Veterinary Surgical Oncology. Группа авторов

volume [CTV], purple line: planning target volume [PTV]) receives a high dose of radiation while the normal tissues (bue lines: eyes, light yellow lines: lenses, pink line: brain, and dark yellow: skin) receive a significantly lower dose.

      Source: Image courtesy Bernard Séguin, technical assistance Dr. Erin Trageser.

Chemotherapy

      Chemotherapy can sometimes be used neoadjuvantly to “down‐stage” (shrink) a primary tumor prior to surgery, and thus make it more amenable to surgical resection with clean margins. This may be appropriate for cutaneous and subcutaneous masses such as hemangiosarcoma (Wiley et al. 2010). Similarly, corticosteroids may be used to pre‐operatively down‐stage mast cell tumors with good success, although it is unknown if local recurrence is less likely with this approach (Stanclift et al. 2008). In this setting, the surgeon needs to involve the medical oncologist prior to surgery. Chemotherapy also can prolong life post‐operatively by addressing systemic metastasis; the classic example is appendicular osteosarcoma in dogs. Chemotherapy can be used immediately post‐operatively or once the wound has healed, at the discretion of the medical oncologist and the surgeon. Surgery may have only a small role, such as for diagnostic biopsy, with the sole treatment being chemotherapy, as is the case with lymphoma. Metronomic chemotherapy uses standard chemotherapy agents in a continuous administration, which requires lower doses to be used. The target of the drug is the tumor’s continually proliferating microvasculature, which is susceptible to chemotherapeutic effects with minimal systemic toxicity (Gately and Kerbel 2001; Mutsaers 2009; Biller 2014). Bisphosphonates concentrate within areas of active bone remodeling and induce osteoclast apoptosis, which is of therapeutic benefit in managing pathological bone resorptive conditions such as osteosarcoma, multiple myeloma, and metastatic bone cancer. Bone pain is decreased, quality of life is improved, and progression of bone lesions is delayed (Fan et al. 2005, 2007, 2008, 2009; Fan 2007, 2009; Spugnini et al. 2009; Oblak et al. 2012).

Embolization treatments include “bland arterial embolization” (without chemotherapy) and chemoembolization (embolization with chemotherapeutic agents) that can be used as a sole therapy or pre‐operatively to decrease tumor mass and size. Chemoembolization delivers chemotherapy to the tumor, allowing prolonged contact of the tumor to the chemotherapy without high systemic toxicity (Granov et al. 2005) and augmenting tumor ischemia (Weisse et al. 2002a). There are several experimental studies of embolization treatments in healthy dogs, including chemoembolization with gemcitabine (Granov et al. 2005), carboplatin (Chen et al. 2004; Song et al. 2009), and cisplatin (Nishioko et al. 1992). Bland arterial embolization resulted in decreased tumor growth, pain palliation, and control of hemorrhage in two dogs and one goat (Weisse et al. 2002a) and decreased primary tumor size in a dog with a soft tissue sarcoma (Sun et al. 2002). A recent review of veterinary interventional oncology discusses embolization treatments (Weisse 2015).

Figure 2.3 (a) Anal sac adenocarcinomas treated with adjuvant megavoltage radiation. (b) Lead block used to spare normal tissue from RT. (c) Final setup including a tissue‐equivalent “bolus” to allow the maximum dose of radiation to reach the tumor.

      Source: Courtesy of Mary‐Kay Klein.

Figure 2.4 (a) focal necrosis on the antebrachium following extravasation of doxorubicin. (b, c) Surgical debridement of the necrotic tissue.

Electrochemotherapy

      Electrochemotherapy (ECT) involves the systemic or local delivery of lipophobic drugs (chemotherapeutics including Cisplatin and Bleomycin) in combination with permeabilizing electric pulses which promotes the uptake of these drugs by cancer cells (Spugnini et al. 2016). Normally, these drugs use protein receptors to enter the cell membrane thus uptake is generally low under normal conditions (Spugnini et al. 2017). The permeabilizing electric pulses enhance the uptake of these drugs by an estimated factor of 700‐fold for bleomycin and 4–8 times for cisplatin (Spugnini and Baldi 2019). When the cancer cell is exposed to the permeabilizing pulses, it will either return to its previous state or reverse the ion fluxes and thereby activating a caspase‐induced apoptosis. Once returning to its steady state with said drug present internally, cell death is instituted by each drug’s respective mechanism of action.

      Heavy sedation or anesthesia (if intraoperative) is required for ECT and protocols have been established. Many resources are available and depending upon geography courses may be available to aid in training. When used in the post‐operative setting, the number of ECT sessions is generally two treatments at q 2‐week intervals (Spugnini et al. 2016; Spugnini and Baldi 2019). In the gross disease setting, ECT is continued until either complete response is obtained or tumor progression (Spugnini and Baldi 2019). Published data exists for canine soft tissue sarcoma, canine perineal and anal sac tumors, canine melanoma, canine mast cell tumor, feline soft tissue sarcoma, and feline head and neck carcinomas among others (Spugnini and Baldi 2019).

Molecular and Targeted Therapies

      These therapies include gene therapy (e.g. viral and non‐viral vectors); targeting signal transduction that regulates cell growth, differentiation, survival, and death (e.g. via inhibition of protein kinase); anti‐angiogenic factors (including metronomic chemotherapy and cyclo‐oxygenase‐2 inhibitors); agents that can inhibit DNA methyltransferase‐1 function; histone deacetylases; proteasome inhibitors; heat shock protein 90 inhibitors; Poly adenosine diphosphate (ADP)‐ribose polymerase (PARP) inhibitors; and carbonic anhydrase IX inhibitors (Argyle et al. 2013).

A thinking surgical oncologist is always aware of the animal as a whole and how the behavior of the specific cancer in the specific patient influences the surgeon’s role. The surgeon is cognizant of paraneoplastic syndromes, appropriate imaging and staging prior to and during surgery, appropriate support and follow‐up care, and how various modalities can be used synergistically to achieve the maximal outcome with minimal morbidity. Tables 2.1–2.3 outline various treatment modalities and published outcomes of these treatments for various types of cancers in dogs and cats.

Complications of Chemotherapy

      Chemotherapy Extravasation

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