of chemotherapeutics at a dosage well below the MTD, without prolonged drug‐free breaks. Unlike MTD chemotherapy, where the tumor cells are the primary targets of therapy, metronomic therapy appears to target cells of the tumor microenvironment including the endothelial cells that support and nourish the tumor. The mechanisms of action include direct apoptosis for dividing endothelial cells, suppression of the mobilization of circulating endothelial progenitor cells (CEPs) from the bone marrow, and increasing the production of the body’s own natural angiogenesis inhibitors. Furthermore, metronomic chemotherapy has been shown to have immunomodulatory effect via inhibition and depletion of T‐regulatory (Tregs) lymphocytes, thereby decreasing immune tolerance (Lana et al. 2007; Elmslie et al. 2008; Burton et al. 2011; Tripp et al. 2011; Leach et al. 2012; Biller 2014). Although metronomic therapy is often considered “antiangiogenic,” to date there is no evidence on whether its use has a detrimental effect on wound healing, as the vast majority have reported its use either weeks post‐surgery or in the treatment of bulky disease.
Use of targeted small molecule inhibitors such as masitinib, which blocks the function of KIT and PDGFR, and toceranib phosphate (Palladia®, Zoetis Inc.), which blocks signaling of KIT, PDGFR, and VEGFR family members, is becoming more commonplace in veterinary medicine (London et al. 2003; Hahn et al. 2008). By virtue of their mechanism of action, these agents are also considered anti‐angiogenic and theoretically could impact wound healing. Information regarding effects on wound healing is only anecdotal at this point and based upon the rare patients that require emergent surgery while on these medications. Ideally, the intermittent dosing of these medications and rather short washout periods suggest that cessation at the time of surgery should be sufficient to prevent post‐operative healing complications.
Complications of Radiation Therapy
Radiation Side Effects
Adverse reactions secondary to radiation therapy are classified as acute (“early”) or late (Figures 2.5‐2.8). Acute side effects occur during or shortly after a treatment course and are related to the death of rapidly dividing normal cells in continuously renewing tissues, most commonly epithelial (skin and mucosal) surfaces (Larue and Gordon 2013). Acute radiation side effects limit the radiation dose per unit time that can be safely given to patients; however, these adverse events are typically self‐limiting. Acute radiation side effects can be exacerbated by the concurrent administration of chemotherapy and molecular targeted agents. Common acute side effects include erythema, moist desquamation, edema, ulceration, and skin necrosis (Larue and Gordon 2013). Late side effects occur months to years after completion of the treatment course and are related to sublethal or lethal damage to non‐proliferating or slowly renewing tissues and subsequent loss of the normal tissue stem cells and replacement of vascular supply by fibrosis. Commonly affected tissues include liver, kidney, bone, connective tissues, muscle, and nerves. Late radiation side effects limit the cumulative dose of radiation that can be safely given to patients (Larue and Gordon 2013). The more severe reactions can be very difficult to treat, may lead to loss of normal tissue function (which can be catastrophic in certain situations), and can even be life‐threatening. Common late side effects include alopecia, leukotrichia, fibrosis, osteoradionecrosis (and subsequent risk of fracture), secondary tumor induction (Larue and Gordon 2013).
Figure 2.5 Mix breed canine with an incompletely resected mast cell tumor on the ventral aspect of the chest, over the sternum. The dog was treated with 18 fractions using intensity‐modulated radiation therapy. (a) Appearance of the skin at the time of the second fraction. No apparent side effects are visible yet. (b) Appearance of the site at the time of the eighteenth fraction. Moist desquamation and erythema are present. (c) Appearance of the skin 2 weeks after the end of radiation therapy. Alopecia is present but the other side effects are resolving: the erythema is resolved and there is mild dry desquamation.
Source: pictures courtesy Dr. Susan LaRue.
Figure 2.6 Beagle canine with an incompletely resected soft tissue sarcoma on the lateral aspect of the stifle treated with 18 fractions using a manually calculated plan and parallel opposed beams of 6 mV. (a) Appearance of the site before the start of radiation therapy. (b) Appearance of the site at the time of the eighteenth fraction. Minimal edema around the surgical scar is present. (c) Appearance of the site 4 weeks after the end of radiation therapy. Alopecia is present and there is dry desquamation and mild erythema.
Source: Pictures courtesy Dr. Susan LaRue.
Figure 2.7 American Staffordshire with an incompletely resected soft tissue sarcoma of the lip treated with 18 fractions using intensity‐modulated radiation therapy. (a) Appearance of the area two weeks after the end of radiation therapy. There is significant moist desquamation and alopecia present. (b) Appearance of the site 10 weeks after the end of radiation therapy. Side effects are resolving: the erythema is resolved and there is mild dry desquamation.
Source: Pictures courtesy Dr. Susan LaRue.
Figure 2.8 Late radiation therapy side effects. Image (a) shows a dog with a stage 4 nasal carcinoma prior to radiotherapy. This dog was irradiated using stereotactic radiation therapy (3 fractions of 10 Gy using a CyberKnife radiosurgical system). Image (b) shows the same dog 6 months after irradiation. This image demonstrates the late RT side effect of leukotrichia. Using stereotactic radiation therapy, a minimal amount of healthy tissue surrounding a tumor receives a clinically significant dose of radiation. This equates to significantly less acute radiation side effects and minimal late radiation side effects to the tissues outside the treatment field.
Source: Images courtesy of Siobhan Haney, DVM, MS, DACVIM (Radiation Oncology); Veterinary CyberKnife Cancer Center, Malvern, PA.
Impact of Radiotherapy on Surgical Outcome
Ionizing radiation damages fibroblasts and blood vessels, two critical players in wound healing. After irradiation, collagen displays reduced proliferation, abnormal maturation, and swelling – changes that lead to significantly weaker collagen scaffolding in the wound bed. Furthermore, irradiation induces acute degenerative changes in the basement membranes of blood vessels, thus increasing vascular permeability. Later changes seen
