Obstetrics & Gynecology:
Pulmonary Embolism After Major Abdominal Surgery in Gynecologic Oncology
Martino, Martin A. MD1; Borges, Elana MD2; Williamson, Eva2; Siegfried, Sylvia MD2; Cantor, Alan B. PhD3; Lancaster, Johnathan MD, PhD3; Roberts, William S. MD3; Hoffman, Mitchel S. MD2
From the 1Department of Obstetrics and Gynecology, The Cancer Center at Lehigh Valley Hospital, Allentown, Pennsylvania; 2Department of Obstetrics and Gynecology, University of South Florida College of Medicine, Tampa, Florida; and 3H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida.
Corresponding author: Martin A. Martino, MD, Gynecologic Oncology Specialists, the Cancer Center at Lehigh Valley Hospital, Department of Obstetrics and Gynecology, 400 N. 17th Street, Suite 201, Allentown, PA 18104; e-mail: Medmartino@aol.com.
OBJECTIVE: To estimate the incidence and prognostic significance of postoperative pulmonary embolism after gynecologic oncology surgery.
METHODS: All patients who underwent gynecologic oncology surgery from June 2001 to June 2003 and received venous thromboembolism prophylaxis with only intermittent pneumatic compression and early ambulation were identified from our database. Patients were grouped by procedure (major/minor abdominal or nonabdominal surgery), diagnosis (malignant/nonmalignant), and cancer subtype. Groups were compared by χ2 analysis and logistic regression. Survival was studied with the Kaplan-Meier method and Mantel-Byar test.
RESULTS: A total of 1,373 surgical patients were identified over the 2-year period, including 839 major abdominal surgery cases and 534 minor abdominal surgery or nonabdominal surgery cases. Of the 839 patients, 507 had a diagnosis of cancer, and 332 were benign. The incidence of pulmonary embolism among cancer patients undergoing major abdominal surgery was 4.1% (21/507) compared with 0.3% (1/332) among patients undergoing major abdominal surgery with benign findings (P < .001, odds ratio [OR] 13.8, 95% confidence interval [CI] 1.9–102.1). The incidence of pulmonary embolism among patients undergoing minor/nonabdominal surgery was 0.4% (2/536). Cancer diagnosis and age more than 60 years were identified as risk factors for pulmonary embolism (P = .009, OR 0.31, 95% CI 0.13–0.74). One-year survival for patients with and those without pulmonary embolism were 48.0% ± 12% and 77.0% ± 2%, respectively.
CONCLUSION: Patients with cancer undergoing major abdominal surgery and using pneumatic compression for thromboembolic prophylaxis had a 14-fold greater odds of developing a pulmonary embolism compared with patients with benign disease. Randomized studies are needed to determine whether additional prophylactic measures may benefit this high-risk group of patients.
LEVEL OF EVIDENCE: II-3
Venous thromboembolism is a major complication after abdominal surgery for cancer. Although the clinical presentation of pulmonary embolism has been associated with tachycardia and leukocytosis, pulmonary embolism has a very nonspecific presentation and may be fatal in up to 25% of patients.1,2 In oncology, as in any specialty, the morbidity and mortality from pulmonary embolism are significant. In this article, we provide the epidemiology and outcomes analysis that would be helpful in designing randomized clinical trials and provide physicians the ability to have an impact on this fatal condition.
With these goals in mind, we designed a retrospective cohort study to identify the incidence of pulmonary embolism among patients undergoing abdominal surgery at our National Cancer Institute Comprehensive Cancer Center during our study period from 2001 to 2003. We identified high-risk subgroups that might benefit from additional measures to reduce surgical morbidity. In addition, we wanted to determine whether there was any relation between postoperative pulmonary embolism and overall survival in cancer patients.
MATERIALS AND METHODS
The H. Lee Moffitt Cancer Center database was reviewed to identify patients who had surgery performed by the gynecologic oncology service from June 2001 to June 2003. Age, final pathologic diagnosis, surgical procedure(s), venous thromboembolism prophylactic method, and any spiral computed tomography (CT) pulmonary angiography or ventilation perfusion scan results were recorded. Other demographic data and medical history were not collected. Cases of sudden death, possibly attributable to pulmonary embolism, were excluded from our study because these cases could not be diagnosed or confirmed. Additionally, patients diagnosed with pulmonary embolism at outside clinics or hospitals were excluded.
Patients were grouped by procedure, with procedures classified as major or minor and abdominal or nonabdominal, as well as by diagnosis (malignant versus nonmalignant disease) and cancer subtype (Fig. 1). Major surgery included all intra-abdominal procedures (eg, laparotomy, laparoscopy, and radical hysterectomy), all breast surgery, radical vulvectomy, groin node dissection, major vaginal surgery, and vaginal hysterectomy. Minor surgeries included placement of radiation sources for brachytherapy, port placement, wound debridement, upper vaginectomy, wide local excisions of the vulva, cold knife cone, dilation and curettage, and examination under anesthesia (see box, “Criteria Selection for Major and Minor Surgery”).
The diagnosis of pulmonary embolism required a diagnostic confirmation by either spiral CT, pulmonary angiography, or ventilation-perfusion scan as interpreted by an attending radiologist. The decision to treat, based on a low, intermediate, or high probability ventilation perfusion scan, was made by the physician examining the patient clinically at the time of the event. The postoperative period extended from the date of surgery through postoperative day 49. Seven weeks (postoperative days 0–49) was chosen as the study period because most patients will have started chemotherapy by the end of 7 weeks and have returned for their final postoperative visit by this time. All patients received prophylaxis with intermittent pneumatic compression and early ambulation, beginning preoperatively and extending through discharge. Intermittent pneumatic compression, also referred to as sequential compression device with early ambulation, was the prophylactic method of choice by the attending physicians. Patients did not receive additional forms of prophylaxis. Patient data were compared by using χ2 contingency tables. High-risk groups were identified by univariate logistic regressions that modeled the probability of pulmonary embolism as a logistic function of other variables. Survival curves were estimated according to the Kaplan-Meier method, with standard errors computed by Greenwood's formula. The Mantel-Byar test was used analyze the effect of pulmonary embolism on survival.3 In this analysis, group membership can change over time because patients are moved from the nonpulmonary embolism group to the pulmonary embolism group when (and if) pulmonary embolism occurs. The analysis is similar to that of the log-rank test, except that the number at risk in the prepulmonary embolism group is decreased and the number at risk in the pulmonary embolism group is increased when a patient experiences pulmonary embolism. This study was approved by the Institutional Review Board at the University of South Florida.
We identified 1,373 patients who had surgery performed by the gynecologic oncology service between June 2001 and June 2003 (Table 1). There were 1,054 major surgical cases and 319 minor surgical cases. Of the 1,054 major cases, we identified 839 cases that involved abdominal surgery with entry into the peritoneum. Within this cohort, 22 of 839 (2.6%) patients developed a pulmonary embolism in the postoperative period. Of the 839 patients with abdominal surgery, 507 were cancer cases and 332 were noncancer cases. Among cancer patients who underwent major abdominal surgery, 4.1% (21/507) developed a pulmonary embolism postoperatively, compared with 0.3% (1/332) of noncancer patients (P < .001, odds ratio [OR] 13.8, 95% confidence interval [CI] 1.9–102.1). Among patients who underwent minor or nonabdominal surgery, 0.4% (2/536) were diagnosed with a postoperative pulmonary embolism. Patients with a diagnosis of ovarian cancer represented the highest risk subgroup (6.8%), followed by those with uterine cancer, cervical cancer, and an “other” category. Age more than 60 years was identified on logistic regression to be a risk factor for pulmonary embolism (OR 0.31, 95% CI 0.13–0.74, P = .009). The mean day postoperatively on which a pulmonary embolism was diagnosed was day 11 (95% CI 5.3–15.7). Seventy percent of patients were diagnosed by postoperative day 9 with a pulmonary embolism. One-year survival rates for patients with and those without pulmonary embolism were 48.0% ± 12% and 77.0% ± 2%, respectively (Fig. 2). Two-year survival rates for patients with and those without pulmonary embolism were 36.0% ± 11% and 61.0% ± 3%, respectively. Although a higher rate of death attributable to pulmonary embolism was suggested by the Mantel-Byar test, these results were not statistically significant (P = .18).
Gynecologic oncology patients have recently been identified to have the highest risk of venous thromboembolism among patients in the United States with any recordable malignancy.4 Specifically, a review of the Medicare database noted that patients with ovarian cancer had a venous thromboembolism incidence of 120/10,000 person-years, which is greater than breast cancer (22/10,000) and lung cancer (61/10,000) combined. In our analysis, we report our experience with 1,373 patients who had surgery for known or suspected malignancy. We have identified a subset of patients at increased risk of developing a pulmonary embolism. These are patients who had abdominal surgery and were diagnosed with cancer. At first look, it appeared that our overall incidence of postoperative pulmonary embolism was 1.7% (24/1,373). However, upon further analysis, we noticed that, in patients with a diagnosis of cancer who underwent major abdominal surgery, there actually was a 14-fold greater odds of developing a postoperative pulmonary embolism compared with patients with benign disease (P < .001, OR 13.8, 95% CI 1.9–102.1). Further, we identified a 6.8% incidence of pulmonary embolism in patients with ovarian cancer, which is consistent with data from the Medicare database described above, which suggest that these specific patients are at the highest risk of developing a pulmonary embolism. These results are summarized in Table 2 and may be helpful in calculating power and sample size for future randomized trials.
Within our group of 319 patients who had minor surgery, there was one patient with recurrent ovarian cancer who had placement of a venous access device for administration of chemotherapy and developed a pulmonary embolism after this procedure, which was diagnosed by computed tomography pulmonary angiography. Although the etiology is unclear, we attribute this to the high risk associated with ovarian cancer and the biology of her disease. There was one patient with vulvar cancer who had a radical vulvectomy with bilateral groin nodes dissected and who developed a postoperative pulmonary embolism, most likely attributable to her sedentary postoperative course.
The use of intermittent pneumatic compression and early ambulation for venous thromboembolism prophylaxis appears to be an effective method for preventing the development of pulmonary embolism in patients with nonmalignant disease. This is a reasonable conclusion given our postoperative incidence of 0.3%, but our study was not established to determine prophylactic efficacy. Our study was designed to determine the baseline incidence of pulmonary embolism in patients with intermittent pneumatic compression and early ambulation who have had major abdominal surgery and a gynecologic malignancy. It is reasonable to conclude that, given a postoperative incidence of 4.1% in patients who have major abdominal surgery and a diagnosis of cancer, intermittent pneumatic compression and early ambulation may not be the most effective tool for preventing patients from developing a pulmonary embolism. In view of the findings of this study, we altered our practice pattern by adding low-molecular-weight heparin to intermittent pneumatic compression in the postoperative period.
To date, there have been a limited number of prospective randomized studies comparing intermittent pneumatic compression and anticoagulants in gynecologic oncology. Furthermore, many of the studies comparing different prophylactic modalities vary in dosing amount, frequency, onset, and duration, making comparisons difficult. In 1983, Clarke-Pearson et al5 evaluated low-dose heparin in a randomized study and determined that it was of no additional benefit in preventing venous thromboembolism in gynecologic oncology patients when compared with controls. The following year, this same group evaluated pneumatic compression with control and reported that, when used both perioperatively and postoperatively for 5 days, pneumatic compression significantly reduced the incidence of postoperative venous thromboembolism.6 In 1993, pneumatic compression was compared directly with low-dose heparin, and both had similar incidences of postoperative venous thromboembolism, but low-dose heparin was associated with an increased incidence of postoperative bleeding complications.7
In 2001, low-molecular-weight heparin (dalteparin) and intermittent pneumatic compression were studied in a randomized trial to compare the rate of postoperative venous thromboembolism and bleeding complications. With regard to bleeding complications, low-molecular-weight heparin was similar to intermittent pneumatic compression and not associated with a higher rate of postoperative bleeding when compared with intermittent pneumatic compression.8 With regard to efficacy, there were no differences in venous thromboembolism between low-molecular-weight heparin and intermittent pneumatic compression, and either method was considered a reasonable option for preventing venous thromboembolism. After this study, Clarke-Pearson et al9 identified age more than 60 years, diagnosis of cancer, and previous deep vein thrombosis (DVT) as factors associated with failure of intermittent pneumatic compression prophylaxis. In their study, patients with 2 of the 3 risk factors (age > 60, cancer, history of DVT) had a 16-fold increased risk of developing postoperative thromboembolism. Our data are consistent with these findings and suggest that women over the age of 60 years undergoing surgery for gynecologic cancer and women with a diagnosis of cancer may benefit from additional thromboprophylactic measures. With our findings of a postoperative pulmonary embolism incidence of 6.8% in patients with ovarian cancer who have major abdominal surgery, new modalities have to be identified to lower this significant source of morbidity and mortality.
In 2004, the American College of Chest Physicians issued guidelines recommending that low-molecular-weight heparin, low-dose unfractionated heparin, intermittent pneumatic compression alone, or a combination of low-molecular-weight heparin/low-dose unfractionated heparin with intermittent pneumatic compression should be given to patients who are having oncologic surgery to lower their risk of developing venous thromboembolism.10 However, a review of the published literature shows variable effectiveness of anticoagulants in conjunction with intermittent pneumatic compression.11 For example, in a study evaluating intermittent pneumatic compression and unfractionated heparin with 168 patients in a gynecologic oncology service, no benefit was identified.12 Furthermore, the dosing for preoperative and/or postoperative low-molecular-weight heparin in combination with intermittent pneumatic compression is yet to be determined. Until further randomized clinical trials of gynecologic oncology patients are performed, questions regarding single or dual prophylaxis and the optimal agents and dosing schedules will remain unanswered. One fact appears consistent with our data and is confirmed by the Medicare literature: There exists an exceedingly high rate of pulmonary emboli in gynecologic oncology patients.
The question of whether to administer low-molecular-weight heparin preoperatively and postoperatively or just postoperatively is still unanswered. Giving a patient an anticoagulant preoperatively raises concerns about increased blood loss and risk of transfusion. Additionally, the number of days to allow for postoperative prophylaxis remains unclear. Although the majority of our patients were discharged home by postoperative day 3, our mean day for diagnosis of pulmonary embolism was postoperative day 10 (range 0–49). European studies suggest a benefit exists with extended low-molecular-weight heparin dosing, but extending injections for 25 additional days after discharge presents a challenging regimen for patients, social workers, pharmacies, nurses, and physicians to administer.13 Prophylactic dosing and scheduling in the in-patient setting and accessibility in the out-patient setting are important questions in gynecologic oncology that remain to be answered.
The authors recognize several weaknesses in this study. Potential confounders, including well-established venous thromboembolism risk factors, other than malignancy, patient age, and surgery, were not collected from the patient database. Additionally, cases of sudden death and pulmonary embolism diagnoses made at outside institutions were excluded. Although there were no deaths specifically attributable to radiologically confirmed pulmonary embolism during this study period, there were reports of sudden death during the postoperative period. These were not included in the total number of pulmonary embolism cases because no autopsies were performed. Patients diagnosed at outside clinics or institutions were also excluded because of inadequate follow-up. These exclusions most likely underestimate the incidence of pulmonary embolism in our population and overestimate the Kaplan-Meier survival curves for pulmonary embolism patients.
Over the next several years, we will be presented with further challenges to prevent thrombosis. For example, antiangiogenic therapy has been associated with an increased risk to colon cancer patients receiving chemotherapy for metastatic disease.14 Also, patients who are receiving erythropoietin during chemoradiation have been described as being at an increased risk of developing venous thromboembolism.15 Obstetricians and gynecologists will be in a position to reduce patient morbidity and mortality as they treat high-risk groups and perform surgery on an increasingly challenging and aging population. Efforts must be made to perform well-designed randomized, blinded, possibly placebo-controlled clinical trials to determine which prophylactic methods are effective treatment strategies for lowering this high incidence of pulmonary embolism and to find answers to some of these unresolved questions.
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5. Clarke-Pearson DL, Coleman RE, Synan IS, Hinshaw W, Creasman WT. Venous thromboembolism prophylaxis in gynecologic oncology: a prospective, controlled trial of low-dose heparin. Am J Obstet Gynecol 1983;145:606–13.
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