"Chemotherapy Protocol Selection - Philosophy" TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 72; October 4, 2002. ======================================================================= THIS WEEK'S TUMOR TIDBIT: CHEMOTHERAPY PROTOCOL SELECTION - PHILOSOPHY ======================================================================= The last in a 3 part review of the Principles of Chemotherapy, this Tumor Tidbit reviews the philosophy of protocol selection when managing a pet with cancer. COMBINATIONS AND SCHEDULING Using drugs in combination maximizes therapeutic potential. The most important criterion for inclusion of a drug into a combination protocol is efficacy as a single agent against the tumor in question. Using closely related drugs in combination usually does not improve efficacy significantly and may increase toxicity, whereas effective combinations generally consist of drugs that target different metabolic pathways. 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. Scheduling of drug administration can be critical since giving it too late may markedly decrease the antitumor effect of a drug, 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. MULTI-MODAL THERAPY Chemotherapy is often used successfully in combination with other therapeutic modalities, particularly surgery and radiation therapy. If multi-modal therapy is to be used, the combination should be planned in advance rather than using different modalities one after the other as each one fails. Preoperative (neoadjuvant) chemotherapy is indicated when a primary tumor is so large that it is inoperable or involves vital structures. Usually, however, chemotherapy is used postoperatively (adjuvant) after incomplete excision or when micrometastases are expected to be present based on a knowledge of the behavior of a particular tumor. In theory, adjuvant therapy should be particularly effective since the growth fraction of residual tumor is likely to be relatively large. DOSE DETERMINATION Because the therapeutic index of chemotherapeutic agents is generally low, accurate dosing is imperative. Although there are numerous examples in humans where clinical pharmacokinetics have been successfully applied to improve anticancer therapy, most veterinary anticancer drug dosages and regimens are based on human dose extrapolation and empirical trial and error. It is important, therefore, to realize there are specific species differences in metabolic rates and pathways (e.g., cisplatin-induced fatal pulmonary toxicity in cats, but not in dogs). Body surface area, an accurate reflection of metabolic rate, has been used to calculate drug dosage in humans. Most anticancer drugs prescribed in veterinary medicine are dosed on a per body surface area basis rather than a per weight basis for similar reasons. However, in recent times many veterinary oncologists have become aware of the fact that in doing so, the smaller-sized patients receive a much higher mg/kg dose than do larger-sized patients. For example, when dosing doxorubicin on a per body surface area basis (30 mg/m2, equivalent to 1 mg/kg), smaller-sized dogs (e.g., 5 kg dog dosed at 30 mg/m2 is given a dose equivalent of 1.74 mg/kg) have higher peak plasma concentrations, greater plasma drug concentrations versus time curves, longer drug elimination half-lives, greater volumes of distribution of the central compartment, more pronounced myelosuppression, and more clinical signs of toxicoses than do larger-sized dogs. Although these findings do not imply a carte blanche revision of anticancer drug dosages in veterinary medicine, application of knowledge regarding species variability in drug pathways, coupled with limited veterinary studies and Phase I and II human pharmacokinetic studies should result in improved veterinary therapy compared to empiric trial and error. ======================================================================= SUGGESTED READING Veterinary Oncology, From "The Practical Veterinarian Series". By Hahn KA. Butterworth-Heinemann Press, 2002. ======================================================================= We hope this info helps and don't hesitate to call us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, Phd, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Residency Completed and Certification Examination Passed, ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com