Background Venous thromboembolism (VIE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non -cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer-related mortality and morbidity. This is the third update of the review first published in 2015. Objectives To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer- orVTE-related mortality and morbidity and to determine which tests for cancer are best at identifyingtreatable cancers early. Search methods The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify additional studies. Selection criteria Randomised and quasi -randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. Data collection and analysis Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of interest were all -cause mortality, cancer-related mortality and VIE -related mortality. Main results No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was downgraded further as detection bias was present in one study with a Low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low -certainty evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the controL group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 950/0 CI 1.05 to 23.76; low -certainty evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with fou r participants in the control group (OR 0.25, 950/o CI 0.03 to 2.28; low -certainty evidence). In addition, extensiveLy tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underLying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; low-certainty evidence). Neither study measured all -cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of Life. When comparing standard testing pLus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all -cause mortality (OR 1.22, 95% Cl 0.49 to 3.04; 1248 participants; 2 studies; moderate certainty evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; moderate -certainty evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; moderate -certainty evidence). Regarding stage of cancer, there was no cleardifference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; Low -certainty evidence) or advanced (OR 1.00, 950/0 CI 0.14 to 7.17; 394 participants; 1 study; low-certainty evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; moderate -certainty evidence). Time to cancer diagnosis was 4. 2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. Authors' conclusions Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earLier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-reLated morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good -quality large-scale randomised controlled trials are required before firm concLusions can be made.
