (GFR + 25)

1. Manipulation of Doses. The dose of an antineoplastic agent administered to a patient depends not only upon patient factors and mathematical calculations, but also upon the treating physician’s practice of rounding or capping of the dose. It is not uncommon for a dose to be rounded if it is within 5% to 10% of the nearest commercially available vial size. The practice of rounding, in fact, is supported by a sizeable literature base and does confer a potential cost savings to the health care system. Overall, modification of the antineoplastic dose must be done cautiously to prevent a clinically significant change from the intended dose.
2. Amputees. None of the above equations included amputees in the patient sample leading to their validation. Furthermore, some of the formulas found a loss in accuracy in children, short and/or obese patients, thereby questioning the accuracy of applying these same equations to amputees. Although the formulas have not been validated, it is recommended to evaluate the data provided by Colangelo et al., proposing two alternative equations for this patient population.
3. Obesity. It was once believed that dosing obese patients on their actual body weight would result in increased toxicities secondary to the distribution of lipid soluble drugs into adipose tissue. Therefore, ideal body weight, an adjusted body weight, or a capped BSA have historically been used to calculate the dose to be administered. Several reports have been published; however, assessing this practice and their results concluded that there was no increase in toxicity observed in obese patients with breast, colon, or small cell lung cancer who received antineoplastic doses based on actual body weight. Furthermore, manipulation of the dose downward in obese breast cancer patients who received cyclophosphamide, doxorubicin, and 5-fluorouracil negatively impacted overall survival. The American Society of Clinical Oncology released clinical practice guidelines on appropriate dosing for obese cancer patients in 2012. The expert panel recommended that full weight-based antineoplastic doses be used to treat obese patients, particularly when the treatment goal is cure.
4. Elderly. As a person ages, many physiologic changes may take place that influence the effects of antineoplastic agents. However, these changes do not take place at the same stage of life for each individual. There are no set guidelines addressing how to handle dose calculations in the elderly, but hypoalbuminemia, reduced hepatic and renal blood flow, cardiac dysfunction, and other comorbidities need to be considered when determining a treatment plan. In addition, this patient population is frequently taking medications that may interact with the efficacy and safety profile of any agent(s) administered.
5. Hepatic dysfunction. Several antineoplastic agents undergo hepatic metabolism and any alteration in their clearance or the metabolic capacity of the liver may result in potential complications. Data are limited in this situation, and many take the simple approach of assessing liver function by evaluating the total bilirubin. Other laboratory values such as the transaminases, serum alkaline phosphatase, and albumin may also impact systemic exposure and the ability of the liver to metabolize these medications. Therefore, all hepatic function tests may need to be taken into consideration prior to deciding the final dosage of an antineoplastic regimen. Although there is little data for combination regimens, there are some individual agents such as the taxanes, vinca alkaloids, anthracyclines, and irinotecan, which are known to necessitate a dose adjustment based on hepatic function. To further complicate the situation, one may find that the liver dysfunction is a result of the tumor and may need to determine whether dose alteration should be considered at all. Currently, there are no consensus recommendations for dosing antineoplastic drugs for tumor-related liver dysfunction.
6. Renal dysfunction. Several antineoplastic agents are eliminated through the kidneys, and even minor alterations in renal function may impact their safety. Furthermore, the literature is limited to case reports and small case series with regard to end-stage renal disease and the dosing of antineoplastics in patients with cancer. The choice and dose of the agent need to be considered carefully, as well as the method and optimal timing of dialysis in patients with renal dysfunction to assure maximal drug exposure while minimizing toxicity.

SUGGESTED READINGS

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Colangelo PM, Welch DW, Rich DS, et al. Two methods for estimating body surface area in adult amputees. Am J Hosp Pharm 1984;41:2650–2655.

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