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Extravasation is one of the most common immediate risks to the patient during chemotherapy administration. The extent of resultant injury is dictated by the vesicant potential of the leaked drug, as well as its volume and concentration (Villalobos 2006). Extravasation of vesicant chemotherapeutic agents including doxorubicin, vinca alkaloids (vincristine/vinblastine/vinorelbine), dactinomycin, and mechlorethamine may cause local pain, regional edema and erythema, and in severe cases, extensive tissue necrosis and sloughing (Figure 2.4a). Mild to moderate extravasation reactions have also been reported anecdotally with other agents that are considered irritants including carboplatin, cyclophosphamide, dacarbazine, mitoxantrone, gemcitabine, and 5‐fluorouracil (Villalobos 2006). Extravasations can occur as a result of multiple punctures of the same vein, coagulopathies, systemic inflammation and vasculitis, inadequate restraint of patients leading to catheter dislodgement, and negligence of the person administering the drug. In order to avoid extravasation, all patients should be properly restrained. If any question exists regarding the ability to properly restrain the animal for safe chemotherapy administration, then sedation should be utilized. Furthermore, exact needle/catheter placement is imperative when administering vesicants. Potent vesicants (doxorubicin, dactinomycin, vinca alkaloids) should be flushed with a minimum of 6 ml of saline before removing the intravenous (IV) needle or catheter. Doxorubicin should always be administered via an in‐dwelling IV catheter, while less severe vesicants and irritants may be safely administered through a carefully placed butterfly catheter. Some oncologists advocate for administration of all agents via an IV catheter. As a rule, vesicant chemotherapeutics should never be administered via an unattended/unmonitored fluid or syringe pump. Instead, the catheter site must be visually monitored for continued proper placement and periodically checked for patency with aspiration/saline flushes prior to, during, and after vesicant drug administration.

Table 2.1 Epithelial.

Neoplasia	Researched Treatment Options and Outcomes
Cutaneous Squamous Cell Carcinoma	Modalities include surgery, radiation therapy, surgery combined with radiation therapy, photodynamic therapy, imiquimod, intralesional chemotherapy (alone or combined with hyperthermia or radiation), electrochemotherapy (ECT) with bleomycin, ECT with bleomycin and doxorubicin, vitamin A–related synthetic retinoids. Cryosurgery is used for small lesions, and there are partial responses with piroxicam in dogs.
Intranasal Carcinoma	Median survival time (MST) without treatment is 95 days; MST of 107 dogs with epistaxis was 88 days versus 224 days for 32 dogs without epistaxis (Rassnick et al. 2006). For curative‐intent radiation therapy (RT), MST is approximately 8–20 months (Adams et al. 1987, 1998, 2005; Evans et al. 1989; Theon et al. 1993; LaDue et al. 1999; Nadeau et al. 2004). However, in one study the MST for nasal carcinomas treated with curative intent RT was only 4.4 months, and dogs with unilateral intranasal involvement without bone destruction beyond the turbinates on computed tomography (CT) had a MST of 23.4 months, versus 6.7 months for dogs with CT evidence of cribriform plate involvement (Adams et al. 2009). Curative‐intent RT followed by surgical debulk (13 dogs) has MST of 47 months in one study (Adams et al. 2005), and 15 months in another (Bowles et al. 2014). In another study, 42 dogs with nasal tumors treated with surgical cytoreduction and orthovoltage RT had a MST of 7.4 months (Northrup et al. 2001). Curative–intent RT with CT planning has MST of approximately 11–20 months. Coarse‐fraction RT (56 dogs) has MST of 7 months (Mellanby et al. 2002), 4.8 months in another study of 48 dogs (Gieger et al. 2008), 16.8 months (although the majority were carcinomas, there were several sarcomas in the study) (Fujiwara et al. 2013), and 6.5 months (with no significant difference with or without cribriform plate involvement) (Maruo et al. 2011). Hypofractionated image‐guided robotic stereotactic radiotherapy either with or without adjunctive treatment for nasal tumors (79% were carcinomas) resulted in a MST of 13.5 months (Glasser et al. 2014), and 10.4 months for nasal carcinomas in another study (Kubicek et al. 2016). In another study of non‐lymphomatous nasal tumors in dogs treated with hypo‐fractionated image‐guided robotic stereotactic radiotherapy without adjunctive chemotherapy, the MST was 19.3 months, and was not significantly different for carcinomas versus sarcomas, or dogs with intracranial extension of disease (Gieger and Nolan 2017). In another study of 12 dogs (75% of dogs had intranasal carcinomas) treated with intensity‐modulated RT, the MST was 15.3 months (Hunley et al. 2010), and at least one eye could be saved in all dogs treated with intensity‐modulated RT in another study (Vaudaux et al. 2007), and both eyes were spared in another study with MST of 13.8 months (Lawrence et al. 2010). Palliative 3D conformal RT (38 dogs) has overall median progression‐free interval of 10 months (Buchholz et al. 2009). Palliative RT in another study resulted in 10.2 months MST (although 39% of the dogs in this study had nasal sarcomas) (Tan‐Coleman et al. 2013). Chemotherapy alone (small numbers of dogs) is investigational (Hahn et al. 1992; Langova et al. 2004). In a study of 37 dogs with reirradiation of nasal carcinomas, the MST from the first dose of RT was 14.9 months and 5.9 months from the first dose of the second course of RT (Gieger et al. 2013). Reirradiation in another study resulted in an overall MST of 2.5 years (Bommarito et al. 2011). Use of radiation sensitizers (some investigational) is generally not better than RT alone. Other treatments include brachytherapy, immunotherapy, cryotherapy, and PDT (all investigational) (MacEwen et al. 1977; White et al. 1990; Thompson et al. 1992; Lucroy et al. 2003b). Slow‐release cisplatin and RT for nasal tumors resulted in MST of 15.6 months (35% of tumors were sarcomas in this study) (Lana et al. 2004). High‐dose‐rate brachytherapy in 15 dogs (not of which had nasal carcinomas) resulted in a 17‐month MST (Klueter et al. 2006). Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib (investigational in 3 dogs) (de Vos et al. 2012). Nasal carcinoma treated with RT and firocoxib was safe and improved life quality in dogs with nasal carcinomas (Cancedda et al. 2015b).
Transitional Cell Carcinoma (Urogenital)	Bladder/urethra (dogs): Surgery: Surgery includes debulk, stent, bypass (e.g. pre‐pubic cystostomy catheter for palliation if obstructed), total cystectomy and urinary diversion, resection of proximal urethra and bladder neck and bilateral ureteroneocystostomy (Saulnier‐Troff et al. 2008), partial cystectomy alone or in combination with unilateral or bilateral ureteral reimplantation (Stone et al. 1996; Marvel et al. 2017). Rarely is there complete excision due to urethral, prostatic, or ureteral involvement. Surgery is generally combined with chemotherapy to improve survival; MST chemotherapy and surgery 475 days, versus chemotherapy alone MST 31 days, versus surgery alone MST 240 days, versus no treatment MST 7 days (Molnar and Vajdovich 2012). Partial cystectomy: 14 dogs treated with partial cystectomy with or without any adjuvant treatment, the MST was 113 days (Norris et al. 1992). Partial cystectomy and long‐term piroxicam (92%) or carprofen (8%) +/− various chemotherapeutic agents were used in 37 dogs with bladder TCC, achieving a MST was 348 days (Marvel et al. 2017). Total cystectomy: Total cystectomy followed by ureterocolonic anastomosis was performed in 10 dogs with TCC the overall prognosis was poor with adverse effects such as severe vomiting and neurologic signs (Montgomery and Hankes 1987; Stone et al. 1988). Total cystectomy and urinary diversion to the vagina have been reported, although persistent urinary incontinence is expected (Boston and Singh 2014; Saeki et al. 2015). Total cystectomy and urinary diversion to vagina or prepuce (with post‐operative chemotherapy) resulted in a MST of 385 days in 10 cases, and although there were fewer gastrointestinal and neurologic complications compared to ureterocolic anastomosis, dehiscence of ureterostomy, pyelonephritis, oliguria, azotemia, ureteral obstruction, and persistent urinary incontinence were reported post‐operative issues (Saeki et al. 2015). Total cystectomy and bilateral cutaneous ureterostomy in 4 dogs had a MST of 279 days (Ricardo Huppes et al. 2017). Resection of proximal urethra and bladder neck and bilateral ureteroneocystostomy: One dog treated with this surgery and adjuvant chemotherapy survived 580 days (Saulnier‐Troff et al. 2008). Debulking surgery: Debulking surgery alone for bladder TCC had a MST of 109 days (Lengerich et al. 1992). Debulking surgery performed by ultrasound‐guided endoscopic diode laser ablation of TCC bladder/urethra in dogs and post‐operative carprofen or piroxicam (given for an unknown duration) had MST 380 days, however, complications included stranguria, hematuria, stenosis, spread of TCC within the lower urinary tract, urethral perforation, and bacterial cystitis (Cerf and Lindquist 2012). Debulking surgery using carbon dioxide laser ablation of bladder TCC (via laparotomy) combined with mitoxantrone and piroxicam achieved a MST of 299 days, with rapid resolution of clinical signs (Upton et al. 2006). In another study, 34 dogs with TCC of the urinary bladder and/or prostate and/or urethra were treated with between one and six doses of doxorubicin concurrently with piroxicam, and 50% of these cases also had surgery (mostly curative intent). Of the 23 dogs with measurable disease, 14 had stable disease, 7 had progressive disease and 2 had a partial response. After documented progression of disease, 15 dogs received additional chemotherapy, consisting of carboplatin (n = 8), mitoxantrone (n = 6), vinorelbine (n = 1) or silibinin (n = 1). Overall median progression‐free survival was 103 days, and MST was 168 days. Cytoreductive surgery did not result in prolongation of progression‐free survival, but significantly prolonged overall survival, with chemotherapy and surgery resulting in a MST of 217 days versus chemotherapy alone MST 133 days (Robat et al. 2013a). Stenting: Stenting of 12 dogs with malignant urethral obstructions; 7 had good to excellent outcome, 3 had fair outcome, and 2 had poor outcome (Weisse et al. 2006). Self‐expanding nitinol stents were successfully placed in 17 of 19 dogs with urethral obstruction due to TCC, MST 78 days, complications included incontinence in 7 dogs, reobstruction from continued growth of urethral TCC (3 dogs), acute reobstruction shortly after the procedure (1 dog), and stent migration (2 dogs) (McMillan et al. 2012). In 42 dogs with obstructive carcinoma (TCC, prostatic adenocarcinoma [ADC], or urinary carcinoma) of the urethra treated with a self‐expanding metallic stent, resolution of urinary tract obstruction was achieved in 41 dogs, in one dog the stent dislodged from the urethra and migrated to the bladder. Severe incontinence occurred in 11 dogs and stranguria in 2 dogs. Stent length, diameter, and location were not associated with incidence of incontinence or stranguria. MST after stent placement was 78 days, and treatment with NSAIDs before and chemotherapeutics (carboplatin, adriamycin, mitoxantrone, Cytoxan, gemcitabine, or vinblastine) after stent placement increased MST to 251 days (Blackburn et al. 2013). Permanent cystostomy: for palliation of obstruction also reported (Smith et al. 1995). Long‐term urethral diversion using a low‐profile gastrostomy tube was used to relieve urethral obstruction in a dog with granulomatous urethritis (Salinardi et al. 2003). Abdominal wall TCC: TCC of the urinary tract, as well as abdominal wall TCC occurred in 24 dogs, and developed significantly more often in dogs that had undergone cystotomy (18/177 or 10%) compared to dogs that had not (6/367 or 1.6%). In 1 dog that had not undergone cystotomy, TCC had invaded through the urinary bladder wall and spread down the median ligament to the abdominal wall. None of the 18 dogs that received anti‐cancer drugs had remission of the abdominal wall TCC, MST after abdominal wall TCC detection was 57 days. It is crucial to minimize the risk of TCC seeding at surgery. Percutaneous sampling of TCC should be avoided (Higuchi et al. 2013). Radiation: Complications of urinary incontinence and cystitis occur with whole‐bladder intraoperative radiation (Walker and Breider 1987; Withrow et al. 1989). Coarse fractionation external beam radiation (with mitoxantrone‐piroxicam) showed no benefit over mitoxantrone‐piroxicam chemotherapy alone (Poirier et al. 2004b). Laparoscopically implanted tissue‐expander radiotherapy shows promise in reducing radiation damage to surrounding tissues (one dog still alive at 21 months) (Murphy et al. 2008). Neoadjuvant chemotherapy, external beam radiation therapy, and adjuvant chemotherapy were reported in 4 dogs (Marconato et al. 2012). Adaptive radiotherapy techniques spared rectal irradiation and maximized bladder irradiation (Nieset et al. 2014). Intensity‐modulated and image‐guided radiation therapy for treatment of genitourinary carcinomas (bladder, prostate, urethra) in 21 dogs resulted in a MST of 654 days (Nolan et al. 2012). Medical: Mitoxantrone‐piroxicam combination with minimal toxicity has a MST of 291 days (Henry et al. 2003). Cisplatin‐piroxicam is not recommended (Greene et al. 2007). For piroxicam alone, MST is 181 days (Knapp et al. 1994). For deracoxib alone, MST is 323 days (McMillan et al. 2011). Gemcitabine‐piroxicam combination – MST was 230 days (Marconato et al. 2011), and carboplatin‐piroxicam combination –MST was 161 days (Boria et al. 2005), and vinblastine alone, MST 147 days (Arnold et al. 2011). In another study there was no significant difference in MST of dogs treated with mitoxantrone‐piroxicam versus carboplatin‐piroxicam combination; however, dogs with prostatic involvement had shorter MST than TCC in other locations (Allstadt et al. 2015). In 14 dogs treated with cisplatin‐firocoxib combination, the remission rate was 57% and MST 179 days, in 15 dogs treated with cisplatin the remission rate was 13% and MST 338 days, and in 15 dogs treated with firocoxib alone the remission rate was 20% and MST 152 days. Renal and gastrointestinal toxicoses were common in dogs receiving cisplatin or cisplatin/firocoxib (Knapp et al. 2013). In another study of 30 dogs, most of which had failed other treatments, metronomic chlorambucil resulted in partial remission in 1 dog, stable disease in 20 dogs, and progressive disease in 9 dogs. The MST of dogs from the time of the start of chlorambucil treatment was 221 days (Schrempp et al. 2013). Subcutaneous 5‐azacitidine treatment – MST not reported, 18 dogs – partial remission in 4, stable disease in 9, and progressive disease in 4 (Hahn et al. 2012). Intravesical administration of mitomycin C in 13 dogs with bladder TCC – 2 dogs had severe myelosuppression, 5 had partial remission, 7 had stable disease (Abbo et al. 2010). Intralesional interleukin‐2 injected via ultrasound guidance or after surgical debulking in combination with meloxicam, piroxicam, or firocoxib, +/− mitoxantrone resulted in an overall MST of 170 days (Konietschke et al. 2012). Folate‐targeted vinblastine conjugate (EC0905) (investigational). Scintigraphy showed folate uptake in both primary and metastatic lesions, partial remission occurred in 56% of dogs (5 dogs), and stable disease in 44% of dogs (4 dogs) (Dhawan et al. 2013). Intra‐arterial carboplatin chemotherapy may be preferable compared to the intravenous route for rapid reduction in tumor volume, however, follow‐up is short and MST is not reported (Culp et al. 2015). Concurrent antibiotics are commonly needed (Budreckis et al. 2015). PDT: PDT is currently under investigation (Lucroy et al. 2003c; Ridgway and Lucroy 2003). Prostatic carcinoma: Prostatectomy is performed for early‐stage disease confined to prostate capsule (but there is a high rate of urinary incontinence) (Hardie et al. 1984; Basinger et al. 1989). Other treatment modalities include transurethral resection (TUR) (electrosurgical and investigational; relieves urethral obstruction, but 2 of 3 dogs had perforated urethra) (Liptak et al. 2004a); Nd:YAG laser (investigational: 8 dogs had MST of 103 days; 3 died from complications within 16 days) (L'Eplattenier et al. 2006); stenting (investigational but very promising, with good to excellent outcome in 8 dogs) (Weisse et al. 2006); bypass obstruction (prepubic catheter); chemotherapy (investigational); non steroidal anti‐inflammatories (NSAIDs) (MST 6.9 months in 16 dogs, compared to 0.7 months with no cancer therapy in 15 dogs) (Sorenmo et al. 2004b); intraoperative prostatic radiation (MST for 10 dogs was 114 days) (Turrel 1987a); PDT (investigational) (Lucroy et al. 2003a; L'eplattenier et al. 2008); and palliative radiation for skeletal metastasis. One dog with ductus deferens and prostate TCC treated with removal of both ductus deferens and long‐term meloxicam lived for 9 months (Guerin et al. 2012). Cats: Bladder TTC in 11 cats treated with meloxicam had a MST of 311 days (Bommer et al. 2012), in another paper of 20 cats with bladder TCC treated with piroxicam, chemotherapy, or surgery, the MST was 261 days (Wilson et al. 2007).
Solitary Primary Lung Mass	Surgery (lung lobectomy) is performed, and regional lymph nodes should be biopsied and ideally removed. Clinical stage is an important prognostic indicator with MST 555 days for papillary T1NoMo versus 72 days for the rest (Polton et al. 2008). Lung lobectomy via thoracoscopy reported, smaller tumors are more amenable to thoracoscopic surgery (Mayhew et al. 2013; Bleakley et al. 2015). All adjuvant chemotherapy is investigational at this stage: systemic chemotherapy (vinorelbine) (Poirier et al. 2004a; Wouda et al. 2015); inhalational chemotherapy (Hershey et al. 1999; Vail et al. 2000); intrapleural chemotherapy for malignant pleural effusion (Moore et al. 1991a), a single case report exists of a dog with grade III bronchoalveolar ADC with vascular infiltration and lymph node metastasis treated with tumor removal, chaperone‐rich cell lysate (CRCL) vaccine administered weekly, topical imiquimod for the first 12 treatments, and a single injection of bacillus Calmette‐Guerin (BCG) at week 30 of treatment, with a survival of 50+ weeks post‐diagnosis (Epple et al. 2013).
Thymoma	Resection is done if possible (89% are resectable) (Gores et al. 1994; Zitz et al. 2008; Robat et al. 2013b), along with chemotherapy (Willard et al. 1980; Aronsohn 1985; Martin et al. 1986; Atwater et al. 1994; Robat et al. 2013b); especially if concurrent megaesophagus relating to a poor surgical candidate; radiation therapy has complete to partial responses, and many also received concurrent surgery or chemotherapy (Hitt et al. 1987; Kaser‐Hotz et al. 2001; Smith et al. 2001; Robat et al. 2013b). Median survival time with and without surgical treatment was 635 and 76 days, respectively, although a small percentage of surgical cases also received chemotherapy and radiation therapy. Recurrent disease after surgery occurred in 15–17%, and prognosis good after second surgery (Zitz et al. 2008; Robat et al. 2013b). Overall MST with surgery alone 790 days (Zitz et al. 2008). Treatment of concurrent myasthenia gravis is accomplished with immunosuppressive and or anti‐cholinesterase therapy, H2 blockers, other supportive care. Portal site metastasis has been reported after thoracoscopic resection of a malignant thymoma in a dog (Alwen et al. 2015). Thymoma‐associated exfoliative dermatitis has been reported in cats and dogs, which resolves with the removal of the thymoma (Forster‐Van Hijfte et al. 1997; Rottenberg et al. 2004; Singh et al. 2010; Tepper et al. 2011; Cavalcanti et al. 2014).
Alimentary	Esophageal: Palliative PDT for esophageal carcinoma in a dog allowed a 9‐month survival time (Jacobs and Rosen 2000). Esophagogastroscopy and loop electrocautery debulking of an esophageal carcinoma with polypoid hyperplasia resulted in at least a 6‐month ST in one dog, and another dog with esophageal ADC was euthanazed after one week after gastrostomy tube placement due to poor quality of life (Arnell et al. 2013). Stenting of an obstructed esophagus due to SCC resulted in effective palliation for 3 months (Hansen et al. 2012). Primary carcinomas of the esophagus were reported in 2 cats (Gualtieri et al. 1999a).Gastric: Localized gastric carcinoma treated with marginal resection and adjunctive carboplatin chemotherapy is potentially curative (Lee et al. 2014), although partial gastrectomy is usually indicated. It is rare that all local disease is resected and metastasis usually occurs early, leading to a poor prognosis after surgery in most cases. In several studies, the median survival time was only 55 days for 29 dogs with gastric ADC treated with surgery (Fonda et al. 1989; Gualtieri et al. 1999b; Swann and Holt 2002). Small Intestinal: usually solitary intestinal masses, treatment is surgery with wide margins (at least 5 cm), biopsy of liver and lymph node at surgery should be done, adjuvant chemotherapy may be considered. Debilitation and hypoproteinemia may complicate treatment. In a study of 18 cats diagnosed with small intestinal ADC, the MST of cats with ADC that underwent surgery was 365 days versus 22 days for those with that did not undergo surgery, and the MST was 843 days for those without evidence of metastatic disease at surgery, versus 358 days for those with metastatic disease at surgery (Green et al. 2011). Cats with advanced disease (including carcinomatosis) treated with surgery can have long‐term survival (Kosovsky et al. 1988). No proven chemotherapy for ADC, but combination of 5‐fluorouracil and cisplatin may be effective (Stanclift and Gilson 2004), second‐look surgery recommended for evaluation of response to chemotherapy (Stanclift and Gilson 2004). Overall MST in dogs treated with surgical resection was 233 days, sex was a prognostic factor with MST for male dogs 272 days v 28 days for female dogs. In this study, only 2 of 15 dogs received adjuvant chemotherapy (Paoloni et al. 2002). Reported adjuvant chemotherapies in dogs include doxorubicin, carboplatin, gemcitabine, doxorubicin, 9‐aminocamptothecin, cisplatin, and 5‐fluorouracil (Paoloni et al. 2002). Intracavitary chemotherapy for carcinomatosis can extend survival time (ST) (Moore et al. 1991a; Charney et al. 2005). Large intestinal: debilitation and hypoproteinemia may complicate treatment, surgical resection with wide margins (4–8 cm), and serosal patching of anastomosis, the colon is more prone to dehiscence than the small intestine. Pubic and/or ischial osteotomy is possible for malignant lesions in the caudal colon (Yoon and Mann 2008), assess/biopsy regional and mesenteric lymph nodes and liver, adjuvant doxorubicin chemotherapy in cats with colonic ADC (Slawienski et al. 1997); intracavitary chemotherapy for carcinomatosis can extend ST (Moore et al. 1991a; Charney et al. 2005); adjuvant doxorubicin chemotherapy in dogs (Paoloni et al. 2002); feline large intestinal ADC more commonly associated with mucosal ulceration and bowel thickening than annular stenosis (Patnaik et al. 1976). Rectal: surgical approaches: rectal eversion, rectal pull‐through, or resection and end‐to‐end anastomosis, fecal incontinence is uncommon if rectal resection <4–6 cm but fecal incontinence and incisional dehiscence are more common if > 4–6 cm rectum is resected with rectal pull‐through surgery, however, the size of the dog plays a role in how much rectum can be resected (Nucci et al. 2014). Resection via an anal approach (and rectal prolapse) was reported in 22 dogs (Danova et al. 2006). Thoracoabdominal stapling devices were used to resect masses of the distal third of the rectum (in combination with rectal prolapse), with a minimum of 0.5–1 cm margins. Meantime to veterinarian follow‐up was 564 days, and no dog had recurrence of disease during this time (Swiderski and Withrow 2009). Transanal endoscopic resection of benign rectal tumors has been described (Holt and Durdey 1999; Holt 2007; Coleman et al. 2014). In another study, 11 dogs were treated with full‐thickness colorectal amputation by either simple transanal or combined abdominal‐transanal pull‐through technique for colorectal carcinoma, two dogs that had a combined abdominal‐transanal approach died within 4 days (Morello et al. 2008). Incontinent end‐on colostomy has been described in the management of 1 dog with rectal ADC (Kumagai et al. 2003). Piroxicam palliative for rectal tubulopapillary polyps if unresectable or as an alternative to surgery (Knottenbelt et al. 2000). No effective chemotherapy for ADC, but combination of 5‐fluorouracil and cisplatin may be effective (Stanclift and Gilson 2004). Mean survival time 22 months following surgery, radical surgery associated with high complication rate and poor survival (<1 week), local appearance may be predictive of survival: mean ST 32 months if pedunculated, 12 months if nodular or cobblestone, 1.6 months if annular, MST 24 months following cryosurgery (Church et al. 1987). Recurrence of clinical signs occurred in 41% of dogs with benign rectal tumors treated with surgery and 18% of rectal polyps underwent malignant transformation (Valerius et al. 1997b). Large polyps (greater than 1 cm in diameter) frequently had marked epithelial atypia and were considered more likely to recur or to become malignant (Seiler 1979). One case of stenting annular rectal adenoma was reported (Culp et al. 2011).
Anal Sac Adenocarcinoma (ASAC)	Wide local resection for the primary tumor is usually not possible due to location, recurrent disease is difficult to resect, sublumbar lymph nodes can be resected with care, and large node size does not preclude resection. In two studies, death was reported as a result of hemorrhage after debulking of sublumbar lymph nodes (Ross et al. 1991; Bennett et al. 2002). Careful dissection and ligation are required, particularly for invasive/adherent lymph nodes. Aggressive surgery may result in sciatic nerve paresis. Overflow urinary incontinence has also been reported (Ross et al. 1991; Emms 2005). Two of 39 dogs (5%) which underwent removal of sublumbar lymph nodes had intraoperative hemorrhage, which was controlled with a combination of electrocautery and topical hemostatic agents, and transfusion was not needed (Barnes and Demetriou 2017). In another series of dogs, there was an increased complication rate in dogs that had concurrent caudal abdominal lymph node extirpation (n = 8/19, 42%) compared with those that did not (n = 3/55, 5%). Complications included perioperative hemorrhage (n = 4), surgical site seroma formation (n = 3), surgical site dehiscence (n = 3) or herniation (n = 1). Dogs that underwent lymph node extirpation had a MST 422–448 days, while dogs that did not undergo lymph node extirpation had a MST of 529–764 days. However, only dogs that had enlarged lymph nodes were selected for lymph node removal (Potanas et al. 2015; Wouda et al. 2016). Anal sacculectomy alone will often result in failure at sublumbar lymph nodes. Given the high metastatic rate to the sublumbar lymph nodes (40–70%) (Ross et al. 1991; Bennett et al. 2002; Williams et al. 2003; Emms 2005; Potanas et al. 2015; Wouda et al. 2016), and the knowledge that primary tumor size and lymph node metastasis at diagnosis is the two main prognostic factors for canine ASAC (Williams et al. 2003; Polton and Brearley 2007; Potanas et al. 2015; Wouda et al. 2016), there is an argument for removal of sublumbar lymph nodes even if they are not enlarged. Removal of sublumbar lymph nodes prior to enlargement/invasion would logically simplify their surgical removal and would allow for histological staging and prognostication and the need for adjuvant therapy for individual dogs. Radiation therapy can be used either intraoperative for treatment of the sublumbar lymph nodes or post‐operative for both the anal sac ADC and sublumbar lymph nodes. A number of different systemic chemotherapy protocols have been used (Goldschmidt and Zoltowski 1981; Ross et al. 1991; Bennett et al. 2002; Turek et al. 2003; Williams et al. 2003; Emms 2005; Wouda et al. 2016). Benefit of chemotherapy is unknown; platinum drugs have shown 31–33% partial response (Bennett et al. 2002) but did not improve ST in other studies (Polton and Brearley 2007; Potanas et al. 2015; Wouda et al. 2016). Mitoxantrone has been combined with radiation therapy post‐operatively to achieve a MST of 956 days in 15 dogs (Turek et al. 2003), piroxicam has no proven effect but anti‐tumor and anti‐angiogenic effects may be beneficial. Toceranib phosphate (Palladia®) has shown 25% PR for a median duration of 22 weeks, and 62.5% stable disease (SD) for a median duration of 30.5 weeks (London et al. 2012). Dogs with sublumbar lymphadenopathy had a significantly shorter MST (422 days), compared with dogs without lymphadenopathy prior to surgery (529 days) (Potanas et al. 2015). In dogs treated with surgery and adjuvant melphalan chemotherapy the MST in dogs with LN metastasis was 20 months versus 29.3 months for dogs with tumor localized to the anal sac (Emms 2005). MST 544 days in 144 dogs treated with surgery, radiation therapy, chemotherapy, or multimodal treatment and dogs treated with chemotherapy alone had significantly shorter survival (median, 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).
Ovarian Carcinoma	Ovariohysterectomy: Intracavitary cisplatin for malignant effusion (Moore et al. 1991a; Olsen et al. 1994). Platinum drugs with tamoxifen is used in metastatic human ovarian tumors. Chemotherapy has the potential to prolong life in animals with metastatic ovarian cancer.
Uterine Carcinoma	Uterine ADC: Treatment is ovariohysterectomy. Role and effectiveness of radiation and chemotherapy are unknown. Squamous cell carcinoma (SCC) of the uterine remnant in a spayed cat has been reported (Hayashi et al. 2013). Uterine remnant ADC and abdominal metastases have also been reported in a spayed cat (Anderson and Pratschke 2011). Endometrial ADC and mucometra in a dog chronically treated with medroxi‐progesterone acetate have been reported (Pena et al. 2006).
Vaginal and Vulval Tumors	Most are benign (leiomyoma and fibroma in cat and leiomyoma and lipoma in dog).
Insulinoma	Modalities include surgery: for resection of primary (preferably partial pancreatectomy rather than enucleation), for staging, and for debulking metastases. Medical management includes frequent feeds, prednisolone, streptozotocin (serious adverse effects reported by Northrup et al. (2013), diazoxide, and octreotide (Leifer et al. 1986; Tobin et al. 1999; Moore et al. 2002; Feldman and Nelson 2004; Robben et al. 2006). Perioperative glucose levels must be managed. A MST of 381 days for dogs that underwent partial pancreatectomy compares to 74 days reported for dogs treated with medical therapy alone (Tobin et al. 1999). Nineteen dogs treated with partial pancreatectomy had a MST of 785 days and dogs treated with prednisolone therapy on relapse had a MST of 1316 days (Polton et al. 2007). Paraneoplastic superficial necrolytic dermatitis has been reported in a dog (Isidoro‐Ayza et al. 2014). Insulinoma is rare in cats; prolonged survival was reported in one cat treated with surgery alone (Greene and Bright 2008).
Thyroid Carcinoma	Dogs: when tumor is mobile, thyroidectomy (Carver et al. 1995; Klein et al. 1995; Panciera et al. 2004), bilateral thyroidectomy with preservation of at least one parathyroid gland reported (Fukui et al. 2015). Bilateral thyroidectomy for mobile, discrete masses has good prognosis (MST 38.3 months), even without preservation of parathyroids, however, supplementation of thyroxine, calcium, calcitriol is required (Tuohy et al. 2012). In another study, the MST for unilateral thyroidectomy was 1462 days compared with 365 days for bilateral thyroidectomy, and MST for dogs with clinical signs for <35 days was 1677 days, and 391 days for dogs with clinical signs for greater than >35 days (Nadeau and Kitchell 2011). Others report the MST after thyroidectomy is around 3 years if the tumor is freely movable and 6–12 months if the tumor is more invasive (Carver et al. 1995; Klein et al. 1995). For fixed/non‐resectable thyroid carcinoma radiation therapy gives 80% 1‐year survival, 72% 3‐year survival (Theon et al. 2000), and MST of 22–24 months (Brearley et al. 1999; Pack et al. 2001). Post‐radiation hypothyroidism was reported (Kramer et al. 1994; Pack et al. 2001; Amores‐Fuster et al. 2015). 131I thyroid ablation can give prolonged survival in dogs with fixed/non‐resectable thyroid carcinoma, with local/regional tumor MST at 839 days and MST 366 days for metastasis (Peterson et al. 1989; Adams et al. 1995; Panciera et al. 2004; Worth et al. 2005; Turrel et al. 2006). Two studies have shown palpation is not always an accurate predictor of local invasiveness (Taeymans et al. 2013; Campos et al. 2014). In one study, 44 dogs were treated by thyroidectomy (MST 22 months, tumor mobility was recorded in 36 dogs; 27 dogs had freely movable tumors and 9 had fixed tumors; thyroidectomy was unilateral in 42 dogs, bilateral in 1 dog, and 1 dog underwent surgical excision of an ectopic thyroid tumor ventral to the larynx.), 3 dogs underwent debulking (MST 10 months), 4 dogs were treated with thyroidectomy and 131I (MST 13 months), 2 dogs were treated with thyroidectomy and chemotherapy (MST 11 months), 1 dog was treated with thyroidectomy and external beam radiation (survival time 13 months), and 6 dogs received no treatment (MST 1.5 months) (Campos et al. 2014). In dogs with surgically excised thyroid carcinoma, macroscopic and histologic evidence of vascular invasion were negative prognostic indicators (Campos et al. 2014). Ectopic sublingual thyroid carcinoma reported MST 562 days (Broome et al. 2014). Partial hyoidectomy was reported to be well tolerated in 5 dogs with ectopic thyroid carcinoma removal (Milovancev et al. 2014). Chemotherapy is considered as adjuvant treatment for non‐resectable primary or large primary carcinoma (>27 cm3), bilateral disease, or for gross metastatic disease (Leav et al. 1976; Jeglum et al. 1983; Ogilvie et al. 1991; Post and Mauldin 1992; Hammer et al. 1994; Fineman et al. 1998; Theon et al. 2000). The MST of dogs treated with surgery and chemotherapy was 518 days, which was not statistically different from that of the dogs treated with surgery alone (Nadeau and Kitchell, 2011). A clinical benefit was seen in 12/15 dogs (4 PR and 8 SD) treated with Toceranib phosphate (Palladia®) for thyroid carcinoma ( London et al. 2012 ).. Boron neutron capture therapy is investigational (Pisarev et al. 2006).
Hyperthyroid Cats	Multi‐nodular adenomatous hyperplasia (majority), malignant carcinomas (1–3%) (Lunn and Page 2013). 131I thyroid ablation is treatment of choice with reported MST 2 years (Petersen and Becker 1995), or 4 years (Milner et al. 2006), compared to 2 years for methimazole treatment (Milner et al. 2006). Treatment options are: oral anti‐thyroid medication (Peterson et al. 1988; Mooney 2001; Trepanier et al. 2003; Trepanier 2007; Frenais et al. 2009; Higgs and Hibbert 2012; Daminet et al. 2014), topical methimazole to pinna (Hoffman et al. 2002; Hoffmann et al. 2003; Sartor et al. 2004; Lecuyer et al. 2006; Hill et al. 2011, 2015a, 2015b, 2015c; Boretti et al. 2013, 2014), topical carbimazole to pinna (Buijtels et al. 2006), iodine‐restricted food (Melendez et al. 2011a, 2011b; Yu et al. 2011; van der Kooij et al. 2014; Scott‐Moncrieff et al. 2015; Hui et al. 2015), thyroidectomy (Flanders et al. 1987; Flanders 1999; Padgett 2002; Birchard 2006; Naan et al. 2006), ultrasound‐guided percutaneous ethanol injections (Wells et al. 2001; Goldstein et al. 2001), and ultrasound‐guided percutaneous radiofrequency ablation (Mallery et al. 2003). Pre‐operative scintigraphy is ideal (Lunn and Page 2013).

Table 2.2 Round cell.

Neoplasia	Researched Treatment Options and Outcomes
Mast Cell Tumor	Dogs: The mainstay of treatment is curative intent surgery with 2–3 cm margins laterally and one fascial plane deep depending on the tumor grade (Simpson et al. 2004; Fulcher et al. 2006), or a modified lateral margin approach (although 15% dirty margins were seen using this system) (Pratschke et al. 2013). High‐grade tumors at greater risk of local recurrence (Donnelly et al. 2015). Smaller margins may be adequate in lower grade tumors and width of complete margins not prognostic for local recurrence (Donnelly et al. 2015). Completeness of excision has been previously shown to be a positive prognostic indicator (Seguin et al. 2001; Weisse et al. 2002b). There was an increased risk of incompleteness of excision (when treated with wide excision with curative intent) when surgery residents performed the surgery, compared with specialist surgeons (Monteiro et al. 2011). Increased tumor size was also a significant risk factor for inadequate surgical margins (Monteiro et al. 2011). Grade I tumors may be completely excised with margins of 1 or 2‐cm laterally and one fascial plane deep (n = 4 cases), but incomplete lateral excision occurred in 2 of 19 grade II MCTs (10%) using the surgical approach of 2 cm lateral margins and one fascial plane deep (Fulcher et al. 2006). In another study, 15 of 20 cutaneous grade II MCTs were completely excised with 1 cm lateral margins and a deep margin of one fascial plane, and all were completely excised with 2 cm lateral margins and a deep margin of one fascial plane (Simpson et al. 2004). Another approach for local control is marginal surgery with adjuvant radiation, which results in 85–95% 2‐year control for stage 0, Patnaik grade I or II (al‐Sarraf et al. 1996; Frimberger et al. 1997; LaDue et al. 1998; Turrel et al. 1988). In another study, local cure was achieved in cases with incomplete margins and radiation therapy in 75–96% of dogs (al‐Sarraf et al. 1996; Frimberger et al. 1997; LaDue et al. 1998; Chaffin and Thrall 2002; Dobson et al. 2004; Hahn et al. 2004; Poirier et al. 2006). The rate of local recurrence for grade‐II MCT is reported to be as high as 50% if margin status is unknown (al‐Sarraf et al. 1996; Macy 1986). In two studies where grade II MCTs were resected with wide margins, the long‐term survival figures for dogs with grade II MCTs were substantially improved to approximately 90% with surgery alone (Seguin et al. 2001; Weisse et al. 2002b). If margins are found to be incomplete or close, additional local therapy with primary re‐excision or radiation therapy improves survival and local control (Kry and Boston 2014). However, another study found the outcome of dogs with incompletely excised grade II MCTs was not affected by adjuvant treatments (surgery, radiation therapy, chemotherapy, or combination), suggesting attentive monitoring and action upon uncommon recurrence (Vincenti and Findji 2017). Assessing the proliferation activity of incompletely excised grade II MCTs may assist in determining the need for ancillary therapy, however, even those with low proliferation activity can recur (Smith et al. 2017). Using the Patnaik system, 93% with Grade I MCT, 44% with Grade II and 6% with Grade III tumors survived 4 years after surgery (Patnaik et al. 1984). Similarly, 100% of dogs with grade I, 44% with grade II, and 7% with grade III MCT were alive at 24 months after surgery (Abadie et al. 1999). However, in other studies, 5–22% of grade II MCTs metastasized (Seguin et al. 2001; Michels et al. 2002; Weisse et al. 2002b; Cahalane et al. 2004; Murphy et al. 2004). The need for adjuvant chemotherapy for completely excised grade II tumors (when not in a poor prognostic location) is unpredictable; close monitoring is advisable (Seguin et al. 2001); and determining mitotic and Ki67 indices may help identify which subset of grade II MCTs may benefit from chemotherapy (Abadie et al. 1999; Scase et al. 2006; Romansik et al. 2007; Webster et al. 2007; Maglennon et al. 2008; Elston et al. 2009; Kiupel et al. 2011; Thompson et al. 2011a, 2011b; O'Connell and Thomson 2013; van Lelyveld et al. 2015), with clinical staging being important regardless of histologic grade (Stefanello et al. 2015). Dogs with stage 2 (loco‐regional lymph node metastasis) grade II MCT, the use of prednisone, vinblastine, and lomustine after adequate local‐regional therapy can provide a median survival in excess of 40 months (Lejeune et al. 2015). In another paper, for dogs with grade 2, stage II MCTs, there was no significant difference in survival times between dogs with and without LN metastasis; however, removal of the metastatic LN may prolong survival (Baginski et al. 2014). Vinblastine‐prednisolone chemotherapy is given as adjuvant to surgery for high‐risk MCT (mucous membrane origin, node‐positive, high‐grade) (Thamm et al. 2006). Vinblastine‐prednisolone chemotherapy increased survival significantly compared to the tyrosine kinase inhibitor masitinib as adjuvant to high‐risk MCTs in another study (Miller et al. 2014). Another approach is marginal surgery with adjuvant chemotherapy (vinblastine and prednisolone) (Davies et al. 2004). In a study of dogs with a median number of 4 MCTs at presentation, 90% of dogs were treated with surgery, and 40% of dogs were treated with only surgery as the sole form of treatment, and 60% of dogs received chemotherapy. There was no significant difference in progression‐free survival or MST in those dogs that received chemotherapy compared to those dogs that did not. Incomplete surgical margins were not associated with decreased survival times (O'Connell and Thomson 2013). Chemotherapy may also be used for dogs with multiple cutaneous mast cell tumors or unresectable/metastatic disease. Multiple cutaneous MCTs may represent multiple de novo events rather than metastatic disease, with a disease‐free survival time of >5 years in 54 dogs reported (Mullins et al. 2006), and no difference in outcome compared to stage 1 dogs in another study (Murphy et al. 2006). However in another study, if any one of multiple cutaneous MCTs was identified as high grade, then there was a worse prognosis (O'Connell and Thomson 2013), and Kiupel et al.(2005) found that dogs presenting with multiple synchronous MCTs had a significant decrease in survival time (Kiupel et al. 2005). In another paper, 23 dogs with MCTs treated with incomplete resection and adjuvant prednisolone and vinblastine chemotherapy, there was a 57% 1‐ and 2‐year disease‐free rate, and some of these dogs had multiple MCTs (Thamm et al. 1999). Other chemotherapy agents include lomustine, vincristine, prednisolone/cyclophosphamide/vinblastine, cyclophosphamide/vincristine/prednisolone/hydroxyurea, lomustine/vinblastine, chlorambucil/prednisolone (McCaw et al. 1997; Elmslie 1997; Gerritsen et al. 1998; Rassnick et al. 1999; Thamm et al. 1999; Davies et al. 2004; Taylor et al. 2009; Cooper et al. 2009), vinorelbine (Grant et al. 2008; Wouda et al. 2015), and inhibitors of tyrosine kinase toceranib phosphate which possess both direct anti‐tumor and anti‐angiogenic activity (Liao et al. 2002; London et al. 2003). Dogs with grade II or III MCTs treated with the tyrosine kinase inhibitor masitinib had a longer time to disease progression (178 days) vs dogs receiving placebo (75 days), although MST was only improved in dogs with KIT mutations (417 days vs 182 days with placebo) (Hahn et al. 2008). In a subsequent study, the MSTs of dogs treated with masitinib or placebo were not significantly different (Hahn et al. 2010). The tyrosine kinase inhibitor Toceranib phosphate (Palladia®) was used to treat bulky (non‐resectable) grade II or III MCTs with an overall 43% partial or complete response rate, and 12% stable disease, with 82% of dogs with KIT mutations responding compared to 54% for those without (London et al. 2009). Vinblastine – toceranib phosphate combination showed a 71% objective response rate in one study (Robat et al. 2012). Water‐soluble micellar paclitaxel was safer with 30% biologic response rate compared to lomustine (11% biologic response rate) in the treatment of non‐resectable grade II or III MCTs (Vail et al. 2012). In another study of non‐resectable MCT, treated with toceranib phosphate‐lomustine‐prednisone resulted in a response rate of 46% and a median progression‐free survival of 53 days (Burton et al. 2015). Non‐resectable MCT can also be treated with radiation therapy combined with chemotherapy (toceranib‐prednisolone), MST was not reached at a median follow‐up of 374 days (Carlsten et al. 2012). Other adjunctive medical therapies include H1 blocker, H2 blocker, omeprazole, sucralfate, and misoprostol. Pretreatment with prednisone prior to surgery (neoadjuvant) can reduce the size of mast cell tumors, facilitating resection with adequate margins in situations where margins cannot be confidently attained because of mass location or size or both (Stanclift and Gilson 2008). ECT with cisplatin administered intratumorally was used to treat 12 cutaneous MCT nodules in dogs. Electrical pulses were delivered to the tumor and surrounding margin. If the tumor did not respond completely to the first session, additional sessions were performed at 2‐ to 4‐week intervals. The median tumor size was 2.9 cm3, there was a 62.5% complete response with a median follow‐up time of 26 months. Tumors >8 cm3 did not respond. Tumor grade prior to treatment was unknown (Kodre et al. 2009). ECT with bleomycin injected into peritumoral tissue has also been reported as adjuvant treatment for incompletely resected MCT in dogs. The overall response rate was 85% with a mean time to recurrence of 53 ± 6.5 months (Spugnini et al. 2006b) Electrogene therapy with IL‐12 was used in 11 canine cutaneous MCTs, resulting in a 13–83% reduction (median 50%) of the original tumor volume (Pavlin et al. 2011). ECT with cisplatin and peritumoral IL‐12 gene electrotransfer was used to treat 18 dogs with canine MCT. Eleven of 18 dogs had pre‐treatment punch biopsies, and all were grade I or II and the median volume of treated tumors was 2.1 cm3. At a median of 40 months, a complete response was achieved in 72% (Cemezar et al. 2017).
Plasma Cell Tumor	Multiple myeloma treatment modalities include chemotherapy using melphalan and prednisolone standard, as well as cyclophosphamide, CCNU, chlorambucil, doxorubicin, vincristine (Osborne et al. 1968; MacEwen and Hurvitz 1977; Drazner 1982; Matus et al. 1986; Brunnert et al. 1992; Fan et al. 2002; Hanna 2005; Gentilini et al. 2005; Vail 2007); surgery (stabilization of pathological fractures) (Banks et al. 2003a; Vail 2007) with or without adjuvant radiation therapy, bisphosphonates (Vail 2007); tyrosine kinase–inhibitor therapy (toceranib phosphate) (London et al. 2003), addressing chronic infectious disease/uncontrolled long‐term stimulation of the immune system could be important (Geigy et al. 2013). Extramedullary treatment modalities (cutaneous) include conservative surgical resection (can add chemotherapy if local recurrence or incomplete margins) (Kryiazidou et al. 1989; Rusbridge et al. 1999). Radiation alone for stable solitary osseous plasmacytoma (MacEwen et al. 1984; Meis et al. 1987; Rusbridge et al. 1999). Surgery plus radiation for solitary osseous plasmacytoma resulting in an unstable long‐bone fracture or surgery with or without radiation for solitary osseous vertebral plasmacytoma resulting in neurological compromise (Vail 2007).
Lymphoma	Various chemotherapy protocols (MacEwen et al. 1981, 1987; Cotter and Goldstein 1983; Carter et al. 1987; Keller et al. 1993; Postorino et al. 1989; Greenlee et al. 1990; Stone et al. 1991; Page et al. 1992; Myers et al. 1997; Valerius et al. 1997a; Khanna et al. 1998; Zemann et al. 1998; Boyce and Kitchell 2000; Chun et al. 2000; Moore et al. 2001; Garrett et al. 2002; Mutsaers et al. 2002; Rassnick et al. 2002, 2007, 2014; Morrison‐Collister et al. 2003; Saba et al. 2007, 2009; Griessmayr et al. 2007, 2009; Sauerbrey et al. 2007; Dervisis et al. 2007; Flory et al. 2008; Bannink et al. 2008; Brodsky et al. 2009; Chun 2009; Northrup et al. 2009; Zenker et al. 2010; Dervisis and Kitchell 2010; Sorenmo et al. 2010; Daters et al. 2010; Beaver et al. 2010; Lori et al. 2010; Fahey et al. 2011; Rebhun et al. 2011; Flory et al. 2011; Tater et al. 2012; Silver et al. 2012; Higginbotham et al. 2013; Gavazza et al. 2013; Burton et al. 2013; Zandvliet et al. 2013; Meier et al. 2013; Elliott et al. 2013; Barnard et al. 2014; Gillem et al. 2015; Collette et al. 2015; Curran and Thamm 2015; Holtermann et al. 2015; Back et al. 2015; Lucas et al. 2015; Wouda et al. 2015); immunotherapy (investigational) (Crow et al. 1977; MacEwen et al. 1985; Jeglum et al. 1988; Rosales et al. 1988; Steplewski et al. 1990; Jeglum 1996; Sorenmo et al. 2011; O'Connor et al. 2012; Marconato et al. 2014, 2015a, 2015b; O'Connor and Wilson‐Robles 2014); radiation therapy for whole body (localize stage I or stage II disease for nasal or CNS or oral lymphoma, palliation of local disease) (Vail and Young 2007; Lurie et al. 2009; Williams et al. 2010; Berlato et al. 2012); bone marrow transplantation and staged half‐body radiation after remission with induction of chemotherapy – both investigational ( Gustafson et al. 2004 ; Williams et al. 2004 ) — or surgery for solitary lymphoma (early stage I) or solitary extranodal, or splenectomy for massive splenomegaly due to lymphoma (Moldovanu et al. 1966; Brooks et al. 1987) or surgery for obstructive or ruptured gastrointestinal lymphoma (Marks 2001).

Table 2.3 Mesenchymal.

Neoplasia	Researched Treatment Options and Outcomes
Soft Tissue Sarcoma (Schwannoma, Neurofibroma, Peripheral Nerve Sheath Tumor, etc.)	Surgery, wide margins, with curative intent (Postorino et al. 1988; Kuntz et al. 1997; Dernell et al. 1998b; Banks et al. 2003b, 2004; Baez et al. 2004; Prpich et al. 2014; Bray et al. 2014b), and surgery‐marginal resection with adjuvant radiation (Evans 1987; Graves et al. 1988; Forrest et al. 2000; McKnight et al. 2000; Demetriou et al. 2012; Kung et al. 2014) are the current standard of care treatments for canine STS. Systemic chemotherapy of possible benefit for highly anaplastic tumors but as yet unproved for grade III soft tissue carcinomas (Selting et al. 2005). Hypo‐fractionated RT for gross STS with or without metronomic chemotherapy also reported (Cancedda et al. 2015a). Marginal resection and localized cisplatin chemotherapy into wound bed (OPLA‐Pt/Atrigel) was reported (Banks and Straw 2003; Havlicek et al. 2009). Metronomic chemotherapy (continuous low‐dose chemotherapy) with cyclophosphamide and piroxicam significantly increased disease‐free interval for incompletely resected soft tissue sarcomas compared to control dogs (Elmslie et al. 2008). Re‐excision for treatment of soft tissue sarcomas is recommended after recent incomplete resection (Bacon et al. 2007). In one large study, STS removal was performed in general practice, 21% showed local recurrence, and 11% developed metastasis in a median follow‐up time of 785 days (Bray et al. 2014a). The time to recurrence was within 1 year for 50%, 2 years for 80%, and in 2 cases recurrence occurred >4 years after the original surgery. In this study, only 6% of STS were grade III, completeness of excision was unknown, and 60% were extremity in location (Bray et al. 2014a). Another study showed an 11% recurrence rate for marginally excised, low‐grade, extremity STS over a median time of 522 days (Stefanello et al. 2011), and despite the marginal excision, margins were histologically “clean” or “clean but close” in 66%. In several papers, trends suggest that STS located on the limbs may have better prognosis; with longer survival, lower metastasis, and better response to treatment (Brehm et al. 1995; Kuntz et al. 1997; Prpich et al. 2014). Other studies have not found tumor location to be prognostic for survival or local recurrence (Baez et al. 2004; Bacon et al. 2007; Chase et al. 2009). Recurrent STS is more difficult to control and is associated with reduced overall survival (Bostock and Dye 1980; Postorino et al. 1988; Kuntz et al. 1997; Banks et al. 2004; Ehrhart 2005b; Heller et al. 2005; Liptak and Forrest 2013; Bray et al. 2014a). The chance of a surgical cure is greatest with the first surgery (Postorino et al. 1988; Graves et al. 1988; Kuntz et al. 1997; MacEwan et al. 2001; Banks et al. 2003b). Both completeness of excision and histological grade predict response to surgery (Kuntz et al. 1997; McSporran 2009; Avallone et al. 2014). Other reported major prognostic factors reported are tumor size, depth of growth, and pathological profiles (Avallone et al. 2014). Another study reported tumor size (<5 cm) and clean surgical margins ensured a good prognosis independently of grade, with a study population of 47.5% grade I, 45.5% grade II, and 7% grade III STS (Stefanello et al. 2011). Twenty‐five dogs with incompletely excised STS (data for chondrosarcoma and haemangiosarcoma excluded as not part of STS grouping) received ECT at the time of suture removal. The dogs were treated with intravenous bleomycin and the tumor bed and margins were infiltrated with cisplatin followed by 8 electrical pulses delivered in bursts of 1300 V/cm (2 cm lateral and deep margins were treated). This was repeated 2 weeks later. Disease‐free follow‐up time for grade 1 STS was 1298 days (1 dog), for grade II STS was a median of 483 days (19 dogs), and for grade III/undifferentiated tumors was median 283 days (3 dogs) Liposarcomas were excluded as the grade was not reported (Spugnini et al. 2019).
Vaccine‐Associated Sarcomas in Cats	Surgery (Davidson et al. 1997; Hershey et al. 2000; McEntee and Page 2001; Lidbetter et al. 2002; Phelps et al. 2011); surgery and radiation therapy (Cronin et al. 1998; Cohen et al. 2001; Bregazzi et al. 2001; Kobayashi et al. 2002); chemotherapy (Barber et al. 2000; Bregazzi et al. 2001; Poirier et al. 2002; Saba et al. 2012); immunotherapy (Kent 1993; King et al. 1995; Quintin‐Colonna et al. 1996; Jourdier et al. 2003). Phelps et al. 2011 reported resection with 5 cm margins around palpable tumor, with an overall MST of 901 days, 14% local recurrence; 20% metastasis post‐op. MST with and without recurrence was 499 and 1461 days, respectively (Phelps et al. 2011). Cats treated with surgery (most with clean margins) achieved a MST of 43 months, cats treated with coarse fractionated radiotherapy (most with either macroscopic disease or dirty margins) reached a MST of 24 months. In cats undergoing coarse fractionated therapy, factors predictive of a better outcome included lack of visible mass (30 versus 7 months MST) adjuvant chemotherapy for gross disease and a smaller number of surgeries preceding radiation therapy (Eckstein et al. 2009). Rate of local recurrence of 42% with pre‐operative radiation and complete excision (Kobayashi et al. 2002). Tumors fixed in formalin that were <3.75 cm were less likely to recur, highlighting the importance of prompt diagnosis and surgery (Porcellato et al. 2017). Patients with a mitotic count of > 20/10 high power fields had a higher risk of recurrence and a lower MST (Porcellato et al. 2017). ECT for macroscopic disease using bleomycin achieved a median time to recurrence of 12 months, and for microscopic disease achieved a median time to recurrence of 19 months (Spugnini et al. 2007).
Intermuscular Lipoma	Careful surgical dissection (peeling out), excellent prognosis (Thomson et al. 1999; Case et al. 2012).
Infiltrative Lipoma	Aggressive surgical resection, adjuvant radiation if margins incomplete (McChesney et al. 1980; Kramek et al. 1985; Bergman et al. 1994; McEntee et al. 2000).
Liposarcoma	Wide surgical resection with clean margins yields good prognosis (Baez et al. 2004). Adjuvant radiation if incomplete resection (Rodenas et al. 2006). Prolonged survival for splenic liposarcoma if no metastasis (MST 767 days), histological grade prognostic (Gower et al. 2015).
Mesothelioma	Surgery, usually debulking, pericardiectomy for palliation (surgical or thoracoscopic), intracavitary and/or intravenous chemotherapy (Moore et al. 1991b; Kerstetter et al. 1997; Dunning et al. 1998; Closa et al. 1999; Jackson et al. 1999; Stepien et al. 2000; Charney et al. 2005; Sparkes et al. 2005; Seo et al. 2007; Spugnini et al. 2008). Early metastasis a concern even if complete resection is achieved (Liptak and Brebner 2006).
Lymphangiosarcoma (LAS)	Surgery, chemotherapy, radiation therapy (Itoh et al. 2004). Survival times reported for 9 dogs for which treatment was pursued; 90 days with prednisone in 1 dog; 182 days with chemotherapy in 1 dog; 240, 267, 487, 630, and 941 days for 5 dogs receiving surgery; and 574 days for 1 dog receiving surgery, radiation and chemotherapy, 1 dog alive with recurrence at 243 days following surgery and carboplatin chemotherapy. Clinical improvement existed in LAS dogs receiving multi‐modal therapies (Curran et al. 2014). One dog treated with surgery and adjuvant doxorubicin had a 6‐month recurrence‐free interval, then treated with metronomic chemotherapy using chlorambucil and meloxicam, which failed to adequately control the disease. Toceranib phosphate was introduced and resulted in almost complete regression of the mass, leaving just a skin plaque (Marcinowska et al. 2013). Disseminated lymphangiosarcoma treated with surgery and adjuvant mitoxantrone (Sicotte et al. 2012).
Synovial Cell Sarcoma	Surgery (high amputation is the treatment of choice because local recurrence is higher with marginal or wide resection) (Vail et al. 1994); chemotherapy may be of benefit if sarcoma is high grade and there is no metastasis, or if the node is positive (Tilmant et al. 1986; Vail et al. 1994; Craig et al. 2002). Adjuvant radiation for incomplete excision investigational.
Oral Fibrosarcoma	Surgical resection with wide margins is the treatment of choice (Schwarz et al. 1991a, 1991b; White 1991; Lascelles et al. 2003; Lascelles et al. 2004; Frazier et al. 2012; Gardner et al. 2015a); if not resectable with clean margins, surgery and radiation therapy (Forrest et al. 2000; Frazier et al. 2012; Gardner et al. 2015a); or radiation therapy alone (palliative) (Thrall 1981; Brewer and Turrel 1982; Theon et al. 1997). Systemic chemotherapy has no known benefit (Gardner et al. 2015a). For histologically low‐grade, biologically high‐grade oral fibrosarcoma, prognosis depends upon early diagnosis and aggressive treatment. Prolonged survival can be achieved in some dogs with surgery, radiotherapy alone, surgery and radiotherapy, and radiotherapy and local hyperthermia (Ciekot et al. 1994).
Oral Melanoma	For local disease, surgery with wide clean margins (Harvey et al. 1981; Bradley et al. 1984; MacEwen et al. 1986; Kosovsky et al. 1991; Schwarz et al. 1991a, 1991b; Wallace et al. 1992; Hahn et al. 1994; Ramos‐Vara et al. 2000; Overly et al. 2001; Kudnig et al. 2003; Esplin 2008; Tuohy et al. 2014; Boston et al. 2014); repeat surgery with wide margins or adjuvant radiation therapy if margins incomplete; radiation therapy alone (Turrel 1987b.; Bateman et al. 1994; Blackwood and Dobson 1996; Theon et al. 1997; Freeman et al. 2003; Proulx et al. 2003; Farrelly et al. 2004; Murphy et al. 2005). ECT using bleomycin was reported in 10 dogs with oral melanoma. The dogs received four weekly sessions. The tumor and a 1 cm margin of grossly normal tissue were injected with bleomycin followed by pulsed electrical bursts of 800 V/cm administered under local or general anesthesia. The overall response rate was 80% with complete remission in 70% and a MST of 6 months (Spugnini et al. 2006a). In a recent study of 67 dogs with oral melanoma treated with ECT, an objective response was seen in 100% (stage 1), 90% (stage 2), 58% (stage 3), and 36% (stage 4) of tumors. The MST was 16.5 months (stage 1), 9 months (stage 2), 7.5 months (stage 3) and 4.5 months (stage 4) dogs (Tellado et al. 2020). A total of 111 dogs with oral melanoma treated with radiation therapy combined with debulking surgery (18 dogs) or chemotherapy (39 dogs), or both (29 dogs). MSTs of stage I, II, III, and IV melanoma were 758 days, 278 days, 163 days, and 80 days, respectively. Dogs with stage III melanoma had a higher risk of death if treated with orthovoltage rather than megavoltage RT (Kawabe et al. 2015). MST for dogs treated with curative intent surgery was 723 days, and the role of adjuvant therapies (chemotherapy, radiation, melanoma vaccine, or interferon treatment) was unclear (Tuohy et al. 2014). Chemotherapy (investigational, several studies fail to show a survival benefit) (Page et al. 1991; Overly et al. 2001; Rassnick et al. 2001; Kudnig et al. 2003; Boria et al. 2004; Murphy et al. 2005; Brockley et al. 2013; Cancedda et al. 2014; Dank et al. 2014; Boston et al. 2014); immunotherapy (investigational) (Moore et al. 1991c; Elmslie et al. 1994, 1995; Quintin‐Colonna et al. 1996; Dow et al. 1998; MacEwen et al. 1999; Bergman et al. 2003a, 2003b, 2004, 2006; Alexander et al. 2006; Grosenbaugh et al. 2011; Finocchiaro and Glikin 2012; Westberg et al. 2013; Ottnod et al. 2013; Riccardo et al. 2014; McLean and Lobetti 2015). Other adjuvant modalities (all investigational) include liposome‐encapsulated muramyl tripeptide phosphatidylethanolamine (L‐MTP‐PE), intralesional cisplatin implants, local hyperthermia combined with intralesional cisplatin (Theon et al. 1991; Kitchell et al. 1994; MacEwen et al. 1999). Itoh et al. (2014) reported a single case of a dog with an oral melanoma treated with high‐temperature hyperthermia, dendritic cell therapy, and lupeol injections with complete remission after 2 months, and no local recurrence or metastasis at 6 months (Itoh et al. 2014). Another two reported cases show benefit of adenovector CD40L immunogene (AdCD40L) treatments (von Euler et al. 2008). Post‐operative lupeol (a triterpene extracted from various fruits and vegetables that reportedly inhibits melanoma cell proliferation in vitro and in vivo) was reported in a small number of cases (Yokoe et al. 2015).
Cutaneous Melanoma	Surgical excision is the treatment of choice (Bolon et al. 1990; Aronsohn and Carpenter 1990; Brockley et al. 2013) with median overall survival of 1363 days and MI index prognostic for survival (Laver et al. 2018a); chemotherapy shows little response (Gillick and Spiegle 1987; Ogilvie et al. 1991; Moore 1993; Rassnick et al. 2001 Brockley et al. 2013); hyperthermia and intralesional cisplatin/carboplatin (Theon et al. 1991) and PDT (Dougherty et al. 1981; Cheli et al. 1987) have short‐lived responses. Radiation therapy likely to be of use if melanoma not surgically excisable (Bergman et al. 2013). Immunomodulation is investigational (Quintin‐Colonna et al. 1996; Hajduch et al. 1997; Dow et al. 1998; Hogge et al. 1999; MacEwen et al. 1999; Bianco et al. 2003; Gyorffy et al. 2005; Alexander et al. 2006; Bergman et al. 2006).
Appendicular Osteosarcoma	Surgery (amputation/limb‐spare) (Vasseur 1987; Mauldin et al. 1988b; LaRue et al. 1989; Thrall et al. 1990; Straw et al. 1991b; Berg et al. 1992; Spodnick et al. 1992; Withrow et al. 1993; Kuntz et al. 1998; Tomamassini et al. 2000; Huber et al. 2000; Morello et al. 2001, 2003; Buracco et al. 2002; Rovesti et al. 2002; Seguin et al. 2003; Pooya et al. 2004; Liptak et al. 2004b, 2005, 2006; Ehrhart 2005a; Irvine‐Smith and Lobetti 2006; Boston et al. 2007; MacDonald and Schiller 2010; Hodge et al. 2011; Boston et al. 2011; Venzin et al. 2012; Gasch et al. 2013; Renwick and Scurrell 2013; Covey et al. 2014; Seguin et al. 2017); hemipelvectomy (Straw et al. 1992; Bray et al. 2014b); partial or total scapulectomy (Kirpensteijn et al. 1994; Trout et al. 1995; Montinaro et al. 2013); ulnectomy (Straw et al. 1991a; Sivacolundhu et al. 2013); limb shortening (investigational) (Boston and Skinner 2018). Local chemotherapy as adjuvant to limb‐sparing (OPLA‐Pt) reduced local recurrence rate (Straw et al. 1994; Withrow et al. 2004). Local chemotherapy (isolated limb perfusion) (Van Ginkel et al. 1995) as adjuvant to limb‐sparing (investigational); radioisotopes (Milner et al. 1998; Aas et al. 1999); radiation therapy to the primary site (palliative as an alternative to amputation/limb‐spare) (Heidner et al. 1991; McEntee et al. 1993; Ramirez et al. 1999; Green et al. 2002; Mueller et al. 2005); adjunctive to limb‐spare (Thrall et al. 1990; Withrow et al. 1993); stereotactic radiation therapy (SRT) with surgical stabilization in dogs with pathologic fracture or at high risk of pathologic fracture showed varying results but high risk of complications (Covey et al. 2014; Boston et al. 2017), SRT +/− adjuvant radiation therapy resulted in a MST of 363 days and was ideally suited in dogs with small tumors with minimal bone destruction (Farese et al. 2004). In 46 dogs with appendicular OSA treated with SRT, the MST was 9.7 months, with a median time to fracture of 4.2 months in dogs with subchondral bone involvement and versus 16.3 months in dogs without subchondral bone involvement (Kubicek et al. 2016). Various chemotherapy protocols have been reported, as adjuvant to limb‐spare or amputation (clear benefit) (Thompson and Fugent 1992; Berg et al. 1995; Bergman et al. 1996; Berg et al. 1997; Kent et al. 2004; Chun et al. 2005; Bacon et al. 2008; Phillips et al. 2009; McMahon et al. 2011; Saam et al. 2011; Simcock et al. 2012; Lane et al. 2012; Skorupski et al. 2013; Bracha et al. 2014; Selmic et al. 2014; Alvarez et al. 2014; Kozicki et al. 2015; London et al. 2015); Toceranib did not improve survival combined with metronomic chemotherapy after carboplatin (London et al. 2015), and metronomic chemotherapy did not increase survival after carboplatin (Matsuyama et al. 2018); chemotherapy neoadjuvant to limb‐sparing to downstage disease pre‐surgery (Withrow et al. 1993; O’Brien et al. 1996); chemotherapy as an adjuvant to palliative radiation (Walter et al. 2005; Fan et al. 2009; Oblak et al. 2012); bisphosphonates (Tomlin et al. 2000; Fan et al. 2005, 2007, 2008, 2009, Fan, 2009, 2007; Batschinski et al. 2014); immunotherapy (investigational) (reviewed by Wycislo and Fan 2015) (Wycislo and Fan 2015), toceranib in dogs with macroscopic pulmonary metastasis of OSA resulted in a clinical benefit in 10% of dogs (Kim et al. 2017), the median progression‐free survival time was 57 days with a median overall survival time of 89 day (Laver et al. 2018b); Radionucleide therapy for palliation (Barnard et al. 2007; Chakraborty et al. 2016). In 51 small‐breed dogs with appendicular OSA, 9 dogs treated non‐surgically had a MST of 112 days, 16 treated with amputation only had a MST of 257 days, and 26 treated with limb‐spare/ amputation and chemotherapy had a MST of 415 days (Amsellem et al. 2014).
Multi‐lobular Osteochondrosarcoma	Surgery as cure of local disease, prolonged survival if local disease cured (MST 14 months even if metastasis present at diagnosis) (Dernell et al. 1998a). If surgical removal not possible, consider surgical debulk plus adjuvant radiation therapy (Straw et al. 1989). Radionuclide therapy (investigational) (Vancil et al. 2012).
Chondrosarcoma	Wide surgical excision significantly improves survival. Median survival time is 540 days treated with amputation alone (Popovitch et al. 1994); chest wall resection MST 1080 days (Pirkey‐Ehrhart et al. 1995); wide surgical excision for non‐nasal sites MST of 3097 days and did not reach MST (Waltman et al. 2007); and MST 979 days for 25 dogs with appendicular chondrosarcoma treated with amputation alone, although grade was found to be prognostic (Farese et al. 2009). Hemipelvectomy MST 1232 days (Bray et al. 2014b). Debulking and adjuvant radiation therapy if the location is not amenable to curative resection, or radiation alone (Popovitch et al. 1994, Lana et al. 1997), objective responses to coarse fraction radiation alone (Ehrhart et al. 2013). Metastasis still occurs in about 25%, even after surgical resection. Grade may be prognostic for survival (Waltman et al. 2007; Farese et al. 2009). Laryngeal and tracheal chondrosarcoma have good prognosis with surgical resection alone (Muraro et al. 2013; Ramirez et al. 2015; De Lorenzi et al. 2015).
Cutaneous Hemangiosarcomas (HSA)	Dogs: Dermal (stage I) HSA all firm, raised, dark red papules/nodules, commonly ventral abdomen/preputial area and solar elastosis common (Culbertson 1982; Hargis et al. 1992; Ward et al. 1994; Szivek et al. 2012). Stage II (hypodermal involvement with or without concurrent dermal involvement) or stage III (any primary tumor with underlying muscle involvement) were firm to soft/fluctuant masses with hemorrhagic discoloration, ulceration frequent and many owners thought this was bruising associated with trauma (Ward et al. 1994). The MST for stage I was 780 days, stage II 172 days, and stage III was 307 days (no statistical difference in MST for stage II and III) and all dogs had no evidence of nodal or distant metastasis and all dogs treated with wide surgical resection alone. Surgery alone is treatment of choice for stage I, with no dogs with stage I tumors dying as a consequence of their disease (Ward et al. 1994). Dogs with dermal HSA treated with surgery alone showed MST of 1570 days in predisposed breeds (lightly haired) compared with 593 days in non‐predisposed breeds, dogs with HSA in typical sun‐exposed ventral abdominal locations had a MST of 1085 days compared with 539 days in other locations, and if biopsies showed solar changes MST was 1549 days compared with 545 days in dogs without solar changes. Factors that did not affect survival included multiple masses at presentation, biopsy margin status/completeness of surgical excision, loco‐regional recurrence, and subcutaneous invasion, although dogs with subcutaneous invasion had an increased risk of metastasis compared to dogs with only dermal involvement (Szivek et al. 2012). Yet in another study of non‐visceral hemangiosarcomas in dogs and cats, completeness of excision was the most important factor in predicting clinical outcome (Schultheiss 2004). Adjuvant doxorubicin chemotherapy should be considered for stage II and III diseases (Ward et al. 1994). The addition of adjuvant chemotherapy increases MST from 211 days (Sorenmo et al. 1993) to 425 days (Hammer et al. 1991) for subcutaneous HSA. In another study, 21 dogs with subcutaneous (17) and intramuscular (4) hemangiosarcomas, with adequate local tumor control and no metastasis at presentation, were treated with adjuvant doxorubicin. Five dogs also received adjuvant radiation therapy. The MST for subcutaneous HSA was 1189 days and for intramuscular was 272.5 days (Bulakowski et al. 2008). Doxorubicin‐based chemotherapy used for non‐resectable canine subcutaneous HSA resulted in a response rate of 38–44%, and its use in the neoadjuvant setting to “downstage” tumors to facilitate complete resection appears promising (Wiley et al. 2010). Subcutaneous or intramusuclar HSA was associated with a MST of 246 days for dogs that received chemotherapy, and adequate local control (surgery +/− radiation therapy) with no evidence of metastasis at diagnosis (Shiu et al. 2011). Non‐splenic HSAs in 20 dogs treated with palliative radiation therapy had a MST of 3 months (Hillers et al. 2007).Cats: Wide surgical excision (metastasis occurs less frequently than dogs, but adjuvant chemotherapy may have a role, depending on the case) (Miller et al. 1992; Kraje et al. 1999; Schultheiss 2004; McAbee et al. 2005). Radiation therapy is considered adjuvantly if incompletely resected local disease.
Visceral HSA	Surgery (e.g. splenectomy) (Brown et al. 1985; Spangler and Culbertson 1992; Spangler and Kass 1997; Prymak et al. 1988; Sorenmo et al. 2004a; Wendelburg et al. 2015); adjuvant chemotherapy of various types can be considered for splenic hemangiosarcomas, with median survival times of 141–179 days reported (Hammer et al. 1991; Vail et al. 1995; Sorenmo et al. 1993, 2000a, 2004a, 2005; Ogilvie et al. 1996), although other studies have not shown a significant survival advantage compared to splenectomy alone (Wendelburg et al. 2015; Gardner et al. 2015b). MST splenectomy alone 55–86 days (Brown et al. 1985; Wood et al. 1998; Wendelburg et al. 2015). Reported MST 125 days for non‐resectable disease (Dervisis et al. 2011). Clinical stage influences prognosis, stage I MST 5.5 months, stage II MST 2 months, stage III 0.9 months (Wendelburg et al. 2015). Although in another study of 21 dogs treated with splenectomy and chemotherapy had an overall MST of 150 days and there was no significant difference in survival based upon the stage of disease, dogs with stage III HSA (n = 11) had a median survival of 149 days (Kahn et al. 2013). Immunotherapy (Vail et al. 1995; U'Ren et al. 2007) and angiogenic therapy are investigational (Sorenmo et al. 2000a). Cardiac hemangiosarcoma treated with doxorubicin had MST 116 days, significantly improved compared to 12 days for untreated dogs (Mullin et al. 2016). Dogs with right atrial HSA that had surgery and adjuvant chemotherapy had a MST of 175 days, compared to dogs treated with surgery alone MST 42 days (Weisse et al. 2005).
Histiocytic Sarcomas (HS)	Localized (skin/subcutis) is treated with aggressive surgery with clean margins (Affolter and Moore 2000); adjuvant radiation therapy if incomplete resection; adjuvant chemotherapy is indicated, following surgery and/or radiation therapy for localized (Skorupski et al. 2009; Liptak and Forrest 2013; Cannon et al. 2015), aggressive local therapy combined with adjuvant CCNU chemotherapy in dogs with localized HS resulted in a MST of 568 days in 16 dogs (Skorupski et al. 2009). Chemotherapy also indicated for primary treatment for disseminated or metastatic disease (Cannon et al. 2015), MST with lomustine‐doxorubicin ± cyclophosphamide was 185 days in 17 cases (6 of which had local therapy as part of treatment) (Cannon et al. 2015). In another study, 59 dogs were treated with lomustine chemotherapy, 20 dogs had received prior local therapy, the MST 106 days. Thrombocytopenia and hypoalbuminemia were negative prognostic factors (<1 month survival) (Skorupski et al. 2007). In another study, anemia, thrombocytopenia, hypoalbuminemia, hypoproteinemia were associated with shorter survival times (Takahashi et al. 2014). Other negative prognostic factors include use of prednisone during therapy and metastatic disease at the time of diagnosis (Klahn et al. 2011). Periarticular HS may have a better prognosis than non‐periarticular HS. Dogs with periarticular HS without evidence of metastasis at diagnosis had a MST of 980 days (Klahn et al. 2011). In another study, dogs that received no/or symptomatic treatment MST was 12 days, and dogs that were treated with surgery and/or chemotherapy had a MST of 85 days (Takahashi et al. 2014). Survival times in other studies are similar in the range of 3–4 months (Skorupski et al. 2007; Rassnick et al. 2010; Higuchi et al. 2010; Klahn et al. 2011). Outcomes may be better in dogs with localized HS treated with local therapy and adjuvant chemotherapy (Skorupski et al. 2009; Klahn et al. 2011). Negative prognostic factors include splenic involvement (Skorupski et al. 2007; Constantino‐Casas et al. 2011), hypoalbuminemia, anemia, thrombocytopenia (Skorupski et al. 2007), use of prednisone during therapy, and metastatic disease at the time of diagnosis (Klahn et al. 2011). Lomustine ± corticosteroids are the most commonly used protocol although other options include doxorubicin, combination protocols, vinorelbine and bisphosphonates (Skorupski et al. 2007, 2009; Rassnick et al. 2010; Higuchi et al. 2010; Hafeman et al. 2010, 2012; Klahn et al. 2011; Clifford et al. 2012; Wouda et al. 2015).
Uterine Leiomyoma and Leiomyosarcoma in Dogs	Prognosis good with complete surgical resection.

Since doxorubicin is one of the most common chemotherapy agents used and is a severe vesicant, extravasations of this agent are of significant concern and will be the main focus of this section. Most perivascular doxorubicin leaks are noticed immediately if careful monitoring is implemented during infusion. Signs may include a focal “bleb,” regional swelling, or erythema over or around the catheter site, and the patient may react as if in discomfort upon extravasation. If signs of a doxorubicin extravasation should occur, then immediate action needs to be taken.

Multiple protocols that describe proper handling of chemotherapy extravasations have been advocated. In general, the initial step of such protocols – aspirating any residual drug back from the extravasation site via the catheter/needle – is standard no matter what type of agent has been extravasated. However, depending on the agent that has leaked, subsequent steps are variable and may include cold compress, warm compress, application of topical agents (DMSO, hyaluronidase, hydrocortisone), administration of IV agents (dexrazoxane for doxorubicin), and general supportive care with analgesics, anti‐inflammatories, and antibiotics as indicated (Bertelli et al. 1995; Hasinoff 2006; Langer et al. 2006; Villalobos 2006; Mahoney et al. 2007; Venable et al. 2012). For most agents, there is no true standard of care for extravasation management. Even for doxorubicin, for which at least some consensus on initial management exists, many of the supplementary therapies are based on empiric, rather than prospectively evaluated techniques and treatments. However, the use of dexrazoxane, a cyclic derivative of ethylenediamine‐tetraacetic acid (EDTA), has been widely accepted in extravasation management protocols for doxorubicin.

Dexrazoxane has been approved by the Food and Drug Administration to decrease myocardial toxicity of doxorubicin in human patients with metastatic breast cancer receiving a cumulative doxorubicin dose greater than 300 mg/m² and was more recently approved for treatment of anthracycline extravasation (Kane et al. 2008). Clinical reports that illustrate dexrazoxane’s role in the successful management of doxorubicin extravasations in humans, dogs, and one cat have supported its use for this purpose (Mahoney et al. 2007; Kane et al. 2008; Venable et al. 2012). Research in mice has demonstrated that dexrazoxane administration prevents wound development after subcutaneous administration of doxorubicin and has provided information about the dosage required for adequate protection (Langer et al. 2006; Mahoney et al. 2007; Kane et al. 2008; Venable et al. 2012). Dexrazoxane penetrates cell membranes and complexes with iron, copper, and other metal ions, thereby removing them and preventing free radical generation and subsequent tissue damage (Langer et al. 2006; Kane et al. 2008).

Other supplementary treatments have also been implemented for doxorubicin extravasation. Dimethyl sulfoxide (DMSO) is a free radical scavenger and topical application can potentially reduce local tissue damage by increasing systemic absorption of the extravasated drug. It also has vasodilatory, analgesic, and anti‐inflammatory properties. Data from early clinical case studies suggested that human patients treated with DMSO were less likely to develop ulcerations after anthracycline extravasation (Bertelli et al. 1995). However, in rodent studies, topical DMSO reduced the effectiveness of systemic dexrazoxane (Langer et al. 2006). Similarly, the topical administration of hyaluronidase has also been advocated but with little clinical data to support its use (Spugnini 2002). Therefore, it appears that the most important early intervention that can be made in the event of doxorubicin extravasation involves the administration of dexrazoxane.

A general protocol for emergent management of doxorubicin extravasation is outlined below.