Feline vaccine-associated sarcoma – myth or reality? (Proceedings)

Vaccination has generally been considered to be a benign procedure in veterinary medicine. Unfortunately, soft tissue sarcoma development subsequent to vaccination (vaccine-associated sarcoma; VAS) in cats has dramatically changed this view within our profession over the last twenty years.

The vaccines generally associated with this disease to date have been the adjuvanted rabies and feline leukemia virus vaccines, however, association with non-adjuvanted FVRC-P vaccines have been occasionally reported. The potential role of inflammation as a necessary antecedent to the development of this disease has been previously published and seems highly plausible based on the aforementioned association with adjuvanted vaccinations. Newer non-adjuvanted vaccines are likely a step in the right direction for the prevention of this disease, and we eagerly await longer-term results on the incidence of tumors with these vaccines.

Currently, VAFSTF (Vaccine-Associated fibrosarcoma Task Force) in concert with the AVMA and AAFP recommend that: 1) use of vaccines packaged in single-dose vials is strongly encouraged, 2) occurrences of VAS or other adverse reactions be reported to the vaccine manufacturer (the United States Pharmacopoeia no longer accepts these reports), 3) vaccination protocols be standardized within practices so that location, type, manufacturer and serial number is entered into the permanent medical record, 4) vaccines limited to panleukopenia, herpesvirus and calicivirus should be administered on the right shoulder, 5) rabies vaccines should be administered as distally as possible on the right rear limb, preferably below the knee, 6) feline leukemia virus vaccines should be administered as distally as possible on the left rear limb, preferably below the knee, and 7) injection sites of ALL other medications be recorded in the permanent medical record. This information can also be accessed at www.avma.org by following the link for the VAFSTF.

If you suspect you are dealing with a VAS in a cat, the appropriate staging diagnostics should include full physical examination, bloodwork/urinalysis, retroviral testing and 3-view chest radiographs. Retroviral testing is recommended to ensure that FeLV is not acting as a helper virus for the production of a feline sarcoma virus-associated sarcoma. Radiography for the evaluation of metastasis is performed since it appears that approximately 5% of cats with VAS have metastasis at presentation, whereas approximately 25-30% have metastasis at necropsy. Confirmation of the suspected diagnosis should be performed by obtaining an incisional biopsy with a Tru-Cut biopsy instrument (or similar incisional biopsy instrument), or small wedge biopsy. The tumor should NOT be removed until a complete diagnosis is made and a consultation with an oncologist or surgeon has been performed.

Recent studies document that RADICAL first excision of VAS is essential for an extended period of time without recurrence. In addition, recent studies also document that the practice of vaccination of the distal portions of the limbs for rabies and/or FeLV vaccinations appears appropriate since patients with VAS of the distal limbs can undergo radical surgical extirpation via amputation which appears to allow for longer survival. Unfortunately, even with aggressive surgery alone in non-distal limb locations, relatively few cats with VAS are cured. Due to poor cure rates with surgery alone, the additional use of adjuvant radiation therapy and/or chemotherapy has been under investigation at multiple veterinary cancer centers for the last few years. It is presently unknown whether it is better to perform radiation therapy prior to radical surgery, or perform radical surgery and then post-operative radiation therapy. However, the combination of radical surgery and radiation therapy in recent studies appears to have a median survival time of 600-800 days, suggesting that additional therapies is worthwhile in the treatment of this disease. Similarly, the use of chemotherapy has been reported by multiple investigators to have efficacy against gross feline VAS. When given to cats with grossly palpable VAS, carboplatin or a combination of doxorubicin and cyclophosphamide resulted in a 50-60% response rate. Feline non-VAS would be expected to have a 5-10% response rate to these forms of chemotherapy, thereby suggesting that feline VAS is a remarkably different tumor than non-VAS. The use of radical surgery, radiation therapy and chemotherapy as tri-modality therapy in feline VAS is likely the best form of therapy for cats with VAS based on recent abstracts from the Veterinary Cancer Society as well as a publication for NCSU (> 3 yr median survival time for VAS cats treated with tri-modality therapy). Unfortunately, these data are extremely immature, but preliminary indications suggest tri-modality therapy will very likely be the preferred therapy for this extremely malignant tumor.

Through the support of VAFSTF, there are a number of research studies which have been completed throughout the country to elucidate the etiopathogenesis, epidemiology, treatment and prevention of this disease (reader is referred to www.avma.org and the VAFSTF link). Unfortunately, the AVMA pulled its continued funding of VAFSTF which precipitated its sunsetting in 2005, even though we continue to see many cases of VAS. It is easy to see that even with aggressive therapies, we many times lose the battle against this remarkable tumor. The key to this disease is a better understanding of what causes this tumor, so that we may determine ways to vaccinate our feline friends without inducing extremely malignant tumors. We eagerly await the results of VAFSTF-sponsored studies which have not been published to date as well as ongoing research studies by the vaccine manufacturers to rid this disease from our profession.

The KEY FACTS to know in feline vaccine-associated sarcoma are:

1) Best to prevent this disease, not treat it after it has occurred!!

2) Staging should include full PE, bloodwork/UA/FeLV/FIV, and 3 view chest films

A. Approximately 5% have metastases at time of presentation

B. Approximately 25-35% have metastases at time of death

3) Strong considerations should be made to perform CT or MRI to delineate the resectability of the VAS. These images are also helpful for RT planning and dosimetry.

4) Very few cats with VAS are cured with treatment because it is so aggressive, recurrent and potentially metastatic

A. Aggressive tumors need to be treated aggressively

B. Single modality treatment invariably fails

5) Treatment options

A. Surgery only

1. Minimal excision

a) Reduced time to recurrence; average survival time 6-8 months

b) Reduced ability to potentially cure the cat

c) Sets cat up for serial debulkings unfortunately

2. Radical excision

a) Increased time to recurrence vs. minimal excision

b) Likely will still be recurrent due to dirty margins or second primary tumor

c) Should NOT be used as sole treatment of VAS (Follow with radiation approximately two-three weeks after surgery)

I. CONTROVERSY

a. What if one obtains clean margins with radical excision VAS?

b. Most oncologists still follow with radiation to the site

c. One exception would be distal limb VAS treated with surgery alone

d. Recent paper shows that the only VAS cases potentially cured with sx were cats with distal limb VAS treated with radical surgical extirpation (ie limb amputation)

B. Radiation only

1. Not presently recommended for VAS

2. Palliative radiation (ie 3-6 larger dose) may be useful to slow tumor down

3. Average survival time likely 3-4 months

4. Usually combined with surgery and/or chemotherapy

C. Chemotherapy only

1. Chemotherapy appears to be useful for VAS

2. Chemotherapy for non-vaccine-associated sarcomas is generally not helpful

3. Agents shown to be of benefit with gross VAS (40-60% response rates)

a) Carboplatin

b) Adriamycin (doxorubicin) + cytoxan (cyclophosphamide)

4. Usefulness in gross VAS argues for use with minimal disease situations such as encountered after surgery and/or radiation, instead of waiting for gross disease recurrence or metastasis to appear

D. Multi-modality

1. Appears to be best way of treating VAS

2. Surgery & Radiation

a) Average survival time approximately 18 months

b) CONTROVERSY

I. Sequence of Rx modality

II. Better to do sx then RT or RT then sx??

III. Presently unknown

IV. Author believes RT then sx

a. Sx then RT involves huge RT field

b. RT then sx results in smaller, less difficult RT field and sx complications of irradiated tissues in cats appears to be minimal

3. Tri-modality therapy

a) RT/Sx/Chemotherapy

b) Average survival time appears to be 2 – 3 years (dataset small & immature)

c) Sequence of RT & Sx still problematic, but follow with chemotherapy

d) See chemo only area above for chemotherapy types found to be useful

e) Studies performed to date evaluating the usefulness of adjuvant chemo in the treatment of microscopic VAS after surgery and/or RT have found chemo to be of limited to no benefit; however, these studies have routinely not had enough statistical power to be able to delineate a survival advantage conferred by adjuvant chemotherapy use. The NCSU paper (Kobayashi et al) has shown that the median survival time of cats with VAS treated with RT, then sx then carboplatin is > 3 years, suggesting tri-modality therapy is optimal.

Selected References

Hershey AE, Sorenmo KU, Hendrick MJ et al. Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-1996). J Am Vet Med Asoc 2000;216:58-61.

Vaccine-Associated Feline Sarcoma Task Force guidelines. Diagnosis and treatment of suspected sarcomas. J Am Vet Med Assoc 1999;214:1745.

Couto CG, Macy DW. Review of treatment options for vaccine-associated feline sarcoma. J Am Vet Med Assoc 1998;213:1426-1427.

Bergman PJ. Etiology of feline vaccine-associated sarcomas: history and update. J Am Vet Med Assoc 1998;213:1424-1425.

Kobayashi T, Hauck ML, Dodge R, Page RL, Price GS, Williams LE, Hardie EM, Mathews KG, Thrall DE. Preoperative radiotherapy for vaccine associated sarcoma in 92 cats. Vet Radiol Ultrasound. 2002 Sep-Oct;43(5):473-9.

Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. J Am Vet Med Assoc. 2002 May 15;220(10):1477-82.

Cohen M, Wright JC, Brawner WR, Smith AN, Henderson R, Behrend EN. Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of vaccine-associated sarcomas in cats: 78 cases (1996-2000). J Am Vet Med Assoc. 2001 Dec 1;219(11):1582-9.

McEntee MC, Page RL. Feline vaccine-associated sarcomas. J Vet Intern Med. 2001 May-Jun;15(3):176-82.

Bregazzi VS, LaRue SM, McNiel E, Macy DW, Dernell WS, Powers BE, Withrow SJ. Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000). J Am Vet Med Assoc. 2001 Feb 15;218(4):547-50.

Barber LG, Sorenmo KU, Cronin KL, Shofer FS. Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma. J Am Anim Hosp Assoc. 2000 Sep-Oct;36(5):416-21.

Macy DW, Hendrick MJ. The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am Small Anim Pract. 1996 Jan;26(1):103-9.