Drug dose and drug choice: Optimizing medical therapy for veterinary cancer

Abstract

Although novel agents hold great promise for the treatment of animal neoplasia, there may be room for significant improvement in the use of currently available agents. These improvements include altered dosing schemes, novel combinations, and patient-specific dosing or selection of agents. Previous studies have identified surrogates for "individualized dose intensity,", for example, patient size, development of adverse effects, and pharmacokinetic parameters, as potential indicators of treatment efficacy in canine lymphoma, and strategies for patient-specific dose escalation are discussed. Strategies for treatment selection in individual patients include conventional histopathology, protein-based target assessment (eg, flow cytometry, immunohistochemistry, and mass spectrometry), and gene-based target assessment (gene expression profiling and targeted or global sequencing strategies). Currently available data in animal cancer evaluating these strategies are reviewed, as well as ongoing studies and suggestions for future directions. K E Y W O R D S canine, chemotherapy, feline, oncology, personalized medicine 1 | INTRODUCTION Although novel agents hold great promise for the treatment of animal cancer, there may be room for significant optimization in the utilization of currently available agents. These improvements may include altered dosing schemes, novel combinations, and patient-specific selection or dosing. This review will discuss human and veterinary examples of alterations in dosing, outcome, or antineoplastic drug choice in specific patient populations, with ideas for future implementation of these observations. | DOSE INTENSITY AND OUTCOME-THE CANINE LYMPHOMA EXAMPLEThe concept of dose intensity can be interrogated in two ways. One is to evaluate the planned dose intensity for a given protocol, which can be quantified by measurement of "summation dose intensity" (SDI), the amount of chemotherapy on a mg/kg or mg/m 2 basis delivered per unit time. The SDI has been shown to modestly influence outcome in human tumors such as breast cancer, osteosarcoma (OSA), and others, although sometimes at the expense of increased adverse events. 1,2 In the studies evaluated to date, planned SDI has not correlated with patient outcome in canine lymphoma, 3,4 and studies in other canine tumor types have likewise failed to demonstrate an association between calculated SDI and outcome. 5,6 The second method is to use pharmacokinetic (PK) or pharmacodynamic (PD) measures to assess surrogates of "individual dose intensity." This approach has merit owing to the demonstrably wide interpatient variability in drug exposure to a given cytotoxic agent. In dogs, this has been best demonstrated in studies evaluating doxorubicin (DOX). 7,8 Wittenburg et al recently demonstrated that DOX exposure following a standard 30 mg/m 2 dose, as estimated from a "limited sampling" PK schema requiring only three time points within an hour of dosing, 9 was a significant predictor of neutrophil nadir, whereas mg/kg dose was not. 8

Clinical and Laboratory Findings in Dogs Undergoing Adjuvant Chemotherapy with Gemcitabine/Carboplatin Combination for Mammary Neoplasia

“…Even though novel drugs are a great promise for cancer treatment in animals, optimizing the use of currently already available agents might bring new benefits (Thamm and Gustafson, 2020). In this regard, both gemcitabine and carboplatin are medications known for decades, but there is still a lack of information about these chemotherapeutic agents association for use in dogs.…”

La citometría de flujo, un universo de posibilidades en el ámbito veterinario. Revisión

“…El uso de esta tecnología en el ámbito veterinario se ha ido incrementado de manera lenta y gradual; se tienen reportadas múltiples aplicaciones no solo en investigación sino en la clínica, tanto para animales de compañía como para animales de vida salvaje. Los aspectos de la medicina veterinaria que más se han beneficiado de la CF son el diagnóstico, el pronóstico y la inseminación artificial (13)(14)(15)(16)(17)(18)(19) ; desafortunadamente en México, su uso en la clínica veterinaria es escaso ya que no hay laboratorios que cuenten con alguno de estos equipos. En el área de investigación veterinaria, diversas instituciones educativas cuentan con equipos en los cuales se pueden realizar ese tipo de análisis, siendo aún poco el uso que se hace de esta tecnología.…”

Identification of new candidate biomarkers to support doxorubicin treatments in canine cancer patients

“…Biomarker development and application of personalized chemotherapy approaches in veterinary medicine is of particular interest in guiding the practice of dose escalation of routinely used chemotherapeutic drugs [ 16 , 17 ]. By identifying predictive biomarkers of patient response, dose escalation strategies can be modified for each individual to benefit both those who are more likely to respond to the drug used and those who are likely to have a poor response or higher risk of treatment-associated side effects.…”