Carboplatin Beads Show Promise In Treating Feline Injection-Site Sarcomas
When Heidi Phillips, VMD, DACVS-SA, adopted a mixed-breed cat named “Sidney” in 1997 as a first-year veterinary student at the University of Pennsylvania, she was excited to have a feline companion. Little did she know that Sidney would eventually develop a sarcoma between his shoulder blades where he had been vaccinated by a veterinarian in preparation for adoption.
Vaccinating cats between the shoulder blades, subcutaneously into the fat and connective tissue, was common practice years ago before the subsequent occurrence of injection-site sarcomas was realized. Since then the incidence rate for feline injection-site sarcomas (FISS) has been reported to be one in 10,000 cats to as high as one in 1,000 cats, depending on the study.1,2
An aggressive cancer, FISS is believed to occur secondary to inflammation from an injection. A malignant transformation of cells results in a tumor, either a movable lump under the skin or a growth that deeply attaches to underlying tissues, occurring weeks, months and even years later. Sidney’s tumor became apparent to Dr. Phillips when she was petting him eight years after vaccination and when she was studying to be a board-certified veterinary surgeon.
“Radical surgery was able to completely remove the tumor from between his shoulder blades,” Dr. Phillips says. “However, the tumor metastasized, and Sidney was euthanized 10 months after his surgery.”
Fast forward 14 years, Dr. Phillips, now associate professor of small-animal surgery at the University of Illinois, is a leading investigator of a novel treatment for FISS that shows promise in providing a safer, effective and less-expensive therapy for the cancer. The treatment involves using carboplatin beads — beads made of calcium sulfate and containing the chemotherapy drug carboplatin — to deliver targeted therapy to the cancer cells.
The need for an alternative therapy is substantial, says Dr. Phillips. The gold standard for treatment, consisting of surgery, radiation therapy and/or chemotherapy, is aggressive and expensive. Surgery, for example, gives cats the best prognosis, but often requires removal of a limb, part of bones of the pelvis or spine, or parts of the abdominal wall.
Sadly, as with Sidney, the tumor may metastasize, and the mass a veterinarian can see and feel may represent only a small portion of the tumor. The cancer spreads in 10 to 20 percent of cases,3 and local recurrence of the tumor is a big problem. Additionally, radiation and intravenous chemotherapy affect not only diseased tissue but also healthy tissue.
“Our hope is that by using the beads, carboplatin’s effect will be limited to and concentrated at the tumor site and the tissue around it and have fewer systemic effects on the body,” Dr. Phillips says. “Placement of the beads can be done in conjunction with radical surgery or be more minimally invasive in some cases.”
A three-phase study at the University of Illinois was used to investigate the efficacy and safety of using carboplatin beads to treat FISS. The principal investigators were Dr. Phillips, Rachel J. Tulipan, DVM, surgical resident, now a board-certified veterinary surgeon in private practice in Georgia, and Elizabeth Maxwell, DVM, surgical resident, now a board-certified veterinary surgeon specializing in surgical oncology at the University of Florida. The results of these studies, two of which were in vitro studies and the third was performed in healthy cats, showed carboplatin beads are a potential effective future therapy for FISS and other types of cancer in cats and dogs.
A Three-Phase Study
The three phases of the carboplatin bead research helped to determine whether the beads could successfully concentrate treatment specifically where it is needed without the systemic side effects of intravenous chemotherapy. The goal was to implant 3-millimeter beads made of sterile calcium sulfate hemihydrate (plaster of Paris) and filled with carboplatin directly into tumor sites to attack tumors with concentrated, sustained treatment.
“The bead material and similar materials have been used for years in people to deliver antibiotics locally to a surgery site, as in open fractures or in joint replacement surgery,” Dr. Phillips says. “In animals, beads are used to deliver antibiotics to localized, hard-to-manage infections. Although carboplatin beads are inexpensive, easily available and not difficult to implant surgically, they had never been studied for delivering chemotherapy, especially in cats.”
“Carboplatin is commonly used in both dogs and cats to treat cancer, but it can be associated with effects on the kidneys, bone marrow or gastrointestinal tract when injected into the bloodstream,” Dr. Maxwell says. “Our goal was to learn if carboplatin could be administered to the tumor without reaching other parts of the body.”
The first phase, a pilot study, involved evaluating carboplatin in test tubes to ensure the chemotherapy agent would be released from the beads into a surrounding medium. The pilot study was published in the November 2016 issue of the American Journal of Veterinary Research.
“In a longer-term study, we left some beads undisturbed in test tubes of fluid, and others were turned over in test tubes to mimic tumor conditions, including different degrees of inflammation and physical movement of fluid in tissues,” Dr. Phillips says. “We also studied what ranges of carboplatin would be released from the beads under these various conditions.” The American Journal of Veterinary Research published an article on this work in its May 2017 issue. In the second phase of investigation, the research team placed the beads in plates of agar gel, a jellylike substance used as a model for cat tissue, to understand how the chemotherapy drug would travel through the tissues and how far apart the beads should be spaced. The study was published in June 2018 in the American Journal of Veterinary Research.
“At the same time, cancer cells were placed in a petri dish, and we investigated how various concentrations affected the growth of cancer. This study helped us determine how many beads might be required to treat tumors when they are implanted,” says Dr. Maxwell. The research was published in the February 2018 issue of Veterinary Surgery.
The third phase of the research involved implanting the carboplatin beads in six healthy cats to determine how the drug would diffuse from the beads through tissues and into the bloodstream. “We chose to first investigate the beads in healthy cats rather than cats with tumors because FISS is associated with an inflammatory response to injected material,” Dr. Phillips says.
“We wanted to make certain the beads themselves would not cause excessive inflammation in the body before recommending them to treat cats with cancer,” says Dr. Maxwell. “Outcomes in cats with cancer would be affected by the characteristics and progression of their own tumors, which would make it difficult to generalize about what to expect.”
Among the variables being studied were how long it takes the beads to release the chemotherapy drug, how the drug diffuses in actual tissue, whether the drug causes local tissue inflammation, and whether the drug was taken up into the bloodstream and in what concentrations.
“We found that the carboplatin bead delivery system offers the potential to maintain high concentrations of the drug over time at the site of disease,” Dr. Maxwell says. “These beads slowly released carboplatin into the surrounding tissues over 21 days. The drug was well-tolerated by healthy adult cats.”
“Thus far, the results have been promising,” says Dr. Phillips. “The cats in this study did not have any significant adverse reactions to implantation of the beads, and the chemotherapy drug was found to diffuse into the tissues around the beads. We learned that implantation of beads was well-tolerated by cats, plus there were no major changes in overall general health noted in any of the cats.”
A Clinical Trial Is Next
Since completing the three-phase study, Dr. Phillips has been testing the efficacy of carboplatin against cell lines taken from five different locally invasive cancers in cats and dogs. Using cancer cell culture and radiation therapy, she expects to produce the most reliable, predictable patient-specific results.
The next step will be a clinical trial to evaluate the effectiveness of the carboplatin beads in treating FISS in cats, as well as in other invasive and aggressive tumors in both dogs and cats. Tentatively, the clinical trial is planned for 2020 or 2021, based on funding support.
In the meantime, veterinarians focus on two things: Cats are vaccinated as far down the limbs as possible to facilitate surgical removal of a tumor, if one were to develop, and they devote attention to early detection and aggressive treatment for better results.
“Developing easier, less-expensive treatment for FISS will help save more affected cats,” Dr. Phillips says. “We hope this approach will have applications to other types of cancer as well and help cats and dogs have a better chance for survival.”
The memory of Sidney motivates her. “With reformulated vaccines and protocols, the incidence of FISS has seemingly decreased, and veterinarians agree that the many benefits of vaccination outweigh the risk of FISS,” says Dr. Phillips. “However, owners and veterinarians together bear the responsibility of adhering to proper vaccination protocols to limit risk of tumor development.” n
1 Bowlt K. Feline Injection-Site Associated Sarcomas. In Practice. 2015;37:2-8.
2 Manunta ML, Gavini E, Chessa G, et al. Carboplatin Sustained Delivery System Using Interjectable Microspheres. Journal of Veterinary Medicine. 2005;52:416-422.
3 Phelps HA, Kuntz CA, Milner RJ, et al. Radical Excision with Five-Centimeter Margins for Treatment of Feline Injection-Site Sarcomas: 91 Cases (1998-2002). Journal of the American Veterinary Medical Association. 2011;239:97-106.
Purina appreciates the support of the Winn Feline Foundation, and particularly Vicki L. Thayer, DVM, DABVP (feline), former executive director, in helping to identify this topic for the Cat Update.
Winn Feline Foundation Helps Fund FISS Research
The Winn Feline Foundation, which focuses exclusively on supporting feline medicine research, provided funding through its Miller Trust for phase three of the carboplatin bead research. This research, conducted in 2016 at the University of Illinois, helped to affirm the safety of the therapy for controlling feline injection-site sarcomas (FISS) without causing a systemic or local toxicity. The findings also support the future use of implantation of carboplatin beads in an effort to improve survival outcomes for cats with FISS.
“One of the main reasons we approved this research proposal was because of its localized approach to treating FISS, which minimized the known side effects of carboplatin treatment in cats, while maximizing the efficacy of the treatment,” says Drew Weigner, DVM, DABVP, president-elect of Winn Feline Foundation. “It is a very innovative and effective approach that is likely to extend the lives of affected cats.”
Guidelines Focus on FISS Prevention
No one knows why some cats develop feline injection-site sarcomas (FISS). A small minority are thought to have a genetic predisposition to develop these tumors, but an exact cause has not been identified. Regardless of why a cat develops an injection-site sarcoma, an inappropriate inflammatory or immunological reaction seems to be the trigger that leads to tumor development.
The first concern of a potential association between vaccination of cats for rabies and development of sarcomas was raised in October 1991 in a letter to the editor published in the Journal of the American Veterinary Medical Association.
In response to an increased incidence of soft-tissue sarcomas at
vaccination sites, the Vaccine-Associated Feline Sarcoma Task Force
was formed in November 1996 to set recommendations regarding vaccine guidelines. Jointly formed by the American Veterinary Medical Association, American Animal Hospital Association, American Association of Feline Practitioners, and Veterinary Cancer Society, the task force set out to research and address the problem during
a three-year period.
Among the outcomes of the study, the task force noted there are
benefits and risks to vaccination, which should be undertaken with
the same thoughtful consideration as any other procedure in veterinary medicine. Aggressive treatment was advised for masses at vaccine sites that are still evident three or more months after vaccination, are 2 centimeters or greater in diameter, or are growing in size one month after vaccine administration.
Meanwhile, the American Association of Feline Practitioners issued
vaccination guidelines in 1998, 2000, 2006, and 2013 to help veterinarians determine best practices for individual cats based on exposure risk and trying to avoid unnecessary vaccination. Vaccination site recommendations in the 2013 report include:
- Avoiding multiple injections at a single site
- Recording vaccine locations and monitoring vaccine sites
- Giving FPV (feline parvovirus), FHV-1 (feline herpesvirus-1), and FCV (feline calicivirus) vaccines below the right elbow; FeLV (feline leukemia virus) vaccine below the left stifle; and rabies vaccine below the right stifle
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