Cancer Investigation, Early Online:1–10, 2015 ISSN: 0735-7907 print / 1532-4192 online C 2015 Informa Healthcare USA, Inc. Copyright  DOI: 10.3109/07357907.2015.1009631

ORIGINAL ARTICLE

Venous Thromboembolism in Cancer: Frequently Asked Questions When Guidelines are Inconclusive A. Palla, A. Celi, L. Marconi, F. Pistelli, L. Tavanti, M. Desideri, and L. Carrozzi

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Respiratory Unit, Cardiothoracic and Vascular Department, University of Pisa, Pisa Italy date of the American Society of Clinical Oncology (ASCO) guidelines recommends that in hospitalized patients, pharmacologic prophylaxis should be given in presence of active cancer and acute medical illness (5). In outpatients, instead, routine prophylaxis is not recommended (5), although patients under multimodality (6) or tamoxifen therapy (7) may be considered as potential candidates. Other issues to deal with patients of VTE and cancer are not fully covered by the current guidelines; in such cases, physicians have to manage patients on the basis of their expertise, supported by the available literature. In the present paper, we report some issues in patients with malignancies and VTE felt as more problematic because these are not fully addressed by current guidelines. To the purpose of the present review, VTE is to be intended as pulmonary embolism associated or not associated with deep vein thrombosis (DVT), thus excluding DVT alone. By definition, the final recommendations were based upon the literature available in the field, and thru the personal experience only.

ABSTRACT Management of Venous thromboembolism (VTE) in cancer patients is difficult when guidelines are inconclusive. To share a reasonable and homogeneous behavior in such circumstances, four issues, which are felt as problematic by oncologists and surgeons, have been selected; all were uncovered or only partially covered by current guidelines. Results from the literature and author’s specific experience in the field were utilized to suggest reasonable solutions to the raised questions. The reported experience is the first to provide real-world management guidance for VTE in cancer patients. The effort of putting together literature review and author’s experience brought to the adoption of a common behavior. Keywords Venous thromboembolism, Cancer, Decision-making

Venous thromboembolism (VTE) is frequent in the general population and even more frequent in patients with cancer. In the latter, moreover, it may present with different features, sometimes difficult to recognize, and may require different diagnostic algorithm and treatment. Most is known about incidence, mortality, risk factors, and other epidemiological issues regarding patients with VTE and cancer. It is known, for instance, that the incidence of VTE in cancer is approximately 15%, ranging from 3.8 to 30.7 % (1) (and it is perhaps higher when considering the amount of asymptomatic VTE); that the mortality rate due to VTE is increased in cancer, VTE being the second leading cause of death in such patients (2); and that the risk of VTE is higher in the first few months of diagnosis, in the presence of distant metastases, in patients with inherited thrombophylic abnormalities. We also know that risk factors commonly associated with VTE include age >65 years, female sex, black ethnicity, use of chemotherapy, primary site of cancer, and presence of co-morbidity (2). In patients undergoing chemotherapy, the mortality rate rises from 3.9 to 5.7%, a relative increase of 47% (3). It is commonly accepted that the risk of VTE is higher in hospitalized than in outpatients (4). Accordingly, a recent up-

About the Literature Revision The literature of the last two decades (from 1993 to 2013) was systematically reviewed by consulting “PubMed” and using the key words: “VTE” and “cancer.” More relevant references are discussed in the text; the remainders are reported in the Appendix. About Authors’ Expertise A center for diagnosis and treatment of VTE is active at the University Hospital of Pisa, Italy since many years. Patients are routinely sent from both the emergency room (outpatients) and hospital departments (inpatients); both surgical and medical (mostly oncologic) patients are being referred there. Following such experience, physicians of the center adopted a sort of common, institutional, standardized

Correspondence to: Prof. Antonio Palla, Respiratory Unit, Cardiothoracic and Vascular Department, University of Pisa, Pisa, Italy. email: [email protected] Received 6 February 2014; revised 5 January 2015; accepted 15 January 2015.





A. Palla et al.

Table 1 . FAQs by hospital physicians Q1.

Q2.

Q3.

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Q4.

If a patient with cancer develops VTE, how often should I expect a recurrence, lethal or not, of VTE? And how should I treat it? Provided the association between VTE and cancer is frequent, should I screen for cancer all patients with VTE, only those at higher risk, or none? Since incidental PE is detected with increasing frequency in cancer patients who undergo routine chest CT, should I treat and then follow such patients in the same way as symptomatic patients? Should I treat patients affected by VTE and cancer in the same way as those with VTE without cancer?

behavior, namely as regards to the issues uncovered or only partially covered by current guidelines. Frequently asked questions (FAQs) raised by physicians of several hospital departments are the body of the paper (Table 1). FREQUENTLY ASKED QUESTIONS (FAQs) If a Patient with Cancer Develops VTE, How Often should I Expect a Recurrence, Lethal or not, of VTE? And how should I Treat it? In general, data from literature are quite consistent in showing an increased occurrence of VTE recurrences in cancer patients compared with non-cancer patients; however, such data may be biased by the lack of a rigorous method of detection of recurrence. Indeed, the capability of detecting recurrences of VTE represents a challenging issue in clinical practice. First, as suggested by Ageno et al. (8), one should formulate a clear definition of recurrence in order to allow a common perception of the event. According to Koopman et al. (9), recurrences may be defined as those events occurring after an initial course of adequate antithrombotic treatment for the first venous thromboembolic event. The use of a clear definition may obviate for misdiagnosis because patients with previous VTE may show symptoms erroneously interpreted as suggestive for recurrences, with the result that only one-third of cases suspected for recurrences may be confirmed (10). Furthermore, the utilization of right diagnostic tools for the detection of recurrence is essential; to this end, it has been demonstrated that the availability of a baseline imaging after the completion of treatment to be compared with that obtained at the moment of suspected recurrence may allow a correct confirmation or exclusion (11, 12). The availability of baseline lung scintigraphy in cases where the diagnosis is made by CT seems to be recommended. Indeed, it was recently demonstrated that unexpectedly high recanalization rate occurs on chest CT in patients with PE treated with anticoagulants alone (13). For this purpose, we routinely perform a baseline pulmonary perfusion scintigraphy in adjunct to chest angio-CT to diagnose PE; moreover, we repeat it at the end of early (day 7 to 10) and late (day 180) anticoagulant treatment. It is essential to have images to compare acute embolization with the end of the treatment (14). At the same time, a leg ultrasound is done to diagnose DVT recurrence.

One of the first papers investigating the incidence of VTE recurrence in cancer patients is by Prandoni et al. (15), who followed patients with symptomatic DVT for 8 years and found a cumulative incidence of recurrent VTE as 17.5% after 2 years (95% CI: 13.6 to 22.2%), 24.6% after 5 years (95% CI: 19.6 to 29.7%), and 30.3% after 8 years (95% CI: 23.6 to 37.0%). Survival after 8 years was 70.2% (95% CI: 64.7 to 75.6%); the presence of cancer increased the risk of death (HR: 8.1; 95% CI:, 3.6 to 18.1). In a prospective follow-up study of patients with cancer and DVT (16), Prandoni et al. enrolled 842 patients, of whom 181 had known cancer at the entry. The 12-month cumulative incidence of recurrent VTE was as much as three times higher (HR: 3.2 [95% CI, 1.9–5.4]) in patients with cancer (20.7%) than in patients without cancer (6.8%). Major bleeding was also significantly higher (12.4% in patients with cancer vs. 4.9% in patients without cancer). The RIETE Registry identified risk factors for fatal recurrence of VTE and fatal bleeding in patients with cancer (17). Among a total of 14,391 patients with symptomatic acute VTE, 2,945 (20%) had cancer. During a 3-month follow-up, the frequency of fatal VTE was 2.6% and that of fatal bleeding was 1.0% (1.4% and 0.3% in patients without cancer, respectively). In a different series of the same Registry, it has been shown that during the first 3 months of follow-up after the acute VTE event, 44% of patients died of recurrent VTE, 29% of bleeding (18). All the above papers also reported the most frequent variables able to predict VTE recurrences in patients with cancer (Table 2). The treatment of detected recurrences is not rigidly standardized (19, 20). According to Prandoni et al. (19), if recurrence occurs in patients already in once-daily weight-based LMWH, long-term administration of full-dose LMWH can be chosen. Instead, patients who develop recurrence while INR is sub-therapeutic, they can be retreated with LMWH for a few days and then reput on warfarin with a therapeutic INR (19). If, on the contrary, patients with recurrence had therapeutic INR, we may switch to once-daily weight-based LMWH. Finally, the inferior vena cava filters may be taken into consideration in patients hemodynamically unstable or at high risk of pulmonary embolism (16). In conclusion, from available data we may state the following: (a) It is mandatory to have a reliable method to detect a VTE recurrence; (b) recurrence of VTE in patients with cancer is almost three times higher than in patients without cancer; moreover, it occurs more frequently within the first month of diagnosis; (c) it is related to cancer severity and factors such as young patient’s age and recent diagnosis of cancer; (d) mortality is increased by at least eight times in the presence of cancer, and several patients die within 3 months due to recurrent VTE. Our Recommendations Our policy in patients with known cancer and VTE is to perform a careful clinical assessment every 3 months in order to suspect early recurrences; to this end, a dedicated VTE follow-up service is active twice a week at the center for Cancer Investigation

Venous Thromboembolism in Cancer  Table 2 . VTE recurrence in cancer: predictive variables Prandoni 1996 (15)

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Study Patients F/U duration Predictive variables

Retrospective 335 8 years Cancer, impaired coagulation

Prandoni 2002 (16) Prospective 842 12 months Cancer severity

diagnosis and treatment of VTE. Also, we reinforce surveillance by instructing patients, family members, and family physician to contact us in case of onset of new cardiorespiratory symptoms. Finally, we regularly perform baseline and follow-up 180-day perfusion scintigraphies and ultrasounds of lower limbs in order to have images for a reliable diagnosis of VTE recurrences in case of necessity. Provided that the Association between VTE and Cancer is Frequent, should I Screen for Cancer all Patients with VTE or only those at higher Risk, or none? Prandoni et al. (21) investigated the association between symptomatic DVT and the risk of subsequent overt malignant disease. Two hundred fifty patients with objective diagnosis of DVT were followed for 2 years and the incidence of cancer was compared in patients having “idiopathic” DVT with those having secondary DVT. At diagnosis, cancer was found in 3.3% of the patients having “idiopathic” DVT and in none having secondary DVT. During follow-up, overt cancer developed in 7.6% and 1.9% of patients respectively (odds ratio 2.3; 95% CI: 1.0 to 5.2). In order to measure possible increase in cancer risk in a population-based analysis of VTE and cancer, the standardized cancer incidence ratio (SIR) was computed in 61,698 patients taken from the Swedish Inpatients Register (22). Out of these, 2,509 cancers were diagnosed at the VTE acute event or during the first year of follow-up. However, even 10 years after admission to hospital, cancer incidence had increased (1.3%). The SIRs of polycitemia (12.9), cancer of liver (6.6), pancreas (7.8), ovary (11.4), brain (7.6), lung (5.5), and Hodgkin lymphoma (7.4) exceeded by 5%. Schulman et al. (23) obtained similar results and demonstrated that in the subgroup of “idiopathic” VTE, the cumulative probability of newly diagnosed cancer was high at least for a 6-year follow-up. Moreover, according to Murchison et al. (24), the risk was high during the first few months after diagnosis but remained elevated for at least 2 years after the diagnosis of the first episode of “idiopathic” VTE. More recently, the incidence of VTE in patients hospitalized with cancer has been investigated by Stein et al. (25). They have found that such incidence was high (2%) and twice that of patients without cancer (1%). Also, Stein et al. demonstrated that PE is a frequent cause of death in patients with cancer: 0.21% in a large series of patients observed over 19-year period of time (26). As to the need for screening, the results are often equivocal. Sørensen et al. found 1,737 cases of cancer out of about 26,000 patients with DVT or PE, with a standardized inciC 2015 Informa Healthcare USA, Inc. Copyright 

RIETE 2006 (17) Registry 2.945 3 months Abnormal renal function, metastasis, recent immobilization

RIETE 2008 (18) Registry 3.805 3 months Age:

Venous Thromboembolism in Cancer: Frequently Asked Questions When Guidelines are Inconclusive.

Management of Venous thromboembolism (VTE) in cancer patients is difficult when guidelines are inconclusive. To share a reasonable and homogeneous beh...
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