Patients with ovarian cancer have a 10–22% incidence of venous thromboembolism.1,2 Previously identified risk factors include obesity, age older than 65 years, histology, advanced stage, CA 125 greater than 500, debulking surgery, and the use of antiangiogenic agents.1,2 Thromboembolism in malignancy is also associated with lower survival and poor quality of life.3,4 It is unclear whether venous thromboembolism is causally related to a reduction in overall survival or reflects a higher tumor burden, more aggressive tumor biology, or both. Nevertheless, preventing thromboembolism is of paramount importance to avoid short- and long-term complications. In addition to the perioperative thromboembolic prophylaxis, prolonged prophylaxis is becoming a standard of care in women with ovarian cancer. Recent studies show decreased thromboembolic events in patients receiving prolonged postoperative prophylaxis for 4 weeks.5,6
However, studies have shown a continued risk of venous thromboembolic events well beyond the perioperative and prolonged prophylaxis periods. During adjuvant chemotherapy, venous thromboembolism occurs in up to 12.5% of the patients.7 These data suggest that active ovarian cancer is a hypercoagulable state. Despite multiple studies examining the perioperative and postoperative phases of care in women with ovarian cancer, the rates of thromboembolism in patients undergoing neoadjuvant chemotherapy remain unknown. The recommended initial treatment for patients with advanced-stage ovarian cancer is surgical debulking followed by adjuvant platinum and taxane chemotherapy.8 However, patients with high likelihood of not achieving optimal debulking or high surgical morbidity frequently receive neoadjuvant chemotherapy.8,9 Given that these factors influencing the choice of neoadjuvant chemotherapy have all been associated with increased risk of thromboembolism, we hypothesized that patients receiving neoadjuvant chemotherapy have a high rate of venous thromboembolism.
MATERIALS AND METHODS
We performed a descriptive retrospective cohort study of women diagnosed with ovarian, fallopian tube, or primary peritoneal cancer at the University of Michigan from January 1, 2009, to May 31, 2014. These dates were selected based on a 5-year timeframe calculated from the time of institutional review board approval of this study. Individual patient electronic medical record review and data collection were carried out using the University of Michigan Health System Electronic Medical Record Search Engine patient data search engine.10 Study data were collected and managed using Research Electronic Data Capture electronic data capture tools hosted at the University of Michigan Medical School.11 STrengthening the Reporting of OBservational studies in Epidemiology guidelines were used.12 The institutional review board of the University of Michigan Health System approved this study (protocol #HUM 00095719).
The primary outcome of this study was the number and timing of venous thromboembolic events in the neoadjuvant chemotherapy ovarian cancer patient population. The secondary objective of our study was to identify patient or treatment factors associated with increased risk of venous thromboembolism.
Women 18 years of age or older with ovarian, fallopian tube, or primary peritoneal carcinoma of high-grade histology undergoing one or more cycles of chemotherapy before undergoing debulking surgery were considered as undergoing neoadjuvant chemotherapy and were included in this report. Patients seeking a second opinion or those who underwent surgery at the University of Michigan but received chemotherapy elsewhere were not included as a result of concerns of incomplete follow-up and limited access to detailed medical records from outside hospitals. For this study, we categorized age as younger than 65 years or 65 years or older, race as white compared with nonwhite, and tobacco use as having smoked within the prior year or not. Date of diagnosis, date of recurrence, date of the last contact, and vital status were recorded.
Medical comorbidities were abstracted from the medical chart and the Charlson comorbidity score was calculated.13 Comorbidities included in the Charlson score are diabetes mellitus (categorized as diet-controlled, noninsulin-dependent, or insulin-dependent), hypertension (if previously diagnosed or multiple recorded blood pressure readings greater than 140/90 mm Hg), obesity (categorized as nonobese if body mass index [calculated as weight (kg)/[height (m)]2] less than 30 or obese if body mass index 30 or greater), history of cardiovascular-related issues (including congestive heart failure, myocardial infarction, percutaneous coronary intervention, and peripheral vascular disease), neurovascular diseases (including transient ischemic attack and cerebrovascular accidents with or without neurologic deficit), chronic obstructive pulmonary disease, chronic kidney disease, and the functional status of the patient (categorized as dependent or independent with regard to performance of basic activities of daily living). Disease histology was categorized as serous, endometrioid, clear cell, mucinous, or other. The primary tumor site was recorded as ovarian, fallopian tube, or primary peritoneal. CA 125 levels were recorded at multiple time points, which included: 1) initial diagnosis, 2) after the completion of neoadjuvant chemotherapy, 3) postoperatively, and 4) postadjuvant chemotherapy. Imaging data were reviewed and disease distribution was dichotomized based on the location of the tumor seen on the images as follows: upper abdomen disease (transverse colon, stomach, liver, liver parenchyma, intraparenchymal hepatobiliary system, diaphragm), mid- and lower abdominal disease (small bowel and corresponding mesentery), the presence of ascites (categorized as minimal or moderate to significant), and the presence or absence of omental disease. The stage of the cancer was recorded. Residual disease at the time of interval cytoreduction was defined as microscopic, less than 5 mm, 5–10 mm, 11–20 mm, or greater than 20 mm. Chemotherapy regimen, route of administration, the platinum sensitivity of the chemotherapy treatment, and the timing of any blood transfusions were recorded.
The number and timing of venous thromboembolic events were placed in one of four time periods: venous thromboembolism before neoadjuvant chemotherapy (at the time of diagnosis), venous thromboembolism development during neoadjuvant chemotherapy before interval cytoreductive surgery, postoperatively (from the time of cytoreduction until reinitiating chemotherapy), or during adjuvant chemotherapy after surgery. Patients were diagnosed with a venous thromboembolism by either a computed tomography scan or Doppler ultrasonography. Patients with venous thromboembolic disease at the time of presentation were excluded from further analysis because they were already on full anticoagulation before initiation of neoadjuvant chemotherapy. Throughout the study, all patients received sequential compression devices and subcutaneous heparin during their hospitalization postoperatively. The institutional policy of prolonged postoperative prophylaxis started at the University of Michigan Hospitals midway through the study period. Therefore, data collection included whether the patient received prolonged prophylactic anticoagulation postoperatively for 28 days after discharge from the hospital. The Khorana score is a risk assessment tool used by medical oncologists for predicting venous thromboembolism during outpatient adjuvant chemotherapy.14,15 This model is relatively simple and contains parameters that are easily obtained during a routine outpatient evaluation for oncology patients. This score uses hemoglobin level, platelet count, and white blood cell count at the time of initial diagnosis along with tumor histology to assign a patient's risk of a venous thromboembolic event during chemotherapy.14 To examine whether this model could serve as a predictor in our study cohort, these laboratory values were collected at each time point and the Khorana score was calculated for each patient.
Descriptive analyses of the patient information were performed. Pearson χ2 tests and Fisher exact test were used for categorical variables. Multivariable regression modeling and predictive analyses were not performed as a result of low sample size.
Six hundred twenty patients with ovarian cancer were identified in the study period. Of these, 161 patients received neoadjuvant chemotherapy and 36 of these patients were excluded because they did not receive their care primarily at the University of Michigan. Of the remaining 125 patients who received neoadjuvant chemotherapy primarily at the institution of study, 13 patients (10.4%, 95% confidence interval [CI] 6.1–17.2%) had a venous thromboembolism before or at the time of diagnosis. These patients were excluded from further analysis, leaving 112 patients in the final cohort who had the potential for a new venous thromboembolism during their cancer care and met all inclusion criteria (Fig. 1).
An overview of the timing and incidence of venous thromboembolism at three different time points is provided in Figure 1. Of the 112 total patients at risk, 30 (26.8%, 95% CI 19.3–35.9%) experienced a venous thromboembolism. Based on the phase of care, 13 (11.6%, 95% CI 6.8–19.1%) experienced a venous thromboembolism during neoadjuvant chemotherapy (with one death as a result of venous thromboembolism), six (5.4%, 95% CI 2.4–11.5%) developed a postoperative venous thromboembolism, and 11 (9.9%, 95% CI 5.5–17%) developed a venous thromboembolism during adjuvant chemotherapy. The mean age of the patients who developed a clot during neoadjuvant chemotherapy was 70.1 (±13.4) years. Eight patients had serous histology; 10 were white, 11 were nonsmokers, and nine were nonobese. Moderate to significant ascites was present in 7 of the 13 patients. Upper abdominal disease was present in 10 of the 13 patients as was omental disease on initial diagnostic imaging. None of the patients in this cohort had a medical history of venous thromboembolic disease.
Figure 2 provides a more detailed analysis of the timing of venous thromboembolism. Patients receiving prolonged postoperative prophylaxis for 28 days after discharge had a lower postoperative venous thromboembolic event rate compared with those not receiving prolonged prophylaxis. From the 112 at-risk patients, there were only four patients with clear cell histology, but two of them developed a venous thromboembolism during neoadjuvant chemotherapy. The rate of thromboembolism in those with nonclear cell histology was 9.4% (10/107). On the univariate analysis, there were no predictors of venous thromboembolism identified for patients undergoing interval debulking after receiving neoadjuvant chemotherapy (Table 1).
Our data demonstrate that one in four patients undergoing neoadjuvant chemotherapy developed a new venous thromboembolism throughout the timeframe of initial treatment of their cancer. Specifically, 1 in 10 patient developed a venous thromboembolism during neoadjuvant chemotherapy, an additional 10% during adjuvant chemotherapy after debulking surgery and the remainder during the postoperative phase. These data are important for several reasons: 1) we observed a venous thromboembolism rate similar to previously reported in the adjuvant chemotherapy phase of care (approximately 10%). However, a similar percentage of patients experiencing thromboembolic events before surgery during neoadjuvant chemotherapy has not been previously reported; 2) despite a low incidence of postoperative thromboembolism after hysterectomy (approximately 2%), prevention of venous thromboembolic disease in the perioperative phase is currently considered a quality-of-care indicator.16,17 In comparison, our data show that the rate of thromboembolism during neoadjuvant and adjuvant chemotherapy is greater than 10%. Based on these data, we recommend that randomized controlled trials of prophylactic anticoagulation during neoadjuvant and adjuvant chemotherapy in ovarian cancer should be strongly considered.
Overall, venous thromboembolism complicated the treatment of one fourth of the patients undergoing neoadjuvant chemotherapy. This is in comparison with previous reports that have demonstrated an overall incidence of venous thromboembolism of approximately 22% in patients with ovarian cancer.1,2 The clinical decision to administer neoadjuvant chemotherapy is generally influenced by the high tumor burden and patient frailty. Because these two factors are also the risk factors for developing thromboembolic disease, it is unsurprising that the incidence of venous thromboembolism was higher in this cohort. Additionally, although we only had four patients with clear cell histology, two (50%) developed a venous thromboembolism during neoadjuvant chemotherapy. These results are similar to previous studies in patients with ovarian cancer in whom clear cell histology has been associated with higher risk of venous thromboembolism.2,18
Previous studies, in other malignancies, examining the risk of thromboembolism during neoadjuvant chemotherapy have shown similar results as the current study. In esophageal cancer, the incidence of venous thromboembolism during neoadjuvant chemotherapy is 12.5%.19 Similarly, in transitional cell carcinoma of the urinary bladder, 25% of the patients receiving platinum-based chemotherapy developed thromboembolic disease (Botten J, Sephton M, Tillett T, Masson S, Thanvi N, Herbert C, et al. Thromboembolic events with cisplatin-based neoadjuvant chemotherapy for transitional cell carcinoma of urinary bladder [abstract]. J Clin Oncol 2013;31(suppl 6):277.). In rectal cancer, patients receiving neoadjuvant chemotherapy concurrently with radiation had an overall 13% incidence of thromboembolic events.20 These consistently high numbers of thromboembolic events in several cancer sites further suggest that patients receiving neoadjuvant chemotherapy have a very high risk of developing clots.
After the institutional policy of prolonged postoperative prophylaxis was started at the University of Michigan Hospital, we observed a reduction in the rate of thromboembolic events in the postoperative setting (6.2% compared with 2.9%). Because our study was not powered to detect the efficacy of prolonged prophylaxis, we are unable to comment on the efficacy of this intervention from these data. However, recent data from other studies support the use of prolongation of postoperative prophylaxis to 4 weeks in patients with ovarian cancer who undergo debulking surgery.6 The institution of this policy midway through our study period does not affect the main finding of our study, which is the high rate of venous thromboembolism during neoadjuvant chemotherapy. Based on these data, as a quality measure, we propose that the institutional-level metrics of the cumulative incidence of thromboembolic disease, in patients with ovarian cancer, during all phases of care (neoadjuvant, postoperative, and adjuvant chemotherapy) and just the postoperative phase of care should be the focus of future studies.
Our study has several limitations worth considering. First, this is a retrospective study with a relatively small sample size. Factors such as Khorana score and extensive upper abdominal disease have been previously validated in large cohorts. Given a small sample size, to prevent type II error, we did not attempt any predictive analysis of known factors in our study. Second, the generalizability of our results may be limited because our study was performed at a single-institutional tertiary referral center. This could have led to an overestimation of overall risk of thromboembolism, because patients in referral centers tend to have more extensive disease. Third, the limited sample size also precluded us from performing meaningful survival analysis. Finally, we do not compare the rate of venous thromboembolism in patients with ovarian cancer who did receive neoadjuvant chemotherapy with those who did not. That is currently the subject of our ongoing investigation. However, we identified such a high incidence of venous thromboembolism in the neoadjuvant chemotherapy cohort that we felt these data needed to be reported given the lack of literature on this subject. Despite these limitations, there are several strengths to our study. The use of a detailed individual patient medical record review allowed for thorough analyses. The retrospective nature of the study also allowed us to identify the temporal sequence and timing of events with relation to phases of care.
Our study identifies the neoadjuvant chemotherapy ovarian cancer population as an extremely high-risk population of developing a venous thromboembolism during the course of their treatment. Thromboembolic prophylaxis in these patients may decrease the incidence of venous thromboembolic events and potentially affect overall survival. This becomes especially relevant because the proportion of patients with ovarian cancer receiving neoadjuvant chemotherapy is rapidly increasing in the United States.21
1. Abu Saadeh F, Norris L, O'Toole S, Gleeson N. Venous thromboembolism in ovarian cancer: incidence, risk factors and impact on survival. Eur J Obstet Gynecol Reprod Biol 2013;170:214–8.
2. Bakhru A. Effect of ovarian tumor characteristics on venous thromboembolic risk. J Gynecol Oncol 2013;24:52–8.
3. Metcalf RL, Fry DJ, Swindell R, McGurk A, Clamp AR, Jayson GC, et al. Thrombosis in ovarian cancer: a case-control study. Br J Cancer 2014;110:1118–24.
4. Vedantham S, Piazza G, Sista AK, Goldenberg NA. Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:68–80.
5. Uppal S, Hernandez E, Dutta M, Dandolu V, Rose S, Hartenbach E. Prolonged postoperative venous thromboembolism prophylaxis is cost-effective in advanced ovarian cancer patients. Gynecol Oncol 2012;127:631–7.
6. Schmeler KM, Wilson GL, Cain K, Munsell MF, Ramirez PT, Soliman PT, et al. Venous thromboembolism (VTE) rates following the implementation of extended duration prophylaxis for patients undergoing surgeries for gynecologic malignancies. Gynecol Oncol 2013;128:204–8.
7. Pant A, Liu D, Schink J, Lurain J. Venous thromboembolism in advanced ovarian cancer patients undergoing frontline adjuvant chemotherapy. Int J Gynecol Cancer 2014;24:997–1002.
8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology—ovarian cancer. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
. Retrieved December 16, 2016.
9. van Meurs HS, Tajik P, Hof MH, Vergote I, Kenter GG, Mol BW, et al. Which patients benefit most from primary surgery or neoadjuvant chemotherapy in stage IIIC or IV ovarian cancer? An exploratory analysis of the European Organization for Research and Treatment of Cancer 55971 randomized trial. Eur J Cancer 2013;49:3191–201.
10. Hanauer DA, Mei Q, Law J, Khanna R, Zheng K. Supporting information retrieval from electronic health records: a report of University of Michigan's nine-year experience in developing and using the Electronic Medical Record Search Engine (EMERSE). J Biomed Inform 2015;55:290–300.
11. Obeid JS, McGraw CA, Minor BL, Conde JG, Pawluk R, Lin M, et al. Procurement of shared data instruments for Research Electronic Data Capture (REDCap). J Biomed Inform 2013;46:259–65.
12. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008;61:344–9.
13. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245–51.
14. Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res 2014;133(suppl 2):S35–8.
15. Khorana AA, Rubens D, Francis CW. Screening high-risk cancer patients for VTE: a prospective observational study. Thromb Res 2014;134:1205–7.
16. Swenson CW, Berger MB, Kamdar NS, Campbell DA Jr, Morgan DM. Risk factors for venous thromboembolism after hysterectomy. Obstet Gynecol 2015;125:1139–44.
17. The Joint Commission—Surgical Care Improvement Project (SCIP) measure improvement set. Available at: https://manual.jointcommission.org/releases/archive/TJC2010B/MIF0061.html
. Retrieved October 19, 2016.
18. Ye S, Yang J, Cao D, Bai H, Huang H, Wu M, et al. Characteristic and prognostic implication of venous thromboembolism in ovarian clear cell carcinoma: a 12-year retrospective study. PLoS One 2015;10:e1021818.
19. Khanna A, Reece-Smith AM, Cunnell M, Madhusudan S, Thomas A, Bowrey DJ, et al. Venous thromboembolism in patients receiving perioperative chemotherapy for esophageal cancer. Dis Esophagus 2014;27:242–7.
20. Mezi S, Musio D, Orsi E, de Felice F, Verdinelli I, Morano F, et al. Incidence of thromboembolic events in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy. Acta Oncol 2013;52:187–90.
21. Melamed A, Hinchcliff EM, Clemmer JT, Bregar AJ, Uppal S, Bostock I, et al. Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States. Gynecol Oncol 2016;143:236–40.