Venous Thromboembolism in Patients with Primary Bone or Soft-Tissue Sarcomas

Mitchell, Sheryl Y. BSc; Lingard, Elizabeth A. MPH; Kesteven, Patrick MB, FRACP; McCaskie, Andrew W. MB, FRCS(Tr&Orth); Gerrand, Craig H. MB ChB, FRCSEd(Tr&Orth)

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.F.01308
Scientific Articles
Abstract

Background: Venous thromboembolism has been independently associated with both malignant disease and orthopaedic surgery. Patients with bone or soft-tissue tumors who undergo orthopaedic surgery may therefore be at high risk for thromboembolic events. The purpose of the present retrospective study was to determine the rate of clinically detected deep venous thrombosis and pulmonary embolism in patients with trunk or extremity bone or soft-tissue sarcomas.

Methods: The medical records of patients with a confirmed diagnosis of primary bone or soft-tissue sarcoma who had presented to our unit between 1998 and 2003 were reviewed with use of a standardized chart abstraction tool. The data that were retrieved included patient-related data (demographic characteristics, diagnoses, and surgical interventions), the use of adjuvant chemotherapy or radiation therapy, additional risk factors for thromboembolism, the use of thromboembolic prophylaxis, and confirmed thromboembolic events.

Results: Of the 252 patients who were identified, ninety-four had a diagnosis of primary bone sarcoma and 158 had a diagnosis of primary soft-tissue sarcoma. Approximately 70% of the cohort received thromboprophylaxis, with 57% receiving low-molecular-weight heparin. Thirty-seven patients were clinically suspected of having a deep venous thrombosis. Nine patients had a deep venous thrombosis that was confirmed radiographically, and in one case the diagnosis was made at another center, resulting in a rate of clinically evident deep venous thrombosis of 4%. Nine patients had a clinically suspected pulmonary embolism. One patient had confirmation of the pulmonary embolism with use of a ventilation-perfusion scan, one patient died of pulmonary embolism, and one patient had diagnosis of the pulmonary embolism at another center, resulting in an overall rate of pulmonary embolism of 1.2% and a rate of fatal pulmonary embolism of 0.4%. All patients with thromboembolic events had a tumor involving the hip or thigh, with the majority of the events occurring prior to definitive surgery.

Conclusions: The risk of a clinically apparent thromboembolic event in patients with bone or soft-tissue sarcomas is comparable with that in other orthopaedic patients. However, tumors in the hip or thigh may be associated with a particularly high risk of thromboembolism. A prospective study is needed to investigate factors that are predictive of thromboembolism and the role of chemical thromboprophylaxis.

Level of Evidence: Prognostic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Author Information

1 Departments of Orthopaedics (S.Y.M. and C.H.G.) and Haematology (P.K.), Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, England. E-mail address for S.Y. Mitchell: sheryl.Mitchell@nuth.northy.nhs.uk

2 School of Surgery and Reproductive Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle Upon Tyne, NE2 4HH, England

Article Outline

In England, 25,000 people die of venous thromboembolism each year1. The association between malignant disease and thromboembolism has long been recognized, with venous thromboembolism being confirmed at the time of autopsy in 50% of cancer patients2. Orthopaedic surgery is also known to be a risk factor for venous thromboembolism3. It could be hypothesized, therefore, that patients with bone or soft-tissue tumors who undergo orthopaedic surgery might be at particularly high risk for venous thromboembolism. However, there is little information in the literature, and there is a need for benchmarking data about the risk of venous thromboembolism in these patients. We identified one retrospective study of a cohort of orthopaedic oncology patients, which demonstrated a 14% risk of proximal deep venous thrombosis but a low rate of symptomatic pulmonary embolism4.

Guidelines for thromboembolic prophylaxis in patients undergoing major surgery are being developed in England and Wales by the National Institute for Health and Clinical Excellence (NICE) but are not in place yet. Scottish guidelines recommend the individual assessment of risk factors for venous thromboembolism and promote mechanical and/or chemical prophylaxis for those who are at increased risk5, and the seventh edition of the guidelines of the American College of Chest Physicians (ACCP) has been published6. Studies have suggested that the extended use of low-molecular-weight heparin significantly reduces the risk of proximal deep venous thrombosis in patients undergoing abdominal surgery for the treatment of cancer7 and that there may be added benefits associated with the use of heparin in terms of its antineoplastic properties8. Despite these findings, the role of thromboprophylaxis in orthopaedic patients with cancer is not clear, and there is a need for guidance in the treatment of this group of patients.

The primary purposes of the present retrospective study were to determine the prevalence of venous thromboembolism in patients with trunk or extremity bone or soft-tissue sarcoma in our unit and to identify risk factors for venous thromboembolism in this group. The secondary purposes were to audit the use of prophylaxis against thromboembolism in our unit and to develop local guidelines for thromboprophylaxis.

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Materials and Methods

The present investigation was a retrospective study that was based on a review of clinical records. Patients who had presented to the North of England Bone and Soft Tissue Tumour Service between 1998 and 2003 with a confirmed diagnosis of primary trunk or extremity bone or soft-tissue sarcoma were included. Patients were excluded if they were less than sixteen years of age, had a benign diagnosis, had been managed elsewhere, or had been lost to follow-up less than three months after treatment.

The data items that were retrieved from a review of the case notes included the age and gender of the patient, the anatomical location and histological type of the tumor, the results of biopsy, the type of surgery, the use of adjuvant chemotherapy and radiation therapy, the presence of additional risk factors for thromboembolism5, and the methods of thromboprophylaxis used. The anatomical location of the tumor was defined as trunk, upper extremity, or lower extremity. Lower extremity tumors were further classified, according to the location of the greatest volume of the tumor, as hip/thigh (including the pelvis), knee, or below-the-knee (including the foot and ankle). The signs and symptoms of suspected thromboembolic events were recorded, as were the investigations that were performed for the evaluation of suspected thromboembolic events and whether or not the thromboembolic event was confirmed.

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Statistical Analysis

Patients with and without venous thromboembolism were compared with regard to age and gender, the anatomical location and histological type of the tumor, surgical intervention, additional risk factors for thromboembolism, and the methods of thromboprophylaxis; chi-square and two-sample t test analyses were used as appropriate. The level of significance was maintained at p ≤ 0.05 throughout.

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Results

Of the 314 patients who presented with bone or soft-tissue tumors between 1998 and 2003, 252 met the inclusion criteria. Sixty-two patients (including twenty-five patients who were less than sixteen years of age, eleven patients who were found not to have had sarcoma, and twenty-six patients who were managed elsewhere) were excluded. The clinical records relating to nine patients could not be located. Of the remaining 252 patients, ninety-four had a diagnosis of primary bone sarcoma and 158 had a diagnosis of primary soft-tissue sarcoma (Table I). The mean age at the time of presentation was fifty-three years (range, sixteen to ninety-four years), and 137 patients (54%) were male. The anatomical distribution of tumors is shown in Table II. Of the 252 patients, 249 underwent orthopaedic surgery; specifically, 147 patients (59%) underwent excision of the tumor, forty-seven (19%) underwent excision and reconstruction (with thirty-one patients undergoing endoprosthetic reconstruction, twelve undergoing flap or vascular reconstruction, and four undergoing excision and bone-grafting), thirty-three (13%) had a primary amputation, thirteen (5%) had an open biopsy, and only nine (4%) had other procedures. Three patients could not undergo surgery because of medical comorbidities.

The characteristics of the patients who were diagnosed with venous thromboembolism are summarized in Table III. Thirty-seven of the 252 patients had clinically suspected deep venous thrombosis. Of the thirty-seven patients with suspected deep venous thrombosis, thirty-three underwent venous ultrasonography, one underwent magnetic resonance imaging, one had a D-dimer level alone, one had no documented investigation, and one received the diagnosis at another center (investigation unknown). Nine patients were confirmed to have deep venous thrombosis on the basis of venous ultrasonography and one patient received the diagnosis at another center (investigation unknown), resulting in a rate of clinically evident deep venous thrombosis of 4%. Two of these ten patients had a deep venous thrombosis after biopsy and went on to have an additional deep venous thrombosis after definitive surgery despite the use of chemical prophylaxis (both patients received low-molecular-weight heparin following definitive surgery, and one also received warfarin and an inferior vena cava filter) (Table III).

Nine patients were clinically suspected of having pulmonary embolism because of shortness of breath, chest pain, or tachycardia. Of these nine patients, five were investigated with a radioisotope ventilation-perfusion scan or computed tomographic angiogram, two had chest radiographs only, one was confirmed to have had a pulmonary embolism at the time of autopsy, and one received the diagnosis at another center (investigation unknown). One patient was confirmed to have had a pulmonary embolism on the basis of a ventilation-perfusion scan, one patient died of a pulmonary embolism, and in one case the diagnosis was made at another center (investigation unknown), resulting in an overall rate of pulmonary embolism of 1.2% and a rate of fatal pulmonary embolism of 0.4%. The patient for whom the diagnosis was confirmed at the time of an autopsy died suddenly following an open biopsy for the evaluation of a large thigh tumor, having already undergone an inconclusive needle biopsy. This was the only fatal pulmonary embolism in the series. Therefore, the rate of clinically evident pulmonary embolism was 1.2% (three of 252) and the rate of fatal pulmonary embolism was 0.4% (one of 252).

The demographic and clinical data for patients with and without venous thromboembolism are compared in Table IV. With the numbers available, there were no significant differences between the patients with and without venous thromboembolism in terms of age, gender, the type of tumor (bone or soft-tissue sarcoma), or the use of low-molecularweight heparin. However, all patients with thromboembolic events had tumors of the hip or thigh (p = 0.0006), with a mean maximum tumor diameter of 16.6 cm (range, 11 to 23 cm). The anatomical site was the acetabulum for one patient (Case 2) and the distal part of the femur for one patient (Case 4); the rest of the tumors were all soft-tissue tumors of the thigh (Table III). The rate of clinically evident venous thromboembolism in patients with hip or thigh tumors was 9.6% (thirteen of 136), compared with 0% for patients with tumors in other anatomical sites. In the group of patients with tumors in the hip or thigh, there were no significant differences between patients with and without venous thromboembolism in terms of age, gender, the type of tumor (bone or soft tissue), or the use of low-molecular-weight heparin, with the numbers available. However, patients with venous thromboembolism had significantly more additional risk factors than did those without (3.2 compared with 2.5; p = 0.012).

The majority of thromboembolic events occurred before definitive surgery. Two patients presented with deep venous thrombosis on referral to the unit; neither had undergone biopsy or treatment before referral, although one was noted to have had reduced mobility for two weeks prior to outpatient consultation. Five of ten deep venous thromboses and two of three pulmonary emboli occurred at a mean of twenty-seven days (range, four to sixty days) after open biopsy but before definitive surgery. Three patients had deep venous thrombosis at a mean of twenty-one days (range, eleven to thirty days) after definitive surgery; one of these patients had been discharged from the hospital at the time of diagnosis. One patient had a pulmonary embolism following chemotherapy but before definitive surgery.

Patients with venous thromboembolism had significantly more additional risk factors than did those without venous thromboembolism (mean, 3.2 compared with 2.4; p = 0.005) (Tables IV and V). There was evidence of appropriate assessment of risk factors for venous thromboembolism at the time of admission and during the hospital stay as patient circumstances changed. Two of the thirteen patients with venous thromboembolism had metastatic disease at the time of presentation (Cases 6 and 12) (Table III). Two of the thirteen patients had a thromboembolic event while receiving chemotherapy (Cases 6 and 8) (Table III), and one patient had a pulmonary embolism following chemotherapy. None of the patients with thromboembolic events had had radiation therapy at the time the venous thromboembolism occurred.

Overall, 172 (69%) of 249 patients in the cohort received some form of chemical or mechanical thromboprophylaxis after definitive surgery; thirty-three patients received both. Of these 249 patients, 141 (57%) received low-molecular-weight heparin. Mechanical prophylaxis was in the form of thromboembolic deterrent stockings for twenty-seven patients and pneumatic compression boots (A-V Impulse System; Novamedix, Andover, England) for twenty-four patients. In five cases, the patient did not receive thromboprophylaxis as prescribed in the operative note. Low-molecular-weight heparin was given for a mean of thirty-nine days (range, six to 183 days) after definitive surgery for patients with venous thromboembolism, compared with thirteen days (range, one to ninety-two days) for those without venous thromboembolism. However, in the majority of cases, low-molecular-weight heparin was given as treatment of a venous thromboembolism rather than as prophylaxis. Of the seven patients who had venous thromboembolism following open biopsy, only one had received low-molecular-weight heparin as thromboprophylaxis following this procedure. Twenty-two patients were receiving aspirin for the treatment of coexisting conditions rather than as thromboprophylaxis.

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Discussion

In the present retrospective study, we determined the rate of clinically evident thromboembolic events in patients with trunk or extremity bone or soft-tissue sarcomas in our center. Of the 252 patients, ten (4%) had a confirmed deep venous thrombosis and three (1.2%) had a pulmonary embolism, one of which was fatal (prevalence, 0.4%). The overall rate of clinically detected thromboembolic events was similar to that seen in other groups of patients undergoing orthopaedic procedures such as primary joint replacement9 and appears to be no higher than the 14% rate of proximal deep venous thrombosis in orthopaedic cancer patients receiving mechanical thromboprophylaxis as reported by Lin et al.4. However, even the relatively minor procedure of open biopsy may lead to thromboembolic events in these patients. All of the venous thromboembolism events that we identified occurred in patients with tumors that were located in the hip or thigh region, and the majority occurred after open biopsy but before definitive surgery.

Our study indicates that patients with large tumors in the hip or thigh region are particularly at risk for venous thromboembolism. This has been suggested in the literature previously10, but to our knowledge the present study is the first to demonstrate this finding in a large cohort of patients. Large tumors in the thigh may impede venous return from the lower extremity mechanically, or they may invade the veins. It seems unlikely that large tumors have a systemic procoagulant effect as large tumors in other anatomic locations were not associated with venous thromboembolism.

The present study demonstrated that venous thromboembolism occurred after open biopsy but before definitive surgery in seven of thirteen cases, raising the question that open biopsy itself could be a risk factor. All three of the patients who had development of deep venous thrombosis after definitive surgery had undergone an open biopsy, and the patient who had development of a pulmonary embolism following chemotherapy also had had a previous open biopsy. Unfortunately, the limitations of the present study mean that we are unable to comment on the contribution of open biopsy to the development of venous thromboembolism. As we are not aware of any studies that have investigated whether open biopsy is a risk factor, we believe that the type and timing of biopsy should be included in prospective studies investigating this question. Clearly, however, clinicians should be alert to the possibility that thromboembolic events can occur after open biopsy, and consideration should be given to excluding the presence of deep venous thrombosis before undertaking definitive surgery.

Given that all thromboembolic events occurred in association with tumors in the hip or thigh, patients with tumors in other anatomical sites are likely to be at low risk of thromboembolism. Of the 116 patients with tumors in other anatomical sites, only fifty were given low-molecular-weight heparin. Nevertheless, there were no thromboembolic events in this group. The risks of chemical thromboprophylaxis may therefore outweigh the benefits in selected patients. Further defining this low-risk group would be a valuable aim of a prospective study.

Overall, 60% of the patients received low-molecularweight heparin at the time of definitive surgery and for the duration of their hospital stay. Although we analyzed the use of low-molecular-weight heparin, the timing and duration of administration were too diverse to allow us to draw conclusions regarding its effectiveness in this cohort of patients. Low-molecular-weight heparin is now widely accepted in Europe as a safe and effective thromboprophylactic agent that is used for cancer patients during hospitalization11 and has an extended role after discharge from the hospital7. Guidelines recommend the use of low-molecular-weight heparin for patients undergoing major orthopaedic surgery such as joint replacement12. Anecdotal evidence suggests that orthopaedic oncology surgeons may be reluctant to prescribe chemical thromboprophylaxis because of concerns about bleeding complications. Findings from the RIETE (Registro Informatizado de Pacientes con Enfermedad Tromboembólica) registry highlighted that patients with cancer had a higher prevalence of major bleeding complications than did patients without cancer and that patients with cancer were at a significantly greater risk for recurrent bleeding complications and fatal pulmonary embolism13. Given that sarcomas are highly implantable, it is certainly a theoretical concern that wound complications such as bleeding or hematoma formation may lead to wider contamination of a surgical field with tumor and an increase in the rate of local recurrence. Balancing these considerations is difficult.

Our study had several limitations. First, the prevalence of venous thromboembolism may have been underestimated because of the retrospective design of the study, for two reasons: (1) thromboembolic events may have been diagnosed and treated elsewhere given that patients were referred from a wide geographical area, and (2) patients may have had subclinical thromboembolic events that were not detected. Second, some of the documentation was found to be poor, particularly that which related to the use of mechanical methods of thromboprophylaxis and the recording of the body mass index for the patients. In addition, because of the low numbers of thromboembolic events, we were unable to identify significant risk factors for venous thromboembolism in this group of patients.

We believe that a prospective study of thromboembolism in this group of patients would be valuable for defining risk factors, determining the contribution of biopsy to venous thromboembolism, and identifying low-risk patients who do not need thromboprophylaxis. ▪

NOTE: The authors thank Shona Murray for allowing her patients to be studied.

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from an unrestricted educational grant from Sanofi-Synthélabo for a research nurse salary. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits of less than $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Leo Pharma). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Investigation performed at the Department of Orthopaedics, Freeman Hospital, Newcastle Upon Tyne, England

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