Page 568 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

546 PART IV Specific Malignancies in the Small Animal Patient

Similarly, the MSTs were not different between control (242 days) microtubule depolymerization might have modest activity for the
and TOC (318 days) groups. 289 management of gross measurable OSA lesions. 294
In addition to cytotoxic agents, TOC has recently evaluated
Increasing the sensitivity of OSA cells to conventional cyto-
VetBooks.ir toxic therapies has the potential to delay the development of meta- for anticancer activity across a broad range of tumor histologies,
Based on the ability of
295
static disease. Suramin, a polysulfonated napthylurea, has shown
including metastatic pulmonary OSA.
promise to increase tumor sensitivity to chemotherapy and has TOC to inhibit multiple signaling pathways, its potential activ-
been evaluated in combination with DOX in 47 dogs with OSA. ity was evaluated retrospectively in 23 dogs with measurable
Suramin was administered at a dose of 6.75 mg/kg IV, and this pulmonary OSA metastases. 296 TOC was orally administered at
was followed 4 hours later with 30 mg/m IV DOX every 14 days a median dose 2.7 mg/kg (every other day or Monday-Wednes-
2
for a total of five treatments. The combination of suramin and day-Friday). A partial response was noted in one dog (4.3%) and
DOX was well tolerated; the median DFI and overall MST were stable disease in 10 dogs (43.5%). Given the initial potential
203 and 369 days, respectively. Although principally a feasibility activity of TOC phosphate in dogs with macroscopic pulmonary
study, the single-arm design precluded any definitive conclusions metastatic disease, its activity was further evaluated in two subse-
to be drawn regarding the ability of adjuvant suramin to augment quent follow-up studies. In one prospective study, 22 dogs with
the anticancer activities of DOX. 290 measurable pulmonary metastases were treated with TOC at a
target dosage of 2.75 mg/kg PO on Monday-Wednesday-Friday
Treating Gross Metastatic Disease schedule. Dogs were reevaluated at weeks 2, 3, 4, and 8 week to
assess for biochemical tolerability, and at 8 weeks for radiographic
Surgery for Gross Metastatic Disease response. In addition to radiographic response, changes in circu-
Resection of pulmonary metastasis from OSA or other solid lating VEGF and Tregs associated with TOC therapy were quanti-
tumors has been reported in dogs and people. 207,291 In one study fied. Nine dogs were withdrawn from study before radiographic
of 36 dogs with metastatic OSA to the lungs, metastasectomy assessment due to reduced quality of life and/or disease progres-
was performed by either local resection or partial or total lung sion. Stable and progressive disease was documented in 17.6%
lobectomy. Chemotherapy was not administered after pulmonary and 83.4% of the remaining dogs, respectively. The median PFS
metastasectomy. Although the initial treatments varied among and overall MSTs were 57 and 89 days, respectively. Circulating
dogs, the overall MST was 487 days. The MST after pulmonary VEGF increased with TOC treatment, but there was no effect on
metastasectomy was 176 days. The criteria established for case Tregs. 297 A second retrospective study in 20 dogs confirmed the
selection for pulmonary metastasectomy to maximize the prob- overall low efficacy of TOC in the treatment of dogs with pulmo-
ability of long survival periods were: (1) primary tumor in com- nary metastases. In this second study, TOC was administered at
plete remission, preferably for >300 days; (2) one or two nodules a median dose of 2.52 mg/kg. A partial response and stable dis-
visible on survey thoracic radiographs; (3) metastasis confined to ease was documented in one dog each for an overall 10% clinical
the lungs (negative bone scan); and perhaps (4) long doubling benefit rate. The median PFS and overall MST were 36 and 90
time (>30 days) with no new visible lesions within this time. In a days, respectively. 298 Based upon these two studies, the anticancer
small series, pulmonary metastasectomy was also effective in ame- activities of TOC as a single agent managing macroscopic OSA
liorating the clinical effects of hypertrophic osteopathy in four metastases is relatively low.
dogs with metastatic appendicular OSA. 292 Strategies to enhance the susceptibility of metastatic cancers
to conventional chemotherapeutic agents have also been inves-
Chemotherapy and Receptor Tyrosine Kinase Inhibitors tigated. By virtue of their chromatin remodeling effects, histone
for Gross Osteosarcoma deacetylase inhibitors (HDACi) used in combination with cyto-
The treatment of gross measurable OSA with conventional cyto- toxic agents may enhance the nuclear accumulation of cytotoxic
toxic agents or receptor tyrosine kinase inhibitors remains unsat- agents and improve therapeutic outcomes. Based on this premise
isfactory. In part, the ineffectiveness of systemic therapies to and a systems biology approach to identifying molecular pathways
cytoreduce gross measurable OSA lesions is likely secondary to altered by HDAC inhibition in OSA, 299 a phase I dose-escalation
drug-resistant clones in conjunction with unfavorable and altered study combining valproic acid and DOX was conducted in dogs
drug biodistribution within large tumor microenvironments. with various spontaneous tumors to determine the tolerability
Because formidable biologic barriers exist within macroscopic and activity of this HDACi-chemotherapy combination. 300 Three
tumors that favor cancer cell survival, the majority of studies dogs with macroscopic OSA pulmonary metastases were treated
demonstrate only marginal effectiveness of conventional cytotoxic with valproic acid and DOX, and one dog achieved durable stable
agents or receptor tyrosine kinase inhibitors for the management disease.
of gross, measurable OSA.
In one study, 45 dogs that had either developed gross meta- Investigational Therapies for Gross Metastatic
static OSA after standard-of-care therapy (amputation and sys- Disease
temic chemotherapy) or diagnosed at presentation with metastatic
OSA were treated with single-agent chemotherapies including Aerosol Drug Delivery
cisplatin, DOX, or mitoxantrone. 293 Only one dog achieved a Two studies have been conducted to evaluate the feasibility, tol-
short-lived (21 days) partial response. These findings suggest that erability, and anticancer activities of aerosolized cytotoxic thera-
conventional cytotoxic agents, which are effective in the adjuvant pies in dogs diagnosed with pulmonary OSA metastases. 301,302 In
setting, are not efficacious for managing macroscopic metastatic one study, six dogs with pulmonary OSA metastasis were treated
OSA. In a second study evaluating the tolerability and antican- with inhaled DOX, paclitaxel, or both every 14 days for a total of
cer activities of paclitaxel in dogs with measurable tumor bur- six treatments. 301 Aerosolization therapy was well tolerated with
dens, two of nine dogs with macroscopic pulmonary metastatic no dose-limiting hematologic or biochemical toxicity; however,
OSA achieved a partial response, suggesting that inhibitors of in dogs treated with aerosolized DOX, pulmonary histologic