Page 219 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

198 PART 3 Therapeutic Modalities for the Cancer Patient

but data supporting efficacy are lacking. The recommended dos- Predictive Evaluations
age for imatinib in dogs and cats is 10 mg/kg PO q24h, but cau- Current clinical practice in both human and veterinary oncology
bases the choice of cytotoxic chemotherapy on descriptive histo-
tion should be used because this is based on small numbers of
VetBooks.ir patients, with most treated for less than 1 month, 356,373,374 with pathology characteristics. For example, a diagnosis of OSA in a
veterinary patient would lead to the use of adjuvant DOX and/
the primary indication being mast cell neoplasia.
or a platinum-based drug (carboplatin or CDDP) after surgi-
Future Directions in Drug Therapies for cal resection of the tumor. Why are these drugs used? The easy
answer is that studies have shown that dogs receiving either of
Cancer these drugs after surgery live significantly longer than dogs receiv-
ing surgery alone. 381 Studies in human patients have shown in
Individualized Dosing a variety of tumor types that in vitro chemosensitivity testing of
Population Pharmacokinetics tumor biopsies and tailoring therapy can lead to increases in anti-
The convention for drug dosing is to normalize the dose to the tumor response. 382–385 Therefore basing therapy on an empirical
weight or surface area of the patient. This is done even though assessment of drug sensitivity rather than on tumor type alone is a
there are often no data to support a relationship between a given strategy that could lead to preferred outcomes. Issues with the use
drug’s exposure in the patient and either of these parameters. of chemosensitivity assessment in clinical practice are the techni-
These conventions are based on the idea that body weight or BSA cal difficulties associated with tissue procurement and culturing
is related to drug distribution and/or elimination in a manner that and measures of drug response. Another approach to predicting
allows for consistent drug exposure in treated individuals. Dosing the chemosensitivity of tumors has evolved around gene expres-
in mg/kg or mg/m is a crude attempt at individualized dosing, sion profiling and an informatics approach. 386,387 Although much
2
and for some drugs, substantial variability is expected. Studies spe- attention has been focused on recent evidence of research impro-
cifically aimed at determining what demographic characteristics in priety and improper validation of predictors used for clinical trials
the patient population determine variability in drug exposure are in human lung and breast cancer, 388,389 and this has dampened
termed population pharmacokinetic studies. some enthusiasm for using genomic predictors in chemosensi-
tivity profiling, it should be noted that extensive review of these
Molecular Profiling data by statisticians 390 and NCI review panels has found that the
errors made were in data handling and consistency in analysis.
Tumor Sensitivity Thus these unfortunate events should not be an indictment of
Tumors have traditionally been classified by descriptive char- “omics” approaches in making clinical decisions but rather a stark
acteristics such as organ of origin, histology, aggressiveness, reminder that correct and careful research approaches and data
and extent of spread. That empiric rubric is being challenged, analysis must be adhered to.
as molecular classifications made possible by microarrays and
other profiling technologies become increasingly common and Novel Combinations
persuasive. 375,376 The reductionist program would suggest that,
eventually, all differences among traditional tumor types will The approval of the first targeted agent for veterinary applications
be reduced to statements about molecules in the tumors and in the United States (TOC) has provided access to a multitargeted
about the interactions among those molecules; hence it might TKI. Biologic agents, including species-specific cytokines, pep-
then be possible to study physiologic processes in one type of tides, monoclonal antibodies, chimeric molecules, and targeted
cancer and extrapolate the results in a predictive manner to toxins will also invariably become more prevalent as experimental
another type through commonalities in their molecular con- therapies in veterinary medicine. The use of these novel agents in
stitutions. But what if we want to do the same thing at the combination with traditional cytotoxic chemotherapy will likely
pharmacologic level-to extrapolate and predict drug sensitivity follow the development pathway seen in human oncology, which
based on molecular characteristics of the tumor? These types includes adding these agents to standard protocols in a disease-
of decisions are already being used in human medicine at a specific manner. Thus changes to current standards of practice and
discrete level for the use of antiestrogens in estrogen recep- care should be expected as these newer agents are incorporated
tor–positive breast cancers, 377 and the use of select molecu- and tested.
larly targeted agents based on the mutation/expression status
of target molecules 378,379 ; however, responses to traditional References
chemotherapy agents, which still make up the backbone of
available therapies both in human and veterinary medicine, 1. Chabner BA, Roberts TG: Timeline: chemotherapy and the war on
are more complex and do not generally sort as responders and cancer, Nat Rev Cancer 5:65–72, 2005.
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acteristics. Examples do exist in which this is the case, such as 68:8643–8653, 2008.
overexpression of ABCB1 and the multidrug resistance phe- 3. Sharma SV, Haber DA, Settleman J: Cell line-based platforms to
notype, 380 but generally a multitude of genes involved in drug evaluate the therapeutic efficacy of candidate anticancer agents, Nat
activation, detoxification, DNA repair, stress responses, and a Rev Cancer 10:241–253, 2010.
myriad of other known and unknown pathways play a role in 4. Fowles JS, Dailey DD, Gustafson DL, et al.: The Flint Animal Can-
determining tumor cell chemosensitivity. Therefore a mecha- cer Center (FACC) canine tumour cell line panel: a resource for
nism that can evaluate multiple factors in a tumor indiscrimi- veterinary drug discovery, comparative oncology and translational
medicine, Vet Comp Oncol 15:481–492, 2017.
nately and determine whether it is sensitive or insensitive to a 5. Begleiter A, Lam H-YP, Grover J, et al.: Evidence for active trans-
given chemotherapeutic agent would be an invaluable adjunct port of melphalan by two amino acid carriers in l5178y lympho-
in determining which drugs to use for which individual tumor. blasts in vitro, Cancer Res 39:353–359, 1979.