Читать книгу Veterinary Surgical Oncology - Группа авторов - Страница 50

Maximum tolerated dose (MTD) chemotherapy is designed to impact rapidly dividing cells, thus a practical concern exists for deleterious effects on wound healing. The timing of the chemotherapy (neoadjuvant versus adjuvant) and specific drug administered may also influence the effects. Various pre‐clinical studies have documented delayed wound healing from chemotherapy; however, it appears transient, it is most apparent when drug is administered during the inflammatory phase of healing and may be ameliorated to a degree with the administration of granulocyte colony‐stimulating factor (Bland et al. 1984; Salm et al. 1991; Shirafuji et al. 2001).

Several clinical evaluations have documented limited impact of chemotherapy on wound healing. In one study of patients with locally advanced mammary carcinoma treated with surgery and perioperative chemotherapy, there were no negative effects on wound healing (Taylor and Kumar 2005). In a separate study evaluating obstetric and gynecologic patients, the incidence of wound complications was 11% and chemotherapy did not increase the risk of wound complications despite being administered soon after cytoreductive surgery (Kolb et al. 1992).

It appears, the most detrimental effects occur when chemotherapy is administered within two weeks pre‐ or one week post‐operatively and the presence of low albumin or hemoglobin is associated with a greater risk of delayed wound healing (Schuller et al. 1988; Drake and Oishi 1995). Nevertheless, in general, it is felt that the benefits of promptly initiating chemotherapy outweigh any immediate complications associated with surgery. It is important to note that the majority of studies, experimental or clinical, that have evaluated the effects of chemotherapy on wound healing have looked at primary wound healing, which is arguably the most relevant for the surgeon. The effects of chemotherapy agents on second intention wound healing are for the most part unknown. In one experimental model, nitrogen mustard decreased granulation tissue and wound contraction (Newcombe and Chir 1966).

In veterinary medicine, there are several factors that likely limit the impact of chemotherapy on wound healing; clearly, the dose intensity used in companion animals is significantly lower than that used in oncology in human patients, neoadjuvant/perioperative chemotherapy is relatively uncommon, and most patients start chemotherapy 10–14 days post‐surgery. A paucity of information exists in the veterinary literature with most of the data limited to dogs with osteosarcoma treated with either cisplatin or doxorubicin either pre‐operatively for 2–3 cycles or 2–10 days post‐surgery. Neither study reported an increase in post‐operative morbidity (Berg et al. 1995, 1997). On the other hand, survival did not appear to improve with these protocols (Berg et al. 1995, 1997). Therefore, general recommendations are to wait 7–14 days after surgery to begin chemotherapy, especially for more high‐risk procedures such as intestinal resection and anastomosis.

The use of metronomic (low dose continuous) chemotherapy is becoming more commonplace. As conventional chemotherapy typically involves the use of pulsatile cycles of chemotherapy given at the MTD with long breaks to allow recovery of normal cells from damage, metronomic chemotherapy instead utilizes continuous (typically once daily) administration 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.