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 in irradiated vasculature include hemostasis and occlusion, edema of the vascular wall, thrombosis, reduced neovascularization, and vascular sclerosis, which can be permanent. Eventually, progressive vascular loss and replacement by fibrous tissue may occur. These fibrous and vascular changes can predispose the patient to a higher risk of both immediate and delayed wound healing complications (Seguin et al. 2005). In general, the late tissue changes caused by radiation are more severe and impactful compared to those seen in the acute phases.
Timing of Radiation Therapy Relative to Surgery
In humans, the timing of surgery and radiation impacts tissue healing and overall outcome. Compared to post‐operative radiation, whose field must not only include the wound bed but also a margin of normal tissue surrounding it, pre‐operative radiation requires a lower dose of radiation to a smaller volume of tissue, thus resulting in fewer late complications and improved functional outcomes. However, pre‐operative radiation is associated with higher rates of acute and late wound healing complications (Griffin et al. 2015). A few studies in human patients and animal models have evaluated the impact of surgical timing following irradiation of the tumor bed. Specifically, pre‐operative radiation has been associated with a higher chance of wound healing complications than post‐operative radiation in patients with extremity soft tissue sarcomas (O'Sullivan et al. 2002), a lower chance of successful outcome compared to patients receiving post‐operative radiation (Wang et al. 2003) for head and neck cancers, and higher morbidity compared to patients not receiving radiation (Halle et al. 2009)for head and neck cancers. O'Sullivan et al. (2003) showed that in general, pre‐operative radiation for head and neck sarcomas is associated with lower rates of major wound complications compared to that for extremity sarcomas (O'Sullivan et al. 2003). As far as specific timing of pre‐operative radiotherapy relative to surgery, Halle et al. (2009) showed that the largest increase in all complication rates was seen when more than six weeks elapsed between the last radiotherapy session and surgery (Halle et al. 2009). Another study by Griffin et al. (2015) showed a statistically insignificant trend toward a higher rate of wound complications for patients who had surgery to remove distal extremity soft tissue sarcomas greater than six weeks after radiation therapy but no difference among the groups of patients that underwent surgery three, four, or five weeks following radiation therapy (Griffin et al. 2015). As for the timing of surgery relative to the radiation, when radiation is done in the neoadjuvant setting, surgery is performed once the skin’s acute side effects are resolved.
Skin Grafts and Flaps in the Radiation Field
In certain scenarios, cutaneous or mucosal flaps are needed to close the defect left after surgical removal of large or anatomically challenging tumors. Depending on the type of flap or graft utilized, the advanced, transposed, or grafted tissue may have a limited or more restricted blood supply (Seguin et al. 2005). Furthermore, in some cases where a flap or graft is employed, tumor excision may still be microscopically incomplete and thus adjuvant radiation therapy is indicated. Unfortunately, post‐operative radiation therapy can negatively impact wound healing and lead to flap failure. Given the known negative effects of radiation on the vasculature, Guo et al. (2012) evaluated the impact of pre‐operative fractionated radiotherapy on aortic grafts in a dog model and showed suppression of neointima migration and growth within the grafts after explant (Guo et al. 2012). In a study of 29 dogs undergoing a combination of radiation therapy and cutaneous or mucosal flapping procedure, 20/26 (77%) had some sort of complication, including dehiscence, flap necrosis, infection, and ulceration. The risk of complications was not higher when radiation was performed before surgery when a graft was not used to treat a radiation complication but the severity was greater. However, the use of a flap to treat damaged tissue secondary to radiation was more likely to result in a complication. Higher dose per fraction (4 Gy versus 3 Gy) was significantly associated with an increased severity of complications (Seguin et al. 2005). Similar to humans, radiation to the head and neck location, other than the oral location, was significantly associated with a decreased severity of complications. A modest population (15%) of dogs had an unresolved complication, therefore, despite a significant number of complications, 85% of dogs received a successful combination of radiotherapy and surgery (Seguin et al. 2005).
Bone Healing and Radiation Therapy
Eisenschenk et al. (2006) showed a significant worsening in bone healing and stability after pre‐ and post‐operative radiation therapy to the wound bed and vascularized bone grafts (Eisenschenk et al. 2006). Such complications can lead to an increased chance of delayed unions, non‐unions, and fracture. Similarly, in a canine study, pre‐operative irradiation significantly impaired allograft incorporation in a limb‐salvage model as determined by radiographic healing scores, histomorphometry, and frequency of non‐unions (Ehrhart et al. 2005).
Minimizing the Negative Impact of Radiotherapy on Surgery
Recent advances in both human and veterinary oncology have allowed for the use of more conformal radiation methods such as stereotactic radiosurgery (SRS). This more focused modality minimizes the damage to healthy surrounding tissues by relying on the highly accurate delivery of radiation dose to the tumor, as well as the steep dose gradient between the tumor and the surrounding normal tissues (Coomer et al. 2009). Thus, the surrounding soft tissues remain well vascularized and are therefore available to be used as transposition flaps in the event of desquamation or skin necrosis within the treatment field.
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