Obstetrics & Gynecology:
Incidence of Venous Thromboembolism After Minimally Invasive Surgery in Patients With Newly Diagnosed Endometrial Cancer
Sandadi, Samith MD; Lee, Stephen MD; Walter, Adam MD; Gardner, Ginger J. MD; Abu-Rustum, Nadeem R. MD; Sonoda, Yukio MD; Brown, Carol L. MD; Jewell, Elizabeth MD; Parameswaran, Rekha MD; Barakat, Richard R. MD; Leitao, Mario M. Jr MD
Department of Surgery, Gynecology Service, and the Department of Medicine, Hematology Service, Memorial Sloan-Kettering Cancer Center, and the Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, New York.
Corresponding author: Mario M. Leitao Jr, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the incidence of postoperative venous thromboembolism among patients undergoing minimally invasive surgery for endometrial cancer, and to characterize risk factors associated with the development of venous thromboembolism.
METHODS: Patients with newly diagnosed endometrial cancer who were scheduled to undergo a planned minimally invasive surgery procedure from May 1, 2007 to December 31, 2010 were identified. The incidence of symptomatic postoperative venous thromboembolism was estimated in the patients who did not require conversion to laparotomy. Various clinicopathologic variables were tested for an association with the development of a postoperative venous thromboembolism using standard statistical tests.
RESULTS: A total of 573 cases were identified. Postoperative low molecular weight heparin was administered to 125 (22%) patients during their immediate postoperative hospital stay. All patients had sequential compression devices placed intraoperatively. Seven (1.2%) patients had development of a symptomatic venous thromboembolism. The factors associated with development of a postoperative venous thromboembolism were: body mass index (BMI) (P=.005); estimated blood loss (P=.03); and operative time (P=.01). A high-risk group was determined to be patients with BMIs of 40 or higher and an operative time of 180 minutes or more. In this group, the incidence of venous thromboembolism was 9.5% (4 of 42) compared with 0.6% (3 of 531) in all others (P=.001).
CONCLUSION: The incidence of venous thromboembolism in patients with newly diagnosed endometrial cancer undergoing minimally invasive surgery is very low. There appears to be no clear justification for the routine use of a heparin for perioperative thromboprophylaxis in the majority of these patients. Thromboprophylaxis with heparin, however, may be a consideration in morbidly obese patients (BMI of 40 or higher) after a procedure that lasts 3 hours or more.
LEVEL OF EVIDENCE: II
Endometrial cancer is the most common gynecologic malignancy worldwide, with 287,100 estimated new cases in 2011 and more than 73,000 estimated deaths.1 In the United States alone, endometrial cancer accounts for 53% of all gynecologic cancers, with a projected 8,010 deaths in 2012.2,3 Traditionally, comprehensive surgical staging has been performed using laparotomy and included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic lymphadenectomy. However, minimally invasive surgery for endometrial cancer has become more common.4 Laparoscopic surgical staging has been shown to be both feasible and safe, with fewer complications compared with laparotomy.5
Venous thromboembolic complications, pulmonary embolism (PE) and deep venous thromboembolism, are major complications after gynecologic surgery. Historically, with the use of fibrinogen phlebography, the incidence of perioperative venous thromboembolism has been reported as approximately 14%6 in benign gynecologic surgery, compared with 38% in gynecologic oncology patients.7 However, venous thromboembolism diagnosed by fibrinogen phlebography is not always related to a clinical event and may not have a true clinical relevance. In patients undergoing surgery for uterine carcinoma with features including advanced stage of disease, weight more than 85.5 kg, and radiation therapy within 6 weeks of the operative procedure, PE is a leading cause of postoperative death.8
Low molecular weight (LMW) heparin has been shown to be as safe and effective as unfractionated heparin in the prevention of venous thromboembolism in patients undergoing major elective surgery for abdominal and pelvic malignancy.9 Results from the Enoxaparin and Cancer (ENOXACAN) II study demonstrated extended prophylaxis with LMW heparin for 4 weeks after abdominal or pelvic cancer surgery significantly reduces the incidence of venous thromboembolism when compared with prophylaxis for 1 week.10 However, only 28 (8.4%) patients had a gynecologic malignancy, thereby potentially limiting the applicability to the gynecologic oncology population. Several studies have investigated the use of either single or dual prophylaxis consisting of external pneumatic compression and an anticoagulant.11–13 No prospective randomized trials have been performed in patients with gynecologic cancers to evaluate single compared with double prophylaxis. Additionally, no consensus has been reached regarding which method is optimal in patients undergoing minimally invasive surgery, and there are limited data regarding the incidence of venous thromboembolism in women undergoing minimally invasive surgery for gynecologic malignancies. The purpose of this study was to estimate the incidence of postoperative venous thromboembolism among patients undergoing minimally invasive surgery for endometrial cancer, and to characterize risk factors associated with the development of venous thromboembolism.
MATERIALS AND METHODS
After approval from the Memorial Sloan Kettering Cancer Center Institutional Review Board was obtained, we identified all patients with newly diagnosed endometrial cancer who were scheduled to undergo a planned minimally invasive surgery procedure from May 1, 2007 to December 31, 2010 at our institution. Medical records, including operative reports, pathology reports, chemotherapy records, pharmacy reports, laboratory results, and radiology reports, were reviewed. Stage at diagnosis was designated based on the 1988 International Federation of Gynecology and Obstetrics staging for endometrial carcinoma.14 High-risk histology was defined as any of the following: serous; clear cell; carcinosarcoma; undifferentiated; and mixed with any of these other high-risk histologies.
The incidence of symptomatic postoperative venous thromboembolism within 90 days of surgery was estimated in the patients who did not require conversion to laparotomy. All venous thromboembolism events were diagnosed using imaging triggered by patient symptoms. Various clinicopathologic variables were tested for an association with the development of a postoperative venous thromboembolism. Dichotomous variables were analyzed using χ2 or Fisher exact tests as appropriate. Median values were compared using the Mann-Whitney U test. A high-risk group was identified based on the results of univariable analysis. Because of the low number of postoperative venous thromboembolisms, multivariable regression analysis was not performed. All statistical analyses were performed using IBM SPSS Statistics 19.0.
We identified 573 patients who underwent minimally invasive surgery for newly diagnosed endometrial cancer and did not require conversion to laparotomy. Clinicopathologic characteristics for this cohort of patients are listed in Table 1. The median age was 61 years (range 27–88), and the median body mass index (BMI, calculated as weight (kg)/[height (m)]2) was 28.2 (range 16.9–66). The majority of patients had stage I disease (n=441, 77%) and low-risk histologies (n=475, 82.9%), mostly endometrioid (n=458, 79.9%) histology. Three hundred ten (54%) cases were completed robotically, and 263 (46%) were completed with standard laparoscopy. Median estimated blood loss was 75 mL (range 0–900) and median operative time was 200 minutes (range 80–533). Postoperative thromboprophylaxis with LMW heparin was administered to 125 (22%) patients during their immediate postoperative stay. Extended prophylaxis beyond the hospital stay was not used in any of these cases. All patients had sequential compression devices placed intraoperatively. All patients were followed-up for a minimum of 90 days (our primary end point) and none was lost to follow-up. Postoperatively, seven (1.2%) patients had development of a symptomatic venous thromboembolism: two had a deep venous thromboembolism only, and five had PE without an identified deep venous thromboembolism diagnosed (Table 2). All patients had symptoms prompting diagnostic imaging with compression ultrasonography of the affected extremity or computed angiography of the chest. Therapeutic doses of LMW heparin were used in the treatment of all seven patients. There were no associated mortalities from postoperative venous thromboembolism.
Univariable analysis for prognostic factors for the development of postoperative venous thromboembolism between patients who had development of a postoperative venous thromboembolism compared with those who did not is shown in Table 3. The factors associated with a postoperative venous thromboembolism were: BMI (P=.005); estimated blood loss (P=.03); operative room time (P=.003); and operative time (P=.01). Additionally, median length of postoperative stay also was associated with venous thromboembolism development (P=.005). Venous thromboembolism was diagnosed in five patients after initial discharge (patients were postoperatively discharged on day 1 in one case, day 2 in three cases, and day 4 in one case). Venous thromboembolism was diagnosed in the other two cases on days 1 and 2 and resulted in a length of stay of 15 days and 7 days, respectively. The cause-and-effect relation of length of stay and postoperative venous thromboembolism could not be assessed further in such a small number of events, but the increased length of stay could possibly be attributable to the management of the venous thromboembolism event. The use of postoperative anticoagulation, stage, tumor grade, and tumor histology were not associated with venous thromboembolism development. Only one patient who had development of a symptomatic venous thromboembolism had a history of venous thromboembolism and none had a documented history of smoking (Table 2). Therefore, the effect of these patient characteristics on the development of postoperative venous thromboembolism was not analyzable beyond mere description. Of note, there were no venous thromboembolisms noted in the 76 cases that were planned for an minimally invasive surgery approach and then converted to laparotomy.
Obesity and operative time were the two most important prognostic factors identified in our univariable analysis (Table 4). Morbidly obese patients with a BMI of 40 or more had an incidence of venous thromboembolism of 5.8% (4 of 69) compared with 0.6% (3 of 504) in patients with BMI less than 40 (P=.005). The relative risk of venous thromboembolism in these morbidly obese patients is 9.7 (95% confidence interval 2.2–42.6; P=.003). The lowest operative time in patients with venous thromboembolism was 180 minutes. A high-risk group was determined to be patients with a BMI of 40 or more and an operative time of 180 minutes or more. In this group, the incidence of venous thromboembolism was 9.5% (4 of 42) compared with 0.6% (3 of 531) in all others (P=.001). The relative risk of venous thromboembolism in this high-risk group is 17.2 (95% confidence interval 3.97–74.2; P<.005). Postoperative LMW heparin was used in 19 of 42 (45%) of the high-risk cases compared with 106 of 530 (20%) in the other cases (Table 3). One (5.3%) of the 19 patients who received postoperative LMW heparin experienced a venous thromboembolism compared with 3 (13%) of the 23 patients who did not receive postoperative LMW heparin (P=.613).
Overall, 4% to 20% of patients with cancer have venous thromboembolism diagnosed, and this is believed to be an underestimation.15,16 Several studies have reported a higher risk of venous thromboembolism in patients with gynecologic cancer, with the rate of deep venous thromboembolism ranging from 11% to 18%17,18 and the rate of PE ranging between 1% and 2%.19 Patients with cancer undergoing surgery have a twofold higher risk of postoperative deep venous thromboembolism and a threefold greater risk of a fatal PE compared with patients without cancer undergoing similar surgery.20
In a recent systematic review, Rahn et al21 described the incidence of venous thromboembolism in gynecologic surgery. The incidence of venous thromboembolism (including “silent” venous thromboembolism based on fibrinogen uptake test) ranged from 0% to 14.8% with prophylaxis and up to 34.6% without prophylaxis.21 In cancer surgical patients, several factors contribute to the increased thrombotic risk, including advanced age, prolonged duration of anesthesia, prolonged postoperative immobilization, and history of venous thromboembolism.22,23 Additionally, gynecologic oncology patients are at an increased risk for thrombotic events secondary to prolonged surgeries involving extensive retroperitoneal and pelvic dissection.21 The incidence of venous thromboembolism between minimally invasive compared with laparotomy groups was not analyzed.
Recommendations regarding the use of thromboprophylaxis after laparoscopic procedures are limited and controversial. Longer operative times, unique patient positioning, and increased intra-abdominal pressures may alter vascular hemodynamics, resulting in venous stasis in the lower extremities. Conversely, factors such as less surgical trauma, infrequent use of retractors, Trendelenburg positioning, and shorter hospital stays may reduce the risk of venous thromboembolism.24–26 In a retrospective review of 849 patients who underwent laparoscopic gynecologic surgery, Nick et al25 reported a symptomatic venous thromboembolism rate of 0.7% (6 of 849 patients). In the subgroup of patients with a history of gynecologic malignancy, 1.2% (5 of 430) had development of postoperative thromboembolic events.25 Malignancy was not found to be a significant factor in the increase of venous thromboembolism; however, surgical complexity was associated with increased risk of venous thromboembolism. The authors concluded that postoperative anticoagulation may be beneficial in patients undergoing high-complexity, minimally invasive procedures.25 Similar to the 0.87% incidence of PE in our cohort of patients, the percentage of patients with PE in the LAP2 study was 1% in both the laparotomy and laparoscopy groups.5 Ritch et al retrospectively reviewed 60,013 cases, both benign and oncologic, that underwent laparoscopic hysterectomy. The rate of symptomatic venous thromboembolism was 1.0%. Although the risk of venous thromboembolism was higher in the cancer cases (2.3%) compared with benign cases (0.9%), this was not reported to be statistically significant on multivariable analysis.27
Similar to previous retrospective reviews, we found the incidence of venous thromboembolism was 1.2% in our cohort of patients. All patients had sequential compression devices placed intraoperatively, and the majority (78%) did not receive postoperative thromboprophylaxis. Body mass index, estimated blood loss, operative time, and length of postoperative stay were found to be significant factors in the development of venous thromboembolism. Specifically, risk group stratification revealed that morbidly obese patients with operative times more than 3 hours were at an increased risk of development of venous thromboembolism. Blood product transfusions were associated with an increased risk of venous thromboembolism in women who underwent surgery for ovarian, tubal, or peritoneal surgery.28 Although packed red blood cell transfusion was found to be statistically significant in our study, only three patients received a packed red blood cell transfusion, thereby making it difficult to formulate any definitive conclusions. Other factors such as the use of postoperative anticoagulation, stage, tumor grade, and tumor histology were not associated with venous thromboembolism development. Previous studies have reported surgical complexity as a risk factor in the development of venous thromboembolism; however, when we compared procedures including pelvic and periaortic lymph node dissection compared with those without, no statistical significance was noted in the rate of venous thromboembolism.
Our study is limited by the inherent biases of retrospective data analyses. The patients in our cohort are from a single institution and therefore possibly limit the ability to generalize our findings. A common criticism of retrospective studies is the heterogeneity of the study population. This is a valid criticism that we acknowledge. However, our cohort all had endometrial cancer diagnosed, and the majority of cases were of low grade, low stage, and endometrioid histology. A potential criticism of our study is that we report the incidence of symptomatic postoperative venous thromboembolism during 90 days of surgery. This follow-up period is significantly longer than that reported by previous studies, including the @RISTOS project, which limited the assessment of venous thromboembolism to 31 days after surgery.22 It is our clinical impression that patients do not have development of venous thromboembolism at later time points unless they receive further cancer therapies or have development of recurrent disease, which is exceedingly uncommon in this cohort of patients.
In this study, we evaluated the incidence of postoperative venous thromboembolism among patients undergoing minimally invasive surgery for newly diagnosed endometrial cancer. Although our study was not designed to determine the most efficacious method of thromboprophylaxis, based on the low incidence of venous thromboembolism (1.2%) there seems to be no clear justification for the routine use of unfractionated heparin or LMW heparin for perioperative thromboprophylaxis in the majority of these patients. Mechanical thromboprophylaxis with sequential compression devices appears to be sufficient based on this retrospective review in the prevention of the majority of venous thromboembolism. One of the key findings of our analysis is the identification of a high-risk group of patients who are morbidly obese and undergo prolonged procedures lasting 3 hours or more. Thromboprophylaxis with unfractionated or LMW heparin, possibly preoperatively and postoperatively, may be a consideration in this select group but would require further prospective analysis. We did note a nearly 2.5-fold increased rate of venous thromboembolism in this group without the use of LMW heparin postoperatively, although not statistically significant, further highlighting the need for further investigation. Data are limited to recommend extended prophylaxis at this point without further study. Further trials are recommended to evaluate the timing of the dose, the duration, and the efficacy in patients undergoing minimally invasive surgery for endometrial cancer.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29.
3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–36.
4. Frumovitz M, Escobar P, Ramirez PT. Minimally invasive surgical approaches for patients with endometrial cancer. Clin Obstet Gynecol 2011;54:226–34.
5. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al.. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;27:5331–6.
6. Walsh JJ, Bonnar J, Wright FW. A study of pulmonary embolism and deep leg vein thrombosis after major gynaecological surgery using labelled fibrinogen-phlebography and lung scanning. J Obstet Gynaecol 1974;81:311–6.
7. Crandon AJ, Koutts J. Incidence of post-operative deep vein thrombosis in gynaecological oncology. Aust NZ J Obstet Gynaecol 1983;23:216–9.
8. Clarke-Pearson DL, Jelovsek FR, Creasman WT. Thromboembolism complicating surgery for cervical and uterine malignancy: incidence, risk factors, and prophylaxis. Obstet Gynecol 1983;61:87–94.
9. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group. Br J Surg 1997;84:1099–103.
10. Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A, et al.. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346:975–80.
11. Clarke-Pearson DL, Dodge RK, Synan I, McClelland RC, Maxwell GL. Venous thromboembolism prophylaxis: patients at high risk to fail intermittent pneumatic compression. Obstet Gynecol 2003;101:157–63.
12. Martino MA, Williamson E, Rajaram L, Lancaster JM, Hoffman MS, Maxwell GL, et al.. Defining practice patterns in gynecologic oncology to prevent pulmonary embolism and deep venous thrombosis. Gynecol Oncol 2007;106:439–45.
13. Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstet Gynecol 2001;98:989–95.
14. Benedet JL, Bender H, Jones H III, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000;70:209–62.
15. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, et al.. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490–505.
16. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632–4.
17. 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.
18. Clark-Pearson DL, DeLong E, Synan IS, Soper JT, Creasman WT, Coleman RE. A controlled trial of two low-dose heparin regimens for the prevention of postoperative deep vein thrombosis. Obstet Gynecol 1990;75:684–9.
19. Einstein MH, Pritts EA, Hartenbach EM. Venous thromboembolism prevention in gynecologic cancer surgery: a systematic review. Gynecol Oncol 2007;105:813–9.
20. Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost 1997;78:126–32.
21. Rahn DD, Mamik MM, Sanses TV, Matteson KA, Aschkenazi SO, Washington BB, et al.. Venous Thromboembolism Prophylaxis in Gynecologic Surgery: A Systematic Review. Obstet Gynecol 2011;118:1111–25.
22. Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al.. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006;243:89–95.
23. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338–400S.
24. Feng L, Song J, Wong F, Xia E. Incidence of deep venous thrombosis after gynaecological laparoscopy. Chin Med J 2001;114:632–5.
25. Nick AM, Schmeler KM, Frumovitz MM, Soliman PT, Spannuth WA, Burzawa JK, et al.. Risk of thromboembolic disease in patients undergoing laparoscopic gynecologic surgery. Obstet Gynecol 2010;116:956–61.
26. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al.. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:381–453S.
27. Ritch JM, Kim JH, Lewin SN, Burke WM, Sun X, Herzog TJ, et al.. Venous thromboembolism and use of prophylaxis among women undergoing laparoscopic hysterectomy. Obstet Gynecol 2011;117:1367–74.
28. Abu-Rustum NR, Richard S, Wilton A, Lev G, Sonoda Y, Hensley ML, et al.. Transfusion utilization during adnexal or peritoneal cancer surgery: effects on symptomatic venous thromboembolism and survival. Gynecol Oncol 2005;99:320–6.
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