Page 319 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 16 Supportive Care for the Cancer Patient 297

Moreover, they are able to trigger lipocortin synthesis and thus Zoledronate is now preferred because of its 100-fold greater anti-
block the production of eicosanoids, such as prostaglandins. 152–155 resorptive potency relative to pamidronate and more rapid infu-
sion rate. It is dosed at 0.1 mg/kg, diluted in physiologic saline,
This pharmacologic targeting can exert an effect both on the
VetBooks.ir PNS and on the CNS because free steroids can cross the blood- and administered as a CRI over 15 minutes. Many practitioners
Currently, in human patients, the evidence
155,156
brain barrier.
give a maximum dose of 4 mg per dog. The infusion time is
is conflicting on the usefulness of steroids for preventing pain- important; longer or shorter treatment times may increase the risk
ful conditions such as acute or recurrent migraines. 157–159 Studies of nephrotoxicity. 177
in neuropathic pain models in rodents have demonstrated that At odds with the fact that clinically apparent analgesic benefit is
steroids could inhibit or attenuate this pain, but the underlying often in excess of a month, many veterinary oncologists currently
mechanism remains unknown. 160,161 Steroid use has been shown recommend that bisphosphonate injections be repeated at 3- to
to provide analgesia in certain human cancer patient subpopula- 5-week intervals. Although this dosing regimen is not substanti-
tions, including those with bone cancer, spinal cord compression, ated by investigations of how bisphosphonate therapy modifies
or brain tumors. 162–166 Likewise, corticosteroids may provide ben- the biomechanical integrity of bone having undergone malignant
efit to veterinary cancer patients, including those with ulcerated or osteolysis or by clinical data reflecting the effect of such therapy on
inflamed cutaneous mast cell tumors or with cerebral edema sec- the risk of pathologic fracture, one hope for such frequent admin-
ondary to intracranial neoplasia. However, the analgesic utility of istration is that modulation of bone turnover will reduce the risk
drugs such as prednisone and dexamethasone have not been sys- of pathologic fracture. In addition to the inhibitory effects of
tematically evaluated in dogs and cats with cancer, and nuisance bisphosphonates on osteoclasts, in vitro reports suggest that they
side effects (polyuria/polydipsia, panting, behavioral changes, may also exert directly beneficial effects on cancer cells, including
anxiety) have the potential to diminish QOL in a substantial frac- canine osteosarcoma (OSA) and fibrosarcoma lines. 178,179 Hence,
tion of treated patients. Additionally, exogenous steroids should the intent to maximize potential antineoplastic effects also has
not be used concurrently with NSAIDs because this dramatically been proffered as a rationale for ongoing monthly administration
increases the risk of side effects, especially gastrointestinal ones. of bisphosphonates. However, caution must be exercised, because
the preclinical data is inconclusive and conflicting. For example,
Bisphosphonates one recent publication describing experiments performed in a
canine OSA xenograft model suggests that zoledronate therapy
Malignant bone disease creates a unique pain state with a neu- may actually increase the incidence of pulmonary metastasis. 180
robiologic signature distinct from that of inflammatory and To better define the ideal treatment protocol, clinical trials are
neuropathic pain. 167–169 Bone cancer–related pain is thought to underway investigating the effect of monthly zoledronate admin-
be initiated and perpetuated by dysregulated osteoclast activity istration on metastatic propensity in canine OSA. Such compara-
and activation of nociceptors by prostaglandins, cytokines, and tive oncologic studies of zoledronate’s potential influence in canine
hydrogen ions released within resorptive pits. Therapies that block OSA metastatic progression might help explain the absence of
osteoclast activity not only have the potential to markedly reduce benefit exerted by adjuvant zoledronate in the upfront setting of
bone pain, but may also mitigate other skeletal complications pediatric OSA. 181
associated with neoplastic conditions, including pathologic frac-
tures, neuronal compression, and hypercalcemia of malignancy. Palliative-Intent Radiation Therapy
Bisphosphonates are synthetic analogs of pyrophosphate, and
their primary effect is to inhibit osteoclast activity through inhibi- RT often is administered with the goal of controlling cancer.
tion of the mevalonate pathway. Bisphosphonates accumulate in Because higher doses of radiation typically are associated with a
metabolically active bone by virtue of their chemical structure, higher probability of favorable tumor control, definitive-intent
and after osteoclast-mediated bone resorption, they are released RT protocols are intensive and typically involve delivery of large
and disrupt cellular functions, resulting in osteoclast death. The total doses of radiation to the tumor. In this situation the goal is
antiresorptive activities of bisphosphonates has been demon- to maximize the antineoplastic efficacy of RT. By contrast, some
strated in normal and cancer-bearing dogs by means of a reduc- patients are irradiated with the primary goal of reducing cancer-
tion in urine N-telopeptide excretion and enhanced bone mineral associated symptoms, including cancer pain. Palliative-intent
density. 170 This activity contributes to the risk of osteonecrosis, RT can be given using a variety of administration techniques.
which is most frequently reported in the mandible. 171,172 Man- For example, samarium is a radioisotope that has been evalu-
dibular osteonecrosis is uncommonly reported in tumor-bearing ated for use in dogs. 182 Although the use of samarium Sm153
dogs that are being treated with bisphosphonates, 173 and it is this lexidronam in veterinary medicine is still limited, the results of a
activity which is also the mechanism likely responsible for signifi- noncontrolled clinical study with subjective assessments reported
cant analgesia that may last for several months in approximately improvement in lameness scores in 63% of dogs, suggesting that
30% of dogs treated with injectable bisphosphonate drugs. 170,174 this therapy may be useful in the palliation of pain in dogs with
Oral absorption of bisphosphonates tends to be poor, and IV bone tumors in which curative-intent treatment is not pursued. 183
dosing is the preferred route of administration in dogs and cats. External beam RT is most commonly applied. Regardless of the
In human cancer patients potential acute adverse effects include delivery system, the dose-response relationships for radiation-
nephrotoxicity, electrolyte abnormalities, and acute-phase reac- induced reductions in cancer pain have not been well studied, but
tions 175,176 ; however, it is the experience of the author (TF) that they are not necessarily the same as the dose-response relationships
these notable toxicities are not observed in companion animals for tumor control. In fact, they are likely quite different. This is
receiving IV bisphosphonate therapies. For many years pamidro- exemplified by the fact that malignant bone pain in humans often
nate was the drug of choice for dogs with malignant bone pain. It can be effectively treated with low total dose, hypofractionated
may be administered at a dosage of 1 to 2 mg/kg over 2 hours as a radiation protocols. For example, high-quality data shows that the
constant rate infusion ([CRI] diluted in saline) every 3 to 4 weeks. pain relief associated with a single 8 Gy fraction is equivalent to