The emergence and characterization of vaccine-associated

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1 Review J Vet Intern Med 2001;15: Margaret C. McEntee and Rodney L. Page Feline vaccine-associated sarcomas have presented many challenges. Initially, the etiopathogenesis and biological behavior of these tumors had to be characterized, and strategies implemented to move tumors away from problematic sites. Next, diagnostic and treatment recommendations evolved as the biologic behavior of vaccine-associated sarcomas forced early and aggressive intervention. Current therapeutic strategies are expensive, at times debilitating, and frequently fail to effect tumor control. This review summarizes the known history, epidemiology, etiology, and clinical management of vaccine-associated sarcomas after a decade of work. The next challenges must be to find more practical and effective solutions, and to eliminate the cause of vaccine-associated sarcomas. Key words: Chemotherapy; Computed tomography; Radiation therapy. The emergence and characterization of vaccine-associated sarcomas in cats has had a profound effect on veterinary medicine. An unexpected consequence of this phenomenon is the evolution of cancer management recommendations for vaccine-associated sarcomas that now represent a new paradigm for cancer management regardless of species or tumor type. The most important lesson learned from cats with vaccine-associated sarcomas is the requirement for aggressive management early in the course of disease. Although this seems obvious now, it embodies several dramatic shifts in behavior by the veterinary profession. Before experience with these tumors, excisional biopsies and close marginal resections were performed routinely. In many situations, excisional biopsies were conducted casually and were often the only therapeutic maneuver. The potential harm of inappropriate and incomplete treatment of vaccine-associated sarcomas is now recognized. Preoperative, incisional biopsies for treatment planning have replaced excisional biopsies and cats with vaccine-associated sarcomas are now referred to specialists capable of aggressive, often multimodality, treatment. In addition, the value of sophisticated diagnostic imaging for treatment planning and the importance of adequate marking of the resected specimen for evaluation of margins is established. These lessons are not new to our profession but we had not previously been challenged to confront such a uniformly aggressive tumor. These experiences led to rapid, widespread acceptance of more thorough staging and more thoughtful treatment recommendations for vaccine-associated sarcomas. The urgency of developing an adequate cancer control policy was never more compelling than with vaccine-associated sarcomas. The lessons could not have been learned so quickly without a community galvanized by the frustration of this dilemma. The effort to overcome vaccine-as- From Cornell University, College of Veterinary Medicine, Department of Clinical Sciences, Ithaca, NY. Reprint requests: Margaret C. McEntee, DVM, Department of Clinical Sciences CVM, Room C5-163, Box 31, Cornell University, Ithaca, NY ; mcm43@cornell.edu. Submitted September 5, 2000; Accepted January 12, Copyright 2001 by the American College of Veterinary Internal Medicine /01/ /$3.00/0 sociated sarcomas in cats has involved diverse groups, large funds, and countless hours. As a result of this effort, cancer awareness and management in veterinary medicine has moved forward collectively such that the ultimate legacy of this terrible consequence may be better cancer control for both dogs and cats. Background Information The prevalence of feline rabies was noted to increase in This was attributed to the small number of vaccinated cats and an outbreak of wildlife rabies in the United States. Additionally, postexposure prophylaxis in humans after exposure to cats with suspected rabies was increasing. In 1987 the state of Pennsylvania enacted a law requiring rabies vaccination of cats. 1 Such public health concern and approval for subcutaneous administration of rabies vaccines in the mid-1980s resulted in increased subcutaneous administration of rabies vaccines in cats in the United States. In 1985, a subcutaneously administered killed aluminumadjuvanted rabies vaccine was approved for use in cats and largely replaced the use of the intramuscularly administered high egg passage modified-live virus rabies vaccine. 2 In 1985, a killed aluminum-adjuvanted feline leukemia virus (FeLV) vaccine was also introduced. 2 Both of these vaccines were widely used by veterinarians to vaccinate cats subcutaneously against rabies and FeLV. The 1st description of a local reaction to rabies vaccination published in 1986 described 13 dogs that developed a focal cutaneous vasculitis and alopecia at sites of inoculation. 3 In 1988, 9 cats were reported to develop local reactions several days after a combined rhinotracheitis-calicivirus vaccine. 4 In the late 1980s, the Laboratory of Pathology at the University of Pennsylvania School of Veterinary Medicine identified an increase in inflammatory injection site reactions in canine and feline biopsy specimens submitted to the lab. 5 A questionnaire sent to veterinarians confirmed that these reactions were in sites of subcutaneous administration of rabies vaccine. 5 All animals had been injected subcutaneously with rabies vaccine or a combination of rabies and other vaccines approximately 2 weeks to 2 months before the reaction. 5 The histopathologic appearance of the lesions in both species was similar. The lesions were well-circumscribed, firm dermal or subcutaneous masses with a variable, peripheral mononuclear leu-

2 jvim 15_316 Mp_177 File # 16em 177 kocyte infiltrate and central necrosis. 5 Additionally, in 4 of 10 specimens a gray-brown material was identified in the necrotic center or within the cytoplasm of macrophages and was interpreted to be adjuvant, vaccine, or both. 5 The 1st report of a possible association between vaccination of cats and the development of fibrosarcomas at injection sites was published in Vaccine injection sites including hind limbs, dorsal cervical region, dorsal lumbar region, flank, and dorsolateral thorax accounted for the majority of the tumors. Noninjection sites showed no increase in fibrosarcoma incidence during the same time period. Of interest, fibrosarcomas have purportedly occurred in areas that had been previously excised and determined on histopathology to be injection site reactions, raising the question of the utility of excising vaccine reactions. 1,6 Additionally, a few cats develop multiple tumors located at separate vaccination sites. 7 Tumors develop in areas of inflammation produced by these adjuvanted vaccines. Interestingly, areas of transition between inflammation and tumor have been frequently observed in vaccine-site tumors, including microscopic foci of sarcoma located in areas of granulomatous inflammation. 1 Epidemiology Epidemiologic evidence has been published showing a strong association between the administration of inactivated FeLV leukemia virus and rabies vaccines and subsequent development of soft tissue sarcomas at vaccine sites. 1,8 10 Associations have been reported between other vaccines (feline panleukopenia, feline rhinotracheitis) and development of postvaccinal sarcomas In 1 report of 34 cats the interval between vaccination and tumor development ranged from 3 months to 3 years. The prevalence of sarcoma development after vaccination is approximately 1/ 10,000, 8 but may be as high as 1/1,000 vaccines administered. 2,12 Because of the relatively low incidence of fibrosarcomas in cats, the association between vaccination and tumor development was made only after millions of doses of the vaccines had been given to cats over approximately a 5-year period. 2 A retrospective study of 345 cats in California and Hawaii confirmed the causal and temporal relations between FeLV and rabies vaccinations and sarcoma development. 8 The authors also reported that the reaction to the vaccines was additive and the likelihood of sarcoma development increased with the number of vaccines given simultaneously at the vaccine site. 8 A prospective study was begun in 1992 to follow approximately 2,000 cats with known vaccination history. 13 Only 1 rabies vaccine a was used in all of the cats in this study. Five cats developed sarcomas, each at the site of rabies vaccination. The average interval between tumor development and the last rabies vaccine given was 26 months. In a separate study, the median time from FeLV vaccination and tumor development was approximately 11 months. 8 Additionally, no difference was found in tumor development noted at vaccine sites versus non vaccine-associated sites based on vaccine manufacturer and brands. 8 In other words, it has not been possible to make an association between specific vaccines and tumor development. Tumors have been reported to occur 2 months to 10 years after vaccination. Etiopathogenesis Many theories have been proposed for the etiopathogenesis of vaccine-associated sarcomas. Variables that have been considered include needle gauge, syringe reuse, temperature of the vaccine when injected, and whether the syringe is shaken or the vaccinated site massaged. Vaccinespecific factors have also been suspected. Local reactions were observed in % of the cats vaccinated with inactivated rabies vaccines, and adjuvanted FeLV vaccines containing aluminum were associated with local reactions, whereas a nonadjuvanted FeLV vaccine did not produce any measurable local reaction. 2,14 Electron probe X-ray microanalysis confirmed the presence of aluminum in postvaccinal sarcomas in cats. 1 Aluminum, present as aluminum hydroxide or aluminum phosphate, may either represent only a marker for previous vaccination or may play a role in tumorigenesis. 1,15 A popular theory is that vaccine-associated sarcomas arise from inappropriate or overzealous inflammatory or immunologic reactions, or both, associated with the presence of vaccine components in vaccine sites. 16 The reaction leads to uncontrolled proliferation of fibroblasts and myofibroblasts that in a subset of patients undergo malignant transformation. A similar phenomenon has been previously recognized in cats. Intraocular sarcomas have developed in cats after ocular trauma or chronic uveitis The relationship between trauma, inflammation, and recovery in the cat is clearly unique and the cellular and molecular events responsible for tumorigenesis are being vigorously investigated. Growth factors are essential for regulation of the cellular events involved in granulation tissue formation and wound healing. When growth factors are added to fibroblast cultures, the cells assume a neoplastic phenotype. Many tumors in humans have been associated with autocrine stimulation (ie, tumors have receptors for growth factors, which they themselves produce in an abnormal or autonomous fashion). Many oncogenes cause cancer by coding for and causing overexpression of growth factors or their receptors (v-sis codes for platelet-derived growth factor [PDGF]; v- erb codes for epidermal growth factor [EGF] receptor). Several studies are focusing on immunohistochemical identification and localization of growth factors and their receptors in vaccine-associated lesions. Vaccine-associated sarcomas have been found to be immunoreactive for PDGF and its receptor, EGF and its receptor, and transforming growth factor-, whereas non vaccine-associated fibrosarcomas are negative or faintly positive. 16 Additionally, lymphocytes in vaccine-associated sarcomas are positive for PDGF, but lymphocytes in non vaccine-associated sarcomas and in normal lymph nodes or aggregated lymphoid follicles (Peyer s patches) are negative. Macrophages in the area also stain positively for PDGF receptor. The neoplastic cells in vaccine-associated sarcomas that are closest to the lymphocytes have the strongest staining for PDGF receptor. These findings led to a hypothesis that lymphocytes in vaccine-associated lesions may secrete PDGF to recruit mac-

3 178 McEntee and Page rophages and cause fibroblast proliferation. Additional work is being done to characterize the lymphocyte populations within these nodules. 16,20 Vaccine-associated sarcomas express c-jun, a proto-oncogene coding for the transcriptional protein AP-1 that is associated with cellular proliferation and oncogenesis in vitro. Non vaccine-associated sarcomas do not express c- jun. 16 Increased growth factor stimulation of fibroblasts by lymphocytes and ultimately via autocrine stimulation has been hypothesized to lead to induction and overexpression of c-jun. Feline vaccine-associated sarcomas are being evaluated for the presence of p53 mutations The tumor suppressor gene p53 encodes a nuclear protein that is a critical component in the regulation of the cell cycle. In response to DNA damage, numbers of normal or wild-type p53 will increase, resulting in arrest of the cell cycle at the G1 interphase. This allows for repair of the damaged DNA before replication, or if damage is too great, the induction of apoptosis. Cells in which p53 is absent or mutated are allowed to proceed unregulated through the cell cycle, giving rise to aberrant clones, which may go on to result in malignancy. Correlation of abnormal expression of p53 with clinical outcome may be possible in cats with vaccine-associated sarcomas. Two anti-p53 antibodies (CM-1 and Mab240) have immunoreactivity in feline sarcomas. In a study of 80 vaccine-associated sarcomas, 81% were Mab240-positive. Cats with cytoplasmic expression for p53 had significantly shorter time to local tumor recurrence than did cats with nuclear expression of p Apparently, FeLV and the feline sarcoma virus that is associated with development of multiple sarcomas in young cats are not involved; FeLV was not detected in vaccineassociated sarcomas with immunohistochemical analysis and polymerase chain reaction. 24 Vaccine-Associated Feline Sarcoma Task Force As the existence of a significant association between vaccination and tumor development became apparent, the veterinary community began to actively address this issue. The California Veterinary Medical Association in August 1996 brought together experts from around the country to discuss this issue and to make recommendations. In November of 1996, the American Veterinary Medical Association (AVMA) and the American Animal Hospital Association jointly sponsored a meeting and the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) was formed. By using the recommendations of the California task force as a template, the VAFSTF devised its own recommendations regarding vaccination protocols, future research goals, and education of veterinarians and the public. In July 1998, a symposium on vaccination site sarcomas in cats was held during the 135th Annual Meeting of the AVMA. The information from that symposium was published in the November 15, 1998, issue of the Journal of the American Veterinary Medical Association. 13,20,25 28 A meeting was also held in Bodega Bay, CA, in February 1999 under the auspices of the Veterinary Cancer Society. Approximately 40 people from around the country met to discuss this issue. Information presented at the meeting was Table 1. Recommendations for the prevention and monitoring of vaccine-associated sarcomas. a Recommendations 1. Do not overvaccinate; vaccinate only when indicated 2. Standardize and separate vaccine injection sites 3. Use single-dose vials only 4. Keep detailed vaccine and injection records for each patient including site of administration, b type of vaccine or other product, manufacturer and serial number of the vaccine 5. Report vaccine-associated sarcomas to the United States Pharmacopeia 6. Decrease the use of polyvalent vaccines 7. Use nonadjuvanted vaccines 8. Avoid use of aluminum-based adjuvants 9. The indiscriminate use of feline leukemia virus vaccine should be stopped, and it is not recommended for strictly indoor cats 10. Vaccines should be administered subcutaneously c a This material in part (points 2 5) is being reproduced with the permission of the Vaccine-Associated Feline Sarcoma Task Force. 29 b Vaccine site location recommendations are as follows: do not give any vaccines in the interscapular space, rabies vaccine should be administered in the distal portion of the right hind limb, feline leukemia virus vaccine should be given in the distal portion of the left hind limb, and all other vaccines should be administered in the right shoulder region. c Intramuscular and subcutaneous administration both apparently result in local inflammation and tumor induction; the use of subcutaneous sites is recommended for all vaccines because it will ensure earlier detection of these tumors. published in part in the September 1999 issue of the Veterinary Cancer Society Newsletter. Substantial contributions to the resolution of the problem have come from the veterinary community, the VAFSTF, and the manufacturers of veterinary biological and pharmaceutical products. Lists of recommendations have been formulated for both the prevention and monitoring (Table 1), and the diagnosis and management (Table 2) of vaccine-associated sarcomas. Patient Evaluation Clients should be informed of the risk of vaccine-associated sarcomas and the occurrence of local vaccine reactions. If the client is made aware of the risk of a reaction at the site then the potential resultant lesion can be excised in an expeditious manner. Any mass located in a vaccine site that persists for more than 3 months after vaccination should be surgically excised. Masses that are detected within a few months of vaccination may just be vaccine reactions rather than neoplastic lesions. Performing a biopsy before the definitive surgery to determine the nature of the lesion is important. A vaccine-associated sarcoma will require wide surgical margins as opposed to a vaccine reaction. The impact of excision of a vaccine reaction on subsequent tumor development at the site has not been elucidated. The initial steps in evaluating a patient with a possible vaccine-associated sarcoma include incisional biopsy, tumor imaging, thoracic radiographs, and, in some instances, abdominal ultrasound. Routine blood work should be done to determine overall health status, including a CBC count,

4 jvim 15_316 Mp_179 File # 16em 179 Table 2. Guidelines for the diagnosis and management of suspected sarcomas. a Guidelines Recommendations for diagnosis 1. Record the anatomic location, shape, and size (measured by caliper and recorded in 3 dimensions) of all masses that occur at the site of an injection. 2. Manage a mass that develops at a previous injection site as if it were malignant until proven otherwise. A lesion should be fully assessed and aggressively treated if it meets any 1 of the following criteria: persists more than 3 months after injection, is larger than 2 cm in diameter, or is increasing in size 1 month after injection. 3. If a mass meets 1 or more of the above criteria, it is recommended that a diagnostic biopsy be performed before surgical excision. Recommendations for management 1. Perform routine thoracic radiographs and preoperative laboratory tests for any malignant mass. 2. Whenever feasible, histologically confirmed vaccine-associated feline sarcomas should be imaged by computed tomography or magnetic resonance imaging. 3. Consult with an oncologist for current treatment options, which may include radiation, chemotherapy, or other modalities, before initiating therapy. 4. Never shell out a sarcoma. Employ oncologic surgical techniques to avoid seeding malignant cells. In some instances, reconstruction of the body wall, removal of bone, or other advanced surgical techniques will be required. 5. Submit the entire excised specimen for histopathology. Mark the excised mass with India ink or suture tags to provide an anatomical reference to facilitate subsequent treatment. 6. Report all histologically confirmed vaccine-associated feline sarcomas to the manufacturer and to the United States Pharmacopeia (USP) Veterinary Practitioners Reporting Program. To make a report or request reporting forms, call USP-PRN ( ) or visit the USP Web site at 7. After tumor removal, recheck by physical examination monthly for the first 3 months, then at least every 3 months for 1 year. a This material is being reproduced with the permission of the Vaccine-Associated Feline Sarcoma Task Force. 30 chemistry panel, and urinalysis. Cats should be tested for FeLV and feline immunodeficiency virus. Although no association is apparent between viral status and tumor development,the course of the disease may be altered because of compromise of the immune system. Biopsy The gross appearance of the tumor is typically a graywhite firm mass typically with a necrotic center. Positioning the biopsy site such that the skin incision and biopsy tract can be easily and completely excised at the time of the definitive surgery is important. Options for the biopsy procedure include punch biopsy, Tru-cut biopsy, b or an incisional biopsy with a scalpel blade. Vaccine-associated sarcomas often have a fluid component and careful attention to hemostasis and prevention of leakage of material at the biopsy site is important because tumor cells can track along fascial planes and seed tumor some distance from the primary mass. Histopathologic features of vaccine-associated feline sarcomas have been extensively described. The most common histopathologic diagnosis is pleiomorphic fibrosarcoma. Other tumor histologies associated with vaccines include undifferentiated sarcoma, osteosarcoma, rhabdomyosarcoma, liposarcoma, and malignant fibrous histiocytoma (or myofibrosarcoma). 7,31 34 The majority of the cells have a fibroblast or myofibroblast phenotype based on immunohistochemical staining characteristics (eg, vimentin- and actin-positive) and multinucleated giant cells are common. 33,35 Vaccine-associated sarcomas have a highly variable mitotic rate, and no association of histologic grade has been observed with outcome. Tumor Imaging The gross appearance of a vaccine-associated sarcoma and apparent size can at times be misleading. Even relatively small subcutaneous tumors on subsequent imaging have been shown to be extensive and invasive. Palpation alone may indicate that the mass is moveable and not fixed to the underlying tissues but this may not be the case. Again, it is important to 1st biopsy the mass and then an appropriate diagnostic and therapeutic plan can be determined. Radiographic examination of the primary tumor site will typically reveal a soft-tissue opacity. Rarely, evidence may exist of underlying bone involvement with bony lysis observed on radiographs. We have recently conducted a study to determine the utility of contrast-enhanced computed tomography (CT) in treatment planning for cats with vaccine-associated sarcomas. The volume of tumor based on the contrast-enhanced CT images was on average twice the size of the tumor based on physical examination (caliper measurements). Additionally, a wide range was noted relative to the number of muscles involved based on the CT images. This study emphasizes the importance of accurate delineation of the extent of disease for planning of surgical treatment, radiation treatment, or both, and therefore it is strongly recommended that a contrast-enhanced CT scan or magnetic resonance imaging be done to determine the extent of disease before therapeutic intervention. Patients are often referred after 1 or more failed attempts at surgical excision. However, even after excision a CT scan may provide useful information on the extent of the surgical field and therefore the area that needs to be included in the radiation treatment field. Treatment Options Surgery Surgery represents the best chance for cure. Attempts at simple excision of vaccine-associated sarcomas are seldom curative and ultimately lead to local recurrence and a more difficult 2nd surgery. An initial appropriately placed incisional biopsy may assist with developing a surgical plan. However, even attempts at aggressive wide surgical excision are often incomplete and result in a 30 70% local recurrence rate. Tumor recurrence after incomplete resection has been observed as early as 2 weeks, 12 but typically

5 180 McEntee and Page occurs by 6 months after surgery. 10 Tumor recurrence in cats has occurred up to 4 times after surgical resection. 10,32 Hind limb amputation may result in a higher rate of cure than does surgery in the interscapular space, but in some instances even amputation, hemipelvectomy, or both may not be curative. Even when a histopathology report indicates no evidence of tumor at the surgical margins, there may be a 50% local recurrence rate. Many cats are now referred with vaccine-associated sarcomas before the 1st surgery. In many instances, involvement from the beginning of a surgeon experienced with aggressive tissue resection in the interscapular and pelvic region is appropriate to increase the likelihood of a successful outcome. The entire resected specimen should be submitted for histologic examination. The specimen should be properly marked and oriented before submission. A variety of systems can be used to mark the surgical margins, including placement of suture tags and the use of marking dyes. 36 India ink can be used to mark the surgical margins. The Davidson Marking System c provides 6 colors (black, blue, green, yellow, red, and orange) that can be used to mark the various surgical margins and allows orientation of the tissue for the pathologist. The dye stays in the superficial layer of the tissue through processing and can be seen on surgical margins when examining the sections under the microscope. The more information provided to the pathologist, the more information can be derived from the biopsy report. Surgical excision often fails to effect complete removal of vaccine-associated sarcomas. Additional local therapy, typically radiation therapy, often is required to effect tumor control. The placement of hemoclips in the surgical bed at the time of the definitive surgery allows the appropriate radiation treatment in terms of placement and size of the radiation field. Exclusion of normal tissues from the radiation treatment field also is important, given that vaccineassociated sarcomas are commonly located over critical healthy tissues such as the heart, lung, kidney, and gastrointestinal tract. Confidence in identifying the surgical bed allows application of a smaller radiation treatment field. Several reports have been made on the results of surgery in the management of vaccine-associated sarcomas. Cats (n 11) treated with 1 surgical procedure had a median tumor-free interval of 16 months, and a median survival time of 16 months. 37 Cats (n 7) that had 2 or more surgeries had a median tumor-free interval of 5 months and median survival time of 13 months. 37 Cats (n 17) treated with surgery and postoperative radiation therapy had a median tumor-free interval of 4.5 months and a median survival of 9 months. 37 The authors concluded that radiation therapy did not extend tumor-free interval or survival. However, cats in this group were irradiated because surgery was not expected to achieve local control and therefore this represented a group of cats at high risk of failure. Overall, cats with complete excisions had significantly longer median tumor-free interval ( 16 versus 4 months) and survival time ( 16 versus 9 months) than those with incomplete excisions. A recent study evaluated the time to 1st recurrence and overall survival in 61 cats treated by excision of the tumor. 32 The median time to 1st recurrence was 94 days and the median overall survival was 576 days. A more aggressive 1st excision resulted in a significantly longer median time to 1st recurrence (325 days) than did marginal 1st excision (79 days). Additionally, cats with tumors located on an extremity had longer median time to 1st recurrence (325 days) than cats with tumors located at other sites (66 days). The authors concluded that a radical 1st surgery is essential for extended time to 1st recurrence. Radiation Therapy Radiation therapy can be used successfully in both the preoperative and postoperative settings. 38 Because local tumor control requires a combination of complete surgical resection and radiation therapy, the combination of surgery and radiation therapy has increased the tumor control rate. Radiation therapy alone is not recommended to treat vaccine-associated sarcomas if the intent is cure. Irradiation of bulky disease is palliative. The goal of palliation in this setting is to reduce the tumor in size and increase patient comfort but is not expected to improve longevity. A report by Cronin et al 39 discussed the results of cobalt 60 radiation therapy followed by surgery in 33 cats. The authors indicated that this was a study of preoperative radiation therapy; however, 24 of 33 (73%) cats had at least 1 surgery before radiation therapy. All cats underwent another surgery after radiation therapy, and hence this work was considered to be a study to assess the efficacy of preoperative radiation. All cats received 48 Gy in 16 daily 3.0- Gy fractions. Acute radiation reactions were limited to dry desquamation. 39 Radiation pneumonitis was seen in some cats but it resolved and was not considered to be clinically significant. 39 The median disease-free interval was 398 days and the median survival was 600 days. A total of 19 treatment failures occurred. The local failure rate was 45% (15/ 33). Eleven cats had local recurrence, 4 cats developed metastatic disease, 3 cats had local recurrence followed by metastasis, and 1 cat had simultaneous local and distant disease. The presence of tumor cells at the surgical margin after irradiation was the only variable found to influence treatment success. The median disease-free interval in 5 cats with tumor cells present at the surgical margin was 112 days, versus 700 days for 26 cats with negative surgical margins. All cats included in this study would be considered advanced stage and most had failed surgery before this treatment regime. Based on the high rate of local recurrence with conventional margins for both radiation therapy and surgery, future treatment recommendations were modified. Larger treatment volumes were planned for irradiation and more aggressive surgery was conducted after irradiation. A retrospective study of 189 cats reported an overall median survival of approximately 19 months (n 43 cats; surgery and radiation therapy) and 26 months (n 26 cats; surgery, radiation, and chemotherapy). 40 The longer median survival with the chemotherapy was not statistically significant. Initial metastatic rate was approximately 5% and after treatment, metastatic rate increased to approximately 17%. 40 The importance of complete surgical excision in the management of vaccine-associated sarcomas cannot be overemphasized. This is in contrast to the relative success of radiation therapy in the postoperative setting for incom-

6 jvim 15_316 Mp_181 File # 16em 181 pletely resected soft tissue sarcomas in dogs. Effecting long-term control of microscopic disease with postoperative radiation therapy is possible in dogs with soft tissue sarcomas. Chemotherapy Several chemotherapy agents, including carboplatin, doxorubicin, liposome-encapsulated doxorubicin, mitoxantrone, cyclophosphamide, and vincristine, have been used in cats with vaccine-associated sarcomas. 26,37,39,41 The use of various chemotherapy protocols has resulted in some partial and complete responses; however, chemotherapy alone should not be considered for definitive therapy. Chemotherapy may have a marked role in a multimodality approach to sarcomas in cats. Chemotherapy in the preoperative setting may reduce the tumor in size, thereby facilitating surgical resection. Chemotherapy has been used in conjunction with radiation therapy as a radiation sensitizer with a low dose. 39 For large unresectable tumors, chemotherapy may provide palliation and allow the patient to live more comfortably. The use of combination doxorubicin and cyclophosphamide in 12 cats with nonresectable fibrosarcomas resulted in a partial response in 50% (n 6 cats), with a significant improvement in survival in those cats that were responders. 41 The median survival in cats that responded to chemotherapy compared with nonresponders was 242 and 83 days, respectively. Incorporation of chemotherapy into a more aggressive treatment plan is being evaluated at several institutions. Some institutions are now taking a more aggressive stance and combining aggressive surgery with pre- or postoperative radiation therapy, followed by or in conjunction with a course of full-dose chemotherapy. Initial reports indicated that metastasis had not been identified or confirmed in cats with vaccine-associated sarcomas. 7,10 Numerous reports have now documented that a risk of distant metastasis exists in vaccine-associated sarcomas. 31,37,39,42,43 Most vaccine-associated sarcomas are locally invasive, but approximately 10% and up to 24% metastasize to the lung and other sites. 37,39 Other sites of metastasis include skin or subcutaneous tissues, regional lymph nodes, mediastinum, liver, and pelvis. 31,39,42 In 1 report of 45 cats with vaccine-associated sarcomas, 2 of the total of 9 cats that developed metastatic disease had extensive metastasis to multiple organs. 37 Systemic chemotherapy may play a role in the delay or prevention of the development of systemic disease in cats with vaccine-associated sarcomas and should be investigated further. Immunotherapy Limited information is available on the use of acemannan as an immunostimulant in combination with surgery and radiation therapy in the treatment of canine and feline fibrosarcomas. 44 Additional studies are necessary to determine the utility of acemannan in combination therapy protocols. The suggestion has been made that because of the apparent role of inflammatory mediators in the pathogenesis of vaccine-associated sarcomas, manipulation of the inflammatory and immunologic mechanisms should be explored. 16 A more thorough understanding of the pathogenesis will likely be necessary before launching a therapeutic strategy utilizing cytokines and monoclonal antibodies against growth factor receptors. 16 Summary A comprehensive protocol for evaluation and management of vaccine-associated sarcomas in cats has evolved over the past decade. However, major questions persist regarding optimal treatment recommendations. Analyses of currently available data, accumulated after the emergence of vaccine-induced sarcomas, have shaped the management recommendations for cats presented with advanced and recurrent disease. A combination of radiation and aggressive surgery is recommended for local control in this subset of patients. The role of chemotherapy for local and distant disease management is yet to be determined; however, early reports are encouraging. It is yet unknown whether aggressive surgery alone will be sufficient for long-term control in cats with relatively small ( 3 cm), discreet, and noninfiltrative tumors that have not previously been resected. Cats with early stage tumors are receiving definitive management and data are currently being collected to evaluate the extent of therapy required for permanent control in this group. Continued efforts to identify biological or clinical parameters that are predictive of behavior is also imperative. Such factors have not been identified to date, making aggressive therapy for all cats with vaccine-associated sarcomas necessary. Prudent vaccination recommendations have resulted in movement of tumors away from anatomic locations where management is particularly difficult. However, the potentially long latency period of tumor development and the only recent development of new potentially nontumorigenic vaccines requires continued efforts to minimize the impact of this problem. We will continue to deal with cats affected with this condition until the cause of tumorigenesis can be identified and overcome. Footnotes a RABVAC 3, Solvay SA, Brussels, Belgium b Tru-cut biopsy needles, Travenol Labs Inc, Deerfield, IL c The Davidson Marking System, Bradley Products, Inc, Bloomington, MN Acknowledgments This work was supported in part by a grant from the Vaccine-Associated Feline Sarcoma Task Force. 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