Page 289 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

268 PART III Therapeutic Modalities for the Cancer Patient

common with metronomic therapy. 304,288,289 These toxicity results volume and permeability measurements in canine intracranial
echo the finding that cumulative dose is a risk factor for SHC in masses using this modality. 319
The area of dose optimization also represents an unmet need for
Close urinary
305
dogs with lymphoma treated with MTD CYC.
VetBooks.ir monitoring is strongly recommended for patients receiving MC, biomarkers in antiangiogenic and metronomic chemotherapy. In
and recent studies demonstrate reduced SHC with concurrent use
the absence of dose limiting toxicities, the choice of drug dose may
of furosemide as a preventative therapy. 306,307 Chlorambucil has be highly empirical without information on target modulation.
also been used as an alternative to CYC that negates the risk of The assessment of Treg may provide insight as a dose optimiza-
SHC. With these drugs and any type of therapy intended to be tion biomarker. A study that utilized serial sampling in canine soft
administered continuously for long periods of time, adverse events tissue sarcoma demonstrated dose-dependent reduction in Treg
2
associated with cumulative dosing must be investigated, as these with MC treatment. Reduced Treg were observed at 15 mg/m
side effects may not be observed in more commonly reported but not 12.5 mg/m doses, leading to the conclusion that 15 mg/
2
short-term clinical trials. m may be a more appropriate dose for future clinical trials. 268 In
2
Although not initially expected, acquired resistance to anti- addition to Treg levels, temporal evaluation of other markers has
angiogenic therapy has become evident from clinical trial results. been studied. Assessment of CECs and/or CEPs has been applied
Given the genetically stable nature of the blood vessel/EC tar- for biomarker analysis of dosing antiangiogenic and metronomic
get compared with the mutation-prone cancer cell population, therapy. 320–322 For example, in the study by Rusk and colleagues,
antiangiogenic treatment was originally postulated to be less decreasing CEC levels in dogs treated with the thrombospondin-1
likely to demonstrate drug resistance. 308 Proposed mechanisms mimetic peptide ABT-526 may have indicated adequate exposure
of resistance to antiangiogenic therapies involve both tumor and to the antiangiogenic drug, which in this study was utilized at a
host-mediated pathways that can be intrinsic or induced by treat- single dose. 227 However, total CEC levels were not associated with
ment. 309 One alarming consequence of antiangiogenic treatment soft tissue sarcoma response to TSP peptides in another trial. 228
that emerged from preclinical studies with certain antiangiogenic Finally, in dogs with solid tumors, temporal increases in plasma
RTKIs is the potential to alter the host microenvironment (e.g., VEGF over 30 days of TOC treatment occurred at doses consider-
in the lungs), leading to metastatic conditioning. 310,311 This phe- ably lower than the FDA-approved MTD. 323 These results suggested
nomenon of increased invasion and metastasis as a result of anti- that biologic activity of TOC through VEGF pathway inhibition
angiogenic drug treatment was observed with sunitinib, an RTKI occurs within an optimal dose range that has an improved adverse
with a similar target spectrum to TOC. 311 However, a randomized event profile compared with the MTD. Blood pressure changes may
clinical trial of TOC used in the adjuvant setting for canine OSA also reflect the biologic activity of this class of drugs and measuring
revealed no difference in the disease-free interval. 290 hypertension has also been suggested as a surrogate biomarker for
VEGF pathway inhibitors, including TOC. 324,300
Biomarkers
Conclusion
The incorporation of biomarkers into clinical decision making is
increasingly important in the era of targeted therapeutics. 312 The Numerous forms of conventional and targeted cancer therapies
aims of validated biomarkers include (1) predicting patients who produce antiangiogenic effects that may contribute to their overall
will or will not respond to treatment, (2) monitoring response to efficacy, and the field of tumor angiogenesis has come of age with
therapy, or (3) determining the therapeutic dose for agents that the successful application of drugs that inhibit the VEGF receptor
often possess optimal biologic activity at doses well below the tra- and other relevant pathways. The metronomic application of che-
ditionally defined MTD. The use of validated biomarkers to guide motherapy has antiangiogenic effects and demonstrates significant
the application of antiangiogenic agents is relevant in all three of immunomodulatory activity that warrants further study, particu-
these areas. larly in combination with other targeted approaches. However,
Tumor tissue expression and/or blood-based circulating growth well-powered prospective clinical trials to evaluate efficacy are
factor levels have been the most popular approaches to predicting currently lacking. Optimization of drug choices, combinations,
response to antiangiogenic treatment, with VEGF being the most and tumor applications remain as significant challenges, as does
studied molecule. 313–315 For example, in a pilot study of MC and the emergence of drug resistance. Biomarker research may provide
celecoxib therapy in 15 dogs with various cancers, low baseline insight into patients that are more likely to benefit, optimal dos-
plasma VEGF was predictive of response. 316 The temporal com- ing for agents with activity below the MTD, and predict clinical
parison of pretreatment with posttreatment levels may provide benefit that may often manifest as sustained stable disease.
the most useful information for certain surrogate biomarkers, as
was demonstrated with urinary bFGF and VEGF with piroxicam
treatment of canine TCC. 242,243 Biomarkers that are particularly SECTION D: NOVEL AND EMERGING
valuable for antiangiogenic therapy may be those that define THERAPEUTIC AGENTS
tumor response because inhibiting angiogenesis does not neces-
sarily result in reduced tumor volume in the short term. A static
tumor response sharply contrasts that observed with successful DOUGLAS H. THAMM AND
MTD chemotherapy approaches that result in overt measurable DAVID J. ARGYLE
tumor shrinkage. Imaging modalities that can provide informa-
tion about vascular function are potentially valuable tools for The recent explosion in available tumor bioinformatic informa-
monitoring tumor angiogenesis and the effects of antiangiogenic tion, rational and combinatorial drug design, and high-through-
therapy. 317 Dynamic contrast-enhanced MRI (DCE-MRI) has put drug screening have resulted in a massive increase in potential
been studied for its ability to quantitatively assess vascular param- therapeutic targets and anticancer treatment strategies. An exhaus-
eters. 318 A study by MacLeod and colleagues demonstrated blood tive survey of all potential novel targets for cancer therapy would