The Balancing Act: Response And Toxicity

oncologyoutlookThe Balancing Act: Response and ToxicityThe Balancing Act: Response and ToxicityThe Balancing Act: Response and ToxicityBy Kevin A. Hahn, DVM, Ph.D.I was asked the other day why no chemotherapy drugs are currently approved for use in veterinary medicine.I was asked the other day why no chemotherapy drugs are currently approved for use in veterinary medicine.

I was asked the other day why no chemotherapy drugs are currently approved for use in veterinary medicine. 

It seems inconceivable that chemotherapy drugs such as vincristine, cyclophosphamide and doxorubicin could reach widespread application in veterinary medicine over the past 20 years without a thorough understanding of the pharmacology in various animal species. 

Why do we use the dosages that we use? Would the dosage be the same in a Chihuahua and a bull mastiff, different in a ferret or a fish?

If you have had cancer or know someone with cancer, you have seen how clinical pharmacokinetics has been successfully applied to improve the safety and efficacy of chemotherapy administration.

One Size Does Not Fit All
But unlike many other classes of drugs (antibiotics, anti-arrhythmics), the anti-cancer agents vary greatly in their physical composition, reactivity, stability, subcellular sites of action and target cell sensitivity. 

Also unlike our human counterparts, veterinarians and veterinary oncologists are presented with species and size variations of patients in their clinical practices. So even though there are dosage conversion algorithms based upon species or body sizes, useful generalizations on the efficacy or toxicoses associated with the anticancer agents among the different species or patient sizes just cannot be made. 

Another concern with chemotherapy dosing is that anti-cancer agents maintain a very narrow therapeutic window between efficacy and normal tissue toxicity. Differences in metabolism and excretion pathways make it difficult to achieve drug concentrations within the “therapeutic window” when dosage regimens are extrapolated across species lines. 

We lack consistent protocols and dosages as well as the pharmacokinetic and pharmacodynamic information about a given drug used in combination with other drugs. We know so very little about the mechanisms of resistance to anti-cancer drugs in companion animals. 

Loeb’s Law of Therapeutics
It would appear that we know very little about why we are using the drugs we use in our treatment plans for pets with cancer. 

Why then, if most of our discipline is based on anecdotal experiences, is it considered an acceptable practice of veterinary medicine?  Because most of us have followed four simple rules to govern our decision making processes and the results have evolved into “dosages” or “protocols.” 

More than 50 years ago, Dr. Robert Loeb at Columbia University developed these four simple rules, or laws. 

Rule 1 is if what you are doing is good, keep doing it. Rule 2 is if what you are doing is not good, stop doing it. Rule 3 is if you do not know what to do, don’t do anything. Rule 4 is never make the treatment worse than the disease.

We veterinarians can easily follow Rules 1, 2 and 3 if we regularly examine the patient (clinical staging) and assess the medical condition of the pet. We should continue to work together with the pet owner to review the effects of the treatment plan on the pet’s quality of life (Rule 4) before initiating any treatment(s). 

Overall, the goal of any cancer treatment is to induce remission without harming the patient. With chemotherapy the goal is to have the anti-cancer drug(s) damage tumor cells to a greater degree than it damages normal cells. 

What is the Best Dose?
The mechanism of cytotoxicity varies with each anti-cancer drug class. In general, however, efficacy is greatest against actively cycling cells, and some agents act specifically on cells in certain phases of the cell cycle. 

Knowing the mechanism of action for each drug will allow for useful drug combinations which may act synergistically, and avoid drugs which may antagonize each other’s mechanism of action. 

As with other medications, the therapeutic index refers to the ratio of the toxic dose to the effective anti-tumor dose.

The therapeutic index of most chemotherapeutic agents is relatively low, necessitating careful dosing. Improvements in therapeutic index can be made by using techniques which either make the drug more effective or protect against toxic effects. 

The optimum dose is at the point on the dose response curve where maximum anti-tumor effect and acceptable toxicity occur. It may be necessary to accept some toxicity or some risk of incomplete response, or both. 

In practice, the optimum dose in a given circumstance depends on the goal of therapy. If the goal is cure, toxic risks are likely. If palliation is the goal, toxicity will be avoided, but incomplete response is likely.

I tell most pet owners that with chemotherapy, the more you give and the more often you give it then the greater the response and toxicity; the lesser given less often reduces the response and toxicity.

Range of Toxicity
Toxicity from chemotherapeutic agents ranges from mild to life-threatening. Tissues with high growth fractions such as bone marrow and epithelial tissues, including the gastrointestinal tract, are normally most susceptible to toxic side effects. Some drugs have additional toxic effects on other tissues, such as urinary tract, myocardium, or pancreas. These effects may be unrelated to the cytotoxic effects and may be idiosyncratic or species specific. 

Using drugs in combination maximizes therapeutic potential. The most important criterion for inclusion of a drug in a combination protocol is efficacy as a single agent against the tumor in question. Using closely related drugs in combination, such as cyclophosphamide and chlorambucil, usually does not improve efficacy significantly and may increase toxicity, whereas effective combinations generally consist of drugs which target different metabolic pathways, such as the use of vincristine and cyclophosphamide. 

Some drugs are synergistic when used in combination, but often the effects are simply additive. Combinations allow the use of a higher total cytotoxic dose when the toxic effects of the individual drugs are different. 

Laws and Order
Scheduling of drug administration can be critical because the anti-tumor effect of a drug may be markedly decreased by giving it too late, either because the growth fraction of the tumor has decreased or because a resistant clone has developed. 

Also, the scheduling of the various drugs in relation to each other is important. Differences and similarities in mode of action, toxicities and mode of resistance should be considered. 

It is critical to avoid overlapping the toxicities of the drugs in combination chemotherapy protocols. The most commonly encountered example of this is in the use of multiple myelosuppressive agents. 

The onset of the neutrophil nadirs of various drugs must be taken into account when planning the sequence and timing of therapy, and since some alkylating agents cause delayed myelosuppression, this may not be readily evident until a second drug is administered. 

Determine the Goal
Ultimately, the goal of chemotherapy must be identified at the outset to determine the aggressiveness and acceptable level of toxicity. Once this is done, therapy should be instituted as soon as possible. 

But remember Loeb’s Laws 2 and 3. Just because you have a goal does not mean you have an effective plan. 

Obtain enough information to develop a treatment protocol rather than guessing (Law 2) and provide sufficient information to the pet owner so that if the treatment does appear to be worse than the disease (Law 4), the expectations of response (less tumor but greater toxicity risk) are realistic.


Kevin A. Hahn, DVM, Ph.D., Dipl. ACVIM (Oncology), is director of Oncology Services at Gulf Coast Veterinary Specialists, Houston (www.gcvs.com/oncology), and is the oncology consultant for YourNetVet (www.yournetvet.com).

06-20-2007

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