Novel Therapies & TK Blood Test Help Advance Lymphoma Treatment

Canine lymphoma is one of the five most common cancers in dogs. Among the affected breeds, German Shepherd Dogs are considered at high risk. While in the past owners sometimes have been reluctant to treat dogs not knowing whether they would respond to chemotherapy, a new blood test determines dogs that would benefit from treatment and their long-term prognosis.

The blood test, used in Europe since 2004, was introduced in the U.S. in 2010 by Veterinary Diagnostics Institute in Simi Valley, Calif. The test determines the amount of thymidine kinase (TK), an enzyme shown to correlate with the proliferative activity of tumor cells, in a dog's blood. When the TK reading is above a certain threshold, it indicates the presence of lymphosarcoma and a dog's expected response to treatment. More than 1,000 dogs, including German Shepherd Dogs, have been tested in the U.S.

"Dogs with malignant lymphoma have significantly higher levels of TK in their blood compared to normal dogs," says Steven Gauthier, director of marketing and clinical studies at Veterinary Diagnostics Institute. "TK levels rise in the early stages of lymphoma and steadily increase as the disease advances. The higher the TK value, the more advanced the disease and the poorer the prognosis."

Not all dogs with lymphoma respond to chemotherapy. Factors that affect the success of chemotherapy and/or radiation therapy include the stage of the cancer, which is based on the number and location of affected lymph nodes and the involvement of other organ systems. Whether a dog shows signs of illness, such as lethargy, anorexia or weakness, is considered as well.

Approximately 100,000 to 200,000 cases of canine lymphoma are diagnosed each year, but only about 9,000 dogs are treated. The expense of treatment and the unknown outcome have kept many owners from pursuing chemotherapy for their dogs. Many owners say they would choose treatment if they knew their dog would respond.

The TK blood test costs around $165, although the price may vary based on individual veterinary clinics and geographical area. The ability to test dogs is particularly helpful in cases that are difficult to detect. Lymphoma is a cancer of the lymphocytes, or white blood cells that fight disease. The tumor typically grows in lymph nodes, which can be felt as enlarged masses under the neck, in front of the shoulders or behind the stifles. It also can occur in lymph nodes in the chest or abdomen or in organ systems, such as the spleen and bone marrow.

A TK reading in a healthy dog is 6 or less U/L (units per liter). Dogs with lymphoma that have lower TK values, such as 30 or less U/L, have a better prognosis than those with TK values of 100 U/L. The former have a mean survival of nine months, with some dogs living even longer, compared with a mean survival of 23 days with or without treatment, for the latter group.

"A TK reading of 100 U/L is a high value that indicates malignancy and advanced stage disease," Gauthier says. "The good thing about the TK blood test is that it provides information that allows veterinarians and owners to make informed choices. When dogs are successfully treated and go into complete remission, their TK values fall back within the normal range. At least three weeks prior to a relapse, the TK values rise again, making the TK test an effective way to monitor the course of treatment and/or disease progression."

Determining Lymphoma 

Lymphoma most commonly occurs in middle-aged and older dogs, but even puppies can be affected. The cancer can creep up on an unsuspecting owner, particularly when a dog's signs of disease are ambiguous.

Peggy Simerson of Star Prairie, Wis., who breeds under the SimCar prefix, recalls how quickly her 3-year-old German Shepherd Dog, SimCar's Bad Boy Boogie, succumbed to lymphoma. "'Boogie' was rambunctious, with endless energy," she says. "In one week, his energy faded."

The first indication something was wrong was a missed meal, followed by another missed meal, and then vomiting occurred between missed meals. Lethargy began to set in. "Boogie never missed meals, so this was a big deal," Simerson says.

The signs indicated a possible gastrointestinal problem, thus the veterinarian prescribed medications to settle the stomach. They did not help, and Boogie's condition continued to decline. Intravenous fluids and antibiotics also failed to help. In less than one week, Boogie became so weak that he could not walk. Swollen lymph glands, the usual sign of lymphoma, were not detected, yet the veterinarian suspected cancer.

The severity of Boogie's condition prompted Simerson to euthanize the dog to end his suffering. A necropsy, performed at the University of Minnesota Veterinary Teaching Hospital, indicated that Boogie had lymphoma and that the cancer had invaded all his vital organs and caused fluid to build up in his heart and lungs. Even the kidneys were affected. If not euthanized, Boogie would have eventually suffered massive organ failure.

A definitive diagnosis of lymphoma involves examination of a tissue biopsy from an affected lymph node. If lymphoma is diagnosed, it is important to learn how widespread the cancer is through radiography and/or an ultrasound. Other testing may include a complete blood count, urinalysis and a bone marrow biopsy.

The standard treatment for dogs with lymphoma is chemotherapy, sometimes followed by radiation therapy. Chemotherapy results in up to 90 percent complete and partial remissions, increasing longevity an average of eight to 16 months.

When the cancer reappears, another round of chemotherapy achieves a second, shorter remission in about 40 percent of dogs. Fewer than 20 percent of dogs achieve a third remission. Chemotherapy is credited with the long-term survival of 30 percent of dogs that achieve a first remission of up to two years, with 10 percent of these dogs considered cured. Though the cost of chemotherapy varies, it typically runs from $3,000 to $6,000, based on the number of treatments.

Treatment Options 

Myra Shear of Oh-My German Shepherd Dogs in Forest Lake, Minn., opted for chemotherapy to treat her 7-year-old dog, Gorgonzola of Oh-My, when he was diagnosed with Stage 4 lymphoma. "Gonzo," who was Shear's beloved companion, received treatment at the University of Minnesota Veterinary Teaching Hospital.

Though Gonzo had advanced lymphoma, he responded quickly to chemotherapy and soon the cancer was in remission. Shear did not notice a change in Gonzo's personality or a decrease in energy while he underwent treatment. "Gonzo's quality of life was terrific during chemotherapy," Shear says. "A few days of nausea following chemotherapy and an occasional bout of colitis were the only ill effects."

After one year of maintenance chemotherapy treatment every three weeks, the plan was to stop Gonzo's therapy. Shear opted to continue the chemotherapy for an additional year, fearing the cancer might come back if the treatment was stopped.

Subsequently, Gonzo died at age 10 ½ due to causes unrelated to lymphoma. "I consider the three and half additional years of life with Gonzo a great success," Shear says.

A new therapy that offers hope for treating dogs with lymphoma is bone marrow transplantation (BMT), a procedure used for many years in humans diagnosed with lymphoma, leukemia and other life-threatening blood diseases. In human lymphoma patients, the BMT procedure, which is based on protocols developed in dogs, has boosted survival rates to 85 percent.

"It will take another few years to really know the cure rate in dogs treated with BMT," says Steven Suter, V.M.D., Ph.D., DACVIM, assistant professor of oncology at North Carolina State University College of Veterinary Medicine. "A dog most likely will have to be cancer free two years following treatment to be considered cured. We need more time to determine definitely. If the canine cure rates emulate human cure rates, eventually this could mean a cure rate of approximately 40 to 50 percent or higher."

The first bone marrow transplantation performed in an academic setting in a dog took place in late 2008 at North Carolina State University Veterinary Teaching Hospital. About 50 dogs have received BMTs at the hospital, the first veterinary academic institution in the world to offer the procedure.

During bone marrow transplantation, stem cells are filtered out of the dog's blood. Then, a dog receives radiation to kill the rapidly dividing cancer cells in the body. The harvested stem cells are later transfused back into the dog, where they begin growing and developing. The first sign that the procedure is successful is an increasing white blood cell count.

The process is painless but takes about six hours, followed by a two-week stay at the veterinary hospital while a dog's blood counts are monitored. Not all dogs are candidates for BMT. Those with significant disease, those that relapsed after chemotherapy, and those with other serious illnesses are considered poor candidates.

In both dogs and humans, a relapse occurs after a short remission. In people, the relapse happens within 12 to 16 months, and in dogs, it occurs within four months. Another 5 percent of humans relapse about five years after BMT, and a few dogs have relapsed 15 to 18 months after the procedure. As Suter explains, "Everything happens quicker in a dog."

Though BMT is a costly procedure for owners to consider, averaging from $13,000 to $16,000, it may not be more than chemotherapy considering that dogs often receive multiple rounds of chemotherapy and the cost is based on the number of treatments. Another treatment being studied in dogs focuses on ways to prevent the recurrence of lymphoma following remission. The research, under way at Louisiana State University School of Veterinary Medicine, is funded by the American German Shepherd Dog Charitable Foundation.

"We are looking at the effect of a protein called aurora kinase that regulates the cell cycle," explains Keijiro Shiomitsu, D.V.M., assistant professor of radiation oncology. "Since cancer is characterized by unchecked cell growth, inhibiting aurora kinase may suppress cell growth and be effective in combating lymphoma."

An effort to learn how to help dogs that are resistant to chemotherapy and the multiple anti-cancer drugs in the therapy is the aim of another Louisiana State University study. Researchers are looking at the role of a protein pump, called P-glycoprotein (P-gp). This research is partly funded by the American German Shepherd Dog Charitable Foundation.

"Multiple drug resistance is a major impediment to the effectiveness of chemotherapy, and that resistance is thought to develop because of P-gp," says Bonnie L. Brugmann, D.V.M., assistant professor. "P-gp is responsible for removing from cells foreign substances, including many of the most commonly used chemotherapy drugs to treat lymphoma.

"It is important for veterinarians to identify elevations in the levels of these pumps. Our work involves evaluating if blood lymphocytes have the same activation as those in the lymph nodes and if we can use the P-gp in the blood to determine when a patient may become resistant to chemotherapy."

Canine lymphoma is a difficult cancer to face with a beloved dog. Treatments that offer quality of life and increased longevity are welcomed. The hope of being able to use the TK blood test to determine the likelihood of cancer and a dog's long-term prognosis is encouraging. New treatments, such as bone marrow transplantation, inhibition of aurora kinase in preventing cancer recurrence and use of the protein pump P-gp to help dogs that are resistant to chemotherapy, also offer promise.

Though Boogie's cancer came on quickly with little chance for treatment, Simerson wishes she would have had more time with him.

Shear opted for chemotherapy for her dog Gonzo despite his having Stage 4 lymphoma. "I would do it again in a heartbeat," Shear says. "I would have done anything for more quality time with him."

Purina appreciates the support of the German Shepherd Dog Club of America Inc. and particularly Ginny Altman, GSDCA past president, health liason and chairwoman of the GSDCA Health and Genetics Committee, and vice president of the American German Shepherd Dog Charitable Foundation, in helping to identify topics for the Purina Pro Club German Shepherd Dog Update newsletter.

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