Page 687 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 31 Tumors of the Nervous System 665

persistent hypercortisolinemia for up to a year after RT. 80,113,116 neuronavigational systems with various tissue resection devices
Thus continued medical management and serial endocrinologic and techniques are being actively investigated for the surgical
The safety
7,9,58,84
biopsy and treatment of canine brain tumors.
evaluations are necessary after RT of PDH. Negative prognostic
VetBooks.ir indicators associated with RT for pituitary masses include severe and feasibility of brain tumor ablation techniques using lasers
neurologic dysfunction at presentation and large relative tumor
and pulsed electrical fields have also been demonstrated in canine
size. 80,115 gliomas. 119 Technologies capable of focally disrupting the BBB to
SRT is actively being investigated for the treatment of mul- allow for CNS drug delivery, such as transcranial focused ultra-
tiple types of brain tumors. SRT offers the distinct advantage of sound and irreversible electroporation, are also being used to treat
a reduced number of anesthetic episodes required for treatment. canine brain tumors. 119
However, SRT is associated with limitations as to the size of Approaches that bypass the BBB and allow for direct intra-
masses that can be treated (likely several centimeters) and it is tumoral delivery of therapeutically relevant concentrations of
not suitable for treating residual microscopic disease after sur- macromolecular drugs, such as convection-enhanced delivery
gery. Preliminary data suggest that SRT results in tumor con- (CED) of chemotherapeutics and implantation of various bio-
9
trol that is comparable to standard fractionated RT protocols degradable nanomaterial drug carriers, have also been investi-
with potentially fewer short-term adverse effects and, in the case gated in dogs. CED of nonselective chemotherapy drugs, such
of pituitary tumors, provide results that are similar to those of as liposomal CPT-11, and novel agents targeting the overex-
hypophysectomy. 111,115–117 pression of cell surface EGFR (EGFRvIII-antibody biocon-
Approximately 10% of brain tumor cases treated with RT will jugated nanoparticles), EphA2, and IL-13RA2 (recombinant
78
experience treatment-related mortality or adverse effects. Fre- bacterial cytotoxins) receptors that occur in canine and human
quently reported adverse effects include aspiration pneumonia, gliomas, have been performed in dogs with glioma. 7,9,67,119–121
pulmonary thromboembolism, acute CNS toxicity which often These studies have illustrated the safety of the CED procedure
manifests as a decreased level of consciousness, damage to organs and have provided preliminary evidence of efficacy of these
in the treatment field including deafness, cataract formation, and investigational agents.
keratitis, and late-onset radiation necrosis. Important radiobio- There is a considerable library of targeted agents being
78
logic considerations when treating brain tumors include the radia- develop for and tested in canine brain tumors, and these agents
tion dose per fraction, total radiation dose, and the volume of the encompass a wide variety of mechanistic approaches includ-
brain irradiated. In one study of hypofractionated RT, delivery of ing protease-conjugated oncolytic viruses, immunomodulatory
a high dose per fraction resulted in the death of nearly of 15% of microRNAs or small interfering RNAs, immune-checkpoint
treated dogs because of suspected delayed radiation side effects. 110 inhibitors, apoptosis promoters, radiosensitizing agents, and
Although significant adverse events associated with SRT have nanoparticular cytotoxic drugs. These compounds have shown
been uncommonly reported in animals to date, the more frequent promising antitumor effects in vitro or in vivo against non-CNS
use of high-dose per fraction prescriptions may eventually influ- tumors, the ability to penetrate the BBB when administered
ence the incidence of observed toxicity. systemically, or favorable safety and pharmacokinetic profiles in
healthy dogs, and are currently in early phase trials in dogs with
Novel Therapeutics tumors. 7,9,122,123 In a proof-of-concept trial, bacterially derived
The identification and use of novel animal models that allow for minicells were packaged with doxorubicin, targeted to EGFR
the study of fundamental cancer drug and device development using bispecific antibodies to EFGR, and administered intrave-
questions would meet a critical and shared need among stake- nously to dogs with brain tumors. Durable and objective tumor
holders in the cancer research and global healthcare communities. responses were seen in 24% of dogs and no significant toxicities
A growing body of evidence indicates that canine brain tumors were observed. 123
are clinically, phenotypically, and molecularly similar to their There has been a paradigm shift away from the brain being con-
human analogs, thus providing unique avenues for preclinical sidered an immune-privileged organ unfavorable to immunothera-
discovery. 7,9,10,118 Translational studies of investigational agents peutic (IT) interventions toward an elucidation and exploitation of
in tumor-bearing dogs can provide a variety of pharmacokinetic, the unique mechanisms that characterize immunocompetency and
mechanistic, toxicity, and antitumor activity data in an immuno- tumor–host interactions within the brain. A diverse array of IT strate-
competent host, and thus offer numerous opportunities to guide gies, whose unifying goal is to introduce, stimulate, or otherwise aug-
the therapeutic development process to mutually improve the lives ment the patient’s T-cell–mediated immune response against cancer
of dogs and humans with brain tumors. 118 cells, are being explored for use in the treatment of companion ani-
The repertoire of agents and techniques that are being inves- mal brain tumors. IT approaches that involve tumor vaccinations
7,9,
tigated in canine brain tumors is rapidly expanding. General with stimulated patient-derived dendritic cells and autologous tumor
areas that capture the efforts of active veterinary neuro-oncology lysates combined with toll-like receptor ligands have demonstrated
research programs can be summarized into (1) macroscopic tumor the safety, feasibility, and potential efficacy of IT for use in canine
targeting or CNS delivery techniques, (2) novel molecular thera- glioma and meningioma. 7,9,93,97
peutics targeting tumor-specific markers or aberrant cellular path- Recent studies have provided data that indicates that novel
ways, (3) immunotherapy, and (4) modifications of the dosing or repurposing approaches using existing drugs are capable of achiev-
chemistry of existing therapeutics based on new mechanistic dis- ing intratumoral drug concentrations that may result in favorable
coveries. Reviews of early-phase trials evaluating these approaches therapeutic and adverse effects profiles compared with traditionally
in dogs with brain tumors are available. 7,9,119 administered doses or other chemotherapy agents with the same
84
The objectives of macroscopic tumor targeting techniques are mechanism of action. An in vitro study of benzimidazole anthel-
to facilitate the gross surgical resection of tumors or to overcome mintics in canine glioma cell line demonstrated that drug treatment
therapeutic drug delivery limitations imposed by the BBB. The increased depolymerization of tubulin and increased tumor cell
use of intraoperative microsurgical or stereotactic equipment and apoptosis compared with the controls. 124