Page 570 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

548 PART IV Specific Malignancies in the Small Animal Patient

delivery within a 2 to 3 mm deposition radius. When 153 Sm is Given that OSA is characterized by focal and aggressive malig-
conjugated to EDTMP, which is a bisphosphonate, the resultant nant osteolysis, the investigation of NBPs has been a focus of
153 Sm-EDTMP compound preferentially concentrates in areas of clinical interest. The first reported description in the veterinary
VetBooks.ir increased osteoblastic activity and binds to exposed hydroxyapa- literature was the use of oral alendronate for the palliative man-
316
By virtue of its osteotropism and defined radius of
agement of two dogs with OSA.
tite crystals.
Based upon the unexpectedly
332
ionizing radiation deposition, 153 Sm-EDTMP is currently used as long STs reported in this anecdotal study, the authors suggested
a radiopharmaceutical for the palliative treatment of multifocal that NBPs therapy may have a role in managing dogs malignant
skeletal metastases in people with breast or prostate carcinoma. 317 bone diseases. Given that IV NBPs have been historically used for
Similar to people diagnosed with skeletal malignant osteoly- the management of malignant osteolysis in people, a prospective
sis, the use of 153 Sm-EDTMP has been investigated for alleviating study principally evaluating the safety of IV pamidronate (PAM)
bone cancer pain in dogs with appendicular and axial OSA. 318–322 was conducted in 33 dogs diagnosed with primary and secondary
In dogs treated with 153 Sm-EDTMP, the predicted radiation dose skeletal tumors. 333 IV PAM (1.0 mg/kg diluted with 0.9% sodium
equivalent achieved within the immediate bone tumor microen- chloride to a total volume of 250 mL) as a 2-hour constant rate
vironment has been estimated to approximate 20 Gy, 318 although infusion (CRI) every 28 days was well-tolerated and, in a subset of
its intratumoral biodistribution is expected to be nonhomogenous dogs, the bone biologic and clinically relevant therapeutic effects
based upon regional differences in reparative osteoblastic activi- of IV PAM were documented with significant reductions in urine
ties. After IV 153 Sm-EDTMP administration, the 63% to 83% N-telopeptide (NTx) concentrations, increases in relative primary
of dogs with OSA demonstrate improved lameness scores and tumor bone mineral density (rBMD) as assessed by dual-energy
activity levels, suggesting palliation of pain. 318–321 In axial skeletal x-ray absorptiometry (DEXA), and subjective pain alleviation.
lesions, four dogs were documented to have an improvement at After the established safety of IV PAM in dogs with skeletal
21 days posttreatment based on reduced tumor size or improved tumors, a second study of 43 dogs treated with IV PAM (1.0
clinical signs, whereas 13 dogs had progressive disease based on mg/kg versus 2.0 mg/kg) was conducted to further characterize
worsening of clinical signs or tumor growth. 322 the biologic activity of PAM specifically for the management of
177 Lutetium ( 177 Lu) is an isotope that emits gamma photons appendicular OSA associated bone pain and pathologic bone
(208 keV) and beta particles (max 497 keV). 177 Lu has been inves- resorption. 334 Overall, 28% of 43 OSA-bearing dogs achieved
tigated when complexed with EDTMP or DOTMP, a macrocy- pain alleviation for more than 4 months. In addition to the sub-
clic analog of EDMTP. 266 177 Lu is proposed to offer greater bone jective analgesic effects of PAM reported by pet owners, changes in
marrow sparing effects in comparison to 153 Sm-EDTMP due to urine NTx concentrations and DEXA-assessed rBMD correlated
a lower soft tissue penetration of 670 μm. The toxicity profile of with therapeutic response.
177 Lu-DOTMP has been evaluated in normal dogs and no sig- Although original studies have focused on the palliative effects
nificant changes in platelet or white cell counts were observed, of PAM when used as a single-agent, a recent study documented
but mild changes in red cell counts were noted on day 84. 323 A the synergistic activity of PAM when coupled with palliative RT
pilot study was performed in four dogs with primary or metastatic in dogs with appendicular OSA. 335 In a prospective, double-blind,
skeletal lesions, and analgesic effect was demonstrated in three randomized, placebo controlled clinical trial, 17 dogs with appen-
dogs. 324 In human patients, 177 Lu-EDTMP appears equally effec- dicular OSA were treated with palliative RT (8 Gy on days 1 and 2)
tive at inducing analgesia compared with 153 Sm-EDTMP with a and either 0.9% saline infusion or PAM once every 4 weeks for
similar toxicity profile. 325 three treatments. Before initial palliative RT and after each IV
treatment with either 0.9% saline or PAM, all dogs were evaluated
Aminobisphosphonates by force plate gait analysis, urine NTx concentrations, numerical
Aminobisphosphonates (NBPs) are synthetic analogs of inorganic lameness evaluation, and owner quality of life (QOL) question-
pyrophosphate that were initially utilized for diagnostic purposes naires. The saline placebo group dogs experienced a significant
in bone scanning based on their ability to preferentially adsorb increase in numerical lameness score between weeks 0 and 12,
to sites of active bone mineral remodeling. The pharmaceutical and PAM significantly lowered the lameness scores on week 12
use of NBPs has gained wide acceptance in the therapy of human compared with saline. In addition, dogs receiving PAM had a sig-
nonneoplastic bone resorptive disorders such as osteoporosis and nificantly greater vertical impulse and total stance time from week
Paget’s disease. 326 In addition to the management of these meta- 4 to week 12. Based on these findings, the addition of PAM to
bolic disorders, NBPs are considered first-line options for the palliative RT appeared to improved limb function compared with
treatment of malignant skeletal osteolytic conditions, including palliative RT alone.
paraneoplastic hypercalcemia, multiple myeloma, and metastatic In a double-blind, placebo-controlled study, 50 dogs with OSA
bone diseases in human cancer patients. 327,328 were treated with palliative RT, DOX, and either a saline placebo
The effective treatment of bone disorders by NBPs is attrib- or PAM . 336 The median pain-free intervals for dogs treated adju-
uted to their differential effect on bone resorption and bone min- vant PAM or saline was 76 days and 75 days, respectively. Despite
eralization. At concentrations safely achievable in vivo, NBPs the apparent lack of pet owner-perceived analgesia, dogs treated
inhibit bone resorption without inhibiting bone mineralization. with adjuvant PAM had better QOL scores and, more impor-
Mechanistically, the bone protective effects exerted by NBPs are tantly, decreased malignant bone resorption in the primary tumor.
through the induction of osteoclast apoptosis, which results in the Collectively, these findings suggest that adjuvant PAM may not
net attenuation of pathologic bone resorption. 329,330 Specifically, subjectively improve analgesia when dogs are already receiving
NBPs interfere with posttranslational prenylation of small GTP- treatment with megavoltage RT and DOX, but PAM still exerts
binding proteins, including Ras, Rho, and Rac. 331 The disruption beneficial bone biologic effects within the bone tumor microenvi-
of these small GTP-binding protein results in the failure of nor- ronment in dogs with OSA.
mal intracellular signaling and interaction with the extracellular Although most palliative studies have documented the effects
matrix, thereby triggering osteoclast apoptosis. of PAM, other more potent IV NBPs for managing malignant