NAVIGATION


Research Advances in Managing Hemangiosarcoma in Boxers

Used with permission from the Purina Pro Club Boxer Update, Nestle Purina PetCare Company
Vol. 4   No. 2   July 2005

While almost nothing is as frightening as a cancer diagnosis, some canine cancers spread faster than others. Hemangiosarcoma is one of those aggressive cancers that typically has metastasized by the time it is diagnosed. The cancer, which occurs in dogs more than any other species, represents about 7 percent of all canine cancers.1

Though it is not known what percent of Boxers is affected by hemangiosarcoma, veterinarians agree it is a concern for the breed. Besides Boxers, other breeds considered at risk for developing this type of cancer are German Shepherd Dogs, Golden Retrievers, Great Danes, English Setters, Pointers, and Skye Terriers.1 While the cancer occurs most often in middle-age to senior dogs, it is also seen in young dogs.

Hemangiosarcoma affects the cells that line the blood vessels, called the endothelial cells. If the cancer is found early when the tumor is easiest to treat with surgery and chemotherapy, a dog may survive seven to eight months. Without treatment, life expectancy is about two months.

Researcher Jaime Modiano, V.M.D., Ph.D., of the University of Colorado Health Sciences Center in Denver, describes hemangiosarcoma as being extremely indolent. “It develops slowly and is essentially painless, so clinical signs are usually not evident until the advanced stages when the tumor is resistant to most treatments,” he says.

Tumors can become larger than a grapefruit, although sometimes it’s not possible to feel the tumor during palpation. After surgery to remove a tumor, dogs can leave the hospital two days later, tail wagging and feeling great, but the tumor will regrow within two to four months, says Stuart Helfand, D.V.M., professor at the new Oregon Cancer Center for Animals (ORCCA) at Oregon State University in Corvallis.

HEMANGIOSARCOMA IS ONE OF THOSE AGGRESSIVE CANCERS THAT TYPICALLY HAS METASTASIZED BY THE TIME IT IS DIAGNOSED. THE CANCER, WHICH OCCURS IN DOGS MORE THAN ANY OTHER SPECIES, REPRESENTS ABOUT 7 PERCENT OF ALL CANINE CANCERS. 1

Signs of hemangiosarcoma are subtle. Once the cancer has spread, a dog may show weakness, a distended abdomen, high pulse and respiration, weight loss, pale mucous membranes (most easily seen on the gums), and anemia. Lethargy and depression are common, and owners typically feel something isn’t quite right but are unable to pinpoint the problem.

Early signs can be intermittent. A dog’s breathing may become labored because internal bleeding reduces the oxygen content within the bloodstream. However, if the bleeding stops, dogs reabsorb blood from the abdomen (auto transfusion), and a dog may appear normal again. Lethargy resolves and constitutional signs, including appetite, improve.

Veterinarians see hemangiosarcoma as a disease primarily in four areas: the spleen, liver, skin and heart. Other less common primary sites include the kidneys, oral cavity, muscle, bone, brain, urinary bladder, and the peritoneum.2 In dogs with multiple tumors, it may be difficult to determine which is the primary tumor site. The lungs and liver are the most common sites of metastases.

Hemangiosarcoma most often originates in the spleen where the tumor ruptures, showering tumor cells within the abdomen that may implant and grow. Many dogs die from acute internal hemorrhaging that occurs secondary to the tumor rupturing or from the rupture of a tumor located near or in a critical area. Because hemangiosarcoma is a cancer of the blood vessel cells, the tumor has a constant blood supply and access to blood vessels, facilitating its spread throughout the body.

“PROGRESS IN HEMANGIOSARCOMA HAS NOT IMPROVED MUCH SINCE I GRADUATED FROM VETERINARY SCHOOL IN 1978. WE’VE PROVED THAT TRADITIONAL TREATMENT METHODS DON’T WORK WELL, AND WE NEED NEW IDEAS.”
STUART HELFAND, D.V.M., OF THE OREGON CANCER CENTER FOR ANIMALS (ORCCA) AT OREGON STATE UNIVERSITY

Firsthand Experience
Boxer breeder Cheryl Robbins of Cherkei Kennels in Newnan, Ga., has lost several dogs to hemangiosarcoma. One died in her arms on the way to the veterinary school at Auburn University, another died at the American Boxer Club’s (ABC) National Specialty. CH Storybooks Rip it Up was not a dog that she bred, but she campaigned him to become the No. 1 Boxer and the No. 1 Working dog. Hemangiosarcoma developed in his lungs, liver and kidney.

“A lot of owners assume that if their dog dies suddenly it is from cardiomyopathy,” says Robbins, who feels hemangiosarcoma and sudden death from the cancer is more prevalent than assumed. “I have necropsies performed on our dogs so that we know for sure the cause of death.” She encourages breeders and owners to share information about health problems in the breed and has created “the wall,” a bulletin board posted at the ABC National Specialty containing photos of dogs that have died with notes about their cause of death.

Anne Gilbert of Broken Arrow, Okla., has a male Boxer named “Dollar” who just began predinisone after being recently diagnosed with hemangiosarcoma. By the time Dollar had an ultrasound and the tumor was found on his spleen, it was also on his liver. “They said the average expectancy is five to eight weeks from diagnosis without treatment, but it depends on how aggressive it becomes,” Gilbert says. “Dogs can become more lethargic and quality of life goes down, but he’s fine now and does all his regular stuff. He chases squirrels; he just gets tired more quickly. My concern is keeping his quality of life where it should be.”

Traditional Treatments
“Progress in hemangiosarcoma has not improved much since I graduated from veterinary school in 1978,” Helfand says. “We’ve proved that traditional treatment methods don’t work well, and we need new ideas. An occasional effort adding immunotherapy has yielded some interesting results. My goal is to find a combination treatment using subcellular pathway blockades in combination with surgery and chemotherapy.”

Cancer is a disease that occurs when normal body cells become mutated and no longer respond to regulatory signals. Because of gene mutations, the cells have gone mad in a systematic way. Scientists believe that hemangiosarcoma risk has heritable components, but have not yet identified what those are. They have identified sporadic events that contribute to tumor progression but even those may be influenced to a degree by heritable factors.

“Chemotherapy has a role in treating hemangiosarcoma, but I don’t think it’s the only one,” Helfand says. Typically, the chemotherapeutic agents used are doxorubicin, cyclophosphamide and sometimes vincristine. Progress finding new treatments involves “probing the cell to see what it takes to grow and to block its growth,” he says.

While some potentially effective developments are being researched, Helfand cautions that research doesn’t move as quickly as dog owners would like and constant sources of funding are necessary to advance the field.

“THE (EARLY DETECTION) TEST WILL EXAMINE A COMBINATION OF MARKERS THAT WILL ALLOW US TO CONFIDENTLY DISTINGUISH BETWEEN NORMAL CELLS AND TUMORCELLS, AS WELL AS BETWEEN HEMANGIOSARCOMA AND OTHER TUMORS THAT CAN SHED CELLS INTO THE BLOOD.”
JAIME MODIANO, V.M.D., PH.D., OF THE UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER IN DENVER

Early Detection Test and a Vaccine
Among new projects under way are development of an early detection test and a therapeutic cancer vaccine. “We don’t know yet how early in the disease process we’ll be able to detect a tumor,” Modiano says.

“We anticipate that it will be before clinical signs become evident, but the assay is still in the developmental and refinement stage,” he says. “The test will examine a combination of markers that will allow us to confidently distinguish between normal cells and tumor cells, as well as between hemangiosarcoma and other tumors that can shed cells into the blood.”

The test is not yet commercially available and a release date has not been set. The impact of early detection on prognosis and outcomes won’t be known until the test has been in clinical use long enough for veterinarians to determine if the disease can be more effectively treated when it’s diagnosed in the early stages. While this bodes promise for future generations of Boxers, it doesn’t help those currently diagnosed with hemangiosarcoma.

Meanwhile, development of a therapeutic vaccine that can be “used to activate the immune system to kill an existing tumor, not to prevent one,” is also under way, says Modiano, who is working on the vaccine. “The technology has been shown to work in various laboratory animal models. The vaccine is undergoing clinical trials in human cancer patients. Since it is not a prophylactic vaccine, any concern regarding ‘over-vaccination’ doesn’t apply in this case because the only patients that would receive it would be those that require the treatment. Based on the available data, the promise for the technology is huge. It could literally change our perception of cancer from an ‘incurable’ disease to one that is treatable.”

“We cannot say with certainty when a vaccine would be available as a treatment option for dogs,” he says. “The first stage is to identify gene targets in hemangiosarcoma that are amenable to this technology. The ‘vaccines’ would only be used in dogs with confirmed disease and only on those that are good candidates for this type of therapy.” There have not been any veterinary trials yet, but new funding from the American Kennel Club (AKC) Canine Health Foundation will help to advance the research.

“I’m optimistic,” Helfand says. “It might be a while before we cure or develop better ways to control hemangiosarcoma, but my vision is that there’s enough novel information emerging that we might make a reasonable impact in five years.”

1    Helfand S, Modiano J. Growth Signaling Pathways in the Pathogenesis and Treatment of Canine Cancer. AKC Canine Health Foundation Invited Grant Proposal. March 2000.

2    Withrow SJ., MacEwen EG. Small animal clinical oncology. W.B. Saunders, Philadelphia. 2001;3:29,p.639.


A Research Renaissance in Understanding Hemangiosarcoma

Stuart Helfand, D.V.M., professor at the new Oregon Cancer Center for Animals (ORCCA) at Oregon State University, says a research renaissance is helping scientists to better understand hemangiosarcoma, a cancer of the cells that line blood vessels, called the endothelial cells.

Helfand relates current progress to a “lock and key” analogy. “We try to find weak links,” he says. “If we can shut down the cancer pathways when the key is in the lock, the net effect is that the normal internal signaling that triggers the cell nucleus to divide may be blocked. If we could prevent the key from going into the lock or disrupt the downstream proliferation signals, we could potentially prevent cell division.”

Immature endothelial cells may have more “doors” in and out of cells than mature cells. As the cells age, the doors get smaller. The “lock” is a protein, the receptor on the cell that is specific to the cell’s function. A variety of growth factors stimulate endothelial cells. “Growth factors are the ‘keys’ that bind these receptors (locks) and improving our understanding of these interactions may be pivotal to fathoming the derangements in hemangiosarcoma and other cancers,” Helfand says.

“Cancer is a disease in which bad cells grow rapidly,” he says. “Sometimes a lock will have more than one key that fits. When a key is in the lock, it communicates with the cell’s internal pathways. We’re trying to block activating pathways in the cell. My laboratory is involved in target discovery that we may be able to manipulate for an improved therapeutic outcome”.

“The ability to fund new studies is paramount and philanthropy to drive research in combination with grants is becoming very important,” Helfand says. “Time, funding and innovative ideas will ultimately determine if we are on the right track.”

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