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Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2683-2689 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.1109 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
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
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.
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.
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
Detection and Reporting of VTE Events 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
A total of 2,743 patients were included in this analysis. Mean age was 57.5 years ± 10.7 years including 1,237 patients (45.1%) older than 60 years. Mean body mass index (BMI; ± standard deviation) was 25.3 ± 4.9 kg/m2 and 397 patients (14.5%) had a BMI higher than 30 kg/m2. FIGO stage IIIC-IV was present in 2,006 patients (73.2%). 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.
Time, Incidence, and Risk Factors for VTE Seventy-six patients (2.8%) experienced a clinically apparent venous thromboembolic event. Of those, 49 (64.5%) had DVT alone, 14 (18.4%) had PE diagnosed without evidence for DVT, and 13 (17.1%) suffered from both DVT and PE. One half of all VTE episodes occurred within the first 2 months after operation and during the first two chemotherapy cycles (Table 2). Demographics and operative characteristics of patients with VTE are summarized in Table 1.
Univariate analysis identified BMI higher than 30 kg/m2 as well as the fact not receiving chemotherapy as significant risk factors for VTE; age older than 60 years could not be identified in the univariate analysis as a risk factor for VTE. However, multivariate analysis identified increasing age (hazard ratio [HR], 1.4; 95% CI, 1.1 to 1.8) and BMI higher than 30 kg/m2 (HR, 3.2; 95% CI, 2.0 to 5.2) to be associated with elevated VTE risk. Chemotherapy (HR, 0.2; 95% CI, 0.1 to 0.7) appeared to have a protective effect against VTE. Only 1% of the total patients and 4% of the VTE patients did not receive even one chemotherapy cycle; the exact reasons for that phenomenon (ie, too ill patients, high postoperative complications rate) are not well defined in the database. 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.
Only a minority of the patients had a venous port system (< 1%), so no subgroup analysis of thrombosis in patients with port systems was undertaken.
Impact of VTE on Overall Survival
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 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).
VTE and Tumor Progression Univariate analysis identified age older than 60 years, ECOG 2 performance status, advanced stage disease (FIGO IIIC), ascites, postoperative macroscopic tumor residual, absence of pelvic and/or para-aortic lymphadenectomy, and bowel resection in the primary surgery to be associated with increased risk of tumor progression. In the multivariate analysis, we could identify age older than 60 years (HR, 1.10; 95% CI, 1.00 to 1.20) and FIGO stage IIIC or higher (HR, 1.63; 95% CI, 1.45 to 1.82) as being associated with a significantly higher risk of tumor relapse. Para-aortic/pelvic lymph node dissection (HR, 0.80; 95% CI, 0.72 to 0.88) and no macroscopic postoperative tumor residuals (HR, 0.42; 95% CI, 0.37 to 0.47) were associated with a significant positive effect. Neither PE nor DVT could be proven to be associated with a higher later tumor recurrence in the multivariate analysis (P = .084 and P = .292, respectively). Data are summarized in Table 5.
In this study, we evaluated the incidence and predictors of VTE in patients with advanced EOC after radical tumor debulking surgery and during first-line systemic chemotherapy with the standardized platinum-based regimen containing paclitaxel and platinum. 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- 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.
The author(s) indicated no potential conflicts of interest.
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
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Trousseau A: Phlegmasia alba dolens: Clinique medicale de lHotel–Dieu de Paris (ed 2). Paris, France, JB Balliere et Fils, 1865, pp 654-712 2. Stolinsky DC: Trousseau's phenomen. Blood 62:1304, 1983[Medline] 3. Sorensen TH, Mellemkjaer Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846-1850, 2000 4. Monreal M, Lensing AWA, Prins M, et al: Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism. J Throm Haemost 2:876-881, 2004[CrossRef] 5. Prandoni P: Cancer and thromboembolic disease: How important is the risk of thrombosis? Cancer Treat Rev 28:133-136, 2002[CrossRef][Medline] 6. Kakkar A, Levine M: Thrombosis and cancer: Implications beyond Trousseau. J Thromb Haemost 2:1261-1262, 2004[CrossRef][Medline] 7. Rickles FR, Levine MN: Epidemiology of thrombosis in cancer. Acta Haematol 106:6-12, 2001[CrossRef][Medline] 8. Tetsche MS, Nørgaard M, Pedersen L, et al: Prognosis of ovarian cancer subsequent to venous thromboembolism: A nationwide Danish cohort study. BMC Cancer 6:189, 2006[CrossRef][Medline] 9. Rodriguez AO, Wun T, Chew H, et al: Venous thromboembolism in ovarian cancer. Gynecol Oncol 105:784-790, 2007[CrossRef][Medline] 10. Tateo L, Mereub S, Salamanoa C, et al: Ovarian cancer and venous thromboembolic risk. Gynecol Oncol 99:119-125, 2005[CrossRef][Medline] 11. Lichtenegger W, Sehouli J, Buchmann E, et al: Operative results after primary and secondary debulking-operations in advanced ovarian cancer. J Obstet Gyn Res 24:447-451, 1998 12. Bristow RE: Surgical standards in the management of ovarian cancer. Curr Opin Oncol 12:474-480, 2000[CrossRef][Medline] 13. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002 14. Tingulstad S, Skjeldestad FE, Halvorsen TB, et al: Survival and prognostic factors in patients with ovarian cancer. Obstet Gynecol 101:885-891, 2003[CrossRef][Medline] 15. Du Bois A, Weber B, Rochon J, et al: Addition of epirubicin as a third drug to carboplatin- paclitaxel in first- line treatment of advanced ovarian cancer: A prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Study Cancer Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J Clin Oncol 24:1127-1135, 2006 16. Du Bois A, Lück HJ, Meier W, et al: Randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320-1330, 2003 17. Pfisterer J, Weber B, Reuss A, et al: Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: A gynecologic cancer intregroup trial of the AGO-Ovar and GINECO. J Natl Cancer Inst 98:1036-1045, 2006 18. International Federation of Gynecology and Obstetrics: Changing in definitions of clinical staging for carcinoma of the cervix and ovary. Am J Obstet Gynecol 156:263-264, 1987[Medline] 19. Minna JD, Higgins GA, Glatstein EJ: Cancer of the lung, in De Vita V, Hellmann S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, 1984, pp 536 20. National Cancer Institute: Cancer Therapy Evaluation Program: Common Toxicity Criteria. http://ctep.cancer.gov/reporting/ctc.html 21. Trotti A, Byhardt R, Stetz J, et al: Common Toxicity Criteria version 2.0: An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13-47, 2000[CrossRef][Medline] 22. Geerts WH, Pineo GF, Heit J, et al: Prevention of venous thromboembolism: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:338-400, 2004[CrossRef] 23. Matsuura Y, Robertson G, Mardsen DE, et al: Thromboembolic complications in patients with clear cell carcinoma of the ovary. Gynecol Oncol 104:406-410, 2007[CrossRef][Medline] 24. Bergqvist D, Agnelli G, Cohen AT, et al: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 346:975-980, 2002 25. Naess IA, Christiansen SC, Romundstad P, et al: Incidence and mortality of venous thrombosis: A population-based study. J Thromb Haemost 5:692-699, 2007[CrossRef][Medline] 26. Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22:1944-1948, 2004 27. Klerk CP, Smorenburg SM, Otten HM, et al: The effect of low molecular weight heparin on survival in patients with advanced malignancy: The MALT study. J Clin Oncol 23:2130-2135, 2005 28. Harter P, Schade-Brittinger C, Belau AK, et al: AGO-OVAR 14: A retrospective study evaluating the reasons for non- participating in trials in patients with ovarian cancer (OC) treated in coordinating centers of the AGO Ovarian Cancer Study Group. J Clin Oncol 22:469s, 2004 (abstr 5081) 29. Committee on Practice Bulletins Gynecology, American College of Obstetricians and Gynecologists: ACOG Practice Bulletin No. 84: Prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol 110:429-440, 2007[CrossRef][Medline] 30. Lee AY, Levine MN: Venous thromboembolism and cancer: Risks and outcomes. Circulation 10:I17-I21, 2003 (suppl 1) 31. Black D, Iasonos A, Ahmed H, et al: Effect of perioperative venous thromboembolism on survival in ovarian, primary peritoneal, and fallopian tube cancer. Gynecol Oncol 107:66-70, 2007[CrossRef][Medline] 32. Browse NL, Thomas ML: Source of non-lethal pulmonary emboli. Lancet 1:258-259, 1974[CrossRef][Medline] 33. Havig O: Deep vein thrombosis and pulmonary embolism: An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand 478:1, 1977 (suppl) 34. Akl E, van Doormaal F, Barba M, et al: Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev:CD006652, 2007 35. von Tempelhoff GF, Harenberg J, Niemann F, et al: Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol 16:815-824, 2000[Medline] 36. Look MP, Van Putten WL, Duffy MJ, et al: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116-128, 2002 37. Falanga A, Marchetti M, Vignoli A, et al: Clotting mechanisms and cancer: Implications in thrombus formation and tumor progression. Clin Adv Hematol Oncol 1:673-678, 2003[Medline] 38. Fernandez PM, Patierno SR, Rickles FR: Tumor angiogenesis and blood coagulation, in Lugassy G, Falanga A, Kakkar AK, et al (eds): Thrombosis and Cancer. London, United Kingdom, Martin Dunitz, 2004, pp 69-98 39. Falanga A: Thrombophilia in cancer. Semin Thromb Hemost 31:104-110, 2005[CrossRef][Medline] 40. Falanga A, Rickles FR: Pathophysiology of the thrombophilic state in the cancer patients. Semin Thromb Hemost 25:173-182, 1999[Medline] 41. Westin SN, Skinner EN, Jonsson Funk M, et al: Incidence of symptomatic deep vein thrombosis with epoetin alpha or darbepoetin alfa treatment of anemia in patients with ovarian or primary peritoneal cancer. Gynecol Oncol 105:414-417, 2007[CrossRef][Medline] 42. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708-714, 2006 43. von Tempelhoff GF, Pollow K, Schneider D, et al: Chemotherapy and thrombosis in gynecologic malignancy. Clin Appl Thromb Hemost5:92-104, 1999[CrossRef] Submitted January 5, 2008; accepted February 27, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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