|
|
              
 |
by
Dr. Karen Albritton Chief, Clinical Affairs, Sarcoma Services Huntsman Cancer Institute
and
Scott Silverstein, MS Clinical Pharmacist Huntsman Cancer Institute
Most chemotherapy regimens prescribed by practicing oncologists are standardized “recipes.” These regimens, which can be very complex, are based on years of preceding studies and thought, to determine the most effective and safe dosing of the drugs. It all begins with a novel agent being tested in a laboratory.
Cell line experiments (tumors grown in a Petri dish, with chemotherapy applied on top) determine the relationship between dose and tumor cytotoxicity, that is, what dose results in what degree of tumor cell death. Drugs that have favorable profiles are moved into animal models, where we get a sense of tolerability of the doses desired. If a dose is known to be active in cell lines and is well tolerated, the drug be reasonable to move to human experimentation. Also determined at this point is the drug “pharmacokinetics”, how it is processed (absorption, distribution, metabolism and elimination) in the body, which can determine how frequently it should be dosed.
Phase I studies are then done to establish the tolerable dose in humans. These studies begin by administering low doses (determined by extrapolation from animal studies), then gradually increasing the doses in subsequent subjects, carefully observing for side effects (and effect on tumor to a lesser extent). Dosing is almost always based on a given number of milligrams of drug for every square meter of body surface area (BSA). The BSA is used to standardize the dose of drug delivery in patients of different heights and weights.
Also being determined is the frequency scheduling- can the drug be administered daily, weekly, or every three weeks. In the design of the study, preset cutoffs of acceptable toxicities have been set; once three patients exceed this benchmark, the dose just below this is called the maximum tolerated dose (MTD). Once the MTD is determined, this is now considered the standard dose of that drug when given as a single agent (by itself, not with other drugs) and that dose can now be evaluated in phase II studies, to determine efficacy in a given tumor. This dose may undergo further adjustment over time, either because of new study information, or because supportive care allows dose escalation (e.g., filgrastim allows higher dosing of drugs whose dose-limiting toxicity is myelosuppression).
Medications that are active as single agents in a disease may be used in combination. The choice of the combination is made based on several factors, most importantly the mechanism of action of the drug and the side effects. Drugs are grouped into “classes” by sharing similar molecular structure and/or mechanism of action. Combining agents of different classes is more likely to attack different clones of the tumor- like air and ground attacks in military battle. The combination can minimize side effects by, e.g., combining drugs that cause diarrhea and constipation, or whose dose limiting toxicity is myelosuppression with others who have little myelosuppression. Many patients ask why we don’t just combine many drugs together in case any will work. To do so, with tolerable side effects, would require significant dose reductions of each agent, making each one less likely to perform at its peak capacity. Again, clinical trials are done to confirm the safety and efficacy of these combinations, and when these results are published they become “practice standards” for oncologists to follow. In practice, adjustments are often made to individualize therapy to each patient. This could be done for several reasons: age, prognosis, body function (liver function, kidney function, etc), signs of toxicity (too much myelosuppression, hearing loss, cardiac dysfunction, etc). This is part of the art of medicine, and individualizes care to the patient. The goal is always to provide the highest dose to the tumor with minimal toxicity to the patient.
V1N4 ESUN Copyright © 2004 Liddy Shriver Sarcoma Initiative.
|
