Alternative modes of cancer treatment have become increasingly available in veterinary medicine. Rather than indiscriminately inhibiting cells engaged in the cell cycle, many newer drugs target specific cellular processes. These novel forms of treatment work in various ways, including through enhanced immune recognition, altered blood vessel formation, or exploitation of specific pathways that are aberrant or overexpressed in neoplastic cells. The widespread use of these newer treatments alone or in combination with conventional chemotherapy has transformed the approach to treating many cancer patients.
NSAIDs as Targeted Antineoplastic Agents in Animals
NSAIDs represent one class of biologic response modifiers that work by inhibiting the frequently overexpressed COX-2 enzyme activity present in many tumor types. Several studies have proposed that these drugs work by decreasing cell proliferation, increasing apoptosis, inhibiting angiogenesis, and modulating immune function. Piroxicam is the drug most researched in dogs; however, any of the newer NSAIDs with more COX-2 selective inhibition (such as firocoxib, deracoxib, or meloxicam) theoretically may yield equal or improved effects. The clinical usefulness of COX-2 inhibitors has been demonstrated in canine transitional cell carcinoma, squamous cell carcinomas, mammary carcinomas, and other tumor types in dogs and cats. NSAIDs are often combined in antiangiogenic protocols.
Metronomic Chemotherapy in Animals
Metronomic chemotherapy—low-dose, continuous chemotherapy—is a novel approach in which low doses of oral chemotherapy agents are administered at short intervals, often daily. This treatment approach targets the tumor neovasculature by leveraging the exquisite sensitivity of endothelial progenitor cells and immature endothelium to modest doses of alkylating agents. Studies indicate that antiangiogenic factors, such as thrombospondin-1, increase during metronomic chemotherapy. In addition, tumor immunosuppression mediated through T regulatory cells may be modulated by metronomic protocols.
Disease stabilization is considered a successful outcome of low-dose chemotherapy, because direct cytotoxicity to neoplastic cells is not the intent of metronomic chemotherapy. Preliminary studies in the veterinary literature suggest that this mode of chemotherapy is a promising alternative to maximally tolerated doses of conventional chemotherapy, particularly in a microscopic disease setting, and it has the added benefit of limited adverse effects. Metronomic chemotherapy often can be combined with other targeted treatments.
Receptor Tyrosine Kinase Inhibitor Use in Animals
Targeting of specific pathways that are aberrant or dysregulated in cancers has yielded novel treatments in a variety of human cancers. Examples of such targets are the receptor tyrosine kinases (RTKs), which mediate processes involved in tumor growth, progression, and metastasis. These drugs are competitive inhibitors of the intracellular ATP-binding site, so they prevent receptor phosphorylation and subsequent downstream signal transduction.
Mutations in c-kit, an RTK gene involved in mast cell differentiation and proliferation, have been reported in ~25% of canine mast cell tumors. Toceranib is approved by the FDA for the treatment of canine mast cell tumors, and biologic response rates of 70%–90% have been reported in dogs that have mast cell tumors with recognized c-kit mutations. Moreover, toceranib has activity against other members of the split-kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor, and others.
Preliminary evidence indicates that toceranib has activity against a variety of carcinomas and metastatic osteosarcoma, leading to tumor regression or more often to prolonged disease stabilization. Dosages of toceranib ranging from 2.4 to 2.9 mg/kg, PO, every 48 hours (less than the label dosage of 3.25 mg/kg, PO, every 48 hours) have been reported as yielding sufficient target inhibition with substantially decreased toxicity. Toceranib has also been used successfully in cats with a variety of carcinomas in small studies. Common adverse effects include diarrhea, anorexia, vomiting, lethargy, muscle pain and/or weakness, weight loss, hepatotoxicosis (particularly in cats), occult fecal blood, and mild myelosuppression.
Cancer Vaccine Use in Animals
Development of a therapeutic vaccine to stimulate active immunity against cancer has long been a goal in both human and veterinary oncology. This approach became a reality with USDA approval of a canine melanoma vaccine. This therapeutic vaccine exploits the immune response induced by human tyrosinase, an enzyme in the pathway of melanin formation. The canine vaccine contains a human tyrosinase gene inserted into a bacterial plasmid, which is administered transdermally. The antibodies and T-cell responses produced by xenogeneic tyrosinase cross-react with the tyrosinase overexpressed on canine melanoma cells.
Initial studies reported prolonged survival in dogs with advanced-stage oral malignant melanoma treated with radiation or surgery of the primary tumor, followed by vaccine administration. Experience in horses has demonstrated arrest or decrease in tumor size, accompanied by the development of anti-tyrosinase immunoreactivity. Studies in dogs have failed to demonstrate a definitive clinical benefit of the melanoma vaccine, and investigations are ongoing. No serious adverse effects have been attributed to the vaccine; however, transient mild erythema and swelling occur occasionally at the injection site.
Therapeutic autologous cancer vaccines use a patient’s own tumor to provide unique tumor-associated antigens. They are often combined with adjuvant to stimulate the immune system to break tolerance to those antigens with the aim of enacting immune destruction of the cancer, particularly microscopic metastatic disease. Although most of these endeavors have met with only anecdotal successes, advancements in immunology and biotechnologies have fueled continued research. A number of biotechnology groups currently offer autologous vaccine preparations within and independent of clinical trials. Nevertheless, these treatments generally are considered investigational in veterinary medicine.
Immunostimulant Use in Animals
Treatments aimed at enhancing the innate antitumor defense mechanisms of the host have been an area of active investigation for decades. Nonspecific immunomodulators, including intact bacteria or bacterial cell components, acemannan, interleukin-2, interleukin-12, interferon alpha, levamisole, and cimetidine, have been reported with variable efficacy to enhance immune responsiveness and improve outcomes after surgery or antineoplastic chemotherapy.
Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is perhaps the best-studied nonspecific immunomodulator in veterinary medicine. This synthetic bacterial wall component has been used effectively with chemotherapy to confer a survival advantage in dogs with splenic hemangiosarcoma and osteosarcoma. Proprietary formulations of mycobacterial cell wall fractions have also received USDA approval for the treatment of canine mixed mammary tumors and mammary adenocarcinomas, as well as equine sarcoids. The intact innate immune system is stimulated via T cells and toll-like receptors on macrophages. Elaboration of cytokines, particularly interleukin-1 by macrophages, is considered the primary driver of the immune response.
Imiquimod is a topical treatment that elicits an innate immune response through toll-like receptor 7, which induces interleukin-12. The drug has been successful in treating superficial skin tumors, such as multifocal carcinomas in situ (similar to Bowen disease) in cats, as well as sarcoids, squamous cell carcinomas, and auricular plaques in horses. Imiquimod induces a strong inflammatory response, and local erythema and edema are common, often necessitating removal of the drug after several hours. In horses with sarcoids treated with 5% imiquimod cream alone, decrease in tumor size was reported in 75% of animals, with 60% experiencing complete resolution of lesions after 8–32 weeks of treatment.
In clinical studies, 5 of 7 dogs (71%) with mammary carcinomas experienced complete remission when treated with imiquimod, as did 9 of 17 horses (53%) with sarcoids. Repeated treatments are often required to achieve local control. The effect on the development of metastatic disease, which is important when primary tumors can be controlled with surgery, is not yet known.
Adverse effects of imiquimod reported in dogs were mild fever, drowsiness, decreased appetite, and local inflammation, which was sometimes associated with marked swelling and pain. In horses, anaphylaxis and severe respiratory inflammation occurred in a few cases early in drug development; these effects appear to have been eliminated by reformulation of the product.
Monoclonal Antibody Use in Animals
The use of passive immunotherapy using monoclonal antibodies has grown substantially in human oncology. Monoclonal antibodies may attach to specific antigens on cancer cells, thereby either marking the cancer cells for destruction by the immune system, or by impairing functional pathways within the neoplastic cells. Monoclonal antibodies may also be conjugated to other antineoplastic agents (such as chemotherapy agents, radionuclides, or other toxins) to enable more targeted delivery of cytotoxic treatment to cancer cells while sparing normal tissues. The introduction of anti-CD20 monoclonal antibodies in human oncology has revolutionized the treatment of B-cell lymphoma, resulting in markedly improved outcomes compared to chemotherapy alone.
Novel Drug Use in Animals
Verdinexor has received FDA conditional approval for the treatment of canine lymphoma. Verdinexor is an antiviral that also binds to the protein exportin-1, preventing its export from the nucleus. Exportin-1 normally shuttles tumor suppressor proteins from the nucleus to the cytoplasm as a cell maintenance process, but when this export is prevented, these proteins accumulate in the nucleus and promote apoptosis in cancer cells.
Administer verdinexor tablets orally at an initial dose of 1.25 mg per kilogram (mg/kg) of body weight twice per week with at least 72 hours between doses. If tolerated after 2 weeks, increase the dose to 1.5 mg/kg twice per week with at least 72 hours between doses. Common adverse effects include anorexia, diarrhea, lethargy, weight loss, and vomiting. Other adverse effects reported in > 10% of patients include proteinuria and low urine specific gravity, elevated liver enzymes, and cough. In dogs with lymphoma, stabilization of the disease was reported more often than objective responses. In clinical studies, verdinexor has demonstrated activity against canine mammary carcinomas, mast cell tumors, melanomas, osteosarcoma, and transitional cell carcinomas. However, conditional licensure demands that use of verdinexor be limited to the approved indication of canine lymphoma.
A local antineoplastic treatment for dogs with nonmetastatic cutaneous mast cell tumors has received FDA approval. Tigilanol tiglate is a short-chain diterpene ester derived from the seeds of the Australian blushwood tree (Fontainea picrosperma). After intratumoral injection, oncolysis occurs in cells in direct contact with the drug. At the same time, activation of protein kinase C signaling cascades within the tumor produces an inflammatory response lasting 48–96 hours, which results in localized tumor hypoxia and recruitment, as well as activation of innate immune cells, principally neutrophils and macrophages.
Additional effects of protein kinase C include the destruction of tumor vasculature that culminates in wound formation at the tumor site in > 90% of cases. In a clinical study, tumor-associated wounds treated with tigilanol tiglate healed by 28 days in 57% of dogs and by 84 days in 96% of dogs without evidence of residual mast cell tumor.
The most common adverse effects reported for tigilanol tiglate include injection site pain, edema, bruising, and/or irritation, as well as lameness in the treated limb, vomiting, diarrhea, anorexia, regional lymph node enlargement, hypoalbuminemia, and weight loss. The veterinarian administering the drug must exercise care when handling it to avoid inadvertently puncturing the skin of any veterinary personnel, because even minute quantities of tigilanol tiglate can cause substantial, prolonged wounds.
