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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1519-1524 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9930 Thromboembolic Events in Children and Young Adults With Pediatric Sarcoma
From the Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda; and Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD Address reprint requests to Ido Paz-Priel, MD, Bunting-Blaustein Cancer Research Building, Room 2M52, Johns Hopkins Hospital, 1650 Orleans St, Baltimore, MD 21231; e-mail: ipazpri1{at}jhmi.edu
Purpose: Adults with malignancy are at increased risk for venous thromboembolic events (TEs). However, data in children and young adults with cancer are limited. Patients and Methods: To determine the risk and clinical features of TEs in children and young adults with sarcoma, we reviewed records on 122 consecutive patients with sarcoma treated from October 1980 to July 2002. Results: Twenty-three TEs were diagnosed in 19 of 122 (16%; 95% CI, 10% to 23%) patients. Prevalence by diagnosis was Ewing sarcoma, eight of 61 (13%); osteosarcoma, two of 20 (10%); rhabdomyosarcoma, four of 26 (15%); and other sarcomas, five of 15 (33%). TEs developed in 23% of patients with metastases at presentation versus 10% with localized disease (odds ratio, 2.59; 95% CI, 0.9 to 7.1; P < .06). Fifty-three percent of patients with thrombosis had a clot at presentation. A lupus anticoagulant was detected in four of five evaluated patients. There was a single fatality due to pulmonary embolism. Patients who were diagnosed with cancer after 1993 had a higher rate of TE (7% v 23%; P < .015). Of the 23 events, 43% were asymptomatic. Main sites of thromboses were deep veins of the extremities (10 of 23; 43%), pulmonary embolism (five of 23; 22%), and the inferior vena cava (four of 23; 17%). TEs were associated with tumor compression in eight of 23 (35%) and with venous catheters in three of 23 (13%). Conclusion: Thromboembolism is common in pediatric patients with sarcomas. Thromboses are detected frequently around the time of oncologic presentation, may be asymptomatic, and seem to be associated with a higher disease burden. Children and young adults with sarcoma should be monitored closely for thrombosis.
Cancer and venous thromboembolic events (TEs) are strongly associated. High rates of thrombosis have been reported consistently in patients with cancer,1-13 and an idiopathic TE frequently is the first manifestation of occult malignancy.2,4,6-9,11,13 TEs are an important cause of morbidity and mortality in cancer patients,12 and their occurrence adversely affects survival.14 Cancer induces a prothrombotic state via induction of tissue factor, the procoagulant properties of the malignant cells, and secretion of cytokines.15-18 In addition, patients with cancer have accompanying risk factors including central venous access devices, chemotherapy,19 surgery, immobilization, and comorbid conditions. Carriers of inherited thrombophilia traits may be at an even higher risk for TEs.3 Cancer is the underlying condition in 7% to 25% of children with thrombosis.20,21 With the exception of acute lymphoblastic leukemia (ALL), limited information is available about the association of TEs with cancer in the pediatric age group.1,2,22-24 Data regarding TEs in adults may not be applicable to children with cancer. Some risk factors such as the type of cancer, advanced age, and comorbid conditions clearly differ between adults and children. Moreover, differences may occur even within similar diagnoses. For example, adults with glioma are well recognized to be at an increased risk for thrombosis.25,26 In contrast, two independent series described a very low risk for TEs in children with brain tumors, even when the different spectrum of brain tumors was taken into account.27,28 Sarcomas, including rhabdomyosarcoma (RMS), Ewing sarcoma, and osteosarcoma, account for approximately 15% to 20% of pediatric cancer. Approximately two thirds of these patients are cured; thus, it is important to define potential causes of noncancer morbidity and mortality. Individuals with pediatric sarcomas have multiple risk factors for TEs; however, there is a paucity of data regarding the occurrence of TEs and associated risk factors in this population.29 The aim of this study was to assess the prevalence of TEs and to identify potential risk factors in children and young adults with sarcoma. We report our single-institution experience demonstrating a high frequency of TEs in children and young adults with sarcomas.
We performed a retrospective cohort study of consecutive patients with sarcoma treated at the Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health (NIH; Bethesda, MD) between October 1980 and July 2002. Patients were identified through clinical trial participant lists. Patients were eligible if they were diagnosed with Ewing sarcoma, osteosarcoma, RMS, or synovial or undifferentiated sarcoma. We included only patients who received their primary treatment after initial diagnosis at the NIH Clinical Center. Those who transferred their care to or from the NIH before completion of the primary treatment were excluded, as were patients who were referred for salvage therapy. During the study period, none of the patients was treated with primary anticoagulant prophylaxis. Throughout the study period uniform disease-based treatment protocols were followed. In general, neoadjuvant chemotherapy was administered, followed by surgical resection and/or radiation treatment, followed by adjuvant chemotherapy. Patients with Ewing sarcoma and high-risk RMS were treated with vincristine, doxorubicin, plus cyclophosphamide, alternating with etoposide plus ifosfamide. Therapy for osteosarcoma included cisplatin, doxorubicin, and high-dose methotrexate. An indwelling venous access device, typically a port device was placed in all patients before initiation of treatment. Patient-specific management of TEs, including the anticoagulation regimen and need for additional work-up, was determined by the attending physician. This study was approved by the NIH Office of Human Subjects Research. Information was extracted from the study participants’ medical records, including demographic characteristics; cancer type, extent, and outcome; TE occurrence, timing, and location; potential thrombosis risk factors (including immobilization, time from surgery, presence of venous access device, blood group, family history, and the results of thrombophilia work-up, when available); and antithrombotic treatment. During the study period, the diagnosis of antiphospholipid antibodies was based on the dilute Russell's viper venom test (Precision BioLogic; Dartmouth, Nova Scotia, Canada) and was confirmed by correction by excess phospholipids.
The diagnosis of TEs had to be confirmed by at least one imaging study or autopsy. Patients were not screened for thrombosis during the study period. Thus, the diagnosis of TEs during this study reflects routine clinical practice. Symptomatic clots were defined as those that were diagnosed as a result of a work-up that was initiated in response to a clinical finding such as limb swelling or respiratory symptoms. TEs were classified as asymptomatic when they were detected as an incidental finding on imaging studies performed for another indication (eg, disease staging evaluation) or on autopsy without antemortem clinical suspicion. Thrombosis was attributed to tumor compression when the involved vessel was impinged on by the mass either directly at the site of the clot or when the blood flow was compromised due to a proximal obstruction. A clot involving a vein or extremity with an indwelling central venous catheter was classified as catheter related, as was right atrial thrombus in the presence of a line. Statistical analysis was performed with the
Information was available for 122 (96%) patients; their characteristics according to occurrence of thrombosis are listed in Table 1. None of the patients had a history of a TE or treatment with anticoagulant before the diagnosis of sarcoma. Twenty-three venous TEs were diagnosed in 19 patients (16%; 95% CI, 10% to 23%). No arterial thrombosis was recorded. Two patients had two events and one patient had three events. Ten (8%; 95% CI, 5% to 14%) patients were found to have a clot at the time of initial evaluation, comprising 53% of patients who were found to have a TE. Of these patients, six had a lower extremity thrombosis, two had an inferior vena cava (IVC) clot, one patient presented with pulmonary embolism without a documented origin of the clot, and another patient presented with upper extremity clot in the absence of a venous catheter. Sixty percent of these patients had symptoms related to their clot, and in 50% the clot was related to tumor compression. Interestingly, 80% of the patients who were diagnosed with TE at presentation also had distant metastases at that time.
The rate of thrombosis was similar in all types of sarcoma and was 10% (95% CI, 3% to 30%), 13% (95% CI, 7% to 24%), 15% (95% CI, 6% to 33%), and 33% (95% CI, 15% to 58%) for osteosarcoma, Ewing sarcoma, RMS, and other sarcomas, respectively. Twelve of 53 patients with metastatic disease (23%; 95% CI, 13% to 36%) developed TEs compared with only seven of the 69 patients with localized disease (10%; 95% CI, 5% to 19% [odds ratio, 2.59; 95% CI, 0.9 to 7.1; P < .06]). Two (10%) of the patients had a TE within 28 days of undergoing a surgery. There was no significant difference in the rate of thrombosis among children (age  18 years; 12%; 95% CI, 6% to 25%) and young adults (age > 18 years; 21%; 95% CI, 12% to 33%; P = .17). Table 2 lists the characteristics of thromboses by patient age group. Similar lack of association was seen with cutoff ages of 15 or 20 years.
Five patients had pulmonary embolism. One was diagnosed at autopsy, but death was attributed to widely metastatic disease. Three of the five patients were symptomatic, including a patient who had a fatal event. Four patients were diagnosed by computed tomography scan, and one of them had a confirmatory pulmonary angiography as well. Only five patients were studied for prothrombotic risk factors, and four (80%) of these had antiphospholipid antibodies detected. One TE-associated fatality occurred in a patient with antiphospholipid antibodies who had a massive pulmonary embolism postoperatively 4 months after the completion of antineoplastic treatment. The rate of cancer recurrence was similar among patients with TEs (nine of 19; 47%) or without TEs (48 of 103; 46%). Because of increased awareness of the risk of TEs over time, we compared the prevalence of TEs in patients who were diagnosed before and after 1993. This time point was chosen because it represents the completion of accrual for a particular clinical trial. Although more patients presented with metastatic disease during the early period (44% v 34%; P < .02), 7% of the 57 patients who were treated during the early period were diagnosed with TEs compared with 23% of the 65 patients in the recent period (P < .015). Asymptomatic events accounted for three (75%) and seven (37%) of the TE events in patients who were treated for sarcoma before and after 1993, respectively. Notably, only one patient with osteosarcoma had been treated before 1993. Exclusion of patients with osteosarcoma from this analysis yielded similar results, with TEs seen in 7% v 28% (P < .004) before and after 1993, respectively. Forty-three percent of the 23 events were asymptomatic, and the characteristics of thrombosis by occurrence of symptoms are listed in Table 3. With the exception of the patient whose pulmonary embolism was diagnosed at autopsy and a patient with nonocclusive IVC clot at presentation, the diagnosis of all other occurrences of asymptomatic clots led to antithrombotic treatment, reflecting their significance as judged by the clinical team. One patient underwent IVC filter placement, two were treated with thrombolysis, and eight were treated with anticoagulation (six with low molecular weight heparin [LMWH], four with unfractionated heparin, and one with warfarin).
Of the 23 clots, eight (35%) occurred in the deep veins of the lower extremities, and two (9%) occurred in the upper extremities, four (17%) occurred in the inferior vena cava, two (9%) occurred in the right atrium, and one (4%) each occurred in the superior vena cava and the superior sagittal sinus. Pulmonary embolism accounted for five (22%) of the events. Three (13%) events were associated with the catheter, and an additional eight (35%) events were associated with tumor compression. Ultrasound was used in the diagnosis of 12 (52%) of the clots, computed tomography was used in the diagnosis of 11 (48%) of the clots, and magnetic resonance imaging was used in the diagnosis of seven (30%) of the clots. One pulmonary embolism was diagnosed by pulmonary arteriogram. More than one imaging modality was used in many of the episodes. Initial treatment for the thrombotic episodes included unfractionated heparin in 10 of 23 (43%), LMWH in four of 23 (17%), thrombolysis in four of 23 (17%), and IVC filter placement in four of 23 (17%). Sixteen patients were treated with secondary prophylaxis with LMWH (14 patients) or warfarin (two patients) for a median duration of 5 months (range, 2 to 6 months). Patients who were treated with anticoagulation received transfusions to maintain a platelet count higher than 50,000, and no patient had a bleeding episode. Although three patients had more than one TE, no patient was diagnosed with recurrent thrombosis, and none was reported to have a postphlebitic syndrome.
Children and young adults with sarcoma have a combination of well-recognized risk factors for TEs,29,30 including malignancy, large tumor masses, indwelling venous access devices, intensive chemotherapy,19 radiation therapy, extensive surgery, and associated limited mobility. This population is distinct from previously described older patients with primarily epithelial malignancies. We report that 16% of children and young adults with sarcoma develop TEs, and patients with high disease burden seem to be at an increased risk. Similarly, Athale et al29 recently reported that 14.3% of 70 patients younger than age 18 years with sarcoma developed TEs. Patients with central venous line dysfunction and metastatic disease were at an increased risk. More than half of the clots occurred outside the veins of the extremities, and pulmonary embolism accounted for 22% of events. Importantly, thrombosis is a potentially preventable source of morbidity and mortality in children and young adults with sarcoma who are likely to be cured of their cancer. Our data suggest association between the tumor burden and the risk of thrombosis. Patients who presented with metastatic disease were 2.5 times more likely to suffer from a clot. Moreover, more than half the patients who had a thrombotic complication had a clot at the time of their initial diagnostic work-up, and half of these patients developed a clot that was unrelated anatomically to the tumor, thus suggesting systemic activation of the coagulation system. A combination of the host response and the prothrombotic properties of the malignant cells may be responsible for this systemic activation.15-18 Approximately half of the events in our cohort were asymptomatic. Similarly, studies in children with ALL indicate that only 14% of TEs are symptomatic.23 Moreover, prospective studies designed to evaluate TE in children with ALL report higher incidences compared with studies designed to evaluate overall outcome.31,32 These studies indicate a high rate of asymptomatic events that would elude diagnosis unless actively sought. Our data suggest that children and young adults with sarcoma should be monitored carefully for the development of TEs and suggestive symptoms should be pursued aggressively. Similar to adults, TEs in children are reported to be associated with long-term complications, including clot recurrence (8%) and postphlebitic syndrome (12%).20 CNS thrombosis in children with ALL is associated with residual neurologic deficit in 16% to 18% of patients.33-35 In our study, there was one death directly related to thrombosis. This rate is similar to a reported thrombosis-associated mortality rate of 2.2% in children.20 Postphlebitic syndrome and clot recurrence were not noted in our cohort. Despite the retrospective nature of this study, we were able to retrieve reliable information for the majority (96%) of our patients. Moreover, all our patients had been enrolled onto clinical trials at the NIH, thus ensuring the quality of data collection and uniformity of treatment. It is likely that some TEs were not detected, especially in view of the high rate of asymptomatic events. Therefore, our data probably underestimate the true frequency of TEs in children and young adults with sarcoma. Similarly, in a retrospective survey of children treated for ALL, 1.7% were found to have TEs,36 in contrast to 14.3% of those evaluated prospectively while receiving similar treatment.37 A higher prevalence of TEs was observed among patients treated after 1993, even though a lower rate of metastatic disease was seen in this group. This is likely due to improved imaging and increased index of suspicion, given that other risk factors remained unchanged. These findings provide additional evidence that our data likely underestimate the true magnitude of this problem. We report a single-institution experience of patients who were treated at the NIH Clinical Center on clinical trials. Thus, not all pediatric oncologic diagnoses are represented. Notably, however, all patients were newly diagnosed and were treated using front-line protocols with standard chemotherapy agents. Thus, we believe our findings can be generalized to disease-specific patient populations. Few patients in our cohort underwent comprehensive evaluation for prothrombotic disorders, and information regarding genetic or acquired risk factors was not available for most patients. Thus, our data do not allow for the assessment of the relative contribution of potential prothrombotic factors to the risk for TEs in patients with sarcoma. The contribution of inherited prothrombotic disorders to the development of TEs in children with cancer is unclear.1,38-42 Nowak-Gottl et al42 reported significantly higher risk of thrombosis in children with ALL who had at least one prothrombotic defect. In contrast, other studies did not demonstrate such an association.23,39 Thus, the effect of inherited thrombophilia may vary between different populations, malignancies, or treatments.1,40,42 Interestingly, in our cohort 80% of evaluated patients were found to have antiphospholipid antibodies. Although our data cannot determine causality, the observed rate markedly exceeds the reported 6% to 10% prevalence in healthy normal individuals.43,44 Antiphospholipid antibodies are observed in a wide variety of malignancies, however the correlation with the risk of thrombosis is variable.45-47 The significance of our finding in young patients with sarcoma and thrombosis is not clear, and it may reflect the immune dysregulation and inflammation seen in this group of patients.48-50 In conclusion, thrombosis is frequent in children and young adults with sarcoma. Future studies should address the role of prospective screening for TEs and prothrombotic risk factors to allow identification of patients who may benefit from prophylaxis.51
The authors indicated no potential conflicts of interest.
Conception and design: Ido Paz-Priel, Lauren Long, Lee J. Helman, Crystal L. Mackall, Alan S. Wayne Administrative support: Lauren Long Provision of study materials or patients: Lauren Long, Lee J. Helman, Crystal L. Mackall, Alan S. Wayne Collection and assembly of data: Ido Paz-Priel, Lauren Long Data analysis and interpretation: Ido Paz-Priel, Alan S. Wayne Manuscript writing: Ido Paz-Priel, Alan S. Wayne Final approval of manuscript: Ido Paz-Priel, Lauren Long, Lee J. Helman, Crystal L. Mackall, Alan S. Wayne
Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. I.P.-P. is the recipient of the American Society of Clinical Oncology Young Investigator Award. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. The views expressed do not necessarily represent the views of the National Institutes of Health or the US government. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test for dichotomous data. Analyses were done using SigmaStat (Systat Software Inc, Richmond, CA). 
