Page 566 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

544 PART IV Specific Malignancies in the Small Animal Patient

improve the outcome in dogs with OSA. In one study, the safety chemotherapy. In one retrospective study of 30 dogs treated with
and efficacy of adjuvant chemotherapy, consisting of two doses amputation, dogs received one of two chemotherapy protocols
2
(carboplatin alone [300 mg/m IV every 21 days for six cycles] or
2
of DOX (30 mg/m or 1 mg/kg in dogs <15 kg) given 2 weeks
VetBooks.ir apart, followed by four consecutive doses of carboplatin (300 mg/ alternating carboplatin [300 mg/m IV] and DOX [30 mg/m IV]
2
2
2
m ) every 3 weeks, was evaluated retrospectively in 33 dogs after
every 21 days for a total of five treatments [three carboplatin and
amputation. Tolerability to this protocol was reasonable with the two DOX]) and concurrent daily piroxicam (0.3 mg/kg PO) and
2
greatest hematologic toxicity occurring post-DOX administra- cyclophosphamide (10–12 mg/m PO). The initiation of combi-
tion; approximately 10% of dogs experienced grade III or IV neu- natorial systemic therapies was started 2 days postamputation and
tropenia. Similarly, 16% of dogs experienced grade III to IV GI metronomic chemotherapy continued indefinitely after the com-
toxicity. The drug combination also exerted anticancer activities pletion of systemic chemotherapy. Although adverse side effects
with dogs achieving median DFI and overall MST of 232 and 247 were tolerable for both combinatorial protocols, grade III to IV
days, respectively. 278 toxicities were more commonly observed in dogs treated with car-
In another study, 38 dogs were treated with amputation and a boplatin alone plus piroxicam/cyclophosphamide therapy. No sig-
combination of three doses of DOX (30 mg/m or 1 mg/kg in nificant difference in DFI was identified between the protocols. 281
2
dogs <15 kg) every 14 days, followed by three consecutive doses of In a second study, the potential benefit of metronomic cyclo-
2
2
carboplatin (300 mg/m for dogs ≥15 kg or 250 mg/m for dogs phosphamide and meloxicam administered as a maintenance
<15 kg) every 21 days. This combinatorial strategy was tolerable therapy after amputation and carboplatin was evaluated retrospec-
with 5.2% of dogs requiring hospitalization for complications tively in 39 dogs. Carboplatin therapy (300 mg/m IV every 21
2
associated with toxicity. Additionally, anticancer activity were days for four to six cycles) was started 10 to 14 days postampu-
comparable to most treatment protocols with dogs achieving a tation. Of the 39 dogs evaluated and treated with carboplatin,
MST of 317 days and 1- and 2-year survival rates of 43.2% and 19 dogs were treated with maintenance metronomic cyclophos-
2
13.9%, respectively. 279 phamide (15 mg/m PO daily) and meloxicam (0.1 mg/kg PO
daily), and the remaining 20 dogs were not treated with mainte-
Head-to-Head Comparison Studies nance metronomic chemotherapy. Sterile hemorrhagic cystitis was
Despite multiple published studies evaluating the anticancer reported in 58% of dogs treated with metronomic chemotherapy.
activities of carboplatin, DOX, or the combination in dogs with The median progression-free (PFS) and MST were 402 and 464
OSA, few investigations can offer prescriptive recommendations days, respectively. Though dogs receiving maintenance metro-
on the best adjuvant treatment options, either due to insufficient nomic chemotherapy did achieve longer median PFS (480 days)
power as a consequence of small study populations or limited and MST (480 days) than dogs treated with carboplatin alone
study design being either retrospective in nature or the absence of (244 days and 458 days, respectively), the differences were not
relevant contemporaneous comparator arms. To address some of statistically significant. 282
these limitations, two recent studies have been published. The first
investigation, although retrospective in nature, included a large Chemoimmunotherapy
number of dogs with OSA treated at a single institution and com- Harnessing and directing the immune system is a highly desirable
pared carboplatin and DOX-based chemotherapy protocols in anticancer strategy. Despite the various forms of immunothera-
470 dogs after amputation. Five different chemotherapy protocols pies, such as monoclonal antibodies and dendritic cell vaccines,
were compared for tolerability and anticancer effects: carboplatin currently used for the treatment of metastatic tumors in people,
2
300 mg/m IV every 21 days for four or six cycles; DOX 30 mg/ only a few canine immunotherapy studies have been conducted
2
m IV every 14 or 21 days for five cycles; and alternating carbopla- as randomized, double-blind trials. The best documented and
2
tin 300 mg/m IV and DOX 30 mg/m IV every 21 days for three clinically effective immunotherapy trials for dogs with OSA have
2
cycles. Overall, the median DFI and MST were 291 and 284 days, evaluated the anticancer immune effects of liposome-encapsulated
respectively. Although no chemotherapy protocol proved superior, muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE).
a lower proportion of dogs treated with six cycles of carboplatin Being a lipophilic derivative of muramyl dipeptide, a synthetic
experienced adverse effects, necessitating treatment delay, dose analog of a Mycobacterium cell wall component, L-MTP-PE
reduction, or hospitalization. 208 has been demonstrated to augment canine alveolar macrophage
In a second study, carboplatin and alternating carboplatin and tumoricidal properties with enhanced cytotoxicity against OSA
DOX were evaluated in a randomized, open-label trial study. Dogs cells in vitro. 283
were treated with either six doses of carboplatin (300 mg/m IV) In an initial clinical study of 27 dogs, the single-agent activ-
2
every 3 weeks or three cycles of alternating carboplatin (300 mg/ ity of IV L-MTP-PE was assessed immediately after amputation.
m IV) and DOX (30 mg/m IV) every 3 weeks. Of the 50 dogs Dogs were treated twice weekly with either L-MTP-PE or empty
2
2
recruited at a 1:1 ratio for either carboplatin alone or alternating liposomes for 8 weeks. Dogs treated with L-MTP-PE had a sig-
carboplatin and DOX, 32 dogs completed their planned chemo- nificantly longer median DFI (168 days) than dogs treated with
therapy protocols and the remaining 18 dogs developed metastatic empty liposomes (58 days). Similarly, the MST was significantly
disease before completion of their targeted chemotherapy course. longer for dogs treated with L-MTP-PE (222 days) than for dogs
Toxicity was similar in both treatment arms. Dogs treated with treated with empty liposomes (77 days). 284 Based upon these
carboplatin alone had a significantly longer DFI (425 days) than findings, it was concluded that L-MTP-PE induced beneficial
dogs treated with the alternating protocol (135 days). 280 immunobiologic effects capable of delaying the development of
pulmonary metastasis.
Conventional Chemotherapy Combined with After establishing the anticancer activity of single-agent
Metronomic Therapies L-MTP-PE when used in the adjuvant setting, two subsequent
Several studies have investigated the combination of systemic randomized, double-blind studies were conducted to determine
chemotherapy with concurrent and/or maintenance metronomic the effectiveness of combining L-MTP-PE with cisplatin. 285 In