Anthony J. Mutsaers, DVM, PhD, DACVIM (Oncology)
Receptor Tyrosine Kinase Inhibitors
The arsenal of the medical oncologist expanded significantly with the relatively recent approval of the receptor tyrosine kinase inhibitors (RTKIs) toceranib (Palladia®) and masitinib (Masivet®, Kinavet®) for veterinary use in treatment of aggressive canine mast cell tumours. These drugs are examples of "targeted" cancer therapy, which began in human oncology with clinical use of drugs such as imatinib (Gleevec®), trastuzumab (Herceptin®), and bevacizumab (Avastin®), which were approved for chronic myelogenous leukemia, breast cancer, and colon cancer, respectively. Now, over 10 years later, there are numerous other RTKI drugs in clinical use, and potentially more that could come to veterinary oncology as well.
Receptor tyrosine kinases are transmembrane proteins that receive signals from extracellular growth factors that bind to the receptor. The intracellular portions of these RTKs contain kinase domains, which phosphorylate tyrosine residues facilitating the propagation of the signal by attracting various intracellular proteins to bind. The signal ultimately culminates in the nucleus and alters gene transcription in favour of cell growth, survival, or other processes. Normal RTK function becomes altered or dysregulated in a number of cancers. In canine mast cell tumours the RTK c-kit may be mutated resulting in constitutive signalling. Drugs such as imatinib, toceranib, and masitinib are able to bind to c-kit and abolish the signal. While these drugs have been used as single agents for the treatment of aggressive recurrent canine mast cell tumours, they may also have activity in other cancer types. Toceranib has shown activity in cancers such as canine anal sac adenocarcinoma, osteosarcoma, thyroid, nasal and oral carcinomas. The mechanism(s) underlying this activity remain to be determined.
The other major category of targeted drugs for RTKs is monoclonal antibodies, such as trastuzumab and bevacizumab. The extracellular target of these drugs may be highly conserved between dogs and man; however, use of antibodies as therapeutics in veterinary oncology has been hampered by the fact that animals will mount a neutralizing immune response, which will negate their anti-cancer effects. However, as biotechnology techniques advance, it is becoming possible to manufacture canine-specific versions of these antibody drugs, and clinical assessment of monoclonal antibody therapy in veterinary oncology may be on the horizon.
There has been a long history of attempting to harness the body's own immune defences to attack malignant cancer cells. Historically, veterinary studies have investigated the potential biologic and therapeutic role of immune cytokines such as interleukins, and non-specific immunostimulation from compounds such as muramyl tripeptide phosphatidylethanolamine (Mifamurtide®). More recently, the focus has shifted to determining the role of T cell subsets in immune surveillance, and designing cancer vaccines based on unique tumour antigens, particularly for treatment of canine malignant melanoma.
Within the T cell family of lymphocytes exist subsets that both enhance and suppress the overall immune response. The presence of a tumour is associated with elevation in T regulatory cells that suppress immune attack, and this has been demonstrated in dogs. Interestingly, low doses of cyclophosphamide, given in a continuous/metronomic fashion have been shown to decrease the fraction of T regulatory cells, which may contribute to the mechanism of action of this form of chemotherapy.
Tumour vaccination has also become a clinical reality with the recent approval of a vaccine (Oncept®) to treat canine stage II or III oral malignant melanoma in the adjuvant setting. This vaccine uses human DNA for the melanoma-specific antigen tyrosinase and is administered using a special transdermal device. It is important that local control of the primary tumour be accomplished with surgery and/or radiation therapy as the vaccine is only effective for suppression of microscopic metastases. Anti-cancer activity has also been reported with the use of other canine melanoma vaccines, which supports the notion that melanoma in particular is an "immunogenic" cancer worthy of this therapeutic approach.
High-Dose Radiation Therapy
The capabilities of external beam megavoltage radiation therapy units continue to expand with technological advances that have real clinical application. While availability is currently limited, these machines are finding their way into an increasing number of veterinary cancer centres. Linear accelerators capable of delivering very focused radiation that spares normal tissue through techniques such as tomotherapy, intensity-modulated delivery, gamma knife, and stereotactic radiosurgery permit changes to conventional fractionation protocols. Currently, frequent low doses of radiation are delivered in curative intent protocols because the dose of radiation given to "late-responding" normal tissues such as bone and nerves must be limited to prevent irreparable damage. With newer technology comes the ability to deliver the same or higher total dose in only one or a few fractions. It has been demonstrated that canine osteosarcoma and transitional cell carcinoma tumours are more sensitive to high dose radiation than conventional fractionated protocols, and preclinical studies may determine whether this is the case for other cancers as well, by calculating their alpha/beta ratio. Finally, some newer radiation therapy units contain on-board imaging CT for modifying the table position prior to each dose to compensate for patient movement, increasing treatment precision. There is no doubt that availability to the latest types of radiation therapy in veterinary medicine will continue to expand as oncology clients continue to request access to the latest treatment options for their pets.
Minimally Invasive Procedures
The emergence of techniques that utilize laparoscopy or interventional radiology has decreased patient surgical morbidity and expanded the number/type of cancer treatment options available in veterinary oncology. Laparoscopic biopsies offer a less invasive approach than surgical laparotomy, while still allowing direct visualization and manipulation of the tumour, including direct control of potential haemorrhage, unlike image-guided biopsy techniques. Laparoscopy has also been utilized to perform pericardiectomy for cases of right atrial hemangiosarcoma with pericardial effusion.
The use of stents for management of neoplastic occlusion of the urethra, ureters, colon, and esophagus has also become available recently. This treatment can prevent life- threatening occlusion, but provides palliation only and does not treat the tumour directly. Finally, image guidance, such as fluoroscopy-guided tumour vascularity studies can facilitate the accurate delivery of chemotherapy at high doses or embolization agents directly into the tumour via feeder arteries. Chemoembolization has been utilized in liver cancer, which is a tumour that is very resistant to conventional chemotherapy in both humans and dogs.
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