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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© 2006 The American College of Obstetricians and Gynecologists
15. Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK. Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation and erythropoietin. Cancer 2003;98:1514–20.