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

BackgroundVenous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonaryembolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and theVTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlyingmalignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for anunderlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis wouldensure 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 toimprovements in cancer-related mortality and morbidity. This is the third update of the review first published in 2015.ObjectivesTo determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of thelower limb or PE) is effective in reducing cancer- or VTE-related mortality and morbidity and to determine which testsfor cancer are best at identifying treatable cancers early.Search methodsThe Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL,MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials RegistryPlatform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identifyadditional studies.Selection criteriaRandomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specifictests for identifying cancer or clinically indicated tests only were eligible for inclusion.Cochrane Vascular Group, Robertson, Robertson, Broderick, Yeoh, and... https://archie.cochrane.org/sections/documents/view?version=z21093...1 of 37 01/10/2021, 09:18Data collection and analysisTwo review authors independently selected studies, assessed risk of bias and extracted data. We assessed thecertainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes ofinterest were all-cause mortality, cancer-related mortality and VTE-related mortality.Main resultsNo new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Twostudies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at thephysician's discretion, while the other two studies assessed the effect of standard testing plus positron emissiontomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at thephysician'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 testingalone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence wasdowngraded 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 twostudies 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 testedparticipants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensivelytested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the controlgroup (OR 5.00, 95% CI 1.05 to 23.76; low-certainty evidence). There was no clear difference in detection ofadvanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensivelytested 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: 1month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time ofdiagnosis 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, VTErelated morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participantsatisfaction or quality of life.When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plusPET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to3.04; 1248 participants; 2 studies; moderate-certainty evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to1.52; 1248 participants; 2 studies; moderate-certainty evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to2.17; 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) oradvanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low-certainty evidence) stages of cancer. Therewas also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248participants; 2 studies; moderate-certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testinggroup and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-relatedmortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.Authors' conclusionsSpecific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stageof the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning theeffectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) inreducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or nobenefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can bemade.