Page 569 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 25 Tumors of the Skeletal System 547

changes were identified at necropsy in some patients, consisting of of liposome DNA complexes were substantiated by the induction
toxin-induced pneumonitis, multifocal interstitial fibrosis, alveo- of fever, leukogram changes, monocyte activation, and increased
natural killer cell activities. After completion of 12 consecutive
lar histiocytosis, and type II pneumocyte proliferation. A partial
VetBooks.ir response was documented in two dogs treated with inhaled DOX weekly IV treatments with liposome DNA complexes, measurable
responses were achieved in three dogs with one complete response
and a complete response in one dog treated with inhaled pacli-
taxel. In the one dog with a complete response, the response was and two partial responses.
durable and persisted for more than 325 days. Other investigations have evaluated alternative strategies for
In addition to DOX and paclitaxel, aerosolized gemcitabine activating the immune system, including IV administration of a
has been evaluated in dogs with metastatic OSA. Gemcitabine, genetically modified and attenuated bacterial species, Salmonella
a pyrimidine antimetabolite belonging to the nucleoside analog typhimurium (VNP20009). 306 Based on the premise that anaero-
family, has anticancer activity when administered through an aero- bic bacteria have potential as novel immunomodulatory cancer
solized route in mouse OSA xenograft models; these are mediated therapeutics, a phase I dose escalation study was conducted with
though the upregulation of Fas receptor expression on the surface VNP20009 in 41 dogs with spontaneous cancers. Dose-limiting
of pulmonary metastatic OSA cells. 303 Because lung epithelium toxicity included fever and vomiting; both were attributed to sys-
basally expresses Fas ligand, the restoration of Fas receptor expres- temic immune activation. Importantly, preferential tumor tissue
sion by OSA cells would consequently render them susceptible to tropism of VNP20009 was confirmed by gene transcription and
Fas receptor/Fas ligand-mediated apoptosis. Based on this preclini- bacterial culture techniques in a substantial proportion of tumor
cal information, a comparative study with aerosolized gemcitabine samples. In a subset of four dogs with OSA pulmonary metastasis,
was conducted in 20 dogs with pulmonary OSA metastasis. 302 one dog had a partial response for a duration of 68 days.
Dogs were treated twice weekly with inhalation gemcitabine and
monitored for toxicity and anticancer activity. Aerosolized gem- Palliative Treatment: Primary and Metastatic
citabine was well tolerated with no dose-limiting hematologic or Bone Cancer Pain
biochemical toxicity reported and minimal histologic lung pathol-
ogy after inhalation therapy. Mechanistic anticancer activities of Palliative Radiation Therapy
aerosolized gemcitabine were supported by the identification of RT is considered the most effective treatment modality for the
increases in percent necrosis, Fas receptor expression, and TUNEL management of osteolytic bone pain in human cancer patients
positivity in macroscopic pulmonary OSA metastatic lesions; and, likewise, has been investigated and extensively applied for
however, clinically relevant responses were not documented. alleviating bone cancer pain in dogs with primary bone tumors.
Mechanistically, the analgesic effects of ionizing radiation can be
Augmentation of Antitumor Immunity partially attributed to the induction of cell death in both malig-
Cytokines are cellular peptides that actively aid or stimulate the nant osteoblasts and resorbing osteoclasts, 307 and this has been
immune system to recognize and attack cancer cells. Although documented in dogs by an assessment of percentage TN. 205,239,308
numerous cytokines participate in shaping the strength, specific- As such, ionizing radiation may reduce overall tumor burden and
ity, and longevity of antitumor immune responses, interleukin-2 attenuate the degree of osteoclast resorption. The rapid onset of
(IL-2) is a critical cytokine necessary for stimulating the growth, analgesia that occurs before a change in tumor volume suggests
differentiation, and survival of antigen-specific cytotoxic T cells. other, as yet unknown, mechanisms are involved in the analgesic
Additional immune effects orchestrated by IL-2 include the effects of RT. Other proposed mechanisms of radiation-induced
facilitation of immunoglobulin production by B cells and the dif- analgesia include depletion of local inflammatory cells and inhibi-
ferentiation and proliferation of natural killer cells. Despite the tion of osteoclast precursor recruitment. 309
pleiotropic and desirable antitumor immune activities of IL-2, its Multiple palliative RT protocols have been evaluated and
systemic administration has been clinically limited due to severe reported in the veterinary literature with the majority of dosing
toxicities. As such, alternative delivery strategies have been inves- schemes using two to four fractions of 6 to 10 Gy. Although vari-
tigated to attenuate IL-2 associated toxicities yet maximize its able and subjectively reported in these studies, the alleviation of
potent immunomodulatory effects. bone cancer pain was achieved in 74% to 93% of dogs. Although
For the treatment of pulmonary metastasis, the localized depo- the majority of dogs symptomatically improved after palliative
sition of IL-2 or the preferential gene expression of IL-2 within RT, the median time interval of subjective pain alleviation was
the lung parenchyma has been investigated as a novel treatment not durable and ranged from 53 to 130 days. 234,310–314 Given that
option in dogs with metastatic OSA. Initial studies evaluated the most conventional palliative RT protocols only include two to
antitumor activities of inhaled liposomal IL-2. 304 Dogs were nebu- four fractions, the total cumulative radiation dose administered is
lized with liposomal IL-2 daily for 30 days. The immunomodula- relatively low (<32 Gy). As a result, acute and late radiation toxici-
tory effects of IL-2 were confirmed by increases in bronchoalveolar ties are not a limiting factor for the majority of patients treated.
lavage effector cell numbers and lytic activities with resultant com- Although megavoltage palliative RT appears effective when used
plete regression of macroscopic pulmonary OSA metastasis in two as a single-agent treatment option for short-term pain manage-
of four dogs. The duration of this response was between 12 and ment, some investigations suggest that the concurrent administra-
20 months. IV gene therapy as liposome-DNA complexes encod- tion of IV systemic chemotherapy along with palliative RT may
ing IL-2 has also been investigated as an alternative to inhaled enhance analgesic response rates, durations of responses, and over-
liposomal IL-2 delivery strategies. 305 Based on its preferential all STs. 313,315
accumulation and subsequent transgene expression within the
lung parenchyma, the tolerability, immunomodulatory effects, Radiopharmaceuticals
and antitumor activity of IV liposome DNA complexes encoding 153 Sm is a radioisotope that undergoes gamma (103 keV) and
IL-2 were evaluated in 20 dogs with chemotherapy-resistant OSA beta decay (max 810 keV), allowing for concurrent biodistribu-
metastasis. After administration, the immunomodulatory effects tion tracking studies as well as therapeutic ionizing radiation