Genetic Research & New Therapies Advance Knowledge Of TCC Bladder Cancer
When her 9-year-old Scottish Terrier, "Frankie," began frequently straining to urinate, Laurie Hoffman of Schereville, Ind., recognized the potential seriousness of the condition. "Immediately a red flag went up in my head because I knew Scottish Terriers have a high incidence of bladder cancer," she says.
Hoffman wasted no time taking Frankie to the veterinarian for an evaluation. A urinary test indicated a bladder infection, and an ultrasound showed a mass in the bladder. The good news was that researchers at Purdue University School of Veterinary Medicine were conducting a clinical trial to study a new treatment for dogs with transitional cell carcinoma (TCC), the most common canine urinary bladder cancer. Though Hoffman did not know whether Frankie had TCC, she made an appointment for the terrier at Purdue, a three-hour round trip from their home.
During a tissue biopsy at Purdue, a substantial portion of Frankie's tumor was removed. The biopsy confirmed that the mass in the bladder was TCC. As with most cases of TCC, the location of the tumor made complete excision impossible. Frankie's diagnosis allowed him to participate in the clinical trial, so he began receiving a drug therapy, mitomycin C, directly in his bladder through a catheter. The drug stayed in the bladder for one hour and then was removed through the catheter.
The intravesical method delivered a concentrated amount of mitomycin C directly to the tumor without the risk of side effects that often accompany intravenous chemotherapy. Frankie and many other dogs in the study did well on the intravesical therapy; roughly half the dogs' cancers went into remission with few side effects.
"Frankie absolutely had no side effects," Hoffman says. "He would sleep in the car on the ride home and when we arrived be ready to eat. Throughout his treatment, he was active and did very well."
For a couple of dogs in the study, however, the drug didn't stay in the bladder; instead, it traveled into the bloodstream and then through their bodies causing severe side effects. As a result, mitomycin C is not used as a front-line treatment in dogs.
During the 10 months that Hoffman took Frankie to Purdue to participate in the study, his condition stabilized and the tumor stopped growing. Then, one day, Frankie began limping. At first Hoffman thought the dog had twisted or turned wrong when running, but the intermittent pain in his foot didn't go away. A radiograph did not show an abnormality, yet the problem got worse. When an MRI (magnetic resonance imaging) indicated the cancer had spread to Frankie's spine, Hoffman decided the time had come to have him euthanized.
"At that point, there was no possibility that Frankie would have a quality life," says Hoffman. "It happened so fast. I am glad he did not have many bad days."
The Most Common Bladder Tumor
Transitional cell carcinoma (TCC) accounts for 90 percent of dog bladder tumors and affects about 20,000 to 30,000 dogs a year in the U.S. Besides Scottish Terriers, at-risk breeds include Beagles, Shetland Sheepdogs, West Highland White Terriers and Wire Fox Terriers. Not surprisingly, the national parent clubs for these breeds have identified TCC as one of their top health concerns.
When Frankie was diagnosed with TCC in 2007, treatment modalities for the cancer were expanding. Before then, once the initial treatment failed, there was less hope for dogs affected by the cancer.
Deborah Knapp, D.V.M., DACVIM, the Dolores L. McCall Professor of Comparative Oncology at Purdue University School of Veterinary Medicine, was the lead investigator of the clinical trial that Frankie participated in and one of the first clinical researchers to evaluate TCC treatment options.
Purdue University clinicians now use at least six protocols involving several drug therapies to treat TCC patients. "Several different treatments are available," Knapp says. "When one drug is no longer effective, we give another drug. There is about a 75 percent chance we can control or cause regression of the cancer in each patient."
"What we can do now for dogs with TCC compared to even 10 years ago is phenomenal," says Patty Bonney, clinical trial coordinator at Purdue University School of Veterinary Medicine. "When I started working with Dr. Knapp in the 1980s, owners had no options or hope for a dog with bladder cancer. Today, dogs may live for more than two years when they receive treatment for bladder cancer."
The two standard treatments most commonly used are: an intravenous chemotherapy drug, mitoxantrone, along with an oral non-steroidal anti-inflammatory drug (NSAID), piroxicam; and piroxicam administered alone. The intravesical mitomycin C therapy that Frankie received still is a possible treatment but is used less due to the risk of serious side effects.
"Both mitoxantrone and piroxicam help to prolong a dog's life and help us to maintain quality of life," Knapp says. "They can help make the tumor shrink dramatically in some dogs or just keep it from growing in other dogs. Unfortunately, the drugs do not elicit a cure in most dogs."
The effectiveness of piroxicam, a nonselective cyclooxygenase (COX) inhibitor, in treating TCC patients was discovered when it was given for pain control to dogs with various forms of spontaneous cancer, which then went into remission. COX inhibitors prevent the production of prostaglandins, or chemicals in the body that cause inflammation, and they have antitumor effects. Other chemotherapy drugs, such as carboplatin and cisplatin, have been used in combination with piroxicam to treat TCC but are used less often because they can cause side effects.
The median survival for dogs with TCC that are treated with piroxicam alone is 195 days compared with a median survival for dogs treated with piroxicam and mitoxantrone of 250 to 300 days. These survival times are averages, thus some dogs will live longer and other dogs not as long.
During treatment, the size of the tumor is monitored using ultrasound. "If we see that the tumor is larger, then we know we need to change therapy," Bonney says. "If the tumor is the same size or smaller, we feel the current protocol is working. Tumor measurements are very important to guide the best recommendations."
Genetic & Environmental Factors
Though the exact cause of TCC is not known, researchers suspect a combination of genetic predisposition and environmental factors is responsible. The highest risk of TCC has been found in dogs of the high-risk breeds that have been exposed to harmful lawn chemicals and insecticides, Knapp says. In contrast, one study showed that Scottish Terriers that ate vegetables at least three times a week had a 70 percent decrease in the risk of developing TCC.
In TCC, a malignant tumor develops from the transitional epithelial cells that line the bladder, invading deeper layers of the bladder wall, including the muscle layers. As the tumor grows, it can obstruct the flow of urine from the kidneys to the bladder or as the urine exits the bladder. A dog can die quickly if the urine flow is completely blocked. The tumor also can grow in other parts of the urinary tract and can spread to other areas of the body, including the lymph nodes, lungs and liver.
A definitive diagnosis of TCC requires a tissue biopsy, which can be obtained surgically or nonsurgically through a fiber-optic scope inserted into the bladder. "We remove a small piece of tissue from the tumor, and a pathologist analyzes it to determine whether it is cancer," Knapp says. "If it is cancerous, we also learn the type of cancer."
The size and extent of the tumor are determined by radiographs, ultrasound or computed tomography. Treatment options depend on whether the tumor is localized to the bladder and where the tumor is located inside the bladder. Complete evaluation and treatment of dogs with invasive bladder cancer may range from less than $1,000 to more than $5,000.
"If the tumor is in part of the bladder where we can remove it surgically, that's what we do," Knapp says. "More often than not, however, it's in part of the bladder where you cannot surgically remove it. Then, we rely on drugs to shrink the tumor and hopefully cause it to go into remission or at least stop growing."
Knapp continues to investigate several aspects of TCC, including risk factors, methods for earlier detection, and improved therapies. Understanding the causes of bladder cancer will allow development of strategies to prevent its occurrence. "If we can prevent bladder cancer, it will be more effective than trying to treat it once it develops," Knapp says.
Bladder cancer also affects humans. More than 65,000 people a year are diagnosed with bladder cancer in North America, and more than 14,000 people die annually in the U.S. from the cancer. Canine TCC is almost identical to intermediate- to high-grade invasive TCC in humans. Similarities include the sites, frequency of metastases, and response to medical therapies.
While more than two-thirds of cases of bladder cancer in people involve a less serious form of bladder cancer referred to as low-grade superficial TCC, most cases in dogs are the high-grade invasive form of the cancer. The invasive form of the cancer in humans, although less common, carries a guarded prognosis.
"It is entirely possible that important information learned from dogs with bladder cancer will lead to an improved outlook for humans with invasive bladder cancer," Knapp says. Efforts to define the genetic causes of canine TCC are being studied by Knapp and Elaine Ostrander, Ph.D., head of the Section of Comparative Genetics at the National Human Genome Research Institute, part of the National Institutes of Health. Their goal is to determine the genetic factors that cause or increase the risk of bladder cancer. The AKC Canine Health Foundation is funding the research, with support from national parent clubs. Ostrander hopes that learning about the genetic basis for canine TCC will increase knowledge about human bladder cancer. "We want to see if these dog genes matter in the human forms of the disease," Ostrander says. "The genetics of human bladder cancer are difficult to understand. Dogs may contribute immense information."
The research has identified regions of genes likely to be associated with TCC in two at-risk breeds: Scottish and West Highland White terriers. When the researchers identify causative mutations that play a role in triggering TCC, potentially they will better understand why some breeds are more susceptible and why the disease progresses faster in some individuals.
The process involves comparing blood samples from healthy, unaffected dogs age 10 and older with samples from affected dogs. "We are making tremendous progress," Ostrander says.
Bonney, the clinical trials coordinator at Purdue University, owns a 12-year-old healthy Wire Fox Terrier that she regularly has screened for TCC. Her Wire Fox Terrier has urinalyses and bladder ultrasounds two times a year, and she closely monitors the dog for warning signs.
"Vigilance is very important," Bonney says. "Any time a dog has blood in the urine, strains or takes a long time to urinate, or urinates a good stream but continues to posture for urination after the stream is over, you should take the dog to be examined by your veterinarian."
Hoffman agrees. Now the owner of a 4-year-old Scottish Terrier, "Dexter," she says, "At first, I didn't think I would get another dog because it was so hard to lose Frankie. We monitor Dexter like a hawk."
"Fortunately, we are making progress and getting closer to finding the gene associated with TCC," Knapp says. "With this information, we hope to develop strategies for detecting the cancer earlier when it may be more responsive to treatment. More importantly, we hope to develop strategies to prevent it."
Owners Can Contribute to TCC Research
Owners of Scottish Terriers, West Highland White Terriers and Shetland Sheepdogs may contribute to research to identify the genetic mutation for transitional cell carcinoma (TCC), the most common canine cancer of the urinary tract. These breeds are considered at high risk for TCC.
The collaborative research involves scientists at Purdue University and the National Human Genome Research Institute. To participate, owners should submit blood samples and veterinary records from affected dogs and healthy dogs age 10 and older. Participation is confidential. For information about the study, visit www.research.nhgri.nih.gov/dog_genome/info_for_dog_owners/ index.html. To request a blood sample kit, please send an e-mail to firstname.lastname@example.org.
Recognizing Signs of TCC
The signs of transitional cell carcinoma (TCC) often mimic those of urinary tract infections. Dogs exhibiting signs should be taken to the veterinarian. The sooner a dog receives treatment, the more likely for a healthy outcome. Though the value of screening for TCC has not been studied, experts believe performing periodic ultrasounds and urinalyses starting at middle age in high-risk breeds will allow earlier detection of the cancer. Common signs of bladder cancer are:
- Blood in the urine
- Straining to urinate
- Frequent recurring urinary tract infections