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.
Guidelines for Doxorubicin Extravasation
The first three steps below are standard no matter what type of agent has been extravasated.
1 Notify the attending doctor.
2 The IV catheter should be kept in place and any residual chemotherapy in the region should be aspirated back.
3 Once as much of the drug as possible has been drawn back, the catheter should be removed.
4 Place an IV catheter in a different vein to administer dexrazoxane (Zinecard®) at 10 times the doxorubicin dose (in mg), at the following intervals:Immediately (within 3–6 hours of extravasation)24 hours48 hours (1/2 dose)
5 Apply cold compress for 20 minutes immediately and every 6–8 hours for 48 hours.
Doxorubicin‐induced tissue sloughing usually appears 7–10 days after extravasation and will progressively worsen over the next several weeks to 2–3 months. Typically, in initial phases, the affected area may appear swollen, erythematous, pruritic, and/or painful. Subsequent moist desquamation, ulceration, and necrosis may then become apparent. Analgesics, anti‐inflammatories, and antibiotics should be prescribed as indicated and an Elizabethan collar placed to prevent self‐trauma from licking, chewing, etc. Open wound management may be adequate for some patients during the wound‐healing period; however, surgical debridement may be indicated if extensive tissue sloughing occurs (Figure 2.4a and b). It is unknown whether the use of negative pressure wound management may be useful clinically. In severe cases, limb amputation may be required if medical management and local tissue debridement is unsuccessful in addressing the tissue damage. Such an event can be catastrophic for a dog that has already undergone amputation for treatment of osteosarcoma, a tumor type for which doxorubicin is frequently utilized. The goal of early intervention with the above‐outlined protocol is to significantly lessen the severity of the ensuing reaction and to hopefully avoid the need for surgical intervention.
Chemotherapy Effects on Wound Healing
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
