212 days) (Williams et al. 2003). The reported MST for combined surgery, radiation therapy, and chemotherapy is 956 days (Turek et al. 2003). 3D conformal treatment planning resulted in homogenous dose distribution for canine anal sac ADC with lower hot spots and dose ranges, however, greater volumes of surrounding normal structures were irradiated (Keyerleber et al. 2012). Poor prognostic signs include lung ± lymph node metastasis, and treatment, with MST significantly shorter with: lung metastasis (219 days v 584 days) ± any metastasis (16 months v 6 months), dogs not treated with surgery (402 days v 548 days), dogs treated with chemotherapy alone (212 days v 584 days). Williams et al. (2003) and Ross et al. (1991) both reported hypercalcemia to negatively impact survival time, whereas Bennett et al. (2002), Emms (2005), and Potanas et al. (2015) reported no difference in survival time between hypercalcemic and normocalcemic dogs (Ross et al. 1991; Bennett et al. 2002; Williams et al. 2003; Emms 2005; Potanas et al. 2015). Williams et al. (2003) found that dogs with ASACs – 10 cm2 in area had significantly shorter survival times, and Polton and Brearley (2007) found that dogs with tumors > 2.5 cm in length had significantly shorter survival times; however, tumor length of <4.2 cm versus ≥4.2 cm was not a prognostic factor in another study by Potanas et al. (2015) (Williams et al. 2003; Polton and Brearley 2007; Potanas et al. 2015). Cause of death is usually renal failure secondary to hypercalcemia or local or distant metastasis. Repeated surgical removal of metastatic lesions may afford prolonged survival (Hobson et al. 2006; Barnes and Demetriou 2017); debulking and omentalization of sublumbar nodes when non‐resectable (Hoelzler et al. 2001); Paraneoplastic hypercalcaemic renal failure requires aggressive saline diuresis ± diuretic therapy prior to surgery. Hypofractionated radiation therapy in 77 dogs with measurable ASAC resulted in a 38% partial response rate, and improvement or resolution of signs related to the tumor in 63%, and resolution of hypercalcemia in 31% with RT, and in 46% with radiation, prednisone, and/or bisphosphonates. Overall MST for radiation therapy was 329 days, with no difference in survival based on radiation protocol, use of chemotherapy, previous surgery, or advanced stage (McQuown et al. 2017).
Mammary
Surgery is the treatment of choice, except for inflammatory carcinoma or if distant metastasis is present. Surgery includes nodulectomy, mammectomy, regional mastectomy, unilateral or bilateral mastectomy, and also lymph node removal for staging. The surgical choice depends on benign versus malignant, size, number, and species (cat versus dog). In dogs, aim to remove all neoplastic tissue with the simplest procedure. Median survival for grade 1 malignant tumors (10 dogs) was 670 days, grade 2 malignant tumors (16 dogs) was 406 days (Betz et al. 2012). Bilateral mastectomy is indicated in cats and can be performed via two‐staged unilateral mastectomies. There is evidence that ovariohysterectomy (OVH) early in life is preventative; however, more studies are needed (Beauvais et al. 2012), and certainly, the prevalence of these tumors decreases in regions where preventive desexing surgery is performed (Sleeckx et al. 2011). OVH as part of treatment is still not proven clearly to be of benefit (Fowler et al. 1974; Brodey et al. 1983; Yamagami et al. 1996; Morris et al. 1998; Sorenmo et al. 2000b). If OVH is performed at the same time as the tumor surgery, it should be done before tumor excision to avoid seeding of the abdomen with tumor cells (Sorenmo et al. 2013). In a study of 18 male dogs with mammary tumors, all tumors were benign (Bearss et al. 2012). There is no known proven effective adjuvant chemotherapy protocol for malignant or metastatic mammary tumors in dogs. Adjuvant chemotherapy is investigational, considered if poor prognostic factors are present (e.g. large, lymph node–positive, invasive, high grade), and administered after complete surgical removal (Sorenmo et al. 2013). In a study of 94 dogs with mammary carcinomas, dogs with lymphatic invasion had a MST of 179 days versus 1098 days for those without, dogs with ulceration had a MST of 118 days versus 443 days for those without, and dogs with incomplete surgical margins had a MST of 70 days versus 872 days for complete margins. In dogs with stage IV disease or lymphatic invasion adjunctive doxorubicin or docetaxel chemotherapy did not increase MST. Factors found to influence the time to metastasis and overall survival included lymph node metastasis, tumor fixation to underlying structures, age, and histologic stage (Tran et al. 2014). In another study, tumor ulceration and necrosis were not associated with a poorer prognosis (Santos et al. 2013). In a study of 14 dogs with stage III disease (T3 N0 M0) and 2 dogs with stage IV disease (any T N1 M0), half had cyclophosphamide and 5‐FU, and half had regional mastectomy alone. The dogs receiving adjuvant chemotherapy had improved survival and disease‐free interval (Karayannopoulou et al. 2001). Another study showed adjuvant gemcitabine chemotherapy post‐surgery in dogs had no benefit (Marconato et al. 2008). In a small study, dogs treated with carboplatin, with or without COX‐2 inhibitors (22 dogs), had a statistically significant longer overall survival when compared to animals submitted exclusively to surgical treatment (7 dogs) (Lavalle et al. 2012). Piroxicam plus radiation therapy has produced best results with inflammatory carcinoma. In 44 human patients with inflammatory breast carcinoma, an 81% of response rate was achieved with combination therapy (fluorouracil, doxorubicin, cyclophosphamide, mastectomy, and adjuvant paclitaxel) (Cristofanilli et al. 2001). A small number of dogs (7 dogs), with inflammatory carcinoma were treated with piroxicam and achieved a MST of 185 days (de et al. 2009). In another study of 30 dogs with inflammatory carcinoma, the MST of 7 dogs given chemotherapy (mitoxantrone, vincristine, cyclophosphamide, or mitoxantrone alone) was 57 days, compared with 35 days for the 23 given only palliative treatment (antibiotics and prednisolone in 14 dogs, and antibiotics and piroxicam in 9 dogs) (Clemente et al. 2009). The role of radiation therapy with incompletely resected mammary tumors has not been investigated. Bisphosphonates and palliative radiation therapy for metastatic bone lesions. Tamoxifen is not recommended (Sorenmo et al. 2013). A pilot study of p62 DNA vaccine in dogs with mammary tumors shows some promise (Gabai et al. 2014). A significantly increased disease‐free survival and overall survival was reported by Hermo et al. (2008, 2011) after administration of desmopressin intravenously pre‐ and post‐operatively. Eighteen dogs given a luteinizing hormone releasing hormone (LHRH) agonist had reduced tumor size (Lombardi et al. 1999). In cats, adequate surgical treatment combined with adjuvant chemotherapy may be of benefit to prolong survival time over surgery alone. In one paper, the MST of cats that received surgery and doxorubicin was 448 days, and the median disease‐free interval (DFI) was 255 days (Novosad et al. 2006). Short‐term partial response (PR) was observed in 50% (7/14) cats with doxorubicin and cyclophosphamide with MST for non‐responders 2.5 months and responders 5 months (Mauldin et al. 1988a). Post‐operative mitoxantrone (12 cats, ranging from 1 to 4 doses) resulted in a 480 day MST (Cunha et al. 2015). In another study of 73 cats with mammary carcinoma treated with radical mastectomy, adjuvant doxorubicin‐based chemotherapy was not found to be of benefit (McNeill et al. 2009). Similarly, adjuvant doxorubicin and meloxicam MST was 460 days, similar to reports in cats treated with surgery alone (Borrego et al. 2009). In cats, the single most important prognostic factor is tumor size, and bilateral mastectomy has been shown to significantly improve survival time; MST 917 days for bilateral mastectomy, 566 days for unilateral mastectomy, and 216 days for subtotal mastectomy (Novosad et al. 2006). MST 1140 days for bilateral mastectomy, 473 days for unilateral mastectomy (Gemignani et al. 2018)
Salivary Gland Carcinoma
Surgery is used for aggressive removal where possible, along with adjuvant radiation if there is incomplete resection (Evans and Thrall 1983; Carberry et al. 1988; Hammer et al. 2001), and chemotherapy (investigational). One reported case of a dog with a gradually enlarging salivary gland over the preceding 3 months treated with surgical excision of gland alone, showed no local recurrence or metastasis over 18 months follow‐up, a final diagnosis of epithelial‐myoepithelial carcinoma with high‐grade transformation was made (Kishimoto et al. 2015). One reported case of a cat with a salivary gland carcinosarcoma with surgical excision and adjuvant radiation therapy, however, pulmonary metastasis was detected 7 weeks post‐op (Kim et al. 2008).
Ear Carcinoma
Surgery is used (radical if malignant, resectable, and no metastases) (Little et al. 1989; Marino et al. 1993, 1994; Theon et al. 1994; London et al. 1996; Bacon et al. 2003). Radiation is used as an alternative to surgery if unresectable or as adjuvant to incomplete resection (Theon et al. 1994); PDT is used for local disease. Better prognosis when tumor limited to external ear canal (London et al. 1996).
