Owners of each dog will give written informed consent to treat prior to study entry. All dogs will be treated at the University of Minnesota Veterinary Medical Center (VMC). The study will be conducted and managed by the Oncology service of the College of Veterinary Medicine, University of Minnesota.
Items in yellow can be the bulleted points
Dogs will receive a baseline complete history, physical examination, and pre-dose laboratory assessment, including a complete blood count (CBC), serum biochemical profile, and urinalysis. Thoracic radiography and abdominal ultrasonography will be performed prior to enrollment to screen for metastatic disease and obtain a baseline for therapy. Owners will be responsible for the costs associated with surgery, histopathologic analysis, diagnostic testing, eBAT administration (all except for the cost of the drug), and standard of care doxorubicin chemotherapy. Depending on the feasibility of surgery, there will be two groups treated with eBAT and doxorubicin chemotherapy:
eBAT will be administered in one cycle of three intravenous treatments at days 1, 3, and 5. To increase drug penetration within the tumor, dose escalation will be applied to patients with disease measurable by calipers, provided the initial dose is well-tolerated. Treatment with doxorubicin chemotherapy will be recommended as part of standard of care therapy, but will not be required for study participation. If elected, doxorubicin will commence on day 21.
Disease reassessment will include physical examination, blood and urine evaluation, thoracic radiography and abdominal ultrasonography prior to doxorubicin treatments 1(Day 21), 3(Day 63), and 5(Day 105). Depending on tumor location, additional imaging modalities such as computerized tomography may be required.
Canine hemangiosarcoma is among the most challenging and mysterious diseases encountered in veterinary practice. It is an incurable tumor of cells that line blood vessels, called vascular endothelial cells. Hemangiosarcoma is relatively common in dogs; it is estimated that this type of cancer accounts for 5-7% of all tumors seen in dogs (300,000 – 420,000 cases/year). Considering the lifetime risk of cancer for dogs is between 1 in 2 and 1 in 3, we can calculate that 1.5 to 2.5 million of the ~72 million pet dogs in the United States today will get hemangiosarcoma and succumb from it. Although dogs of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly in dogs beyond middle age (older than 6 years), and in breeds such as Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Bernese Mountain Dogs, Flat Coated Retrievers, Boxers and Skye Terriers. According to the Golden Retriever Health Study published in 2000, the estimated lifetime risk of hemangiosarcoma in this breed is 1 in 5, illustrating the magnitude of this problem.
Unlike other cancers, hemangiosarcoma is almost an exclusive disease of dogs. In people, a similar type of tumor (angiosarcoma) occurs only rarely in association with workplace exposure to vinyl chloride and polychlorinated biphenyls (PCBs). An even smaller fraction of women who receive high dose radiation therapy for cancer (usually breast cancer) can develop angiosarcoma of the skin. Yet, angiosarcomas account for much less than 1% of all tumors seen in people.
In dogs, the common primary sites for hemangiosarcoma are the spleen, the right atrium of the heart, and the subcutis, which is the tissue beneath the skin. The pattern of growth for these tumors involves infiltration into normal tissues surrounding the tumor as well as distant spread (metastasis). The disease does not cause pain and the rate of growth in the early stages is relatively slow. Dogs harboring even large hemangiosarcomas may show no clinical signs or evidence that they have a life threatening disease. Generally, the tumor cells retain some normal aspects of behavior, so they try to make blood vessels. But these vessels are tortuous and malformed, and blood cells tend to pool in them and clot which then prevent blood and nutrients from reaching tumor cells, causing them to die. This creates small ruptures in the tumor through which blood may escape into the abdomen, heart sac, chest, or subcutaneous space. Depending on the amount of blood lost, affected dogs may show non-specific signs such as lethargy and weakness, but these are transient and resolve as dogs reabsorb the blood components and make new blood cells. The clinical signs are recurrent, but they also are subtle enough to go unnoticed for some time. Since hemangiosarcoma tends to metastasize aggressively to lungs, liver, intestines, and mesentery (the membranous connective tissue that supports the intestines), distant spread has inevitably occurred once the disease is finally diagnosed. The eventual outcome for patients with this disease often follows the rupture of a large or rapidly growing tumor, which results in acute, severe hemorrhage, collapse, shock, and death.
We do not precisely know what causes canine hemangiosarcoma. The observations that the disease occurs more commonly in dogs than in other animals, and that some breeds are at higher risk than others tell us that heritable factors must contribute to risk. Ultimately, the interactions of these heritable risk factors with the environment probably lead to the spectrum of mutations that give rise to the tumor. As a matter of brief review, it is important to understand that “cancer is a genetic disease, although it is not always heritable.” Tumors arise when cells accumulate mutations that eliminate normal constraints of growth and genetic integrity. These mutations provide cells a selective growth advantage within their environment, essentially the same evolutionary phenomenon that we call natural selection, albeit on a microscopic scale. Most mutations arise because the enzymes that control cell division are not foolproof. About 1 mutation occurs for each one to ten million bases that are replicated when a cell divides (genomic DNA in dogs consists of about 2.5 billion base pairs; in other words, when a cell divides, it must copy 2.5 billion bases and the inherent error rate of the DNA replication machinery will introduce between ~250 and 2,500 errors, or mutations, to the DNA of each daughter cell). Since some cells in the body divide continuously to replace others that die or are damaged (for example, blood cells, skin cells, and gut cells), mutations are pretty much introduced constantly into cells in the body. For this reason, we say the greatest risk factor for cancer is “being alive”. As mentioned above in the example of humans that are at risk to develop angiosarcoma, mutations also can occur from exposure to environmental toxicants. Fortunately, most of these mutations are silent (they neither help nor hurt the cell or the organism), and the body has mechanisms to eliminate most cells that acquire deleterious mutations. A relatively new concept about how cancer happens invokes the theory that only “stem cells” can give rise to tumors, making the acquisition of mutations in somatic cells (any cell that is not a sperm or an egg) a lesser concern. For now, it is important to understand that simply carrying a mutation does not necessarily mean an individual will get cancer - it only means that his or her risk is elevated. The practical implication of this statement is that we will probably never eliminate cancer completely from our population (human or canine), but we can achieve a significant reduction in the number of cases as we learn more about how the disease happens and we work to diminish risk factors or detect the disease early enough to treat it before it becomes a life-threatening condition.
The news is not all bad. For example, most of these tumors make growth factors that they need to survive, or they “coerce” cells in their environment to do this for them. One of these growth factors is vascular endothelial growth factor-A or VEGF, which acts by binding specific receptors on the hemangiosarcoma cells.
There is presently no readily available, effective test for early diagnosis of hemangiosarcoma. Careful analysis of blood samples by experienced pathologists may hint at the presence of chronic hemorrhage and blood vessel abnormalities that are suggestive of hemangiosarcoma. However, this method is neither sensitive nor specific to confirm the diagnosis. Non-invasive imaging methods are useful aids to diagnose the disease. In particular, ultrasound is moderately specific, but it is not sensitive, and the tumor must be large enough to be grossly visible. In addition, biopsies are required for confirmation of imaging results.
The majority of dogs diagnosed with hemangiosarcoma die within 1 year of diagnosis, with a large proportion of dogs not surviving beyond 6–8 months. With respect to HSA involving the spleen, surgery alone has been associated with extremely short survival times.Median survival for dogs treated with surgery alone is approximately 90 days, and that is extended to approximately 180 days by the addition of chemotherapy using one of several protocols available. Because the goal for chemotherapy in pet dogs is to extend life with good quality, toxicity is generally not a major issue of concern, and when it occurs it is most often managed without much difficulty.
The addition of doxorubicin (DOX)-based chemotherapy protocols (DOX alone, DOX/cyclophosphamide and vincristine/DOX/cyclophosphamide) following surgery has resulted in modest increases in median survival time (5–6 months on average), however the 1 year survival rate is 10 % at best.
Regrettably, the standard-of-care for this disease has not seen significant advancement over the past 20 or 30 years. The options for therapy of canine hemangiosarcoma are limited, largely because the disease is not diagnosed until the late stages. The standard consists of surgery to shrink or remove the primary tumor, when possible, followed by intensive chemotherapy. In some cases, surgery is not feasible, or it can be impractical or inappropriate (for example, if there is evidence of extensive metastatic spread to sites beyond the primary tumor). There is no other therapy that has been proven to be effective to manage or control hemangiosarcoma.
Several alternative and complementary approaches (diet, herbs, mystical energy, etc.) have recently become popular as people try to find treatments for canine hemangiosarcoma. This usually follows extensive publicity after a dog receives these treatments and survives longer than anticipated, leading proponents to advertise this as success and evidence that their approach is curative for hemangiosarcoma. The danger of attributing curative power to treatment approaches after an anecdotal response cannot be overstated. There is no reported case where one of these therapies has been consistently successful (or even as good as the standard of care) after it has been tested without bias to try to replicate the anecdotal response. In fact, sometimes such treatments can actually interfere with - or increase the toxicity of chemotherapy drugs.
Dr. Modiano completed his veterinary training and PhD in Immunology at the University of Pennsylvania in Philadelphia (1984-1991), followed by a residency in Veterinary Clinical Pathology at Colorado State University in Fort Collins, CO (1991-1993), and a post-doctoral fellowship at the National Jewish Medical and Research Center in Denver, CO. He was Assistant Professor of Veterinary Pathobiology at Texas A&M University between 1995 and 1999, returned to Denver from 1999 to 2007, where he held Scientist and Senior Scientist appointments at the AMC Cancer Research Center and was Associate Professor of Immunology and Full Member of the Cancer Center at the School of Medicine of the University of Colorado, Denver. Between 2001 and 2003, Dr. Modiano served as Director of Cancer Immunology and Immunotherapy for the Donald Monk Cancer Research Foundation; he also is a partner at Veterinary Research Associates, LLP, a company focused on development and implementation of diagnostics for veterinary medicine and a founder/scientist at ApopLogic Pharmaceuticals, Inc., a biotechnology company focused on development of cancer therapeutics. In July of 2007, Dr. Modiano joined the College of Veterinary Medicine and the Masonic Cancer Center, University of Minnesota, where he continues his research program as Professor of Comparative Oncology holding the Al and June Perlman Endowed Chair.
Doctors and scientists take part in many kinds of research studies. Clinical research helps researchers understand how best to treat patients or helps them learn more about a particular condition or disease. There are many different forms of clinical research. One common form is a clinical trial. In a clinical trial, researchers test new drugs, medical devices or treatments.
Clinical trials may seek to discover new drugs, new ways of giving patients approved drugs, new combinations of approved drugs, new surgical techniques, devices, or biological products. Clinical trials are also conducted to test cutting-edge and novel therapies, like studies that involve gene therapy or gene transfer.
Informed consent is a process that helps you learn about the research study. After learning about the study, you will be able to ask the researcher or his/her staff questions. You should only agree to take part after you clearly understand the study and feel comfortable. You should take time to talk over your decision with your doctors, family, and friends. If you agree to take part, you will be asked to sign an "informed consent form."
You may consider having your pet participate in a study because:
You might consider not taking part in a study because:
There is no guarantee that a clinical trial will help your pet’s condition, but the results will contribute to knowledge that may make a difference in the future care of patients.
Clinical trials test new drugs, devices, or treatments. In some cases, taking part will not cost you anything. In other studies, the research team may bill you for drugs, devices, and services they provide. The study informed consent form will describe any costs to you in detail. If the information in the consent form is not clear, you should ask the research team to explain any costs before you sign the consent form.
Most randomized trials will only disclose this kind of information when the study has been completely finalized; this is done to protect the integrity of the research data and results. If the trial is a "double-blind" trial, the doctor will not even know which substance your pet received. Most protocols will have information with respect to when a study will be "unblinded." If this is something that you want to know more about, ask the investigator what the study's policy is before you agree to participate.