Systematic Review: The Trousseau Syndrome Revisited: Should We Screen Extensively for Cancer in Patients with Venous Thromboembolism?

Context Screening and surveillance for occult cancer in patients with unprovoked venous thromboembolism (VTE) is poorly understood. Contribution The authors systematically reviewed studies of occult cancer in patients with newly diagnosed unprovoked VTE. In 36 studies, the combined prevalence of occult cancer was 6.1% at baseline and 10.0% at 12 months after VTE diagnosis. The proportion of occult cancer diagnosed at baseline was 49.4% with limited screening and 69.7% with extensive screening. Caution The report did not describe the outcomes of newly diagnosed cancer associated with VTE. Implication Because only two thirds of cases of occult cancer are diagnosed at baseline, patients with unprovoked VTE need ongoing surveillance. The Editors Deep venous thrombosis and pulmonary embolism, collectively termed venous thromboembolism (VTE), can be the first manifestation of cancer (14). Armand Trousseau first described this association in 1865: The diagnosis in a patient with gastric pain and leg or arm phlegmasia alba dolens is the presence of cancer (5). Two years later, on 1 January 1867, after suffering for weeks from abdominal pain, Trousseau declared to one of his students: I'm lost. A thrombosis developed overnight, which doesn't leave me any doubt of the nature of my disease (5). Trousseau died of gastric cancer shortly thereafter. Identifying previously undiagnosed cancer in patients with VTE may be important for several reasons: It may be at a curable stage, or if detected later, may no longer be curable; treating cancer earlier may prevent cancer-associated morbidity (for example, pathologic fractures and compression syndromes); and cancer-associated VTE is now initially treated with low-molecular-weight heparin for 6 months rather than vitamin K antagonists (6), which can reduce the heightened risk for recurrent VTE with cancer-associated thrombosis (7) and potentially increase survival in patients without metastatic disease (8, 9). Although retrospective studies suggested that limited cancer screening, including a careful medical history, physical examination, and basic blood work, was adequate to detect most cases of undiagnosed cancer in patients with VTE (10, 11), 2 recent prospective studies suggest that a more extensive screening strategy involving limited screening plus imaging studies or tumor marker measurement can increase the rate of cancer detection (12, 13). However, extensive screening may cause anxiety, may lead to test complications and unnecessary further testing for false-positive results, and is invasive and expensive. To counsel patients with VTE on the risks and benefits of cancer screening, clinicians require estimates of the absolute risk for previously undiagnosed cancer in patients and patient subgroups (provoked and unprovoked VTE), estimates of the additional cases of cancer detected by extensive screening strategies compared with more limited screening strategies, and estimates of the potential additional risks and benefits (morbidity and mortality) of an extensive screening strategy. To address these knowledge gaps, we performed a systematic review of the literature to summarize the period prevalence of previously undiagnosed cancer at baseline and during different intervals of follow-up, and the additional yield and complications of extensive screening strategies. Methods Data Sources and Searches We conducted a systematic literature search strategy to identify potential trials on MEDLINE (1950 to the first week of November 2007), EMBASE (1980 to week 45 of 2007), the Cochrane Register of Controlled Trials (4th quarter, 2007) and Evidence-Based Medicine Reviews (4th quarter, 2007) by using the Ovid interface. We also sought publications through a hand-search of personal and potentially relevant journals and of the International Society on Thrombosis and Haemostasis conference proceedings for the past 2 years (2005 to 2007). Our systematic search strategy is documented in Appendix Table 1. We restricted the search to human trials. We made no restrictions on language, year of publication, or type of publication. We also searched the references of included studies and narrative reviews for potential studies. Appendix Table 1. MEDLINE Search Strategy Study Selection Using a structured question format to aid our literature search strategy, we reviewed abstracts of observational or randomized, controlled trials (RCTs) that reported the prevalence or incidence of previously undiagnosed cancer after VTE. To determine the period prevalence of previously undiagnosed cancer at baseline and during different follow-up intervals, we reviewed potentially relevant studies that satisfied all of the following criteria: study of adult patients with newly diagnosed VTE (deep venous thrombosis or pulmonary embolism); study that reported prevalence or incidence of cancer detection at diagnosis and at 6 or 12 months; and observational study or RCT. To assess the efficacy of limited and extensive cancer screening, we reviewed potentially relevant studies that satisfied all of the following criteria: study of adult patients with newly diagnosed VTE (deep venous thrombosis or pulmonary embolism); patients were screened for cancer by using history, physical examination, basic blood work, chest radiography (limited cancer screening), and serum tumor markers or abdominal ultrasonography or computed tomography (extensive cancer screening); observational study or RCT; and study reported 1 or more primary or secondary outcome measures. Outcome Measures The primary outcome measure was detection of previously undiagnosed cancer. We defined previously undiagnosed cancer as any new case of cancer detected after the index VTE diagnosis until the end of follow-up in patients with no known history of cancer. We defined a prevalent case of previously undiagnosed cancer at baseline as a case of cancer detected at, or shortly after (1 month), the index VTE diagnosis in patients with no known history of cancer. We defined newly diagnosed cancer after baseline as a new case of cancer diagnosed between the index visit of VTE (>1 month) and the end of follow-up. We defined limited cancer screening as a combination of medical history, physical examination, routine laboratory blood tests, and chest radiography. We defined extensive cancer screening as a combination of limited screening and 1 of the following: ultrasonography of the abdomen or pelvis, computed tomography of the abdomen or pelvis, or tumor markers. We followed the definitions of provoked VTE provided in the original studies. We defined unprovoked VTE as VTE with no predisposing factor. We excluded patients with a previous diagnosis of cancer. Secondary outcome measures included proportion of early-stage cancer, cancer-related mortality, and screening complications. We classified early-stage cancer by using the tumor/node/metastasis classification as T1-2N0M0. We defined screening complication as any complication arising directly from the screening (for example, biopsy) or from any other subsequent investigations to confirm or refute a malignant condition. Data Extraction and Quality Assessment Two reviewers independently applied the 2 sets of inclusion criteria to the identified articles from the initial search strategy. They discussed articles for potential full review and independently extracted baseline characteristics, number of cases of previously undiagnosed cancer, time of diagnosis (baseline, 2 to 6 months, or 7 to 12 months), type and stage of cancer, and diagnostic test used for diagnosis. The 2 reviewers extracted data for all patients with any, unprovoked, or provoked VTE. A third reviewer noted and adjudicated discrepancies. A priori, we planned to evaluate the methodological quality of observational studies by using the validated NewcastleOttawa Quality Assessment scales (14). The NewcastleOttawa quality score was designed to assess the quality of nonrandomized studies in meta-analyses (14). The scale assesses cohort and casecontrol studies by using 3 broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of the outcome of interest or the exposure for cohort studies and casecontrol studies, respectively. We also extracted data identified as being important markers of quality in case series and cohort studies (explicit inclusion criteria, length of follow-up, and outcomes assessed by using objective criteria) (15). Post hoc, we also used the NewcastleOttawa scale to assess the RCT quality because there was only 1 RCT, and we used the 2 groups of the RCT as 2 cohorts without comparing outcomes between them. We further assessed quality of RCTs by examining allocation concealment (16). For all eligible studies, 2 reviewers independently assessed trial or study quality and extracted the data by using a standardized data abstraction form. Likewise, a third reviewer documented and adjudicated any discrepancies. Data Synthesis and Statistical Analysis We defined period prevalence as the proportion of the VTE population with previously undiagnosed cancer detected over a specific period of time. To estimate the period prevalence at baseline and after different intervals of follow-up, we extracted data from the individual studies (including the 2 groups of the RCT [13]) to form a cohort of patients followed over time. We defined the cohort as a group of patients without previously known cancer at the time of the VTE diagnosis. The period prevalence at baseline includes all prevalent cases of previously undiagnosed cancer from the time of VTE diagnosis to 1 month. The period prevalences, between 2 to 6 months and between 7 to 12 months, include all cases of newly diagnosed cancer during follow-up. The period prevalence from baseline to 6 months and baseline to 12 months combines all cases of previously undiagnosed cancer over the specific time periods. We calculated the 95% CI for each period preva