chemotherapy has any beneficial impact on patient outcome or surgical margins (Bray 2016; Elmslie et al. 2008; Kuntz et al. 1997; Rassnick 2003; Schlieman et al. 2006).
In cats, doxorubicin chemotherapy may play a role in extending the disease‐free interval in combination with radiotherapy for treatment of incompletely excised soft tissue sarcomas (Hahn et al. 2007). Radiotherapy was performed on an alternate‐day schedule, with a total dose of 58.8–63 Gy delivered in 21 fractions. Doxorubicin was administered every 21 days for 3–5 cycles. Median DFI with concurrent radiotherapy and doxorubicin chemotherapy (15.4 months) was significantly longer than median DFI with radiotherapy alone (5.7 months). However, survival time was not significantly different between groups.
Electrochemotherapy uses electroporation to increase cell membrane permeability to cytotoxic drugs. This is done by locally applying electric field pulses over the tumor area or tumor excision bed to enhance transmembrane uptake of locally or systemically administered cytotoxic agents. Complete and partial responses have been reported in few cases of macroscopic STS after electrochemotherapy with intravenous bleomycin administration in dogs (Torrigiani et al. 2019). Interesting results have been published of adjuvant electrochemotherapy to treat the scar/wound bed after incomplete excision of STS of different grades with perilesional bleomycin injections (Spugnini et al. 2007a), systemic bleomycin administration (Torrigiani et al. 2019), and a combination of local cisplatin with systemic bleomycin (Spugnini et al. 2019) in dogs. In cats, both intraoperative and postoperative adjuvant electrochemotherapy with local application of bleomycin has been studied (Spugnini et al. 2007b) and remarkable long‐term local control has been described for adjuvant electrochemotherapy with local cisplatin injections of the scar/wound bed after incomplete surgical excision of FSAs (Spugnini et al. 2011), and a combination of local cisplatin with systemic bleomycin for incompletely excised FISASs (Spugnini et al. 2020).
Immunotherapy
The expression of genes encoding for immunostimulatory cytokines or tumor‐associated antigens that may negatively influence tumor viability is being used more frequently. Several attenuated poxvirus vector systems have been developed, for example, NYVAC (Copenhagen vaccinia virus), TROVAC (Fowl pox virus), and ALVAC (Canary pox virus) viral vectors (Paoletti et al. 1995). These recombinant viruses have been administered without any major side effects to animals and humans (Fries et al. 1996). To prevent the recurrence of FSA, ALVAC‐ or NYVAC‐based recombinants expressing feline or human IL2, respectively, were administered to domestic cats. In the absence of immunotherapy, recurrence was observed in 61% of animals within a 12‐month follow‐up period after treatment with surgery and iridium‐based radiotherapy. Only 39% of the cats receiving NYVAC‐human interleukin‐2 (IL‐2) and 28% of the cats receiving ALVAC‐feline IL‐2 exhibited tumor recurrences (Jourdier et al. 2003). Additionally, intratumoral administration of histoincompatible cells expressing human IL‐2 in spontaneous canine melanoma and feline FSA, in combination with surgery and radiotherapy, has been shown to increase the disease‐free period and survival time (Quintin‐Colonna et al. 1996). Haagsman et al. (2013) reported no effect of local interleukin‐2 therapy on canine PNSTs after marginal surgical excision in a double‐blind randomized placebo‐controlled study.
Angiogenesis plays an essential role in tumor growth, invasion, and metastasis. Vascular endothelial cell growth factor (VEGF) is one of the key growth factors regulating the process of angiogenesis. In a study of De Queiroz et al. (2013), serum VEGF was measured by enzyme‐linked immunosorbent assay quantitative method. Dogs with hemangiopericytoma showed higher serum VEGF levels compared to the patients with malignant PNSTs. Serum VEGF decreases after sarcoma resection. Serum VEGF and neutrophil counts are positively correlated, and negative between VEGF and hemoglobin content in dogs with sarcoma (De Quieroz et al. 2013). Kamstock et al. (2007) evaluated the effect of xenogeneic VEGF vaccination in dogs with cutaneous STS. A total of six immunizations with a human VEGF vaccine were administered intradermally to dogs once every other week for three immunizations, then once every four weeks for three additional immunizations. Eventually, four out of nine dogs remained long enough in the study to receive five or more immunizations. The five dogs that failed to receive greater than three immunizations were removed from the study due to progressive tumor growth. A decrease in plasma VEGF concentration was observed in three of the four dogs that received five or more VEGF immunizations. Tumor microvessel density (MVD) was evaluated in biopsy specimens on weeks 6 and 16 of the study from these four dogs. Two of the four multiply vaccinated dogs demonstrated a significant (>50%) decrease in tumor MVD at one or more time points. It should be noted that in one of these dogs, tumor MVD increased at a later time point coincident with progressive growth. In the other two dogs, tumor MVD remained relatively constant after immunization of the tumor. Based on these results, it appeared that repeated VEGF immunization was capable of inhibiting tumor angiogenesis in at least half of the dogs.
Palliative Procedures
Surgery, radiotherapy, or chemotherapy (doxorubicin/cyclophosphamide) may be used for palliation: to slow the progression of disease, and to alleviate presumed discomfort (Lawrence et al. 2008). For example, Plavec et al. (2006) treated 15 dogs with unresectable STS with a total tumor radiation dose of 24 Gy, given in three weekly 8 Gy fractions. Tumor responses in 15 dogs included one partial remission (liposarcoma), 13 tumors with stable disease and one progressive disease; median time to progression and median survival time were 263 and 332 days, respectively. None of the treated dogs developed serious complications, even though brachial plexus (in one case) and bones were in the radiation field. The only side effects of radiation therapy were slowed hair growth rate or change of the color of growing hair. It is important to note, however, and to communicate with the owner, that palliative care aims to improve the quality of life in the short‐term (Plavec et al. 2006).
Prognosis
The prognosis of STS depends on tumor size vs. site, histologic grade, mitotic index, infiltrative growth in surrounding structures, potentially presence of metastasis, and completeness of removal (i.e. the surgical margins) (Ettinger 2003; Kuntz et al. 1997; Dennis et al. 2011). Size is reported to be a prognostic factor for STS (Kuntz et al. 1997), because of the increased difficulty of achieving wide surgical margins for larger tumors in respect of patient morbidity (Liptak and Forrest 2013). Tumor size was also significantly related to survival in feline patients (Dillon et al. 2005).
Mitotic index is an important feature determining histological tumor grade and provides information on the proliferative activity of the tumor. Mitotic index is also independently associated with increased and earlier rates of tumor recurrence, higher rates of metastasis, and reduced overall survival (Bray et al. 2014; Dennis et al. 2011; Ettinger et al. 2006; Kuntz et al. 1997; McSporran 2009).
The most important prognostic factor for local recurrence is complete surgical margins (Baker‐Gabb et al. 2003; Dernell et al. 1998; Kuntz et al. 1997; McSporran 2009; Simon et al. 2007). If complete resection can be achieved most dogs with STS have in general a good prognosis (Bray et al. 2014; Dennis et al. 2011; McSporran 2009; Kuntz et al. 1997).
Following resection, the chance of local tumor recurrence depends on histologic grade and completeness of surgical margins. Most grade I STSs with “close” margins will not recur, but propensity for recurrence increases with grade. Marginal resections lead to recurrence in up to 75% of tumors (in grade III STSs) (McSporran 2009).
Further research is needed to determine more precise estimates for recurrence rates and survival as related to completeness of surgical margins and to delineate potential differences in metastatic rate and median survival time between grades. Other potential indicators of prognosis that presently require further investigation include histologic type, tumor dimension, location, invasiveness, stage, markers of cellular proliferation, and cytogenetic profiles (Bostock and Dye 1980; Bray et al. 2014; Chase et al. 2009; Stefanello et al. 2008).
