|MINI SYMPOSIUM: SUPPORTIVE CARE
|Year : 2012 | Volume
| Issue : 1 | Page : 119-124
Pulmonary embolism in cancer patients
SP Sawant, S Banumathy, A Daddi, AA Dhir
Department of General Medicine, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||25-Jul-2012|
A A Dhir
Department of General Medicine, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Aims and Objectives: Pulmonary embolism (PE) is rare in the Indian population and is under-reported in patients with malignancy. We studied the clinical profile and outcome of patients with PE and cancer in the Indian population. Materials and Methods: Data of cancer patients with PE, admitted in a tertiary cancer centre, was analyzed. The prevalence of PE was calculated as the number of patients with PE per 10,000 hospital admissions. The demographic data, details of cancer, co-morbidities, details of PE, and treatment given for PE and their outcomes were recorded and analyzed. Results: There were 56,425 hospital admissions in the study period. The prevalence of PE was 6.4 per 10,000 hospital admissions .Thirty-six cancer patients were diagnosed to have PE. In females, gynecological malignancies (36.84%) and in males gastrointestinal, head and neck cancers, and hematological malignancies were the most common sites (17.7% each). PE was associated with DVT in 41.7%. Dyspnea was the most common presenting symptom. Five patients (13.88%) were asymptomatic and were incidentally detected to have PE . The most common echocardiographic finding was right ventricular dysfunction (55.55%). Mortality among the treated patients was 22% (7 / 31) and in untreated patients it was 80% (4 / 5). The factors that had an impact on a three-month survival were, the presence of massive PE (P = 0.019) and the presence of RV dysfunction at presentation (P = 0.005). Conclusion: The prevalence of PE and mortality due to PE is high in cancer patients. Risk stratification for venous thromboembolism (VTE) should be done in all cancer patients and thromboprophylaxis should be optimally used.
Keywords: Cancer, India, pulmonary embolism
|How to cite this article:|
Sawant S P, Banumathy S, Daddi A, Dhir A A. Pulmonary embolism in cancer patients. Indian J Cancer 2012;49:119-24
| » Introduction|| |
Pulmonary embolism (PE) is a substantial cause of morbidity and mortality in cancer patients.  The risk of venous thromboembolism (VTE) is influenced by the kind of cancer, stage of the disease, and the co-morbidities of the patients. , The procoagulopathic state in cancer patients is associated with proximal deep venous thrombosis (DVT), which in turn is associated with higher rates of PE. , Malignancy induces not only thrombotic PE, but also tumor PE and tumor invasion into large veins.  Oncology patients have a four-to-eight fold higher risk of dying after an acute thrombotic event than patients without malignancy. , VTE with and without PE is second among the causes of death in cancer patients, and the incidence is reported to be about 10 to 15%.  Prompt diagnosis of PE is essential as it can recur and have fatal sequelae, thereby affecting morbidity and survival in cancer patients.
Venous thromboembolism, although previously considered to be rare in Asia has been reported to be increasing in incidence.  There is a paucity of data on PE in Indian cancer patients. We are reporting the findings of the Cancer Thrombosis Clinic at a tertiary referral cancer centre.
| » Materials and Methods|| |
The study was conducted at a tertiary referral cancer center. Registered cancer patients who were detected or suspected to have VTE were referred to the Cancer Thrombosis Clinic at the center. In clinically suspected patients, deep venous thrombosis (DVT) was confirmed by a lower limb Duplex Doppler. 2D Echocardiography (2D Echo) Computerized tomography (CT) chest /CTpulmonary angiography was performed to diagnose PE in suspected patients. Patients who were diagnosed to have VTE were registered. The demographic data, details of the malignancy site, stage, histopathology, cancer treatment, co-morbid factors, and treatment for VTE (medical and surgical) and the outcomes were recorded. We conducted a retrospective analysis of patients with cancer and PE, registered in the Cancer Thrombosis Clinic during the period January 2006 to August 2009. The effect of factors affecting the overall survival at three months was analyzed.
The prevalence of PE was calculated as the number of patients with PE per 10,000 hospitalized patients. The CT findings of PE were recorded as central (filling defects in the pulmonary arteries, main stem with or without peripheral vessel involvement) or peripheral (filling defects in one or more peripheral vessels). PE was designated as massive if the systolic BP was less than 90 mm Hg at presentation. Right ventricular dilatation with right ventricular hypokinesis on 2-D echocardiography was noted as the right ventricular dysfunction.
Statistical analysis - The clinical data was entered into a Predictive Analytics SoftWare (PASW, Version 18; Chicago, IL). Fisher's exact test (dichotomous variables) and the Mantel-Haenszel Exact chi-squared test (ordered categorical variables) were used for analyzing the variables. The primary efficacy variable was the Overall survival (OS), and was calculated by the Kaplan-Meier method using the log-rank test, for group comparison. All the tests were two-tailed and conducted at a 5% significance level.
| » Results|| |
During the study period, there were 56,425 hospital admissions. Of these 36 cancer patients were diagnosed to have PE. The prevalence of PE was 6.4 per 10,000 hospital admissions. There were 19 females with a mean age of 48 years (range 15 - 72 years) and 17 males with a mean age of 49 years (range 20 - 62 years). In 31 (86.11%) patients cancer preceded the development of PE, in two patients (5.55%) PE preceded the diagnosis of cancer, and three patients (8.33%) presented with concomitant cancer and PE.
[Table 1] gives the distribution sites of the primary malignancies. Adenocarcinoma was the most common histopathological type (33.33%). All except one patient had active disease and of these most (69.4%) had an advanced stage of cancer. Associated risk factors for the development of PE were immobilization in 16 (42.1%), surgery in 7 (19.44%), tamoxifen in one (2.7%), morbid obesity in one (2.7%), varicose veins in one (2.7%) and hyperhomocysteinemia in one (2.7%). The mean postoperative duration after which patients developed PE was eight days (range 1 - 15 days). Only three patients out of the seven patients who developed postoperative PE (42.8%) had received postoperative DVT prophylaxis. Ten patients developed PE while on chemotherapy and one patient during radiotherapy.
[Table 2] gives the details of symptoms at the time of presentation with PE. Five patients (13.88%) were incidentally detected to have PE and were asymptomatic. Eleven patients(30.6%) had massive PE.
[Table 3] gives details of the venous Doppler and CT scan chest findings. In 32 patients (88.88%) PE was diagnosed on the basis of CT chest and / or pulmonary angiography. In four patients, the CT scan of the chest was not done and PE was diagnosed on the basis of a 2-D Echo. Of these, one patient had a free floating thrombus in the RA and RV. Two patients had signs of RV dysfunction on 2-D Echo and associated documented DVT on the Venous Doppler. One patient had signs of severe RV dysfunction on 2-D Echo and was hemodynamically unstable. Venous Doppler was done in 24 patients (66.66%). Fourteen patients had proximal DVT and one had distal DVT. 2-D Echo was performed in 32 patients (88.88%). The most common finding was RV dysfunction, which was seen in 17 patients (55.55%). RA and RV were dilated without RV hypokinesis in five (15.6%) patients. Two patients had moderate tricuspid regurgitation, with raised pulmonary artery systolic pressure, with normal RV and RA size. 2-D Echo was normal in eight patients.
Five patients were thrombolysed, three with streptokinase and two with urokinase. Surgical thrombectomy was performed in two patients, first was a 31-year-old female, with recurrent oligodendroglioma. On postoperative day five, she developed massive saddle PE. As thrombolysis was contraindicated due to the immediate postoperative period and neurosurgery, surgical intervention was done. The second patient was an operated case of endometrial cancer, who developed PE in the postoperative period. 2-D Echo showed a free floating thrombus in the right atrium and ventricle. The histopathology in this patient revealed venous thrombus. Both patients were referred to another center for surgical thrombectomy .Twenty-four patients were anticoagulated with heparin (Unfractionated-11, Low molecular weight heparin-13) followed by oral anticoagulation with warfarin.
Five patients did not receive treatment. Two patients had massive PE and died before treatment could be started. Three patients had contraindications to anticoagulation. Of these two patients had thrombocytopenia and one patient had active upper gastrointestinal bleeding due to gastric cancer. Inferior vena cava filter (IVC filter) was inserted in three patients. Of these, one patient had active upper gastrointestinal bleeding, one patient was with massive PE and bilateral varicose veins, and one patient was with submassive PE and bilateral ileofemoral DVT. Two out of the five patients who were thrombolyzed had major bleeding, requiring blood transfusions. No patient in the anticoagulation group had major bleeding. In one patient with liver metastases, anticoagulation had to be discontinued due to the deranged coagulation profile. Anticoagulation had to be stopped in one patient with lung cancer, due to recurrent hemoptysis.
Eleven patients expired due to PE. Of these , three with massive PE died despite thrombolysis, three were not anticoagulated due to contraindications, three had recurrent massive PEs while on anticoagulation, and two patients died before treatment.25% (9 / 36) died within two weeks of diagnosis of PE (range 1 - 60 days). Mortality among the treated PE was 22% (7 / 31) and in the untreated patients it was 80% (4 / 5). Six patients were lost to follow-up at three months; four of these had advanced disease and were advised palliative care. The factors that impacted a three-month survival were massive PE (P = 0.019) and presence of RV dysfunction at presentation (P = 0.005) [Table 4]. Stage of cancer and presence of central PE were not significant predictors of a three-month survival.
| » Discussion|| |
Until recently it was thought that VTE was not so common in the Indian population. In a recent Indian study by A D Lee et al., the incidence of VTE was 17.46 per 10,000 admissions. Malignancy (31%) was the most common predisposing factor, followed by postoperative status (30%).  In a recent global epidemiological study, 52% (42% medical and 64% surgical) of 68,183 (55% medical and 45% surgical) inpatients in 358 hospitals across 32 countries were found to be at risk for developing VTE.  India contributed 2058 patients (46% medical and 54% surgical), where 54% (45% medical and 61% surgical) of hospitalized patients had risk factors for VTE; same as in the rest of the world. In USA the incidence of VTE was much higher, 130 per 10 000 hospital admissions.  The relatively low incidence of VTE in Asians and Hispanics has not been explained, but may be related to a lower prevalenceof genetic factors predisposing to VTE, such as factor V Leiden in Asian populations (0.5%) compared to Caucasians (5%). 
In a study by Agnelli et al., out of 2119 patients with VTE ,18% were diagnosed cases of carcinoma, while 2.4% were diagnosed simultaneously.  Idiopathic PE can be a predictor of occult malignancy and has been reported to have a 10% frequency of concurrent cancer.  In our study 5.55% patients were diagnosed with PE prior to the diagnosis of cancer and 8.33% were diagnosed concurrently.
Lee et al., in their study, have also found the most common association of DVT with gynecological (31%) and gastrointestinal tumors (19%).  Agnelli et al., in their study, found genitourinary cancer (26.5%) to be the most commonly associated malignancy, followed by gastrointestinal and hematological malignancies.  This pattern was also noted in our study. A high index of suspicion for VTE should be considered in this group of patients. As noted in our study, the risk of PE is higher in patients with an advanced stage of cancer. 
Cancer itself is a predisposing factor for PE. In our study the most common contributing risk factors were the postoperative state and immobilization. Imberti et al., in their study, found the postoperative state to be a contributing factor in 20.3% patients, followed by immobilization in 13.7% of the cases.  Among the patients with postoperative PE only 42.8% of the patients had received DVT prophylaxis. This reflected the under-use of DVT prophylaxis. The risk of VTE Increases significantly in patients undergoing major surgical procedures for cancer. In patients with gynecological cancers it is recommended to give extended duration of DVT prophylaxis postoperatively, in high-risk cases. 
Malignancy alone is associated with a four-fold increased risk of venous thromboembolism without chemotherapy, and cytotoxic immunosuppressive therapy increases the risk to more than six-fold.  The most common chemotherapy agents associated with VTE are thalidomide, lenalidomide with or without dexamethasone, L-asparginase, bevacizumab, tamoxifen, estramustine, capecitabine, erlotinib, sunitinib, vinorelbine, trastuzumab, paclitaxel-albumin-bound, letrozole, and bortezomib.  Eleven of our study patients developed PE while on chemotherapy. In our study, one patient was on tamoxifen. In addition to chemotherapy agents, central venous catheters (CVC) also act as predisposing factors. The incidence of venographic CVC-related DVT in cancer patients varies from 27 to 66%. 
Gladish et al., have reported an incidence of asymptomatic PE in 4% of the oncology population.  In our study incidental PE was higher (13.9%). Dyspnea including intermittent dyspnea was the most common presenting symptom, seen in 92% of the patients in a study by Hasenberg et al. and Zhu et al.,  and this is similar to our study. In two large international studies, massive pulmonary embolism accounted for 4 - 4.5% of the patients, whereas, it was almost seven times higher in our study. ,
Hasenberg et al., found that cancer patients were at a higher risk for central PE than patients without cancer, however, the authors stated that central PE and peripheral PE did not necessarily differ in clot load, because a large embolus that floated into the pulmonary artery could be fragmented and could cause multiple segmental or subsegmental occlusions.  In our study there was no significant difference in mortality at three months in the central and peripheral PE.
Transthoracic echocardiography (TTE) allows evaluation of the severity of pulmonary embolism. Acute obstruction of more than 30% of the pulmonary arterial bed often results in abnormal right ventricular (RV) function, usually defined as RV dysfunction, dilatation or hypokinesis. The presence of such changes strongly increases the clinical probability of pulmonary embolism (PE) (specificity, 81 to 94%; PPV, 71 to 86%) and indicates a worse prognosis. Normal echocardiography indicates a good prognosis. Integrating TTE with venous ultrasound and transesophageal imaging increases the possibility of immediate definitive justification for a specific therapy.  A transesophageal echo may directly demonstrate thrombotic masses in the main pulmonary arteries, or less often, floating intracavitary thrombi. TTE allows repetitive, noninvasive assessment of the cardiovascular and hemodynamic status of the patient and the response to the therapeutic interventions.  In our study, the three-month mortality was significantly lower in patients without RV dysfunction. Zhu et al., documented that 47.7% acute PE patients had positive RV dysfunction. 
Thrombolysis is the recommended treatment in massive PE. ,, The use of thrombolysis in non-massive PEs is still debated. In our study most patients received low-molecular-weight heparin (LMWH) than unfractioned heparin (UFH), reflecting the increasing use of LMWH in the treatment of PE. Pulmonary embolectomy is a valuable therapeutic option in patients with high-risk PE, in whom thrombolysis is absolutely contraindicated or has failed. Histopathology of the embolectomy specimen would be useful, especially in cancer patients, as they can sometimes have tumor embolism. Catheter embolectomy or fragmentation of the proximal pulmonary arterial clots may be considered as an alternative to surgical treatment in high-risk PE patients, when thrombolysis is absolutely contraindicated or has failed. The inferior vena cava (IVC filter) is considered for patients with contraindications to anticoagulation.
The mortality for patients presenting with massive pulmonary embolism is between 30 and 60% in many studies. ,, In non-massive pulmonary embolism, the death rate is less than 5% in the first three to six months of anticoagulant treatment.  Death occurs in 12% of the PE cases within one month of diagnosis.  The overall mortality rate at three months, for cancer patients with PE, was high in our study (36.66%). It was the highest in the first two weeks. The three-month mortality rate in patients with massive PE (80%) was significantly higher than in patients with non-massive PE (20%).
The limitation of this study is that it is a retrospective study. Venous Doppler and 2-D echo have not been done in some patients, hence, there is some missing data. Also the prevalence of PE could be underestimated. We studied the predictive factors for mortality in PE in the study group of cancer patients, however, there could be confounding bias and a prospective study with a control group of PE, without cancer, would be more useful.
| » Conclusion|| |
Our study is one of the few conducted on the prevalence and outcome of PE in cancer patients, in the Indian population, and indicates that the prevalence of PE in cancer patients in India is not as low as it was originally thought to be. The mortality related to PE is high in cancer patients. The three-month mortality is significantly higher in patients with massive PE and those with right ventricular dysfunction, at presentation. Treatment of venous thromboembolism in cancer surgical patients remains a clinical challenge due to the high mortality rate. Larger studies are needed to address the challenging issues in treating cancer patients with PE. Thromboprophylaxis is largely under-used in cancer patients. This is probably due to the concern regarding the risk of bleeding or the common perception that PE is uncommon in the Indian population. Risk stratification for VTE should be done in all cancer patients. All hospitals should formulate guidelines for the prophylaxis and management of VTE. Active education to raise awareness and to ensure implementation of these guidelines is required. This will help to reduce the burden of VTE in patients with cancer.
| » References|| |
|1.||Kearon C. Natural history of venous thromboembolism. Circulation 2003;107(23 suppl 1):I22-30. |
|2.||Lee AY, Levine MN. Venous thromboembolism and cancer: Risks and outcomes. Circulation 2003;107:I17-21. |
|3.||Khorana AA, Connolly GC.Assessing risk of venous thromboembolism in the patient with cancer.JClinOncol 2009;27:4839-47. |
|4.||Kroger K, Fischer A, Hinrichs A, Gocke C, Rudofsky G. Patients with a malignant tumor have more extended thrombosis than patients without. Angiology 1998;49:923-8. |
|5.||Mostbeck A, Partsch H, Kohn H, Konig B. Pulmonary embolism in leg and pelvic vein thrombosis. Results of a prospective study-diagnosis, frequency, nuclear medical and clinical appearance. Wien KlinWochenschr 1980;92:464-71. |
|6.||Sakuma M, Fukui S, Nakamura M, Takahashi T, Kitamukai O, Yazu T, et al., Cancer and Pulmonary embolism- Thrombotic embolism, tumor embolism and tumor invasion into a large vein. Circ J 2006;70:744-9. |
|7.||Carson JL, Kelley MA, Duff A. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240-5. |
|8.||Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M,et al.,. The long term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7. |
|9.||Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J ThrombHaemost 2007;5:632-4. |
|10.||Cheuk BL, Chung GC, Cheng SW. Epidemiology of venous thromboembolism in a Chinese population. Br J Surg 2004;91:424-8. |
|11.||Lee AD, Stephen E, Agarwal S, Premkumar P. Venous thromboembolism in India. Eur J VascEndovascSurg 2009;37:482-5. |
|12.||CohenAT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, et al.,.Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): A multinational cross-sectional study. Lancet2008;371:387-94. |
|13.||Stien PD, Beemath A, Olson RE. Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients. Am J Cardiol 2005;95:1525-6. |
|14.||Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997;277:1305-7. |
|15.||Agnelli G, Verso M, Ageno W, Imberti D, Moia M, Palareti G,et al.,. The master registry on venous thromboembolism-Description of the study cohort. Thromb Res2008;121:605-10. |
|16.||Hettiarachchi RJ, Lok J, Prins MH,Prandoni P.Undiagnosed malignancy in patients with deep vein thrombosis: Incidence, risk indicators, and diagnosis. Cancer1998;83:180-5. |
|17.||Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and risk of venous thrombosis. JAMA2005;293:715-22. |
|18.||Imberti D, Agnelli G, Ageno W, Moia M, Palareti G, Pistelli R,et al.,. Clinical characteristics and management of cancer associated acute venous thromboembolism-Findings from the MASTER Registry. Haematologica 2008;93:273-8. |
|19.||Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann HJ. Executive Summary: American College OfChest Physicians Evidence-Based Clinical Practice Guidelines.8th ed. Chest2008;133:71S-109S. |
|20.||Heit JA, Silverstein MD, MohrDN, Petterson TM, O'Fallon WM, Melton LJ.Risk factors for deep vein thrombosis and pulmonary embolism: A population-based case-control study.ArchIntern Med 2000;160:809-15. |
|21.||Saraiya B,Goodin S. Management of venous thromboembolism and the potential to impact overall survival in patients with cancer.Pharmacotherapy2009;29:1344-56. |
|22.||Verso M, Agnelli G.Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.J ClinOncol 2003;21:3665-75. |
|23.||Hasenberg U, Paul T, Feuersenger A, Goyen M, Kroger K. Cancer patients and characteristics of pulmonary embolism. EurRadiol 2009;69:478-82. |
|24.||Zhu L, Yang Y, Wu Y, Zhai Z, Wang C. Value of right ventricular dysfunction for prognosis in pulmonary embolism. Int J Cardiol 2008;127:40-5. |
|25.||Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation2006;113:577-82. |
|26.||Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: Clinical outcomes in the InternationalCooperative Pulmonary Embolism Registry ICOPER. Lancet 1999;353:1386-9. |
|27.||Torbicki A, Pruszczyk P. The role of echocardiography in suspected and established PE.SeminVasc Med2001;1:165-74. |
|28.||Mookadam F,Jiamsripong P, Goel R, Warsame TA, Emani UR, Khandheria BK.Critical appraisal on the utility of echocardiography in the management of acute pulmonary embolism Cardiol Rev 2010;18:29-37. |
|29.||British Thoracic Society Standards Of Care Committee Pulmonary Embolism Guideline Development, Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58:470-83. |
|30.||Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N,Pruszczyk P,et al.,. Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology.Eur Heart J2008;29:2276-315. |
|31.||Tapson VF. Acute pulmonary embolism. N Engl J Med 2008;358:1037-52. |
|32.||Wood KE. Major pulmonary embolism: Review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121:877-905. |
|33.||Meyer G, Planquette B, Sanchez O. Long-term outcome of pulmonary embolism. CurrOpinHematol2008;15:499-503. |
|34.||White RH.The epidemiology of venous thromboembolism.Circulation2003;107:14-8. |
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||The impact of co-morbidity on the disease burden of VTE
| ||Sonja Kroep,Ling-Hsiang Chuang,Alexander Cohen,Pearl Gumbs,Ben van Hout,Manuel Monreal,Stefan N. Willich,Anselm Gitt,Rupert Bauersachs,Giancarlo Agnelli |
| ||Journal of Thrombosis and Thrombolysis. 2018; 46(4): 507 |
|[Pubmed] | [DOI]|
||Multimodal management of muscle-invasive bladder cancer
| ||Jong Chul Park,Deborah E. Citrin,Piyush K. Agarwal,Andrea B. Apolo |
| ||Current Problems in Cancer. 2014; 38(3): 80 |
|[Pubmed] | [DOI]|