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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 2  |  Page : 344-349

Clinical characteristics and prognosis of cancer patients with venous thromboembolism


1 Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
2 Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, National Center of Respiratory Disease, Beijing, China
3 Department of Respiratory Medicine, Beijing Eden Care Hospital, Beijing, China

Date of Web Publication1-Apr-2019

Correspondence Address:
Prof. Lin Li
Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing 100730
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_121_18

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 > Abstract 


Aims: The aim of this study is to analyze the clinical features and prognosis of cancer patients with venous thromboembolism (VTE).
Subjects and Methods: This was a retrospective observational study that selected cancer patients with a new VTE event from January 2003 to 2013 using the hospital information system in Beijing Hospital. The patients were divided into three groups according to the site of thrombosis as follows: pulmonary thromboembolism (PTE), deep venous thrombosis (DVT), or PTE plus DVT. The clinical manifestations and prognosis among the three groups were compared.
Results: Among the 18,531 patients diagnosed with a malignant tumor, 280 (1.51%) patients presented with VTE at first diagnosis or during the disease course; of these, 26 had incidental pulmonary embolism (IPE). Dyspnea was the most common symptom in the PTE group (51.65%), and lower limb swelling was found mostly in the DVT group (65.27%). Approximately 53.92% and 63.21% of patients had VTE events within the first 3 and 6 months after cancer diagnosis, respectively. The median survival time of all VTE patients was 24.0 ± 7.85 months, with the DVT group having the longest survival time among the three groups (P < 0.05). About 29.23% of the 130 patient deaths occurred within the first 30 days after VTE diagnosis, and 46.92% occurred within the first 3 months.
Conclusions: The incidence of IPE in cancer patients was not rare. Most VTE events occurred within the first 6 months after the cancer diagnosis, and nearly half of the deaths occurred within the first 3 months of VTE diagnosis in cancer patients.

Keywords: Cancer, deep vein thrombosis, pulmonary thromboembolism, venous thromboembolism


How to cite this article:
Wang H, Xu X, Pu C, Li L. Clinical characteristics and prognosis of cancer patients with venous thromboembolism. J Can Res Ther 2019;15:344-9

How to cite this URL:
Wang H, Xu X, Pu C, Li L. Clinical characteristics and prognosis of cancer patients with venous thromboembolism. J Can Res Ther [serial online] 2019 [cited 2019 Jul 18];15:344-9. Available from: http://www.cancerjournal.net/text.asp?2019/15/2/344/255083




 > Introduction Top


Venous thromboembolism (VTE) is closely related to malignant tumors. The incidence of VTE in tumor patients is reported to be 4%–20%.[1] Complications of anticoagulant therapy in tumor patients is higher than that in the general population.[2] More importantly, VTE is the second leading cause of death in cancer patients.[3],[4],[5] Unfortunately, VTE's severity remains underestimated by many oncologists.

This study retrospectively analyzed the clinical data of cancer patients with VTE and aimed to explore the clinical characteristics and prognosis and probably improve the prevention and prognosis of patients with malignant tumors concomitant with VTE.


 > Subjects and Methods Top


Patients

This was a retrospective, observational study including patients diagnosed with cancer and/or VTE during the period of January 2003–2013 using the hospital information system (HIS) in Beijing Hospital, which provides data for all hospitalizations, including diagnosis and procedures. Patients with a new VTE event and diagnosis of cancer were screened and analyzed in this study, excluding patients with isolated cancer or isolated VTE. Ethical approval was obtained from the ethics committee of Beijing Hospital, China. Written informed consent was provided by all patients or their family members.

Methods

Patients' medical information on VTE and cancer were collected from HIS or medical record system. VTE-related information included symptoms, signs, auxiliary examination results, treatments, risk assessment of VTE, and pulmonary thromboembolism severity index. Cancer-related information included the time of diagnosis, staging, and treatments. The survival information was obtained from the medical record system, outpatient follow-up, or telephone follow-up. Follow-up was terminated in the event of patient death. The deadline for follow-up was December 2014, and the median survival time was then calculated. Survival time was defined as the time from diagnosis until death or truncation. Truncation events included patients who were either lost to follow-up or still alive at the time of study termination. VTE diagnosis was confirmed by objective medical imaging methods. The diagnosis and risk classification of PTE are based on the European Society of Cardiology, the Guide of Diagnosis and Treatment of Acute Pulmonary Embolism in 2014.[6] The diagnosis of deep venous thrombosis (DVT) is based on the treatment of DVT on the 9th edition of the American College of Chest Physicians.[7] The TNM staging standard of malignant tumors is based on the 2007 edition of the American Joint Committee on Cancer guide.[8]

In addition to the overall evaluation of tumor-related VTE, patients were divided into three groups based on the site of the thrombosis as follows: PTE group, combined positron emission tomography (PET) and DVT group, and DVT group. Clinical features and prognosis were compared among the three groups.

Statistical analysis

Statistical analysis was performed using SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA). Chi-square test was used to compare the clinical characteristics of the study groups. Kaplan–Meier method was used to draw survival curve, and the Log-rank test was made to compare the corresponding curve. The value of P < 0.05 was considered statistically significant.


 > Results Top


Incidence of patients with cancer-related venous thromboembolism

From January 2003 to 2013, a total of 1402 patients with VTE and 18,531 patients with a malignant tumor were admitted to our hospital at the same time. A total of 280 patients were diagnosed with VTE at the time of or after the diagnosis of cancer, accounting for 19.97% (280/1402) of patients with VTE during that period. No patients had experienced VTE event before cancer diagnosis in this study. Among the 280 patients, 157 were male and 123 were female cancer patients with VTE (median age: 66.60 ± 12.60 years). Among the 280 patients, 41 had isolated PTE (14.64% of the cancer-associated VTE), 189 had isolated DVT (67.50%), and 50 had PTE with DVT (17.86%). The incidence of VTE in cancer patients was 1.51% (280/18531) in 10 years (2003–2013); among these, the incidence of isolated PTE, isolated DVT, and combined PTE and DVT in cancer patients was 0.22%, 1.02%, and 0.27%, respectively.

A majority of VTE events occurred shortly after the diagnosis of cancer. Among the cancer patients, 53.92% had their VTE event within the first 3 months, 63.21% within the first 6 months, and 68.93% within the first 9 months [Table 1].
Table 1: The distribution of venous thromboembolism events

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Presentation, diagnosis, and treatment of venous thromboembolism in patients with cancer

The symptoms, signs, and scores of tumor-associated VTE are shown in [Table 2] and [Table 3]. Among the 91 patients with PTE, 65 (71.42%) were symptomatic (suspected pulmonary embolism,); of these 65 patients, 60 were diagnosed with the computed tomography pulmonary angiography (CTPA) and five with ventilation/perfusion scan. The remaining 26 patients (9.29%) were accidentally diagnosed during a regular contrast-enhanced computed tomography (CECT) of the chest while assessing the curative effect (incidental pulmonary embolism, [IPE]); of these 26 patients, 15 had lung cancer and 11 had digestive tract tumors. Common sites of the embolus were the lower lobes of the bilateral lung pulmonary artery and its branches.
Table 2: Conditions of patients with tumor-related pulmonary thromboembolism

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Table 3: Conditions of Patients with tumor-related deep venous thrombosis

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A total of 239 (85.36%) patients received pharmacologic or mechanical thromboprophylaxis for VTE, and 41 (14.64%) were not anticoagulated regarding a low platelet count, hemoptysis, or gastrointestinal bleeding. Among the 239 patients who received thrombolysis and anticoagulation therapy, 24 (10.04%) showed complications with hemorrhage, including gastrointestinal bleeding (n = 14), hematuria (n = 3), respiratory tract hemorrhage (n = 4), and skin bleeding (n = 3). Severe hemorrhage (gastrointestinal bleeding) occurred in two patients, and blood transfusion was required. One patient had a history of peptic ulcer, while the other did not; none of the two patients have a digestive tract tumor.

Prognosis of cancer patients who developed venous thromboembolism

At the end of the follow-up (December 2014), 130 cancer patients with VTE died (23 in the isolated PTE group, 29 in the combined PTE and DVT group, and 78 in the isolated DVT group), whereas 105 survived, and 45 were lost to follow-up. A majority of the patients died of progression of underlying cancer (n = 87, 66.92%). Among the noncancer-related deaths, PTE was the leading contributor (n = 18, 13.85%), followed by infection (n = 13, 10.00%), cardiac insufficiency (n = 5, 3.85%), and other reasons (n = 7, 5.38%). Among the 130 patients who died, 29.23%, 46.92%, 69.23%, 80.77%, and 83.08% died within 30 days, 3, 6, 9, and 12 months after diagnosis of VTE, respectively [Table 4]. No statistically significant difference was observed among the three groups according to the time of death (P = 0.963).
Table 4: The distribution of death in patients with cancer-related venous thromboembolism

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The survival curves during the entire follow-up period for the three groups were different. Kaplan–Meier survival analysis showed that the median survival time of patients with tumor-related VTE was 24.0 ± 7.85 months, and the survival rate at 1-, 2-, and 3-year follow-up after the diagnosis of VTE was 61.43%, 56.78%, and 55.35%, respectively [Figure 1]. The median survival time of patients with isolated PTE was 16.0 ± 10.50 months; combined PET and DVT, 6.0 ± 1.99 months, and isolated DVT, 42.0 ± 9.52 months. The Log-rank test showed significant differences among the three groups [P = 0.015; [Figure 2]. No statistically significant difference was observed between the isolated PTE group and combined PTE and DVT group, as well as between isolated PTE group and isolated DVT group with respect to median survival time, with P = 0.382 and 0.150, respectively. The median survival time was significantly different between combined PTE and DVT group and isolated DVT group (P = 0.005).
Figure 1: The survival curve of cancer patients with venous thromboembolism

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Figure 2: The survival curve of the three groups on venous thromboembolism

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 > Discussion Top


Cancer and the occurrence of VTE were strongly associated.[9],[10],[11] Active cancer with and without chemotherapy increases the risk of VTE by five- to six-fold,[12] and 20% of VTE events was estimated to occur in patients with cancer.[13] The incidence of cancer-associated VTE reported in previous epidemiologic studies varies from 0.6% to 7.8%, depending on the population studied.[14],[15],[16] It is reported to be 5.4% in hospitalized cancer patients.[16] In this study, tumor-associated VTE accounted for 19.97% of all VTE occurrences in our hospital during the last 10 years. The occurrence rate of cancer-related VTE was 1.51%; isolated PTE, 0.22%; combined PTE and DVT, 0.27%; and isolated DVT, 1.02%, which were consistent with those of the previous studies.[13],[17],[18],[19],[20]

The risk of VTE significantly increased during the first 6 months after the diagnosis of cancer; however, the risk of VTE in patients who underwent chemotherapy and/or surgery was also significantly increased.[18],[21] This research showed that VTE risk rapidly increased in the first 3 months after cancer diagnosis, accounting for more than half of all VTE events. As time progressed, the increase in VTE risk gradually slows down. Cancer-associated VTE may be caused by the hypercoagulable state, direct effects of therapies on the vascular endothelium, or bedridden after the operations. As a result, cancer patients with potential VTE risk should be properly monitored, especially during the first 3 months after the diagnosis of cancer.

Activation of coagulation promotes tumor growth and angiogenesis, leading further credence to the association of the clinical hypercoagulable state and worse prognosis, and prophylactic anticoagulation therapy in patients with cancer can significantly reduce thrombotic events; however, the conclusions on the risk of bleeding are still different.[22],[23],[24] Bleeding in cancer patients occurs through the complex interplay of disease-and treatment-related factors. For example, chemotherapy often leads to thrombocytopenia, and the tumor itself can also cause abnormal clotting mechanism, which therefore leads to an increased risk of bleeding in patients with cancer who received anticoagulant therapy making drug prevention for cancer patients with VTE difficult. In this retrospective study, the overall bleeding incidence rate was 10.04%, with the major bleeding events rate of 0.84%, which were lower than that of the previous studies.[18] This may be because the patients enrolled in this study received treatments other than chemotherapy. Only 13.93% of patients took measures to prevent VTE, and the proportion of patients who took prophylactic pharmacologic anticoagulation was even lower, which may result in an insufficient understanding of the risk of VTE in cancer patients; however, the concern about anticoagulation was more important. The concerns about the risk of bleeding also lead to low compliance with prophylaxis in the cancer population. Our data failed to answer the question of whether cancer patients with VTE should receive more aggressive anticoagulation than other patients with thrombosis.

Mortality was significantly and consistently higher among patients who developed VTE as compared to those who did not.[19] In this study, we could not compare the survival time between patients with or without cancer. The results indicated that the risk of death rapidly increased in the first 3 months after the diagnosis of VTE, especially in the 1st month. After that, as time progresses, the risk of death slowly decreased. Almost one-third of the deaths occurred within the 1st month, half of the deaths occurred within the first 3 months, and 69.23% of deaths occurred within the first 6 months after the diagnosis of VTE. The median survival time of the combined PTE and DVT group is shorter than the isolated DVT group. The two leading causes were tumor itself and PTE, which is consistent with those of the previous studies.[25]

The symptoms of tumor-related VTE were associated with thrombosis location. The most frequent symptoms of PTE were dyspnea (47/91, 51.65%) and syncope (10/91, 10.98%). The most frequent symptoms observed in patients with DVT were limb swelling (156/239, 65.27%) and pain (99/239, 41.42%). The occurrence of a cough, dyspnea, chest pain, heart palpitations, and syncope was higher in combined PET and DVT group than the isolated DVT group, and limb swelling was more common in the combined PET and DVT group than the isolated PTE group. Therefore, cancer patients with VTE who showed these symptoms should not only be attributed to the primary tumor. Among the 239 patients with DVT, only 50 of them were also diagnosed as PTE, probably because of insufficient recognition of VTE in early cases. Some patients with DVT did not undergo CTPA, which would have resulted in lower incidence of PTE. In the recent years, this situation is gradually reduced with the deepening understanding of VTE. In addition, the occurrence rate of thrombus in the upper extremity, internal jugular vein, and subclavian vein was high, which were related to vascular endothelial injury and slow blood flow caused by the deep venous indwelling catheter, local tumor, or regional lymphadenopathy.

It should be noted that some patients with PTE were diagnosed when they underwent a regular chest CECT examination, which is called IPE, with the occurrence rate of 1.5%–3.4%,[26],[27] whereas the occurrence rate of IPE in cancer patients is 4.4%.[28],[29],[30] A total of 26 patients in this study were accidentally diagnosed with PTE, accounting for 9.29% of the cancer-related VTE, which was much higher than that of the previous studies. One possible reason was that patients were asymptomatic or symptoms of PTE were atypical and were covered by the primary disease symptoms. Patients with advanced diseases often suffered from dyspnea due to tumor progression, merger pleural effusion, or lung infection, which is difficult to distinguish from PTE symptoms. In addition, concomitant diseases in elderly patients should also be considered. Undiscovered VTE may be the cause of sudden death or deteriorating condition in cancer patients.

This study retrospectively analyzed the characteristics of cancer-associated VTE in the past 10 years. No patient was diagnosed with VTE before the detection of cancer, which was large because few patients with VET were followed for surveillance or extensive screening for occult cancers. Lack of awareness on the association between cancer and VTE might also be an important factor. Although a small randomized clinical trial found that more occult cancers were detected at an early stage with extensive screening, which theoretically could improve cancer treatment potential, no difference in the survival was noted between this strategy and the usual care.[31] Opinions still differ regarding screening for an underlying occult cancer after an idiopathic VTE event.


 > Conclusions Top


Symptoms of tumor-related VTE were associated with thrombosis location. IPE in cancer patients was not rare. More than half of the VTE event in cancer patients occurred within the first 3 months after the diagnosis of tumor, and nearly half of the deaths happened within the first 3 months of VTE diagnosis. The assessment and monitoring of VTE in cancer patients should be strengthened and necessary preventive measures should be taken after weighing the pros and cons.

Financial support and sponsorship

This work was supported by the National Key R&D Program of China (2016YFC0902003).

Conflicts of interest

There are no conflicts of interest.



 
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