Page 287 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

266 PART III Therapeutic Modalities for the Cancer Patient

on two small studies in which circulating Treg were significantly
decreased when CYC was given alone or in combination with Clinical Trial Evaluation
268,269
Interestingly, dogs receiving the two drugs concur-
TOC.
VetBooks.ir rently had significant increases in serum concentrations of IFN-γ Summary of Human Clinical Trials
Nearly 20 years ago, the results of a pivotal clinical trial
that were inversely correlated with Treg numbers after 6 weeks of
treatment. 269 were reported in which women with metastatic breast cancer
Administration of low, noncytotoxic concentrations of other received daily low dose CYC and twice weekly methotrexate.
chemotherapeutic agents such as paclitaxel, DOX, methotrex- This study found a disease control rate (defined as a complete
ate and gemcitabine have also been shown to improve antitu- or partial response or durable stable disease) of 32% and a low
mor immunity. Mechanisms for this vary but include dendritic incidence (13%) of mild to moderate leukopenia. 282 As most of
cell activation, improvement of cytotoxic T-cell function and the women had already failed MTD chemotherapy protocols
reduction of MDSC activity. 270–272 For example, administration containing CYC, these results stimulated significant interest
of low doses of paclitaxel to mice with metastatic lung tumors in further investigation of MC for the treatment of advanced
led to a selective decrease in Treg number and function without cancers.
interfering with tumor-specific cytotoxic T cell function. 273 The Since that time, numerous phase I and II studies have described
nucleoside analog gemcitabine appears to decrease MDSC accu- the clinical benefits of MC, many reporting encouraging tumor
mulation within tumor tissues, likely in part through the differ- control rates and very low toxicity rates. The majority of these
entiation of MDSC into functionally active immunostimulatory studies have paired a conventional chemotherapy drug with a
DCs. 265,266 noncytotoxic drug that also targets angiogenesis. Noncytotoxic
Similar to CYC, the alkylating agent temozolomide (TMZ) drugs typically include those with indirect effects on angiogenesis
has also been shown to reduce circulating Treg numbers in human such as COX inhibitors, tetracyclines, and thalidomide or those
cancer patients. 274 Denies and colleagues recently investigated with more direct effects such as bevacizumab.
daily low dose TMZ therapy in 30 tumor-bearing dogs, adminis- In a meta-analysis of 80 published human clinical trials, the
tered either alone or in combination with daily low-dose CYC. 275 most frequently used cytotoxic drugs were CYC (43%) followed
In these dogs the primary study endpoints were circulating Treg by capecitabine, etoposide, and vinorelbine. 283 In this systematic
numbers and plasma concentrations of TSP-1 and VEGF. The literature review, most studies (80%) were reports from single-arm
2
investigators found that dogs receiving CYC (12.5 mg/m /day) trials, often relying on historical controls. In 72% of the trials, the
2
or the combination of CYC and TMZ (6.6 mg/m /day) had patient sample size was 50 or less. Of the few trials with multiple
significantly lower percentages of Treg after 2 weeks of therapy arms (n = 16), only seven were randomized. Recent clinical data
whereas dogs receiving TMZ alone did not. Neither drug nor compiled from larger MC clinical trials for cancer patients living
the combination was found to influence pre- and posttreatment in India have found that methotrexate and celecoxib are used most
plasma concentrations of TSP-1 or VEGF. As TMZ has been well often, likely owing to the wide availability and low cost of these
tolerated in dogs at higher doses in conventional chemotherapy agents. 284
protocols, additional pharmacodynamic studies may lead to iden- To date there has been only one double-blinded, placebo-
tification of a biologically effective dose when used in the metro- controlled randomized clinical trial reported in human cancer
nomic setting. 276,277 patients. 285 This study compared a four-drug metronomic regi-
men of daily celecoxib and thalidomide with alternating peri-
Other Targets of Metronomic Chemotherapy ods of etoposide and CYC to placebo in 108 pediatric patients
Dormancy is a stage of tumor development in which viable neo- with solid tumors (mostly OSA or primitive neuroectodermal
plastic cells are present but inactive as a result of dynamic equi- tumors). The primary study end point was the progression-free
librium between apoptosis and proliferation. Dormancy may rate (PFR) as defined by the proportion of patients without dis-
arise in the early phases of tumor progression before conditions ease progression at 6 months after starting MC. Unfortunately,
are in place to adequately support tumor cell proliferation and there was no difference in PFR between the two groups as more
again in the posttreatment remission period. Not surprisingly, than 96% of patients developed progressive disease within 3
reactivation of dormant tumor cells represents one reason for months. Interestingly, patients receiving MC for a tumor type
the development of progressive disease after completion of con- other than a bone sarcoma demonstrated significantly longer
ventional MTD chemotherapy protocols. 278 Similar to dormant overall progression-free survival (PFS) time compared with
tumor cells, cancer stem cells (CSCs) may also be present both those receiving placebo. The authors concluded that MC may
before and after conventional anticancer therapy. Also known not display efficacy across all classes of pediatric solid tumors,
as tumor initiating cells, CSCs display a unique and formidable underscoring the importance of tumor histology in predicting
phenotype within the tumor cell population, characterized by treatment response.
their capabilities for self-renewal and DNA repair. Accumulat-
ing experimental data suggest MC may be able to target CSCs Summary of Veterinary Clinical Trials
and dormant tumor cells because of the tendency of both cell
populations to reside in close proximity to tumor vasculature. 279 Similar to human clinical studies, veterinary clinical trials eval-
For instance, in mice with glioma and hepatocellular carcinoma, uating MC have been mostly small, phase I and II and/or ret-
antiangiogenic therapy was found to disrupt this close associa- rospective. Metronomic administration of CYC, given alone
tion, leading to apoptosis of CSC and bystander damage to dor- or in combination with a nonsteroidal antiinflammatory drug
mant tumor cells immediately adjacent tumor vasculature. 280,281 (NSAID), has been the approach most often tested; however, the
Whether this mechanism of action of MC will translate into a treatment protocol, disease setting and outcomes assessed have
therapeutic benefit for human or veterinary patients awaits fur- all varied considerably. The majority of trials have investigated
ther investigation. dogs with various malignancies and advanced disease, using the