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Incidence of Venous Thromboembolism in Patients With Ovarian Cancer Undergoing Platinum/Paclitaxel–Containing First-Line Chemotherapy: An Exploratory Analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

Christina Fotopoulou, Andreas duBois, Alexandros N. Karavas, Ralf Trappe, Behnaz Aminossadati, Barbara Schmalfeldt, Jacobus Pfisterer, Jalid Sehouli

From the Department of Gynecology and Obstetrics, Charité University Hospital, Berlin; Department of Hematology and Oncology, Charité University Hospital, Campus Virchow Klinikum; Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Klinik, Wiesbaden; Coordinating Center for Clinical Trials, University Marburg, Marburg; Department of Obstetrics and Gynecology, Klinikum rechts der Isar Technical University Munich, Munich; Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany; and the Department of Surgery, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA

Corresponding author: Christina Fotopoulou, MD, Department of Gynecology and Obstetrics, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany; e-mail: christina.fotopoulou{at}charite.de

	ABSTRACT

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Purpose Venous thromboembolism (VTE) has been associated with negative prognosis in cancer patients. Most series reporting on VTE have included different tumor types not differentiating between recurrent or primary disease. Data regarding the actual impact of VTE on primary advanced ovarian cancer (AOC) are limited.

Patients and Methods Between 1995 and 2002, the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group (AGO–OVAR) recruited 2,743 patients with AOC in three prospectively randomized trials on platinum paclitaxel-based chemotherapy after primary surgery. Pooled data analysis was performed to evaluate incidence, predictors, and prognostic impact of VTE in AOC. Survival curves were calculated for the VTE incidence. Univariate analysis and Cox regression analysis were performed to identify independent predictors of VTE and mortality.

Results Seventy-six VTE episodes were identified, which occurred during six to 11 cycles of adjuvant chemotherapy; 50% of them occurred within 2 months postoperatively. Multivariate analysis identified body mass index higher than 30 kg/m² and increasing age as independent predictors of VTE. International Federation of Gynecology and Obstetrics stage and surgical radicality did not affect incidence. Overall survival was significantly reduced in patients with VTE (median, 29.8 v 36.2 months; P = .03). Multivariate analysis identified pulmonary embolism (PE), but not deep vein thrombosis alone, to be of prognostic significance. In addition, VTE was not identified to significantly affect progression-free survival.

Conclusion Patients with AOC have their highest VTE risk within the first 2 months after radical surgery. Only VTE complicated by symptomatic PE have been identified to have a negative impact on survival. Studies evaluating the role of prophylactic anticoagulation during this high risk postoperative period are warranted.

	INTRODUCTION

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Malignancy has long been described as a risk factor for venous thromboembolism (VTE) including its life-threatening presentation, pulmonary embolism (PE).^1,2 The diagnosis of VTE may be the first symptom of occult malignant disease and has been shown to significantly affect overall survival in patients with cancer.^3,4 In addition, cancer-related therapeutic interventions, such as surgery and systemic chemotherapy, further sustain and even increase this thrombophilic predisposition.^5-7 Recent retrospective series on patients with ovarian cancer indicated that survival may be adversely affected by the presence of VTE.^8-10

Surgical radicality aiming at maximal tumor debulking and platinum-based adjuvant chemotherapy build the cornerstone of adequate management of primary ovarian cancer.^11-14 The impact of surgical debulking techniques, like intestinal resection and systematic pelvic and para-aortic lymphadenectomy, as well as the role of tumor specific characteristics, such as International Federation of Gynecology and Obstetrics (FIGO) stage and ascites on the overall incidence of VTE, have not been thoroughly investigated in this context.

The objective of this study was to further elucidate the pattern of VTE, predisposing factors, and the impact on patients' overall and recurrence-free survival in a large cohort of patients with primary diagnosed advanced epithelial ovarian cancer (EOC), who were treated by primary surgery and adjuvant platinum-based chemotherapy within prospectively randomized trials.

	PATIENTS AND METHODS

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Databases
This study was conducted using pooled single patient data from three large prospective randomized trials on platinum/paclitaxel-based chemotherapy in patients with advanced primary EOC. All studies were conducted by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group (AGO–OVAR). Only the data collected in the German centers were used for our study. Characteristics of patients and treatment protocols have been described elsewhere in detail.^15-17 We report characteristics pertaining to our present analysis.

Patients
A total of 2,743 patients, 18 years or older (median, 58.7; range, 19.6 to 83.6 years), with histologically proven primary EOC FIGO stage IIB-IV,¹⁸ who had not previously undergone any systemic treatment for ovarian cancer, were included in these three AGO-OVAR studies between October 1995, and March 2002. All patients enrolled within 6 weeks after debulking surgery. Eastern Cooperative Oncology Group (ECOG) performance status¹⁹ ranged between 0 and 2 and all patients had initially adequate hematologic, renal, and hepatic function and received paclitaxel and platinum-based chemotherapy in both arms of each study. The regimens evaluated in the experimental arms contained a third drug which was added as a triplet (epirubicine) or given sequentially (topotecan) in two of the studies, namely OVAR5 and OVAR7. No specific protocol addressed VTE prophylaxis. This was left up to the individual center's practice to use either unfractionated or low molecular weight heparin. The majority of the patients of our analysis were treated as inpatients. The protocol remained stable precluding so differences in management.

Detection and Reporting of VTE Events
A review of the prospectively collected data of this study cohort was performed to determine the incidence of VTE during primary chemotherapy as documented by the investigators. VTE events were recorded as adverse events, they were classified according to the National Cancer Institute Common Toxicity Criteria (CTC; version 2.0)^19,20 and they were registered both during reporting of severe adverse events (SAE) as well as toxicity evaluation. Recording of observed adverse events started at time of entry onto the study and was continued during chemotherapy administration. Patients were observed up until death or end of study period. Toxicity and SAE, such as symptomatic VTE, were recorded on a frequent interval of 3 weeks or fewer only during the chemotherapy period which, therefore, was chosen as observation period of this analysis.

Deep vein thrombosis (DVT) and PE were defined using the CTC code CG14, with CTC grades 1 to 4.^20,21 Patients with superficial thrombophlebitis were identified but not included in this analysis as VTE events.

Date of thromboembolic event was considered the date of diagnosis. Considering surgery as the first major thrombogenic event, time from surgery to VTE has been used for all time-to-event analyses. VTE was diagnosed based on clinical suspicion and physical examination during the chemotherapy (0 to 11 cycles) and follow-up visits. Because there was no routine VTE screening, only clinically symptomatic thromboembolic events were identified and those were confirmed with imaging studies, which included doppler sonography or other radiologic measures.

Statistical Analysis
Statistical analysis was performed using STATA (StataCorp LP, College Station, TX). The Fisher's exact test and Mann-Whitney U test were used for the univariate analysis of dichotomous and continuous independent variables respectively. Multivariate analysis was performed using logistic regression. Survival and time-to-event analysis was estimated using the product limit method and survival curves were compared using log-rank test (Fig 1). Prognostic factors were assessed for significance using Cox regression analysis. All reported significance was two tailed at a level of .05. The follow-up time was calculated starting on the day of surgery as this was determined to constitute the most significant risk factor for VTE during the study period. The variable age was used as a dichotomous variable with a cutoff value 60 years to be consistent with seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy.²²

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier survival curve for the venous thromboembolism (VTE) and non-VTE group.

	RESULTS

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Macroscopic complete tumor resection was accomplished in 940 patients (34.2%). Seven hundred fifty patients (27.3%) and 1,257 patients (45.8%) underwent para-aortic and pelvic lymphadenectomy. Further details of patients' characteristics are summarized in Table 1. Almost all patients 2,719 (99.0%) received at least one chemotherapy cycle. Maximal six to 11 cycles of adjuvant chemotherapy were applied, according to the chemotherapy regime of each study group.

Other commonly reported prognostic factors, such as advanced FIGO stage (IIIC-IV), ascites, radical operative procedures (ie, lymphadenectomy and bowel resection), postoperative tumor residuals, and supportive therapy with leukocyte stimulating factors (granulocyte colony-stimulating factor) and erythropoietin, did not have any significant effect on the incidence of the thromboembolic episodes. Data of the univariate and multivariate analysis regarding the predisposing factors of VTE are presented in Table 3.

Impact of VTE on Overall Survival
One-year mortality for the entire cohort was 9%. One-year mortality for patients with VTE versus no VTE was significantly different (21% v 9%; P < .001).

Univariate analysis revealed the following parameters to negatively affect overall survival in patients with primary ovarian cancer: increasing age, ECOG status 2, advanced stage disease (FIGO IIIC), postoperative macroscopic tumor residuals, ascites, bowel resection, no chemotherapy, and VTE. However, multivariate analysis did not identify VTE as independent prognostic factor, but solely PE (HR, 2.86; 95% CI, 1.82 to 4.5). Of 27 patients who developed PE, 21 died; six of them within the first 2 days after the event and other seven within the first month after occurrence. Mean time of occurrence of PE was 2.3 ± 2.7 months and mean number of chemotherapy cycles on patients with PE were 3.6 ± 4 cycles.

Other independent predictors affecting survival were increasing age (every decade increase in age; HR, 1.17; 95% CI, 1.1 to 1.23), FIGO stage IIIC or higher (HR, 1.68; 95% CI, 1.46 to 1.93), and postoperative macroscopic tumor residuals (HR, 2.76; 95% CI, 2.41 to 3.16; Table 4). Patients who received chemotherapy appeared to have a significant better overall survival (HR, 0.48; 95% CI, 0.27 to 0.88).

	DISCUSSION

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Thromboembolism presenting clinically as DVT or PE had an incidence of 2.8%, with one third of patients presenting as PE. This incidence seems to be lower than described previously in other reports.^9,10 A prior study based on cancer registry data recording data from more than 13,000 patients reported an incidence of 5.2% over a period of 24 months.⁹ Matsuura et al²³ also reported of a higher VTE incidence in 641 patients with primary advanced ovarian cancer; they described an incidence of 6.1% of patients with nonclear cell ovarian carcinoma, a study based on the California Cancer Registry. Another retrospective study based on recorded data of 253 cases with primary epithelial ovarian malignancy reports an incidence of symptomatic VTE of 8.8% after tumor diagnosis (2.4% in the postoperative period and 6.4% during first-line chemotherapy).¹⁰ Several factors may account for the differences in reported data. Our study has evaluated clinical data, which were not based on coded conditions in administrative databases. This approach excluded diagnoses only related but not identical to VTE, such as superficial thrombophlebitis, or suspected but not confirmed cases, which were nevertheless registered in the cancer registry databases as events. Besides, as the protocol of the three AGO studies did not include routine screening for DVT or PE, clinically latent cases would have not been identified, thus underestimating the true incidence.^24-27 A further possible selection bias is that our cohort selection has included only patients with advanced ovarian cancer who were able to tolerate chemotherapy after radical surgery and fit enough to be recruited for a prospective study. Therefore, patients having already experienced a severe VTE or PE right after surgery might not be included in the protocol. This would fit to the well described effect of selection processes for clinical studies.²⁸ Still, because we were unable to find a significant correlation in the univariate (P = .20) or the multivariate analysis regarding ECOG status and VTE incidence, we cannot explain the lower incidence described based mainly on the fact that we had a more favorable patient population selected by protocol.

The pattern of VTE occurrence in our cohort did not differ from experiences by others. One half of all VTE episodes occurred within the first 2.5 months and 96% during the first 6 months postoperatively. This finding is in accordance with the report of Rodriguez et al⁹ who also found a high VTE incidence within the first 3 months after diagnosis of malignancy in a cohort more than 13,000 patients with ovarian cancer. The occurrence of VTE within this short interval but, at least clinically, after immediate recovery, discharge, and enrollment into a chemotherapy study raises the question already addressed in some reports, the ACCP guidelines, and the American College of Obstetrics and Gynecology suggesting continuation of thrombosis prophylaxis for 2 to 4 weeks after hospital discharge in patients who received surgery for gynecologic malignancies.^22,24,29

Data on decreased overall survival in patients with cancer with VTE were described by Sørensen³; further studies followed and reinforced these findings.^8,9,30 The study by Black et al,³¹ describing the overall survival of 559 patients with ovarian, primary peritoneal, and fallopian tube cancer treated for VTE within 30 days of initial surgery, failed to identify VTE as significant predictor of mortality in the 30-day postoperative period. Our data, to the contrary, clearly confirmed a survival disadvantage in patients who suffered a thromboembolic event. One-year mortality was 21% in those with VTE and 9% in those with no VTE. The difference was mainly attributed to the episodes of pulmonary embolism rather than DVT alone. DVT alone, once diagnosed, prompts initiation of anticoagulation reducing the risk of fatal PE, because more than 90% of cases of acute PE are due to emboli emanating from the proximal veins of the lower extremities.^32,33

We believe that many patients with VTE died due to consequences of the embolic event and not necessarily due to progression of the actual tumor disease, because 13 of 21 patients with embolism who died did so already within 4 weeks after the embolic event. A further factor that supports this hypothesis is that we could not demonstrate any significant correlation between postoperative residual tumor and thromboembolic events. There is enough evidence that postoperative tumor residuals predict chemotherapy resistance and tumor progression.^13,14 Moreover, we showed that progression-free survival was not significantly different between patients with VTE and without VTE. Nevertheless an autopsy was performed in only a very small minority of the deceased patients, so that we cannot possibly identify the true cause that led to death.

Our results may be related to findings of recent major prospective randomized trials,^26,27,34 according to which low molecular weight heparin appeared to have a survival benefit in patients with cancer in general, and particularly in those with limited cancer and/or a life expectancy longer than 6 months. This may at least partially be related to the prevention of postoperative thromboembolic events.³⁵ No definitive answer can be given for our patients population whether there was a difference in prophylaxis or in VTE treatment during this 7-year study period regarding the use of low molecular weight heparins, due to lack of concrete prophylactic anticoagulation data for each patient. It can be suggested though, that the use of low molecular weight heparins has significantly increased with time, especially the last 4 to 5 years, analogous to the current ACCP guidelines, which rather favor the use of low molecular weight heparins in patients with cancer.²²

We identified the well-established VTE risk factors of increasing age (HR, 1.4; every past decade between 35 and 81 years) and high BMI (HR, 3.2; by a BMI > 30 mg/m²) as significant predictors of VTE also in patients with EOC. The impact of lack of chemotherapy in the incidence of VTE may be related to the conditions of the patients being too sick to tolerate systemic chemotherapy thus representing a confounder rather than a true predictor of VTE. The analysis regarding surgical parameters as risk factors for VTE failed to identify any significant impact of pelvic or para-aortic lymphadenectomy, amount of tumor reduction, or bowel resection.

We were unable to find an association between use of erythropoiesis stimulating agents and VTE.

Some authors have suggested a correlation between higher tumor aggressiveness and thrombotic events.^36-40 It has been speculated that fibrinolytic proteins play a major role in tumor invasion, tumor cell proliferation, and metastatic pathways. These factors have been long under evaluation as potential predictors of recurrence-free and overall survival in malignant disease.^36,41,42 Tumor cells synthesize and release inflammatory cytokines, like tumor necrosis factor- and interleukin-1b, as well as vascular endothelial growth factor, which induce the expression of tissue factor procoagulant activity by endothelial cells and monocytes and induce thrombotic events.^37,38 Falanga,³⁹ reviewing thrombophilia in cancer, interestingly emphasizes that most of the hemostatic properties of tumor cells potentially also affect certain pathways of malignancy by means of clotting independent mechanisms, interfering with metastatic mechanisms. However, we could not confirm any significant prognostic impact of VTE on the progression-free survival in patients with EOC except the acute mortality associated with PE which mainly occurred shortly after surgery. We observed only a trend for both DVT and PE, but this did not reach statistical significance. Due to the design of our study however, which described the VTE incidence solely during the postoperative period and during chemotherapy, it is highly probable that a high percentage of the thromboembolic events have been due to these well established risk factors (ie, operation and chemotherapy)⁴³ and not necessarily due to the aggressiveness of the malignancy per se. The fact that para-aortic/pelvic lymph node dissection and complete tumor resection appears to have a significant positive effect regarding progression-free survival could possibly be regarded as a selection bias due to the fact that rather fit and younger patients with less tumor load have undergone a systematic lymphadenectomy and a complete tumor resection.

In conclusion, the incidence of clinically significant VTE in patients with primary advanced EOC undergoing radical surgery and adjuvant chemotherapy is 2.8%. One half of those events were diagnosed within the first 2 months after primary surgical cytoreduction. While DVT was not shown to significantly affect overall survival, PE did. This study was not able to identify cancer-related characteristics to impact the VTE incidence. There was, however, a trend toward positive correlation between DVT and PE and the recurrence of ovarian cancer without this reaching a statistical significance. Further prospective studies evaluating the role of prophylactic anticoagulation beyond the hospital period for the first 3 months postoperatively are warranted to overcome the negative impact of VTE on overall survival.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Christina Fotopoulou, Ralf Trappe, Jalid Sehouli

Administrative support: Christina Fotopoulou, Andreas duBois, Behnaz Aminossadati, Barbara Schmalfeldt, Jacobus Pfisterer, Jalid Sehouli

Collection and assembly of data: Christina Fotopoulou, Andreas duBois, Alexandros N. Karavas, Behnaz Aminossadati, Jalid Sehouli

Data analysis and interpretation: Christina Fotopoulou, Andreas duBois, Alexandros N. Karavas, Ralf Trappe, Jalid Sehouli

Manuscript writing: Christina Fotopoulou, Andreas duBois, Alexandros N. Karavas, Ralf Trappe, Barbara Schmalfeldt, Jacobus Pfisterer, Jalid Sehouli

Final approval of manuscript: Christina Fotopoulou, Andreas duBois, Alexandros N. Karavas, Ralf Trappe, Barbara Schmalfeldt, Jacobus Pfisterer, Jalid Sehouli

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted January 5, 2008; accepted February 27, 2008.

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