Cancer in Cats and Dogs

Gregory Ogilvie works with both animal and human cancers. Not too long ago, when a dog or cat owner learned that a pet had cancer, it meant a death sentence for the animal. But things have changed. There is a "very sophisticated population of animal owners," notes Donald Thrall, professor of radiology and radiation oncology at North Carolina State University (NCSU) College of Veterinary Medicine. These people are "very informed and sometimes almost demand state-of-the-art cancer treatment" for their animal companions. An ill dog or cat can now benefit from computed tomography (CT), magnetic resonance imaging (MRI), and sophisticated radiation therapy or chemotherapy. Coming down the pike are tumor-specific therapies that will have limited side effects. It sounds very much like the diagnostic and therapeutic procedures used in humans. In looking at the past 25 years, says Rodney L. Page, director of the new comparative cancer program at Cornell University College of Veterinary Medicine, the major advances in knowledge about cancer include use of noninvasive diagnostics (ultrasound, CT scans, and MRI scans); improved use of traditional therapies (surgery, radiation, and chemotherapy); advances in palliative and support care to treat cancer-related pain; and the "explosion" of basic scientific knowledge about the disease, including its genetic basis. Both humans and companion animals are the recipients of these advances. The similarity to human treatment has a biological basis. Those in the veterinary medicine and cancer research communities acknowledge that the similarities between animal and human cancers are striking, and information gleaned from one species could be used to help the other. "I would say that the types of cancer that we see in companion animals--many of them have a similar incidence and what we call biological behavior. They behave very similarly in animals as they do in humans: They spread to other parts of the body," explains clinical veterinary oncologist E. Gregory MacEwen of the University of Wisconsin School of Veterinary Medicine. "Many of them will respond in a similar way to the traditional therapies as used in humans. They look identical histologically under the microscope." MacEwen's is a joint appointment in the department of medical sciences at the School of Veterinary Medicine and in the university's Comprehensive Cancer Center. Other veterinary cancer researchers also have joint appointments: University of California, Davis, veterinarian and epidemiologist Philip Kass has one in the School of Veterinary Medicine and the School of Medicine. Page points out that the BRCA1 gene in humans is similar to the BRCA1 gene in dogs. He adds that the areas of mutation within that gene that led to an increased risk for breast cancer in some women are extremely conserved. Therefore, although specific mutations in the canine BRCA1 gene have not been reported yet, some breast cancers in dogs are likely to be associated with similar mutations as found in women. "The genetic basis of many human cancers may be similar in dogs and cats," says Page. The presumed commonality of genotype between human and companion animal cancers makes our pets excellent models, especially for therapeutics. MacEwen notes that scientists have a long way to go before pinpointing the genes that result in cancer in companion animals, but cancers occur spontaneously in the pet population. And owners take these animals for treatment. Causes of cancer in animals--as in people--may be multifactorial. Page, who is charged with setting up a comparative cancer program "to promote human and animal health" at Cornell's Ithaca, N.Y., campus, says that there is a "real crossover between cancer in dogs and in people." He notes that lifestyle factors--such as smoking and diet--that affect human cancer rates are not often considered germane in dogs. "Dogs don't have that propensity to hurt themselves," he states. However, "dogs not only share our environment, they get down and dirty in our environment." While humans may drink bottled water to avoid certain contaminants, dogs drink water from taps, sewers, and other sources that humans don't use. Thus, they may have higher exposure risks for environmental pollutants than humans. Page points out that large amounts of normal feline and canine tissue--the ovaries and testes of spayed and neutered companion animals--are going to waste. Such tissue could be used as a resource in studying environmental risk of exposure to carcinogens or heavy metals: "Even normal young dogs that are neutered have some sort of accumulation histories that may be screened." He envisions a canine and feline cancer registry beginning in New York state, where he is located, that could be used alongside the human cancer registry to better monitor neighborhood cancer incidence. Resources Papers M.J. Hendrick et al., "Postvaccinal sarcomas in cats," Journal of the National Cancer Institute, 86:341-43, 1994. P.H. Kass et al., "Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats," Journal of the American Veterinary Medical Association, 203:396-405, 1993. B.E. Kitchell, "Cancer and the aging companion animal," California Veterinarian, Sept./Oct.:6-7, 1999. S.E. Lana et al., "Related article: identification of matrix metalloproteinases in canine neoplastic tissue," American Journal of Veterinary Research, 61[2]:111-14, February 2000. G.K. Ogilvie et al., "Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: a double-blind, randomized placebo-controlled study," Cancer, 88:1916-28, April 15, 2000. K.D. Valerius et al., "Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin," Journal of the American Veterinary Medical Association, 214:353-56, 1999. Web Sites Colorado State University College of Veterinary Medicine & Biomedical Sciences: www.cvmbs.colostate.edu Philip Kass' home page: faculty.vetmed.ucdavis.edu/faculty/phkass For information about cancer in animals search OncoLink: oncolink.upenn.edu U.S. Pharmacopeia: www.usp.org Vaccine-Associated Feline Sarcoma Task Force: www.avma.org/vafstf/default.asp Translational Research But absent significant amounts of data on the etiology of canine and feline cancers, researchers are concentrating on improved treatment modalities that may be used both in pets and in humans. "We're doing translational research," says veterinary internist and oncologist Gregory Ogilvie, head of medical oncology and the Medical Oncology Research Laboratory at the Animal Cancer Center at Colorado State University (CSU) College of Veterinary Medicine and Biomedical Sciences. Ogilvie notes that the CSU veterinary cancer program has been funded by the National Cancer Institute (NCI) for the past 20 years, longer than any other veterinary cancer research program. "The NCI has agreed that the work that we do not only benefits animals with cancer, but, most importantly, can be used as a foundation to be able to expedite the diagnosis and treatment of cancer in people," Ogilvie says. There are advantages to carrying out clinical trials of cancer therapies on cats and dogs. It allows studies to move from mouse models to canine or feline models--which may be more similar to humans--rather than from mice directly to humans. "We think this translation from the laboratory from animal tumors to humans will shorten the time it would [take to] go from the laboratory to the human clinic," says Thrall. Cancers in dogs occur spontaneously. "We do not induce their cancer, which would be objectionable to animal rights activists. These are our patients," says MacEwen. Although for most companion animals with cancer, standard treatments include surgery followed by radiation or chemotherapy, researchers are studying new chemotherapy methods that will have fewer systemic effects than the standard intravenous infusion of a chemotherapeutic drug. Thrall notes that hyperthermia--the heating of a tumor site--along with radiation "has been shown now in randomized trials in both dogs and people to be more effective in local tumor control than radiation therapy alone in some tumors and some sites." Veterinary researchers at NCSU, working with Chuan Li and colleagues at Duke University, are using hyperthermia along with gene therapy to destroy solid tumors. They are injecting an adenovirus vector that contains a gene for production of interleukin-12 (IL-12) directly into the solid tumors (in this case, sarcomas) in cats. They then apply heat only to the tumor. The heat turns on the heat-shock response, which acts as the promoter for the production of IL-12, which, in turn, helps to destroy the cancerous tissue. Researchers at NCSU are also introducing heat-sensitive liposomes that contain the chemotherapeutic doxorubicin. The theory is that liposomes, injected intravenously, tend to concentrate within tumors "because the vessels in the tumor are leaky," notes Thrall. "In cats, local hyperthermia increases the liposomes that will be extravasated into the tumor." Using a heat-sensitive liposome developed by David Needham and his colleagues at Duke, Thrall's team has begun testing hyperthermia as an agent to increase liposome delivery of doxorubicin into tumors and as a way to increase release of the doxorubicin from the liposome. MacEwen's team at the University of Wisconsin is developing genetically modified vaccines to treat melanoma. "We culture the animal's own tumor. We genetically modify these tumor cells in the laboratory so that they will express certain cytokines so they will enhance the animal's immune system," explains MacEwen. The two cytokines that are expressed are GM-CSF (granulocyte/macrophage-colony stimulating factor) and interleukin-2 (IL-2). They also are using a liposome vector to carry an IL-2-releasing gene directly to the tumor site, and they are introducing a canine endostatin with antiangiogenic activity directly into tumors through injection of a cationic liposome. As with Thrall's group, MacEwen and colleagues are delivering liposomes containing chemotherapeutic drugs directly to tumors. They are also using inhalation chemotherapy on dogs with lung cancer. "In many tumors," MacEwen says, "we see a greater effect through an inhaled route rather than a systemic [intravenous] route, with less toxicity." And they have had success treating dogs with melanoma with a liposome-encapsulated macrophage activator called muramyltripeptide (MTP). "What we found there was [that in] dogs with stage 1 melanoma, about 75 percent of those were probably cured of their disease," says MacEwen. These dogs are still alive two to three years after treatment. Only 20 percent of dogs in the control group, which was treated with empty liposomes, survived two to three years after treatment. At CSU, says Ogilvie, "We are involved in understanding the relationship between tumor oxygenation and pH and sensitivity to radiation and hyperthermia. We are involved in the in vivo and in vitro evaluation of modulators of drug resistance." One of the group's recent studies has been on the role of metalloproteinases in tumor angiogenesis. "Metalloproteinases are key enzymes that allow tumors to survive locally and to spread throughout the body," says Ogilvie. "Identifying approaches to inhibit these enzymes is essential to control cancer in animals and people." CSU is a leader in studies on the use of micronutrients such as polyunsaturated fatty acids and some amino acids to change the pharmacokinetics of anticancer drugs to make them work more effectively. It also is studying the anticancer effects of some of these micronutrients. Another concern is "to ameliorate the adverse effects associated with radiation therapy while enhancing tumor cell kill," says Ogilvie. They have been studying radioprotectants that will do this. Other fields of interest include innovative limb-sparing surgeries for animals with tumors in the legs, sustained-release polymers to deliver chemotherapeutic agents or growth factors to specific areas of the body, and use of gene therapy techniques. Vaccine-Associated Feline Sarcoma All of the above methods could find their ways into human cancer treatment regimens. But there is one baffling cancer that is uniquely feline and for which the specific etiology is unknown: vaccine-associated feline sarcoma. As any cat owner knows, cats receive two or three combination vaccinations during their first year of life and then, depending on the vaccine and the recommendation of the veterinarian, annual vaccination against some infections and triennial vaccination against others. This works out to a lot of vaccinations during the approximately 12-year lifespan of the average cat. In 1991, University of Pennsylvania School of Veterinary Medicine pathologist Mattie Hendrick coauthored a letter to the editor in the Journal of the American Veterinary Medical Association1 describing increased numbers of fibrosarcomas in the interscapular area in cats seen by her service at the university. Cats usually are vaccinated over their shoulder blades. "She was finding increased inflammatory reaction at the sites and also found foreign material," notes James R. Richards, director of the Cornell Feline Health Center at Cornell's College of Veterinary Medicine. He is one of 10 members of a group organized to aid in investigating and preventing these malignancies and educating veterinarians and the public about them: the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF). "This was indeed a foreign substance that contained aluminum and oxygen," says Richards. Aluminum is a common adjuvant in vaccines. But, Richards adds, it's not known "if this is a cause-and-effect situation or whether the adjuvant was there and showed up" but did not cause the tumors. Veterinary oncologist Barbara E. Kitchell of the University of Illinois College of Veterinary Medicine in Urbana, who has been studying the etiopathogenesis of these tumors, notes that they have been reported to occur "as close as one month after vaccination and after 10 years. Ninety percent of cats who develop tumors do so within four years of vaccine; 59 percent developed within one year." There have been a number of theories about what is causing these tumors, from macrophage ingestion of aluminum resulting in fibroblast production to activation of exogenous or endogenous (within the feline genome) retroviral elements, to mutations of the p53 gene predisposing some cats to develop these tumors. Kass has been studying the epidemiology of the tumors with financial support from VAFSTF. (VAFSTF awards grants for research from money donated by vaccine companies, especially Pfizer Animal Health, veterinary associations such as the American Animal Hospital Association Foundation, and research groups such as the Cornell Feline Health Center.) Although he has not yet analyzed the data--supplied by several hundred veterinarians who have reported on the numbers, types, and brands of vaccines used; their vaccination technique; and any adverse effects--he estimates that between one and three cats per 10,000 develop vaccine-associated sarcoma per year. One of the problems in even estimating the extent of the problem is "the underreporting is just vast." In 1994, the U.S. Pharmacopeia (USP), Rockville, Md., a nonprofit public health organization, launched the Veterinary Practitioners' Reporting Program to which veterinarians could report adverse events and other problems associated with the use of vaccines, drugs, and pesticides in animals. Reporting is purely voluntary, and the information veterinarians supply on vaccine-associated sarcomas to the USP is limited to the last vaccine given at the site of sarcoma development, notes veterinarian E. Kathryn Meyer, who coordinates the program. From April 30, 1996, through May 8, 2000, veterinarians reported 586 cases of vaccine-associated sarcomas in cats to the USP, says Meyer. "Not every sarcoma that develops is reported," she says. But 190 veterinarians reporting these sarcomas to USP in 1998 and early 1999 were invited to enroll in Kass' epidemiological study, and 72 participated. "Cats," Kass observes, "are totally different organisms than dogs. They just react strangely to chemicals," differently from dogs, horses, other animals, and humans. Yet the desire to find cures to human disease is a big motivator for veterinary oncologists. Says MacEwen: "They [the dog and the cat] provide an opportunity for enhancing the effectiveness of treatment in humans. That's why I went into the field in the first place." Myrna E. Watanabe is editor of Cornell University's newsletters for pet owners, CatWatch and DogWatch. 1. M. Hendrick and M.H. Goldschmidt, "Do injection site reactions induce fibrosarcomas in cats?" Journal of the American Veterinary Medical Association, 199:968, 1991.

Cancer in Cats and Dogs

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