re‐excision of the wound bed with wider margins (Bacon et al. 2007; Dernell et al. 1998; Forrest et al. 2000; McKnight et al. 2000). A reported 15% recurrence rate after re‐excision (Bacon et al. 2007) which is comparable to recurrence after radiation therapy for incompletely resected STS (17–31%) (Forrest et al. 2000; McKnight et al. 2000; Simon et al. 2007). Median survival time after re‐excision is also comparable to that after surgery alone (1416 days) (Bacon et al. 2007; Kuntz et al. 1997) and incomplete resection combined with adjuvant radiation therapy (2270 days) (Forrest et al. 2000; McKnight et al. 2000). Grade III STS have significantly shorter survival periods, ranging from 236 to 856 days (Kuntz et al. 1997; Selting et al. 2005).
Forrest et al. (2000) treated hemangiopericytoma, FSA, and other STS with radiation therapy after tumors were excised to microscopic disease, with a dose that ranged from 42 to 57 Gy given in 3 to 4.2 Gy daily fractions on a Monday through Friday schedule. Median time to local recurrence was more than 798 days. STS tumors at oral sites had a statistically significant lower median survival (540 days) as compared to other tumor sites (2270 days). In the same year, McKnight et al. reported a 5‐year survival rate of 76% and median disease‐free interval of 1082 days after delivery of a total dose of 63 Gy delivered in 3 Gy fractions on alternate days (McKnight et al. 2000).
Typical protocols for treating incompletely excised STSs involve curative intent radiation with a total dose more than 50 Gy. Forty‐eight dogs with histologically confirmed incomplete or closely excised STSs were treated with a hypofractionated protocol that is typically reserved for palliative radiation therapy (6–8 Gy/weekly fractions to a total dose of 24–32 Gy). In total, 10 dogs (21%) developed local recurrence, 11 dogs (23%) developed metastasis, and 3 dogs developed both (included in each group). The median progression‐free survival was 698 days. The local failure‐free probability at one and three years was 81 and 73%. The one‐ and three‐years tumor‐specific overall survival was 81 and 61%. Long‐term local tumor control was achieved in the majority of dogs. This protocol is described by the authors as reasonable to prescribe in older patients or when financial limitations exist (Kung et al. 2016). Demetriou et al. (2012) reported adjuvant use of hypofractionated radiotherapy after planned marginal canine limb STS resection. Incomplete margins were present in 81–100% of cases. The protocol consisted of four weekly 6–9 Gy doses to a total dose of 24–36 Gy. Local recurrence was reported in 18–21% of cases. Metastases occurred in 2–25% of dogs with follow‐up periods of 240–2376 days (median 681–1339 days).
Lawrence et al. (2008) reported that coarsely fractionated radiation therapy may be a reasonable palliative option for the management of macroscopic canine STS. The treatment protocol used single parallel‐opposed fields with a 3 cm margin surrounding the palpable edge of the tumor, if possible, using a cobalt teletherapy unit. CT scans were used, when available, to help estimate field size and depth of treatment, but true image‐based computer planning was not performed. The total dose of radiation applied to the tumor was 32 Gy to the isocenter, delivered as one 8 Gy fraction on days 0, 7, 14, and 21. The overall objective response rate was 50% and included seven partial and one complete response (a cutaneous hemangiosarcoma on the left ventral thorax of a dog that was also treated with chemotherapy). The median progression‐free interval was 155 days, with a range of 72–460 days.
Radiotherapy in combination with chemotherapy can be used for STS that have metastasized or have a high risk of metastases, such as high‐grade STS and feline vaccine‐associated sarcoma. Acute side effects of radiation therapy on the skin include moist desquamation and alopecia. Late effects of radiation therapy on the skin include fibrosis, contraction, nonhealing ulcer, and leukotrichia. The higher the dose per fraction, the higher the probability of late effects (Forrest et al. 2000; McEntee 2006; Moore 2002). A 5 × 6 Gy radiation therapy protocol was well tolerated and provided long progression‐free interval and overall survival in 50 dogs with macroscopic STS. The addition of metronomic chemotherapy yielded a significantly longer overall survival (757 days) compared with dogs that did not receive systemic treatment (286 days) but did not influence progression‐free interval. Toxicity was low throughout all treatments (Cancedda et al. 2016).
Stereotactic body radiation therapy (SBRT) is an emerging type of radiation to treat soft tissue sarcomas in dogs. In one study, 36 and 11% of tumors had a partial or complete response, respectively (Gagnon 2020). The medians for progression‐free survival time, time to progression of disease, overall survival time, and disease‐specific survival time were 521, 705, 713, and 1149 days, respectively. Low histologic grade and extremity locations of STSs were positive prognostic factors for patient survival times (Gagnon 2020).
Thermoradiotherapy is a therapeutic process that applies radiation therapy to a tumor while the local temperature of the irradiated tissue has been raised by artificial means to increase the radiosensitivity of the tissue being treated. Chi et al. identified two distinct STS subtypes with significant differences in their gene expression and treatment response to thermoradiotherapy, as defined by changes in diffusion‐weighted MRI (DWI). The two tumor subtypes could also be readily identified by pretreatment gene expression. They performed a gene expression analysis in 22 spontaneous STS before and after the first hyperthermia treatment combined with radiotherapy. In parallel, DWI was done prior to the treatment course and at the end of therapy. STS with high expression levels of hsp70 and centrosomal proteins are likely to have stronger response to thermoradiotherapy (Chi et al. 2011).
Chemotherapy
STS are a heterogeneous group of tumors. Because of this heterogeneity, it is hard to obtain sufficient data to set up a solid treatment protocol based on adequately proven clinical trials. The effectiveness of chemotherapy as an adjuvant therapy after resection of STS is thus unclear. Chemotherapy may be beneficial in cases of metastasis, incomplete resection of high‐grade tumors, and tumors not treatable with surgery or radiation therapy. Several chemotherapy protocols are used either as single agent or in combination. Metastases are uncommon in STS, however, and are reported to be 13% for low‐grade to 44% for high‐grade cutaneous STS. Single‐agent doxorubicin, mitoxantrone, or combination protocols using vincristine, doxorubicin, and cyclophosphamide have been reported to have effectiveness for STS (Thornton 2008). One study evaluating adjuvant doxorubicin for high‐grade STSs in dogs failed to find a benefit (Selting et al. 2005).
Elmslie et al. (2008) treated 30 dogs after incomplete removal of soft tissue sarcoma by metronomic, continuously low dose, cyclophosphamide (10 mg/m2), and standard‐dose piroxicam (0.3 mg/kg) therapy. Disease‐free interval (DFI) was 410 days for STS at all sites (trunk, extremities) in treated dogs compared to 211 days for 55 untreated controls. Even though the median DFI was not reached for the treated dogs, it was significantly prolonged. It is important to note that a selection bias in the control population may have skewed the conclusions of this study because 100% of the control dogs developed tumor recurrence or were censored from the analysis.
Local chemotherapy to prevent the local recurrence of an STS has been evaluated by using intralesional cisplatin‐impregnated bead placement following marginal excision of the tumor. About 47% of dogs had local toxicosis and 29% of tumors recurred locally (Bergman et al. 2016).
No clinical studies in the dog suggest whether neoadjuvant 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