Page 288 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 15 Molecular/Targeted Therapy of Cancer 267

disease control rate as the main indicator of tumor response. Combination of Metronomic Chemotherapy
A handful of studies have also examined pharmacodynamic with Other Treatment Modalities
measures of response including biomarkers of angiogenesis or
VetBooks.ir immunomodulation. 268,269,277 The question of whether concurrent MC and conventional MTD
chemotherapy can be safely administered has been the focus of
Veterinary Trials with Alkylating Agents several recent clinical trials. In dogs with various malignancies, the
combination of MTD DOX with concurrent metronomic CYC
Thus far there have been roughly 20 published reports of was found to be well tolerated in a recent phase I study. 294 DOX
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clinical trials investigating metronomic delivery of an alkylat- (30 mg/m intravenous [IV]) was given once every 3 weeks for
ing agent in dogs with cancer; only two have included cats. four treatments with concurrent daily oral CYC. Dose escalation
Of these about 80% have utilized CYC with the remainder for CYC was performed according to a standard 3 + 3 cohort
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employing other alkylators. An early trial by Lana et al tested schema starting at 10 mg/m /day and extending to 15 mg/m
the administration of oral CYC (12.5–25 mg/m /day) alternat- by 2.5 mg/m increments. There were no significant toxicities in
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ing with etoposide (50 mg/m PO, daily) and combined with dogs of any cohort but the duration of the treatment period was
daily piroxicam for the adjuvant treatment of dogs with splenic potentially too short to determine the incidence of SHC or DOX-
HSA. 286 These investigators found that the approach had similar induced cardiomyopathy. Unfortunately, administration of DOX
efficacy and less toxicity compared with control dogs receiving was associated with nonselective depletion of circulating lympho-
conventional DOX chemotherapy. The metronomic protocol cytes such that any potential benefits of Treg depletion by low-
was well tolerated over a 6-month period although two of nine dose CYC would have been lost.
dogs developed a transient sterile hemorrhagic cystitis (SHC). RT combined with MC is another area under active inves-
A more recent investigation by Wendelburg and colleagues tigation in both people and companion animals. In one study,
found a similar result when comparing metronomic CYC che- Cancedda et al treated 50 dogs with macroscopic soft tissue sar-
motherapy versus conventional DOX chemotherapy for dogs coma using a 5 × 6 Gray hypofractionated RT protocol. Twenty
with splenic HSA. 287 In this study, however, the median overall of these dogs then received daily oral piroxicam and thalidomide
survival time (OST) was strikingly short (3.4 months) for dogs plus every other day oral CYC. The addition of this MC protocol
receiving either adjuvant metronomic or conventional chemo- had no effect on PFS but treated dogs displayed a significantly
therapy and not significantly different from dogs treated with longer OST compared with dogs treated with RT alone (757
splenectomy alone. vs 286 days, respectively). 295 RT has also been combined with
Metronomic delivery of CYC has also been investigated in metronomic dosing of lomustine in the treatment of dogs with
the maintenance setting after completion of adjuvant MTD OSA. 296 When combined with palliative RT, the lomustine was
chemotherapy in dogs with HSA or OSA. For dogs with HSA well tolerated but did not extend the OST compared with dogs
treated with splenectomy and six doses of DOX, daily or receiving RT alone.
every other day CYC plus an NSAID had no effect on PFS or As in the human oncology field, there is significant interest in
OST. 288 In dogs with OSA, the addition of daily CYC with an combining MC with immunotherapy for dogs and cats with can-
NSAID after limb amputation and four doses of carboplatin cer; however, published reports are few. Cicchelero et al investi-
yielded similar PFS and OST as dogs treated with amputation gated the immunologic and antiangiogenic effects of intratumoral
and carboplatin alone. 289 In a larger multicenter study, dogs electrogene therapy with IL-12 in six dogs that also received daily
with OSA were randomized to receive piroxicam and CYC oral CYC at 12.5 mg/m . Although study design did not permit
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with or without TOC after limb amputation and four doses determination of the contribution of each treatment separately,
of adjuvant carboplatin. 290 Compared with historical control there was a significant decrease in circulating Treg numbers from
dogs treated with amputation and four doses of carboplatin, pretreatment values and decreased intratumoral blood volume in
there was no improvement in the median PFS or OST in dogs five of the six dogs. The intratumoral concentration of the angio-
of either treatment arm. genic inhibitor TSP-1 was significantly increased compared with
Other alkylating agents including chlorambucil, lomustine, and baseline for the duration of the 35-day study period.
TMZ have also been evaluated in veterinary treatment protocols.
In most of these trials the primary study endpoint has been toxic- Adverse Events
ity, with tumor response evaluation a secondary goal. 275,291–293
When administration of lomustine at a daily oral dose of 2.84 Despite the therapeutic index achieved by treating activated versus
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mg/m was tested in 81 dogs with a various malignancies, an dormant vasculature, there is still potential risk that drug effects
unexpectedly high incidence of adverse events occurred and led on vessels have unwanted consequences. For bevacizumab, poten-
to the discontinuation of the therapy in nearly 30%. 293 Oral tial side effects of a vascular etiology include hypertension, edema,
chlorambucil is typically well tolerated when given at 4 mg/m / hemorrhage, thromboembolism, proteinuria, intestinal perfo-
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day in metronomic protocols. But when given at higher daily ration, and impaired wound healing. 298 Similarly, in veterinary
doses of 6 or 8 mg/m , a retrospective study found significantly oncology, side effects for TOC may include hypertension, protein-
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increased gastrointestinal and bone marrow toxicities with no uria, dose-dependent gastrointestinal upset, bleeding, myelosup-
improvement in tumor response. 292 Chlorambucil at 4 mg/m / pression, azotemia, anemia, lethargy, lameness, or disruption of
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day combined with monthly doses of lomustine was also well the hypothalamic–pituitary–thyroid axis. 299–302
tolerated based on investigation of eight dogs with glioma. In CYC is a commonly employed drug for metronomic schedul-
this study, three of the dogs developed grade I or II thrombocy- ing but is associated with the potential for SHC. 303 The incidence
topenia after 8 to 16 months of chronic therapy but there was no of SHC may be more frequent in metronomic protocols. Recent
neutropenia attributable to chlorambucil and no grade III, IV, or reports document that cystitis may occur in up to 34% of cases,
V bone marrow toxicity. 291 and SHC risk increases with longer treatment duration, which is