Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE

Abstract

Background<br/>Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary<br/>embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the<br/>VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying<br/>malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an<br/>underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would<br/>ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore,<br/>an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to<br/>improvements in cancer-related mortality and morbidity. This is the third update of the review first published in 2015.<br/>Objectives<br/>To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the<br/>lower limb or PE) is effective in reducing cancer- or VTE-related mortality and morbidity and to determine which tests<br/>for cancer are best at identifying treatable cancers early.<br/>Search methods<br/>The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL,<br/>MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry<br/>Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify<br/>additional studies.<br/>Selection criteria<br/>Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific<br/>tests for identifying cancer or clinically indicated tests only were eligible for inclusion.<br/>Cochrane Vascular Group, Robertson, Robertson, Broderick, Yeoh, and... https://archie.cochrane.org/sections/documents/view?version=z21093...<br/>1 of 37 01/10/2021, 09:18<br/>Data collection and analysis<br/>Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the<br/>certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of<br/>interest were all-cause mortality, cancer-related mortality and VTE-related mortality.<br/>Main results<br/>No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two<br/>studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the<br/>physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission<br/>tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the<br/>physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias<br/>(early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing<br/>alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was<br/>downgraded further as detection bias was present in one study with a low number of events.<br/>When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two<br/>studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality<br/>(odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low-certainty evidence).<br/>One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested<br/>participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively<br/>tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control<br/>group (OR 5.00, 95% CI 1.05 to 23.76; low-certainty evidence). There was no clear difference in detection of<br/>advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively<br/>tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; lowcertainty evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1<br/>month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of<br/>diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95%<br/>CI 0.59 to 2.93; 396 participants; 2 studies; low-certainty evidence). Neither study measured all-cause mortality, VTErelated morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant<br/>satisfaction or quality of life.<br/>When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus<br/>PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to<br/>3.04; 1248 participants; 2 studies; moderate-certainty evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to<br/>1.52; 1248 participants; 2 studies; moderate-certainty evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to<br/>2.17; 854 participants; 1 study; moderate-certainty evidence). Regarding stage of cancer, there was no clear<br/>difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; low-certainty evidence) or<br/>advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low-certainty evidence) stages of cancer. There<br/>was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248<br/>participants; 2 studies; moderate-certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testing<br/>group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related<br/>mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.<br/>Authors' conclusions<br/>Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage<br/>of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the<br/>effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in<br/>reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no<br/>benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be<br/>made.

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