The Effects of Radiation on Wound Healing

To understand the complications of surgery in the previously irradiated field, it is important to discuss the pathophysiologic effect of radiation on tissue and wound healing. The process of wound healing begins at the moment of injury and is classically divided into four phases: hemostasis, inflammation, proliferation, and maturation. Each stage is predictable in its onset and mediated by the interactions of numerous cell-signaling molecules in a sequential cascade. This complex process of healing can be interrupted directly or indirectly at several stages by the effects of radiation. The direct effects of radiation on cell proteins and DNA leads to inhibition of cell replication, or cell death through instability or apoptosis. The indirect effects of radiation involve the excitation of intracellular molecules and the generation of free radicals that in turn damage genetic material, signaling mechanisms, and other cell components.

Radiation’s effect on the cell signaling molecules in the wound-healing cascade has been studied in a large and growing field of research. Radiation-induced alterations in the expression of several cell-signaling molecules have been documented in both human and animal models. These include interferon-γ (IFN-γ), transforming growth factor beta (TGFβ), vascular endothelial growth factor (VEGF), nitric oxide (NO), and tumor necrosis factor (TNF), as well as a variety of interleukins (IL) and matrix metalloproteinases (MMPs). The downstream effects of these alterations include disorganization of extracellular matrices; impairment of neovascularization and cell migration; and disordered collagen deposition leading to compromised blood supply, tensile strength, and the inability to recover from subsequent insults, all contributing to surgical complications in the irradiated field. The severity of these effects is dependent on a variety of factors, most importantly the total dose of radiation, dose per fraction, and surface area of the treatment field. Individual sensitivity to radiation may also vary and has been shown to play a part in determining the extent of radiation-induced injury.

Preoperative Evaluation and Patient Selection

An important step to improve surgical outcomes in the previously irradiated patient is minimization of risk factors for poor wound healing such as tobacco use, hyperglycemia, and poor nutritional status. Whenever possible these issues should be addressed preoperatively through patient counseling, referrals to specialists, or changes in medication.

Diabetic control can be assessed preoperatively though serum hemoglobin A1C (HbA1c) testing. Retrospective studies have identified increased length of stay and worsened surgical outcomes in diabetic patients with HbA1c levels at 7% or greater. While the implications of rapid correction of HbA1c have been debated, and no widely accepted preoperative “cutoff” guidelines exist, diabetic control should be assessed via serum glucose and HbA1c testing in order to facilitate preoperative counseling regarding outcomes, especially in the previously irradiated patient. If the situation permits, referrals to diabetic nutritionists and endocrinologists should be pursued in order to maximize glycemic control preceding surgery.

Combustible tobacco use is a significant inhibitor of wound healing, necessitating cessation when at all possible prior to surgery. Smoking decreases oxygen levels in tissue, impairs cell migration, decreases neovascularization, and increases the presence of inflammatory mediators. This has been shown to result in increased rates of wound dehiscence, increased healing time, worse cosmetic outcomes of surgical scars, reduced skin graft take, increased rates of postsurgical infections, and increased overall complication rates. With tenuous tissue characteristics already present in irradiated tissue fields, the impact of smoking greatly increases the risk for poor outcomes following surgery. Sørensen and colleagues have shown that smoking cessation results in restoration of tissue oxygenation and blood flow within 1 day, and restoration of inflammatory cell functions within 4 weeks. This short timeline of reversal makes smoking cessation counseling a necessary step in the perioperative management of not just previously irradiated, but all urologic patients.

Optimization of nutritional status is an important step in achieving good surgical outcomes. Several studies show improvements in surgical outcomes and complication rates with better preoperative nutritional status as measured by serum albumin and validated tools such as the Nutritional Risk Classification, or Nutritional Risk Screening 2002. Enteric supplementation is universally preferred in patients who can tolerate it. However, studies evaluating the impact of short course (~10-day) preoperative enteric supplementation on postoperative complications and outcomes have yielded conflicting results. Similarly, meta-analyses of studies on preoperative parenteral nutrition were also indeterminate as to its actual impact on outcomes. Still, the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines suggest that there may be a benefit to preoperative short-term (7- to 10-day) parenteral nutrition prior to surgery in a select group of severely malnourished patients unable to sustain enteral supplementation. The American Society for Clinical Nutrition and Metabolism (ASPEN) recommends nutritional supplementation only when enteral intake is impaired. Although consensus is lacking, an assessment of nutritional status through albumin measurement, combined with patient characteristics through a nutritional screening tool, would allow the urologist to properly advise patients on their individual risk of complications related to poor nutrition.

Hyperbaric Oxygenation

Hyperbaric oxygenation (HBO) represents a potential perioperative therapy for carefully selected patients with a history of radiation. HBO has been used for over three decades in the treatment of post-radiation complications of head and neck cancers and has been well explored in the treatment of radiation cystitis. A recent meta-analysis on the use of HBO for a variety of surgical procedures, including pelvic surgery, suggests that preoperative HBO may reduce wound breakdown, infection, fistula formation, and flap loss after surgery in the irradiated patient. Mechanisms of action discussed in this meta-analysis include stimulation of angiogenesis, reduction of fibrosis, improved tissue oxygenation, and stimulation of stem cells and stem cell derivatives.

In a small series of patients with a history of complications from pelvic radiation for gynecologic, bladder, and spinal malignancies, Pomeroy and colleagues showed a reduction in radiation-related post-surgical complications in patients treated with HBO prior to planned pelvic surgery. Patients underwent 30 HBO “dive” sessions at 2.0 atmospheres prior to bladder augmentation, urinary diversion, or palliative resection of recurrent pelvic tumor, followed by 10 sessions postoperatively. The authors noted fewer radiation-related complications in these patients, which they attributed to the stimulation of angiogenesis and promotion of wound healing. Although limited by its size, this study indicates a possible role for pre- and postsurgical HBO therapy in reducing surgical complications in the previously irradiated patient.

General Intraoperative Considerations

The hallmarks of the irradiated surgical field are a paucity of reliable tissue planes, an abundance of scar tissue, and tissue atrophy. Preoperative stents, catheters, or wires (through fistula tracts or small strictures) are useful in the identification of relevant genitourinary structures while operating in irradiated fields; the authors recommend their placement whenever possible. Additionally, the inhibition of collagen content remodeling seen with radiation leads to a decrease in tissue tensile strength. As a result, maneuvers such as “sweeping” and other blunt dissection techniques may result in tissue damage rather than a separation of planes. Sharp dissection under visualization is key throughout any case in an irradiated field, with care taken to establish and reestablish anatomic landmarks during the procedure. Bony landmarks are most reliable, as they do not change post-radiation; however, palpation may be difficult in some areas due to patient size and fibrotic scar tissue.

General principles for wound closure in an irradiated field are shown in Box 19.1 . A watertight closure of the urinary tract in multiple layers should be completed with irradiated tissue. The integrity of such closures should be tested via irrigation intraoperatively and reinforced if necessary. In situations where tissue integrity of the genitourinary tract is questionable, as in most post-radiation cases, the diversion of urine through urethral or suprapubic catheterization, or percutaneous nephrostomy drainage is prudent in order to maintain a dry anastomosis and prevent fistula formation and wound breakdown. Fecal diversion is mandatory in a post-radiation enteric fistula to the urinary tract, and should be performed prior to urologic repair. In cases of urinary diversion, a stepwise approach to “un-diversion” is advisable with replacement of catheters if urine leak is suspected. Often this process can take several weeks or months due to the slow healing nature of irradiated tissue. While algorithms have been described for periodic assessment and un-diversion, there are no established guidelines for fecal un-diversion. Most studies, however, advocate waiting at least 3–6 months post successful repair. In cases of rectal sphincter involvement or damage, consideration of a permanent diverting colostomy should be considered. Following fistula repair, fecal un-diversion should be attempted last, after urinary un-diversion and a period of observation to ensure proper closure of the urinary tract. Premature fecal un-diversion holds the risk of contamination, infection, and potential wound breakdown in the already tenuous irradiated field.

The interposition of nonradiated, healthy tissue into the irradiated field can be challenging and may be determined by the surgical approach. With perineal surgery, access to gracilis flaps, labial flaps, tunica vaginalis, or dartos tissue flaps should be considered. During transabdominal procedures the omentum is a reliable source of healthy tissue for interposition. Proper mobilization of a tension-free flap based on the right gastroepiploic artery allows for extension of the omentum as far inferiorly as the proximal urethra and should be utilized liberally in transabdominal procedures. Kulkarni and colleagues have described laparoscopic mobilization of omentum during the perineal approach for posterior urethroplasty. In this series of patients undergoing repair of complex and re-do pelvic-fracture–associated urethral injury, omentum was mobilized inferiorly through a peritoneal incision and placed between the prostate and rectum. However, due to the close proximity of the rectum and the difficulty of dissection in this area, the use of omentum through this approach should be considered a last resort if no other healthy tissue is available.

Wound closure of the abdominal cavity and perineum is as crucial to operative success as any other factor in post-radiation surgery. A large retrospective analysis of 160 previously irradiated patients undergoing abdominoperineal resection of the rectum (APR) with perineal wound closure found that the rate of major wound complications more than doubled in patients with a history of pelvic radiation as compared to patients who did not receive radiation preoperatively (41% vs 19%, p < 0.02). The rate of fascial dehiscence with major abdominal surgery for both irradiated and nonirradiated patients ranges from 1% to 6%, with an average mortality of 25%. While retrospective reviews have not associated prior radiation with an increased risk of abdominal dehiscence, there is a lack of data in this patient population. The use of retention sutures to prevent postoperative abdominal-wall fascial dehiscence is controversial and has not been proven to provide benefit at the cost of greater patient discomfort and local complications at the suture site. Abdominal binders may reduce pain postoperatively; however, similar to the use of retention sutures, there is a lack of evidence to support the use of abdominal binders to prevent seroma formation or reduce the rates of wound dehiscence. Further information on abdominal wound closure is covered in detail elsewhere in this book.

Urethral Stricture

Santucci and colleagues estimated the incidence of male urethral stricture disease to be about 0.6% of the general population. Radiation therapy, through any modality, has been shown to increase this incidence. Among those who have had pelvic radiation, the incidence of urethral stricture increases from 1.7% to as high as 5.2% for those receiving combination brachytherapy and EBRT. Overall, urethral strictures are most commonly associated with EBRT. The pathophysiology of urethral stricture in the post-radiation patient is related to chronic oxidative stress subsequently leading to vascular damage, ischemia, and poor wound healing of the surrounding tissue. The resulting fibrosis of the corpus spongiosum leads to urethral stricture formation, which can present several years following the completion of therapy, and is typically found in the bulbar urethra extending to the prostate. Endoscopic management of these strictures, regardless of location and the type of intervention, carries a high rate of recurrence, upward of 50–60%. Additionally, repeat endoscopic procedures have been shown to increase the complexity and length of a stricture.

The first step in management of the post pelvic radiation urethral stricture is the diagnosis of stricture length and location via a retrograde urethrogram (RUG). A suprapubic tube may be necessary in patients with obliterative urethral strictures. In these situations, antegrade cystoscopy and concomitant retrograde urethrogram can define a stricture’s length and location ( Fig. 19.1 ).

Simultaneous antegrade and retrograde urethrogram (“up-and-down-ogram”) using a flexible cystoscopy though the suprapubic tract. The white arrow denotes stricture and the red arrow denotes the cystoscope.

Urethroplasty in the irradiated pelvis can be a challenge due to tissue fibrosis and obliterated surgical planes of dissection. Utilization of a suprapubic cystostomy assists the surgeon in identifying the proximal extent of the urethral stricture which extends to the prostatic urethra during perineal dissection. It is advisable to start dissection distally, where the urethra is less affected by pelvic radiation, continuing proximally once the proper tissue planes are identified. As previously described, the typical bulbomembranous location of most radiation-induced strictures requires proximal dissection to the prostatic urethra. Once proximal dissection is achieved, resection of necrotic tissue at or to the prostate may be necessary in order to expose healthy mucosa for an anastomosis. Surgical instruments such as a pituitary rongeur have been utilized to accomplish prostatic resection. The Capio device (Boston Scientific, Massachusetts) has proven useful in the authors’ experience to deliver anastomotic sutures to the prostatic urethra when conventional suture placement is not feasible. This device, often used in female prolapse surgery, allows passage and suture capture in limited space and operates at oblique angles, which makes it ideal to capture prostatic or bladder mucosa through the perineum.

Grafts or fasciocutaneous flaps may be utilized for the repair of lengthy post-radiation urethral strictures, with good results seen in small series. However, graft uptake in the irradiated perineum can be somewhat tenuous due to the often fibrotic and avascular resection bed. Buccal mucosa appears to be the most ideal graft in these situations due to its thin lamina, good vascularization, and remote location away from the irradiated field. For excision and primary anastomosis (EPA), surgical maneuvers such as splitting of the corpora, re-routing the urethra around the corpora, or resection of the pubic bone have been described, but are rarely necessary once adequate mobilization of the proximal and distal urethra have been achieved.

Data evaluating the efficacy of urethroplasty specifically in post-radiation patients are limited to retrospective case series with limited follow-up. Nonetheless, acceptable outcomes following urethroplasty for post-radiation urethral strictures have been reported. In one multi-institutional retrospective series of 72 men with radiation-induced strictures EPA was the predominate technique used. The average stricture length was 2.4 cm in this cohort, with most strictures located in the bulbar or bulbomembranous urethra. Overall success was 70% in these men at an average of 2.9 years’ follow-up. Stricture recurrence in this series was associated with stricture length >2 cm and treatment center. Substitution urethroplasty in this series was reported on six patients; four patients with a graft and two with a flap. Mean stricture length in these men was 4.3 cm. Stricture recurrence was reported in one of these patients after 7 months.

In cases of relatively short (<3 cm) recurrent bulbar urethral strictures in the irradiated pelvis, repeat EPA should be considered in order to excise as much surrounding ischemic spongiosum as possible. Aggressive mobilization of the urethra is necessary and is feasible in the proximal bulbar urethra. In lengthier stricture recurrences, pedicled fasciocutaneous genital skin flaps may be more successful than graft substitution due to the added benefit of the flap retaining its own blood supply as compared to a graft placement into an irradiated host bed. Overall in irradiated patients, several studies have demonstrated successful outcomes using perineal, scrotal, or penile skin as both flaps and grafts, as well as gracilis muscle as a carrier for grafts.

Urinary incontinence is a potential complication following bulbomembranous urethroplasty in the irradiated pelvis. In one series the onset of new postoperative urinary incontinence was 36–50%; however, 20% of these patients (3/15) experienced spontaneous resolution of their incontinence 4 weeks after surgery. If incontinence does not resolve, an artificial urethral sphincter can be offered.

As in nonirradiated patients, it does not appear that erectile function is significantly altered following urethroplasty in men with previous pelvic radiation.

Rectourethral and Colovesical Fistula

The development of rectourethral (RUFs) or colovesical fistulas (CVFs) are troublesome complications seen in the post-radiation prostate cancer patients. While historically associated with surgical injuries during rectal or prostate surgery, an increasing number of patients have been reported with radiation-induced fistula. The incidence of RUF after radiation ranges from 0.2% to as high as 2.9% in patients receiving multimodality radiation therapy for prostate cancer. Lane and colleagues reported that since 1998, 50% of reported cases of RUF involved pelvic radiation (mainly EBRT, brachytherapy, or combination), as opposed to 3.8% prior to 1998. No matter what the approach, the repair of these fistulas can be tedious and difficult. Surgical planning and a multidisciplinary approach are necessary for a successful outcome.

Common signs and symptoms of RUF and CVF include fecaluria, urine per rectum, recurrent urinary tract infection (UTI), pelvic pain, and hematuria. Patients with prior radiation have been reported to have a higher incidence of wound infection, transfusion requirements, and increased time to fecal un-diversion as compared to nonirradiated patients. Identification and localization of RUF and CVF involve history, physical exam, imaging, and endoscopy. Physical examination includes evaluation of the perineum for cutaneous tracts, as well as digital rectal exam to palpate the fistulous tract and determine its distance from the anal verge. The fistula tract will generally feel firm and fibrotic on rectal exam. Computed tomography with triple infusion (oral, intravenous, and rectal contrast), followed by cystoscopy with retrograde urethrogram and cystogram, is recommended to localize the fistula and plan the reconstructive approach ( Fig. 19.2 ). Cystoscopy has a high sensitivity (80–100%) for fistula diagnosis within the bladder and allows for measurement of the size and location of the fistula in relation to the ureteral orifice, prostate, bladder neck, and external urinary sphincter. Small fistula tracts may not be visible, but can present as bullous edema of the urothelium, seen with raised erythematous edges ( Fig.19.3 ). Larger fistula can present on cystoscopy with an easily identifiable tract into the rectum ( Fig. 19.4 ). Biopsy of the fistula tract during cystoscopy is recommended if there is a suspicion of malignancy. Anoscopy or colonoscopy is also useful in surgical planning and should be performed by appropriate specialists in order to identify the enteric fistula location and size.

Appearance of a rectourethral fistula on retrograde urethrogram. Contrast is seen filling the rectum (arrow), with brachytherapy seeds noted in the prostate.

A rectourethral fistula seen on cystoscopy with raised, bullous, mucosal edges and erythema (arrow).

A large rectourethral fistula noted on cystoscopy with a clear view of the rectal mucosa (arrow) seen from the lumen of the urethra.

In the previously irradiated patient, fecal diversion in conjunction with urinary diversion is mandatory. Temporary suprapubic urinary diversion is useful for two reasons: It allows the diversion of urine away from the fistula, and it allows “urethral rest” in order to evaluate the patient for concurrent urethral stricture formation. One study puts the incidence of concurrent urethral strictures at 30% in patients with RUF. Although conservative management with both urinary and fecal diversion has been successful in some patients with small, less fibrotic fistulas, it is rarely successful in our experience with post-radiation RUF or CVF. Furthermore, HBO therapy has not been shown to reduce the need for surgical management. Assessment of a patient’s functional and health status is key, as operative management tends to be more complex with a longer postoperative recovery in the irradiated patient. The location of these fistulas can range from the bladder to the bulbar urethra, highlighting the need for both cystoscopy and radiologic imaging to fully assess the extent of disease. Preoperative ureteral stenting can be considered prior to repair of fistulas that appear to be in close proximity to the ureteral orifices, especially in post-prostatectomy patients.

Options for management of radiation-induced RUF and CVF depend on the location, size, and etiology of the fistula. Due to the rarity of these fistulas, combined with their heterogeneity in type and patient characteristics, there are little data on the standard approach to surgical management. Prior to incision, placement of a small catheter or guidewire may aid in identification of the fistula tract. Surgical approaches to the fistula include trans-sphincteric, transanal, transperineal, or transabdominal. General surgical principles necessary to achieve the best outcomes for a fistula in a previously irradiated pelvis are shown in Box 19.2 . While some studies have noted worse outcomes of fistula repair in post-radiation or cryotherapy patients, Whick and colleague’s meta-analysis of all available RUF patients undergoing repair showed comparative success rates (90%) for irradiated and nonirradiated patients alike, with the exception of patients who underwent transanal repair. A transabdominal approach was most commonly utilized in previously irradiated patients undergoing RUF repair (74.4%). However, direct comparison of groups in this case series was difficult as operative approaches and postoperative permanent fecal and urinary diversion rates were significantly different for irradiated and nonirradiated patients. Additionally, 25% and 42.5% of irradiated patients were unable to have their fecal and urinary diversions reversed after RUF repair, respectively, as compared to only 4% of nonirradiated patients. Similar to urethral stricture repair, urinary incontinence was not uncommon after RUF repair (up to 71% in one cohort of both irradiated and nonirradiated patients). For those patients with moderate-to-severe urinary incontinence following RUF repair, successful treatment with AUS implantation has been reported.

The transphincteric approach was developed circa 1960 by English surgeon Aubrey York Mason, for whom it is now commonly named. Utilizing this approach, the patient is placed in a prone jackknife position ( Fig. 19.5 ). An incision is made from the anal verge to the coccyx, allowing dissection through subcutaneous tissue with exposure of the posterior rectal wall. The posterior rectal wall is opened, exposing the anterior rectal wall and fistula tract. This dissection requires careful division and reapproximation of the rectal sphincter. With proper technique, the risk of postoperative fecal incontinence is negligible. The York Mason approach was described for RUF repair in 1969 by both Kilpatrick and Mason. This approach is beneficial in providing excellent visualization of proximal RUF and CVF fistulas near the bladder neck. Closure can be accomplished in three layers (urothelium, interposed mucosa, and rectal wall), and this approach is generally well tolerated with relatively limited recovery time. However, interposition of healthy tissue between the urinary tract and rectum is limited to tissue immediately adjacent to the fistula, which may also be damaged from prior radiation. Interposition of distant healthy tissue such as a gracilis flap requires a separate perineal incision, which increases operative morbidity. While good results have been shown for many iatrogenic RUFs, the York Mason approach has a higher rate of recurrence with radiation-induced strictures (4/7 patients recurred in one study) and larger diameter fistulas and is, therefore, not recommended for complex post-radiation RUF, re-do RUF repair, or post-radiation fistulas greater than 2 cm.

Prone jackknife positioning.

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