Abstract
More than 91,000 women in the USA will be diagnosed with a gynecologic malignancy in 2013. Most will undergo surgery for staging, treatment or both. No therapeutic intervention is without consequence, therefore, it is imperative to understand the possible complications associated with the perioperative period before undertaking surgery. Complication rates are affected by a patient population that is increasingly older, more obese and more medically complicated. Surgical modalities consist of abdominal, vaginal, laparoscopic and robotic-assisted approaches, and also affect rates of complications. An understanding of the various approaches, patient characteristics and surgeon experience allow for individualized decision-making to minimize the complications after surgery for gynecologic cancer.
“To err is human” is an age-old behavioral observation that became the keynote message of the Institute of Medicine's 1999 report on the safety of healthcare [1]. This report, and the massive lay media attention generated from its dissemination, initiated a new era of systematic thinking to curb preventable medical errors. In surgery, some errors are entirely avoidable whereas others are not. The latter is more often the case in pelvic oncologic surgery where the anatomy may be severely distorted by the cancer, with critical organs proximate to, or even directly involved with, malignant growth. Some percentage of complications in gynecologic surgery is inherent to the disease process, procedure modality and patient characteristics. If we are to individualize the approach to treatment, as suggested in the Institute of Medicine report, we must be familiar with these variations and their associated risks.
The National Cancer Institute estimates that more than 91,000 new cases of gynecologic cancer will be identified in 2013 in the USA alone (see Table 1 for a breakdown according to cancer type) [101]. Most gynecologic malignancies, such as ovarian, endometrial and vulvar cancer, are surgically staged and treated. Cervical and vaginal cancers are clinically staged. Surgery for all types of gynecologic cancer involves not only resection of the primary tumor, but also evaluation for local and distant spread. As our patient population becomes older, more obese and more medically complex, the complications from those surgeries pose an increasing challenge to gynecologic oncologists and their patients.
2013 estimates of incidence and death by type of gynecologic cancer.
Data taken from [101].
This review of the complications most common to gynecologic oncologic surgery was undertaken to identify trends by patient characteristic and treatment modality. It was conducted through PubMed and all English language results from 1 January 2008 to 13 May 2013 were included. Intraoperative complications include hemorrhage and injury to the bladder, bowel, vessels and nerves. Postoperative complications include venous thromboembolism (VTE), gastrointestinal dysfunction, infection, impaired wound healing and lymphatic problems. Long-term complications, such as adhesive disease and incisional hernia, are beyond the scope of this review. As each complication is explored, it is imperative to consider the cancer type, surgical modality (open vs minimally invasive), surgical route (abdominal vs vaginal) and patient characteristics (age, BMI and comorbidities).
Hemorrhage
Intra- or post-operative hemorrhage led to transfusion after surgery for gynecologic cancer in <1 to >30% of patients, depending on surgical modality, radicality and patient BMI. In one study of obese patients undergoing surgical staging for endometrial cancer, six out of 129 patients having robotic and eight out of 110 patients having laparoscopic staging required transfusion postoperatively [2]. Another study examining 82 patients undergoing laparoscopic staging for ovarian cancer resulted in one patient receiving intraoperative transfusion [3]. Other studies looking across gynecologic cancer types show rates of transfusion of up to 30% [4]. Two studies looking at deep vein thrombosis (DVT) prophylaxis regimens found no increased risk of transfusion after perioperative receipt of low-molecular-weight heparin [4,5]. Rates of vascular injury vary from <1 to 4.5%.
One large study by Leiserowitz et al. examined endometrial cancer and found vascular injury in 2.9% of laparoscopic-assisted vaginal hysterectomies compared with 4.5% of open cases [6]. However, some other studies have reported higher rates in laparoscopy compared with the abdominal approach [7,8].
The surgeon can minimize hemorrhage by creating optimal exposure of the surgical site and having comprehensive knowledge of anatomy. Throughout the surgery, the surgeon must identify bleeding vessels and have synthetic, nonabsorbable monofilament sutures (5–0 or smaller) readily available for arterial repairs. Application of pressure and hemostatic agents (Table 2) can also minimize blood loss and the need for transfusion. All patients undergoing surgery should have an active type and screen, and the hospital blood bank should be readily equipped to perform a transfusion, should it become necessary. Although preparation, minimization and recognition are important for all surgeries, certain populations require increased diligence. Those with ovarian cancer and undergoing bowel resection have the highest rates of transfusion [9]. However, visualization poses a particular challenge in obese patients, and those with cardiac comorbidities or history of bleeding require an artful balance to achieve the appropriate level of anticoagulation.
Commercially available hemostatic agents.
Venous thromboembolism
VTE consists of DVT and pulmonary embolism (PE), and can be one of the most devastating complications of oncologic surgery. Malignancy creates a hypercoagulable state. The endothelial injury caused by surgery and subsequent venous stasis created by the postoperative period of bed rest, complete Virchow's triad to put patients at increased risk for VTE [10]. Low-molecular-weight heparin is more expensive, but allows once-daily dosing with 40 mg for the general population. The dose should be increased to 0.5 mg/kg for obese patients. With such a regimen, VTE complicates only 1–2% of most gynecologic cancer surgery compared with up to 38% before implementation of dual prophylaxis [4]. Rates are higher in ovarian cancer and with prolonged or complicated surgeries, but are still generally below 10%. Risk of PE also increases with age over 60 years and every BMI increase of 5 kg/m2 [11]. Treatment of VTE includes hemodynamic support, supplemental oxygen and therapeutic levels of anticoagulation within 24 h. In acute PE, thrombolytic therapy and/or intubation may be initiated. For patients in whom contraindications to anticoagulation and thrombolysis exist, placement of an inferior vena cava filter, and even embolectomy, may be warranted.
In general, all surgical patients should receive compression stockings and ambulate as soon after surgery as possible (Table 3) [12,13]. For those patients undergoing treatment for malignancy, the addition of dual prophylaxis with heparin/low-molecular-weight heparin and segmental compression devices, as described above, is essential. Owing to their increased expense, use of direct thrombin inhibitors should be limited to patients with contraindications to heparin, such as previous heparin-induced thrombocytopenia. Factor Xa inhibitors are both expensive and lacking in long-term data, but may be considered for prolonged prophylaxis due to their ease of oral administration. Candidates for anticoagulation 4 weeks postdischarge include those patients with ovarian cancer and those over 60 years of age or with a BMI of 30.
Agents for venous thromboembolism prophylaxis.
b.i.d.: Twice daily; DTI: Direct thrombin inhibitor; HIT: Heparin-induced thrombocytopenia; LMWH: Low-molecular-weight heparin; p.o.: Per os; q: Every; sc.: Subcutaneous.
Bowel complications
Over 70% of ovarian cancer patients present with the International Federation of Gynecology and Obstetrics stage IIIC or beyond at the time of diagnosis, with metastasis to the upper abdomen and involvement of lymph nodes, the bowel, or both. Therefore, optimal cytoreduction of ovarian malignancy often involves manipulation or resection of the small and large bowel. This can lead to intraoperative bowel injury or postoperative complications, such as intestinal ileus, obstruction, anastomotic leak or fistula formation. With resection of the bowel, anastomotic leakage is observed in 3–13% of patients. In a review by Guenaga et al. of the 13 prospective randomized trials, including 4777 patients undergoing bowel resection, anastomotic leakage occurred in 4% of patients with preoperative bowel preparation and in 3% without [14]. Wound infection was also comparable between groups, indicating that preoperative mechanical bowel preparation does not decrease the complication rate and is therefore unnecessary. Intraoperative bowel injury, small bowel obstruction and ileus each complicate approximately 2% of surgeries across modalities, but are significantly more common in open surgery compared with minimally invasive approaches [15–17].
These complications increase with increased surgical complexity, such as exenteration, radical cytoreduction of ovarian cancer, and dual therapy with radiation therapy as is often employed in uterine cancers. Two studies by Minig et al. demonstrated that early feeding after surgery, defined as a clear liquid diet on postoperative day 1 then a regular diet, led to lower rates of complications overall, including ileus, anastomotic leak and intestinal complications [9,18]. Small bowel obstruction, ileus and urinary retention may sometimes be attributable to intraoperative nerve injury [19–21]. Nerve injury is more often evaluated as a separate entity in studies of endometrial and cervical cancer owing to the proximity of the uterus to the hypogastric plexus, and has been found to be <2%. Identification and avoidance of the hypogastric nerves in radical hysterectomy for cervical cancer is a key area of ongoing investigation [22].
Small bowel obstruction/ileus is a common reason for readmission after surgery. In a study by Fauci et al., this complication was the most frequently cited for readmission after cytoreductive surgery for epithelial ovarian cancer [23]. Diagnosis is made by clinical presentation and abdominal radiography. Initial treatment of obstruction is decompression of the bowel by a nasogastric tube and aggressive fluid resuscitation. The patient is monitored closely for signs of strangulation and sepsis due to perforation. If these are present or conservative management fails, the patient undergoes a laparotomy [102]. Brief treatment and prevention methods for other intestinal complications are detailed in Table 4.
Intestinal complications, prevention and treatment.
Infection
Perioperative infection may occur in the urinary tract, wound site or bloodstream, and has been shown to decrease response to chemotherapy, leading to a shorter progression-free survival in ovarian cancer (median time: 8.4 vs 17.6 months in infected vs not infected in postoperative period, respectively; p = 0.001) [24]. Across all types of gynecologic cancer, urinary tract infections have been shown to complicate up to a third of surgeries [25]. This has a significant impact on quality of life. Wound infection is also commonly reported, although the use of perioperative antibiotics can significantly decrease this risk [26,27]. Rates generally range from <1 to approximately 4%, but can be as high as 30% in obese patients, those undergoing exenteration or those with vulvar squamous cell carcinoma [2,28,29]. In vulvar cancer, the triple incision technique is preferred over en bloc resection for avoidance of wound infection and breakdown [30]. Similarly, pelvic or abdominal abscess formation occurs in 0–2% of surgeries across gynecologic cancer types, but approaches 30% in complicated surgeries such as exenteration and vaginectomy [4,19,31]. Rates are slightly higher in robotic-assisted cases compared with other modalities [15,16,30,32]. Sepsis complicates approximately 1% of gynecologic oncology surgeries, but can lead to intensive care unit admissions and even death [32].
Infection prophylaxis consists of a single administration of first-generation cephalosporin within 1 h preceding skin incision [29]. If the surgery extends beyond 3 h, a second dose should be given. Patients should be maintained in normothermia throughout the surgery to minimize vasoconstriction, thereby maximizing tissue perfusion and oxidative killing of bacteria [33]. Postoperative infection becomes apparent through fever, an increasing white blood cell count or new patient complaints. A good physical examination and communication with the patient will usually reveal the source of the infection. The postoperative fever may merely be due to inflammation, but may portend something more serious. In the first 1–2 days following surgery, aspiration pneumonia is of greatest concern. On days 3–5, urinary tract infection, DVT/PE and wound infection become more likely. When the source is not readily apparent, imaging by MRI or computed tomography may reveal an abscess. Close monitoring of vital signs is essential for early recognition of sepsis. In all cases, blood, urine and wound cultures should be sent and utilized in tailoring antibiotics, beginning with broad-spectrum antibiotics while waiting for culture results, and then adjusting the medications accordingly. Infection requires immediate treatment and may delay adjunctive therapies. Efficacy of radiation therapy decreases with every day it is delayed and chemotherapy-associated neutropenia is dangerous in patients already fighting infection. Medication itself may cause fever and treatment of infection with antibiotics may lead to Clostridium difficile diarrhea. Treating complications is a delicate balancing act, in which the complication itself, gynecologic malignancy and patient must all be considered.
Lymphatic complications
Lymphadenectomy of the pelvic and para-aortic lymph nodes is a crucial part of staging for many gynecologic cancers. It is also a frequent cause of postoperative complications, including lymphocele, lymphedema and ascites. Lymphoceles are a reported complication in 1–50% of gynecologic surgeries. They generally appear 7–15 days post-operatively and most resolve spontaneously [34]. The highest rates are found after surgery for vulvar cancers owing to extensive resection of inguinofemoral lymph nodes. For this reason, the greatest interest in sentinel nodes (SLN) has occurred in vulvar cancers. Moore et al. found that SLN biopsy in squamous cell vulvar cancer reduced the lymphocele rate to 5.5% in one small study [35]. Larger studies, such as the GOG trial 173, showed that when SLNs identified by lymphoscintigraphy are limited to the ipsilateral side, groin dissection, lymph node dissection and sampling may be performed unilaterally. This new standard applies even when the primary tumor is <2 cm from the midline [36]. Patients with midline tumors should still undergo bilateral SLN removal for tumors <4 cm and dissection for tumors >4 cm; however, this finding may improve both lymphatic complication rates and overall surgical morbidity for approximately 16% of women with vulvar cancer 0–2 cm from the midline and unilateral SLNs.
Lymphedema of the lower extremities is a longer term problem and is also much more frequent in vulvar cancer. It can also occur after radical hysterectomy and lymphadenectomy in cervical cancer, thus generating some experimental interest in the use of SLNs in this context. Cosmetic implications of lymphedema are common, but can lead to pain, inhibition of daily activities and psychologic stress. Across cancer types, an increasing number of lymph nodes resected is associated with an increased risk of developing ascites and lymphedema [15,37]. In endometrial cancer, removal of circumflex iliac nodes and postoperative radiation therapy also increase this risk. Therefore, radiation therapy should be avoided when alternative strategies exist and these particular nodes have been removed [38]. A Cochrane review demonstrated that retroperitoneal drainage of lymphatic fluid led to lymphocyst formation and is, therefore, not recommended [39]. Neither vapor-heated fibrin nor drain placement improved these rates and drain placement was associated with an increase in inguinal wound breakdown in one study [40]. Nonetheless, short-term drain use is often performed to allow for the skin and subcutaneous tissue to heal without disruption from accumulation of underlying lymphatic fluid in groin dissections. Treatment of lymphedema focuses on symptom control with leg elevation, fitted support hose and physical therapy to increase collateral circulation. In refractory cases, referral to a lymphedema therapist with use of wraps and other more sophisticated therapies is prescribed. There does not seem to be a correlation between increased BMI and lymphedema, but both can predispose to cellulitis, as can increasing age and venous insufficiency, which is often associated with diabetes [17]. Standard therapy consists of antibiotics. Obesity may decrease penetration of those antibiotics into the affected tissue and prolong the treatment.
Intraoperative urologic injury
Intraoperative genitourinary complications are a fairly rare consequence of gynecologic surgery. One large study of 2616 patients undergoing surgery for uterine cancer found that approximately 1% of patients experienced bladder injury whereas another study found that approximately 1% of patients experienced ureteral damage [41,42]. A review of several studies across gynecologic cancer types found urinary system complications in 1.9% of robotic-assisted surgeries, 4.7% of laparoscopic surgeries and 3.3% of abdominal cases [43]. When extensive resection occurs near the bladder, it is standard practice to leave a Foley catheter in situ for 7–10 days postoperatively. One study with 30 patients in each arm compared radical hysterectomy by robotic-assisted laparoscopy with open surgery and found significantly more urinary retention in the robotic arm (eight vs one patient at 7 days and two vs no patients at 1 month, respectively; p = 0.0001) [44]. Resolution occurred in all patients by 90 days. Kidney injuries, such as acute tubular necrosis, acute renal failure and hydronephrosis, are infrequently reported.
The key to minimizing sequelae of intraoperative injury is recognition. When ureteral injury is suspected, indigo carmine 40 mg in 5 ml may be injected intravenously. It is a deep blue color that concentrates in the urine and passes within approximately 10 min. The operative field may be observed from above for spillage of blue dye. A cystoscope is then inserted through the urethra to observe blue jets from the openings of both ureters into the bladder. Recognition of injury prior to closure allows for immediate repair and decreases the need for reoperation. Table 5 outlines particular urologic injuries and their associated repairs. If injury is suspected postoperatively, an intravenous pyelogram may be performed to image the kidneys, ureters and bladder.
Intraoperative urologic Injuries.
Postoperative complications
Fistula formation is a rare but devastating complication of surgery. It occurs when tissue becomes ischemic or injured. Inflammation follows, and erosion and abnormal healing lead to inappropriate communication between organs. Vesico- and uretero-vaginal fistulas are most common and can be evaluated by the tampon test. A tampon is inserted into the vagina and then the bladder is back-filled with methylene blue dye. The patient walks around for a short period of time before the tampon is examined for blue color. Rectovaginal, enterocutaneous and other fistulas are rare, but have also been noted [30,45–47]. Most studies report <1–2% rate of fistula formation, but can be as high as 13.9%, as in one series of pelvic exenterations [28]. Multiple studies have demonstrated that the robotic-assisted approach is complicated by fistula formation approximately twice as often as laparoscopy [7,43,48,49].
Cardiopulmonary complications are often reported as general events. Specified complications, such as myocardial infarction or pneumothorax, following surgery are rare. Other rarely reported events also include mental status changes, retinitis and lateral common bile duct injury. Implementation of checklists, operating room counting protocols and radiopaque instrumentation has greatly reduced the incidence of corpus alienum, or retained foreign bodies [8]. Mortality is rare in the immediate postoperative period for routine surgery, but does occasionally occur. Cited reasons are DVT, sepsis or pre-existing cardiac condition [30,34,50]. Moore et al. found a 12.9% mortality rate among octogenarians undergoing cytoreductive surgery for ovarian cancer [51]. They also found high rates of other rare complications, and propose that for the elderly population there may be an alternative treatment strategy.
Special populations
Obese patients comprise another cohort with higher rates of complications. Many studies find that obesity is associated with worse perioperative outcomes, including wound complications and PE [12,52]. Increased BMI leads to increased rates of conversion from minimally invasive surgery to laparotomy [53] and may decrease the number of lymph nodes dissected, leading to suboptimal staging procedures [7,18]. One study examined patients with a mean BMI of 40 and found a 15.6% conversion rate [17]. Complication rates for obese patients were comparable between robotic-assisted and laparoscopic surgeries, although either has better rates compared with open procedures [17,54]. This implies that any minimally invasive approach has reduced complication rates compared with open surgery and should be pursued in obese patients whenever feasible. However, conversion rates are high and staging may be suboptimal, implying that there are still advantages to the abdominal approach in many patients. There is variation among minimally invasive modalities too. For example, vaginal cuff complications, such as dehiscence after surgery for endometrial cancer, occur in <1% of patients undergoing traditional laparoscopy, but that number doubles or more when using the robotic-assisted approach [2,24,47,48]. Clearly, both short- and long-term outcomes for special populations need to be stratified by this approach.
Conclusion & future perspective
Complication rates during and after surgery for gynecologic malignancy are greatly affected by surgical modality and patient characteristics, such as cancer type and stage, age, BMI and comorbidities. Many examples in this review highlight such differences, but clear answers about modality remain elusive. Each patient presents a unique set of challenges. It is essential that as our population becomes increasingly older, more obese and more medically complicated, we continue to research how these variations affect them in the perioperative period. A deeper analysis of these complications will allow us to develop an individualized approach to surgical planning in gynecologic oncology. Perhaps rubrics may be developed to optimize an approach based on cancer type and stage, patient age, BMI, and comorbidities. However, we are a long way from this occuring. The choices regarding surgical modality, use and timing of radiation therapy and chemotherapy, such as neoadjuvant versus adjuvant, must be further characterized among these special populations. Once we develop answers based on age, BMI or comorbid status, we will have the ability to apply our experience as doctors to these data to make the best decision for the patient. As our knowledge base expands, we will potentially develop decision models to tailor surgery to each patient's unique health status, but this will never fully replace critical thinking. Only an individualized approach will reduce the risk of complications after surgery for gynecologic cancer and help us to ‘err’ less often while optimizing patient outcomes.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Executive summary
Transfusion rates after gynecologic oncologic surgery range from <1 to >30%, depending on surgical modality, radicality and BMI.
There is no increased risk of needing a transfusion when appropriate venous thromboembolism prophylaxis regimens are administered.
Surgical technique and intraoperative recognition of hemorrhage are key to minimization.
Patients are at increased risk owing to the hypercoagulable state created by malignancy, endothelial injury of surgery and venous stasis of postoperative bed rest.
Dual prophylaxis with sequential compression devices and subcutaneous heparin/low-molecular-weight heparin given pre- and post-operatively, at least until ambulation, significantly reduce the rates of venous thromboembolism.
Age over 60 years, increasing BMI and increasing length/complexity of surgery all increase the risk of deep vein thrombosis and pulmonary embolism.
Intestinal ileus, obstruction, anastomotic leak and fistula formation rates increase in patients who have undergone bowel resection, exenteration or radical cytoreduction of ovarian cancer. These complications also increase in incidence with the addition of adjuvant radiotherapy.
Preoperative mechanical bowel preparation does not decrease the complication rate and should not be undertaken.
Small bowel obstruction/ileus is a commonly cited reason for readmission and should be treated initially with nasogastric tube placement and reoperation, only when conservative management fails.
Perioperative infection may occur in the urinary tract, wound site or bloodstream, and decreases the response to chemotherapy.
Infection prophylaxis consists of a single administration of first-generation cephalosporin within 1 h preceding skin incision.
Lymphadenectomy of the pelvic and para-aortic lymph nodes is a frequent cause of lymphocele, lymphedema and ascites.
The highest rates are found after surgery for vulvar/vaginal cancers.
Sentinel lymph node biopsy identified by lymphoscintigraphy is a promising way to decrease complexity of some surgeries and their associated lymphatic complications.
Treatment consists of leg elevation, fitted support hose and exercise to increase collateral circulation.
Intraoperative genitourinary complications are fairly rare at approximately 1%.
When extensive resection occurs near the bladder, it is standard practice to leave a Foley catheter in situ for 7–10 days.
Use of indigo carmine and cystoscopy allow for recognition of injury prior to closure and immediate repair rather than reoperation.
Fistula formation is a rare but devastating complication of surgery.
Mortality is rare in the immediate postoperative period for routine surgery, but increases when older patients undergo more complex surgeries.
Increasing age, BMI and surgical complexity increase the risk of complications.
Surgical modality must be chosen based on particular patient characteristics.
Investigation of the appropriate surgical modality for patients who are obese, elderly and/or have medical comorbidities will give specific information necessary for surgical planning.
Timing of radiation and use of adjuvant and neoadjuvant chemotherapy in patient populations at higher risk of complications should be similarly characterized.
Development of validated guidelines and surgical care pathways are required to optimize patient safety and quality outcomes.