Current Pharmacology in Onocolgy
Despite the advances in cancer treatment, the oncology field still reports the lowest efficacy rates of any of the major medical therapeutic areas. Cancer is a very complex disease and is in fact not one disease, but rather a broad group of various diseases, which compound the challenges of effective treatment and cure. This is all the more reason the medical community should utilize the tools available as effectively as possible.
Many of the recent breakthroughs in improving the effectiveness of cancer treatment are a result of “personalized medicine,” which involves tailoring medical treatment to the individual characteristics of each patient rather than the “one-size-fits-all” approach of the past. Much of the focus in personalized medicine has been placed on understanding a person’s unique molecular and genetic profile. This “pharmacogenomics” profile can be used to predict what makes patients susceptible to cancer or to predict the most optimal course of treatment. These are remarkable and clinically significant advancements.
Although pharmacogenomics can provide the patient’s tumor genotype to identify the optimal drug for an individual, it cannot define the specific dosage necessary to achieve the optimal systemic blood exposure to provide the best therapeutic effect with minimized side effects.
The current standard of care for dosing patients with chemotherapy drugs is Body Surface Area (BSA). BSA still represents the outdated “one size fits all” approach to patient care in this age of personalized medicine. This method of dosing, which takes into account only the patient’s height and weight, was derived in 1916 based upon the study of only eight patients as a means of estimating the conversion of drug doses in animals to human doses.(1) For lack of any better methodology, BSA was subsequently adapted in the 1960’s to dosing of the newly developed chemotherapy drugs.(2) However, there is no rigorous scientific basis for the use of BSA with cancer drugs and there is growing scientific evidence this approach is invalid and does not deliver the best care for cancer patients.(3-9)
Several studies have shown that BSA-based dosing is associated with a high degree of drug blood level variability from one patient to another (“interpatient pharmacokinetic or PK variability”) and is a poor metric of optimal drug exposure. Many factors besides height and weight impact how individuals absorb, distribute, metabolize and excrete drugs. These factors may include disease stage, organ function, sleep-wake cycles, age, race, drug-drug interactions, food, interaction with nutritional and herbal supplements, among others.(9) The overall effect of these factors is a high degree of interpatient PK variability. For example, the distributions of exposure for 5-fluorouracil (5-FU), a commonly used chemotherapy drug, has been demonstrated to be as much as 30 to 100-fold. This means that if two patients receive equal 5-FU doses based upon BSA, one patient may have 30-to-100 times the drug level in their bloodstream than the other.
Similar results have been reported with other cancer drugs. In one study, BSA was found to be marginally effective in controlling interpatient drug blood levels in only 15% of 33 new investigational cancer drugs tested between 1991 and 2001.(5) Another report found the variation in clearance of the most commonly used chemotherapy agents was between 25% and 70%, and most drugs showed interpatient blood level variability higher than 35%. (See chart below)(4)