A case-control analysis of the impact of venous thromboembolic disease on quality of life of patients with cancer: Quality of life in cancer (QCA) study

cance s A icle A Case-Con ol Analysis o he Impac o Venous Th omboembolic Disease on Quali y o Li e o Pa ien s wi h Cance : Quali y o Li e in Cance (Qca) S udy Lucia Ma in-Ba e a 1, And es J. Muñoz-Ma in 2, Edua do Rios-He anz 3, Ignacio Ga cia-Escoba 4, Ca men Bea o 5, Ca me Fon 6, Es e ania Oncala-Sibajas 7, Al onso Re uel a-Rod iguez 8, Ma ia Ca men A eses 9, Vic o Ri as-Jimenez 10, Ma ia Angeles Mo eno-San os 11, Ai o Ballaz-Quincoces 12, Juan-Bosco Lopez-Saez 13, I ia Gallego 2, Te esa Elias-He nandez 1, Ma ia Isabel Asensio-C uz 1, Ley e Chasco-Eguilaz 12, Gonzalo Ga cia-Gonzalez 2, Pu i icacion Es e ez-Ga cia 14, Remedios O e o 1, Jo ge Lima-Al a ez 15 and Luis Ja a-Paloma es 1,* 1 Respi a o y Depa men , Medical Su gical Uni o Respi a o y Diseases, Hospi al Vi gen del Rocio, CIBERES, 41013 Se illa, Spain; [email p o ec ed] (L.M.-B.); [email p o ec ed] (T.E.-H.); [email p o ec ed] (M.I.A.-C.); o e o@sepa .es (R.O.) 2Medical Oncology Depa men , Hospi al Gene al Uni e si a io G ego io Ma añón, 28009 Mad id, Spain; [email p o ec ed] (A.J.M.-M.); [email p o ec ed] (I.G.); [email p o ec ed] (G.G.-G.) 3Hema ology and Hemo he apy Depa men , Hospi al Uni e si a io Vi gen de Valme, 41701 Se illa, Spain; [email p o ec ed] 4Medical Oncology Depa men , HGU de Ciudad Real, 13003 Ciudad Real, Spain; [email p o ec ed] 5Medical Oncology Depa men , Hospi al Uni e si a io Vi gen Maca ena, 41009 Se illa, Spain; [email p o ec ed] 6 Medical Oncology Depa men , DIBAPS/T ansla ional Genomics and Ta ge ed The apeu ics in Solid Tumo s, Hospi al Clínic, 08036 Ba celona, Spain; [email p o ec ed] 7Eme gency Depa men , Hospi al Vi gen Maca ena, 41009 Se illa, Spain; [email p o ec ed] 8Medical Oncology Depa men , Hospi al Uni e si a io Cen al de As u ias, 33611 O iedo, Spain; [email p o ec ed] 9Medical Oncology Depa men , Hospi al de O ense, 32616 O ense, Spain; ka melea [email p o ec ed] 10 Medical Oncology Depa men , Hospi al de Je ez de la F on e a, 11407 Cádiz, Spain; [email p o ec ed] 11 Medical Oncology Depa men , H. U. Pue o Real, 11510 Cádiz, Spain; [email p o ec ed] 12 Respi a o y Depa men , Hospi al de Galdakao-Usansolo, 48960 Bizkaia, Spain; ai o [email p o ec ed] (A.B.-Q.); [email p o ec ed] (L.C.-E.) 13 In e nal Medicine Uni . H. U. Pue o Real, 11510 Cádiz, Spain; [email p o ec ed] 14 Medical Oncology Depa men , Hospi al Vi gen del Rocio, 41013 Se illa, Spain; [email p o ec ed] 15 Respi a o y Depa men , Hospi al Uni e si a io Vi gen de Valme, 41701 Se illa, Spain; [email p o ec ed] *Co espondence: [email p o ec ed]; Tel.: +34-6-67-95-64-80; Fax: +34-9-55-01-21-90 Recei ed: 4 Decembe 2019; Accep ed: 24 Decembe 2019; Published: 26 Decembe 2019   Abs ac : Al hough he e is published esea ch on he impac o enous h omboembolism (VTE) on quali y o li e (QoL), his issue has no been ho oughly in es iga ed in pa ien s wi h cance —pa icula ly using speci ic ques ionnai es. We aimed o examine he impac o acu e symp oma ic VTE on QoL o pa ien s wi h malignancies. This was a mul icen e , p ospec i e, case-con ol s udy conduc ed in pa ien s wi h cance ei he wi h (cases) o wi hou (con ols) acu e symp oma ic VTE. Pa icipan s comple ed he EORTC QLQ-C30, EQ-5D-3L, PEmb-QoL, and VEINES-QOL/Sym ques ionnai es. S a is ically signi ican and clinically ele an di e ences in e ms o global heal h s a us we e examined. Be ween 2015 and 2018, we en olled 425 pa ien s (128 cases Cance s 2020,12, 75; doi:10.3390/cance s12010075 www.mdpi.com/jou nal/cance s Cance s 2020,12, 75 2 o 12 and 297 con ols; mean age: 60.2 ± 18.4 yea s). The mos common malignancies we e gas oin es inal (23.5%) and lung (19.8%) umo s. We ound minimally impo an di e ences in global heal h s a us on he EQ-5D-3L (cases e sus con ols: 0.55 e sus 0.77; mean di e ence: − 0.22) and EORTC QLQ-C30 (47.7 e sus 58.4; mean di e ence: − 10.3) ques ionnai es. The e we e minimally impo an di e ences on he PEmb-QoL ques ionnai e (44.4 e sus 23; mean di e ence: − 21.4) and a signi ican ly wo se QoL on he VEINES-QOL/Sym ques ionnai e (42.7 e sus 51.7; mean di e ence: − 9). In conclusion, we showed ha acu e symp oma ic VTE ad e sely a ec s he QoL o pa ien s wi h malignancies. Keywo ds: neoplasm; quali y o li e; enous h omboembolism; pulmona y embolism; enous h ombosis 1. In oduc ion Venous h omboembolic disease (VTE) consis s o pulmona y embolism (PE) and deep ein h ombosis (DVT). In he gene al popula ion, PE anks hi d among all causes o ca dio ascula mo ali y— ollowing myoca dial in a c ion and s oke [ 1 ]. The bu den o his condi ion is e en highe in pa ien s wi h malignancies [ 2 ]. Pa ien s wi h umo s also p esen a ma kedly inc eased isk (up o a ou - old) o VTE han hose wi hou . Con e sely, app oxima ely 20% o pa ien s wi h VTE ha e an ac i e malignancy [ 3 ], which in u n po ends a highe isk o complica ions (i.e., bleeding, ecu en VTE, and dea h) [4–7]. Heal h- ela ed quali y o li e (QoL)—de ined as he pe cep ion a pa ien has o he e ec s o a disease o i s ea men on dis inc domains, including physical, emo ional, and social well-being [ 8 ]—has ecen ly become a subjec o in ense in es iga ion. Se e al gene ic ques ionnai es aimed a assessing QoL in e e yday clinical p ac ice ha e been de eloped. Howe e , disease-speci ic ques ionnai es a e gene ally mo e sensi i e in he de ec ion o sub le QoL changes in selec ed clinical popula ions. Di e en ques ionnai es a e cu en ly a ailable o he speci ic assessmen o QoL in pa ien s wi h VTE. The Venous Insu iciency Epidemiological and Economic S udy-Quali y o Li e/Symp oms (VEINES-QOL/Sym) [ 9 , 10 ] and he Pulmona y Embolism Quali y o Li e ques ionnai e (PEmb-QoL) [11,12] ha e been designed o pa ien s wi h DVT and PE, espec i ely. Al hough he e is published esea ch on he impac o DVT [ 13 ] and PE [ 14 ] on QoL, his issue has no been ho oughly in es iga ed in pa ien s wi h cance [ 15 ] and, pa icula ly, using speci ic ques ionnai es. We he e o e designed he Quali y o li e in Cance (QCa) s udy o examine he impac o acu e symp oma ic VTE on QoL o pa ien s wi h malignancies. 2. Me hods 2.1. S udy Design The QCa s udy is a mul icen e , p ospec i e, case-con ol in es iga ion conduc ed in pa ien s wi h malignancies. Rec ui men was conduc ed be ween June 2015 and Janua y 2018 in he ou pa ien acili ies o 13 Spanish hospi als. The s udy in es iga o s we e in specialis s in oncology, hema ology, in e nal medicine, and espi a o y medicine. Pa ien s wi h cance ei he wi h (cases) o wi hou (con ols) acu e symp oma ic VTE we e included. Con ols we e deemed eligible a any ime du ing he cou se o hei disease and we e equi ed o comple e he QoL ques ionnai es a inclusion. Cases we e included in he s udy a he ime o acu e symp oma ic VTE, and quali y o li e we e illed 30 days a e he index h ombo ic e en (30 ± 2 days). All ques ionnai es we e comple ed a he same ime poin o a oid a sou ce o po en ial con ounding. All clinical da a and esponse o ques ionnai es we e sepa a ed om pe sonal in o ma ion and analysed in an anonymized ashion. The s udy p o ocol was e iewed and app o ed by he Resea ch E hics Commi ee o he Vi gen del Rocio Hospi al, Se illa, Spain (code: 0191-N-14) and subsequen ly a i ied by each pa icipa ing cen e . All pa ien s p o ided Cance s 2020,12, 75 3 o 12 w i en in o med consen be o e inclusion. The comple e p o ocol has been p e iously desc ibed in de ail [16]. The main esea ch o he s udy was o in es iga e he impac o acu e symp oma ic VTE on QoL o pa ien s wi h malignancies. Wi h his aim, we compa ed he global heal h s a us o cases and con ols using ou QoL ques ionnai es. Seconda y endpoin s included he compa isons o di e en QoL dimensions and h ee subg oup analyses (PE e sus DVT, men e sus women, analysis acco ding o umo si e). The ollowing ques ionnai es we e used: (1) Eu opean O ganiza ion o Resea ch and T ea men o Cance quali y o li e ques ionnai e (EORTC QLQ-C30) e sion 3.0 [ 17 ], which is designed o assess QoL in pa ien s wi h cance ; (2) he gene ic EQ-5D-3L ques ionnai e [ 18 ]; (3) he PEmb-QoL ques ionnai e, which is speci ic o pa ien s wi h PE [ 11 ], and (4) he VEINES-QOL/Sym ques ionnai e [ 9 , 10 ], which examines speci ic symp oms o DVT and ocuses on limi a ions o daily li ing ac i i ies. The EQ-5D-3L ques ionnai e is a commonly used gene ic heal h ques ionnai e capable o compa ing di e en diseases [ 18 ]. I allows he calcula ion o a u ili y index (UI), which comp ises i e di e en dimensions (mobili y, sel -ca e, daily ac i i ies, pain/discom o , and anxie y/dep ession) [ 18 ] which a e sco ed om 1 (no p oblems) o 5 (unable o/ex eme p oblems). The esponses a e combined o ob ain a 5-digi numbe ( om 11, 111 o 55555) ha summa izes he pa ien ’s heal h s a us. This alue is subsequen ly con e ed in o he UI, which may ange om 0.208 (wo s possible heal h) o 1.000 (bes possible heal h). The minimally impo an di e ence (MID) on he EQ-5D ques ionnai e o pa ien s wi h malignancies is 0.06−0.08 UI [19]. The EORTC QLQ-C30 ques ionnai e, which has been speci ically designed o pa ien s wi h malignancies, comp ises i e unc ioning scales (physical, social, ole, cogni i e, and emo ional unc ioning), h ee symp om scales ( a igue, pain, and nausea/ omi ing), one global heal h scale, and six independen i ems (dyspnea, sleep dis u bances, ano exia, cons ipa ion, dia hea, and economic impac ). High sco es on he global heal h scale and unc ioning s a us e lec a be e QoL, whe eas high alues in he symp oms scale indica e a educ ion in QoL (owing o he p esence o cance -associa ed symp oms) [ 20 – 22 ]. The index sco e anges om 0 (dea h) o 1 ( ull heal h), wi h highe sco es ( om 0.654 o 1) e lec ing a be e heal h s a us. The MID on he EORTC QLQ-C30 ques ionnai e a ies om 6 o 15 poin s [23–25]. The PEmb-QoL ques ionnai e—a disease-speci ic ques ionnai e o pa ien s wi h PE [ 11 ]—has six di e en dimensions ( equency o complain s, limi a ions in daily li e ac i i ies, wo k- ela ed p oblems, social limi a ions, in ensi y o complain s, and emo ional complain s). Highe sco es e lec a lowe QoL and he minimally clinically impo an di e ence (MCID) is 15 poin s [ 26 ]. The VEINES-QOL/Sym ques ionnai e [ 9 , 10 ], which akes in o accoun he symp oms, limi a ions, and daily li e ac i i ies o he las ou weeks, p o ides he VEINES-QOL sco e (which e lec s QoL) and he VEINES/Sym sco e (which p o ides a quan i a i e measu e o symp oms). Highe sco es e lec a be e QoL. 2.2. Sample Size Calcula ion The planned case-con ol a io was 1:2. To achie e a powe o 80% o de ec di e ences (in con as o he null hypo hesis) using a wo independen -sample S uden ’s - es wi h an alpha e o o 0.05, unde he assump ions o a mean in he con ol g oup o 55.75 uni s, a mean in he case g oup o 45.26 uni s, and a s anda d de ia ion in bo h g oups o 26.05 uni s, a o al o 98 cases and 196 con ols we e equi ed ( o aling 294 subjec s). Unde he hypo hesis o a 5% d opou a e, we planned o ec ui a minimum o 104 cases and 208 con ols ( o aling 312 subjec s). 2.3. S a is ical Analysis Fo each ques ionnai e, he dis ibu ions o sco es, means, medians, and he pe cen age o esponden s wi h minimum/maximum sco es (indica ing loo ing and ceiling e ec s) a e p esen ed. The c i e ia o accep abili y o each ques ionnai e we e as ollows: (1) less han 10% missing da a o summa y sco es, (2) e en dis ibu ion o endo semen equencies ac oss esponse ca ego ies, Cance s 2020,12, 75 4 o 12 and (3) less han 10% loo and ceiling e ec s o summa y sco es. We applied he ela i e e iciency (RE) s a is ic and calcula ed he e ec size (Cohen’s d) o es ima e he ques ionnai e pe o mance (i.e., sensi i i y o de ec di e ences) in each s udy g oup. The RE s a is ic was de ined as he a io o F-s a is ics in he analysis o a iance (ANOVA) es s o he di e ences in sco es be ween known g oups [ 27 ]. Highe F-s a is ic alues indica e a g ea e e iciency o disc imina ion ( e sus he compa a o ). The e ec size was calcula ed using he di e ence in mean sco es di ided by he pooled s anda d de ia ion. The h eshold alues o e ec sizes we e de ined as small (0.2), mode a e (0.5), and la ge (0.8). Figu e 1p o ides a iolin plo . Violin plo s allow plo ing nume ical da a and can be ega ded as a combina ion be ween box plo s and ke nel densi y plo s. Ke nel densi y es ima ion (KDE) is a non-pa ame ic app oach o es ima e he p obabili y densi y unc ion o a andom a iable. Mo eo e , hese plo s show he ac ual dis ibu ion o he obse ed alues (do s in cases and iangles in con ols), ul ima ely allowing a ep esen a ion o he sco es used in he s udy. Boxplo s depic s he median (black line inside he box) and he in e qua ile ange ( he edges o he box). The ke nel densi y plo (g ey line) ep esen s he p obabili y densi y unc ion. La ge sec ions o he iolin plo indica e a highe p obabili y o obse a ion a a gi en alue, whe eas hinne sec ions co espond o a lowe p obabili y. S a is ical calcula ions we e pe o med using R ( e sion 3.5.3; Ma ch 11, 2019) and R S udio ( e sion 1.1.456) equipped wi h he dply ( e sion 0.8.3), e size ( e sion 0.7.4), PMCMR ( e sion 4.3), ca spec ( e sion 0.97), and ggplo 2 ( e sion 3.1.0) packages. The ull ep oducible code is p o ided in he Supplemen a y Ma e ials. 2.4. Da a Sha ing S a emen Fo o iginal da a, please con ac [email p o ec ed]. Indi idual pa icipan da a will no be sha ed. 3. Resul s The s udy sample consis ed o 425 pa ien s (128 cases and 297 con ols; mean age: 60.2 ±18.4 yea s; 58% men) (Table S1 include ec ui men pe cen e ). O hem, 77% we e ecei ing an icance ea men and 20% had a cen al enous ca he e . The mos common malignancies we e gas oin es inal (23.5%) and lung (19.8%) umo s. Dis an me as ases we e iden i ied in 68% o he s udy pa ien s, and he Eas e n Coope a i e Oncology G oup (ECOG) pe o mance s a us was 0–1 in 89% o he pa icipan s (Table 1). Adenoca cinoma was he mos equen his ology ype (58.8%). The dis ibu ion o VTE was as ollows: DVT (54.7%), PE (25%), and DVT plus PE (20.3%). The e we e no signi ican di e ences be ween he ime om cance diagnosis and he inclusion in he s udy be ween cases (14.76 ± 21.34 mon hs) and con ols (15.01 ± 25.57 mon hs). Mo e han hal o all cases (54.5%) and con ols (58.1%) we e included wi hin 6 mon hs om cance diagnosis. All cases ecei ed weigh -adjus ed low molecula weigh hepa in a inclusion. Table S2 shows he ma i al s a us, educa ion s a us, employmen s a us, and g oss income o he s udy pa icipan s. 3.1. Impac o Venous Th omboembolism on Quali y o Li e o Pa ien s wi h Malignancies The p esence o h ombosis in pa ien s wi h malignancies had a s a is ically signi ican and clinically ele an nega i e impac on he quali y o li e acco ding o he esul s o ou di e en ques ionnai es. O he 425 pa ien s included, 84% comple ed he EQ-5D ques ionnai e (n =355), 83% he EORTC QLQ-C30 ques ionnai e (n =354), 72% he Pemb-QOL ques ionnai e (n =306), and 72% he VEINES-QOL/Sym ques ionnai e (n =305). Cases and con ols di e ed signi ican ly in e ms o EQ-5D-3L esul s, and such di e ence was la ge han he MID (0.55 e sus 0.77, espec i ely; mean di e ence: − 0.22). Simila esul s we e ob ained on he EORTC QLQ-C30 ques ionnai e wi h ega d o he global heal h s a us (47.7 e sus 58.4, espec i ely; mean di e ence: − 10.3), physical unc ioning (64.4 e sus 80.6, espec i ely; mean di e ence: − 16.2), ole unc ioning (53.9 e sus 74.7, espec i ely; mean di e ence: − 20.8), and social unc ioning (62.2 e sus 74.1, espec i ely; mean di e ence: − 11.9). As a as symp oms a e conce ned, cases sco ed highe in e ms o a igue (48.4 e sus 33.7, espec i ely; Cance s 2020,12, 75 5 o 12 mean di e ence: +14.7), pain (36 e sus 23, espec i ely; mean di e ence: +13). and dyspnea (23.5 e sus 13, espec i ely; mean di e ence: +10.5; Table 2). Table 1. Clinical cha ac e is ics o he s udy pa ien s. Va iable Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) En i e Coho Male sex, n (%) 65 (50.8%) 180 (60.8%) 245 (57.8%) Age, yea s (n =425); mean ±SD 63 (11.4) 59.1 (20.6) 60.2 (18.4) Body mass index, kg/m2(n =321), mean ±SD 27.2 (5.7) 26.1 (4.9) 26.4 (5.2) A e ial hype ension (n =392), n (%) 55 (44.0%) 88 (33.0%) 143 (36.5%) Dyslipidemia (n =391), n (%) 33 (26.6%) 58 (21.7%) 91 (23.3%) Diabe es melli us (n =392), n (%) 18 (14.4%) 43 (16.1%) 61 (15.6%) As hma (n =392), n (%) 3 (2.4%) 4 (1.5%) 7 (1.8%) Acu e co ona y synd ome (n =392), n (%) 3 (2.4%) 6 (2.2%) 9 (2.3%) S oke (n =392), n (%) 6 (4.8%) 7 (2.6%) 13 (3.3%) Smoking (n =392), n (%) 30 (24.0%) 61 (22.8%) 91 (23.2%) Non-s e oidal an i-in lamma o y d ugs (n =392), n (%) 12 (9.6%) 20 (7.5%) 32 (8.2%) S a ins (n =392), n (%) 22 (17.6%) 32 (12.0%) 54 (13.8%) Ac i e an icance ea men , n (%) 95 (75.4%) 203 (77.5%) 298 (76.8%) Cen al enous ca he e , n (%) 7 (5.6%) 70 (26.7%) 77 (19.8%) ECOG pe o mance s a us (n =364) 0, n (%) 30 (25.4%) 105 (42.7%) 135 (37.1%) 1, n (%) 65 (55.1%) 125 (50.8%) 190 (52.2%) 2, n (%) 17 (14.4%) 13 (5.3%) 30 (8.2%) 3, n (%) 5 (4.2%) 3 (1.2%) 8 (2.2%) 4, n (%) 1 (0.8%) 0 (0.0%) 1 (0.3%) Me as asis (n =341), n (%) 80 (64.5%) 173 (69.8%) 253 (68%) Tumo si e (n =425) Gynecologic, n (%) 24 (18.8%) 19 (6.4%) 43 (10.1%) Lung, n (%) 37 (28.9%) 47 (15.8%) 84 (19.8%) Diges i e, n (%) 18 (14.1%) 82 (27.6%) 100 (23.5%) Geni ou ina y, n (%) 11 (8.6%) 17 (5.7%) 28 (6.6%) Lymphoma, n (%) 9 (7%) 49 (16.5%) 58 (13.6%) O he si es, n (%) 29 (22.7%) 83 (27.9%) 112 (26.4%) Abb e ia ions: VTE: enous h omboembolism; SD: s anda d de ia ion; HDL: high-densi y lipop o ein; LDL: low-densi y lipop o ein; ECOG: Eas e n Coope a i e Oncology G oup. Cance s 2020,12, 75 6 o 12 Table 2. Di e ences in he Pemb-QOL, EORTC QLQ-C30 unc ional and symp oms scales, EQ-5D-3L, and VEINES scale sco es be ween cases and con ols. Pemb-QOL 1Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) Mean Di e ence E ec Size (95% CI) Rela i e E iciency (95% CI) Quali y o li e 44.4 23.0 +21.4 ** 0.99 (0.6; 1.5) 0.93 (0.6; 1.2) F equency o complain s 33.6 21.0 +12.6 ** 0.86 (0.6; 1.4) 0.51 (0.2; 0.8) Ac i i ies daily li ing limi a ions 52.1 29.3 +22.8 ** 1.06 (0.7; 1.7) 0.79 (0.4; 1.1) Wo k- ela ed p oblems 72.9 39.5 +33.4 ** 0.84 (0.5; 1.3) 0.74 (0.4; 1.0) Social limi a ions 37.2 15.5 +21.7 ** 1.47 (0.9; 2.3) 0.78 (0.4; 1.1) In ensi y o complain s 33.9 15.5 +18.4 ** 1.32 (0.9; 2.1) 0.86 (0.5; 1.1) Emo ional complain s 36.4 17.0 +19.4 ** 1.33 (0.9; 2.1) 0.89 (0.6; 1.2) EORTC QLQ-C30 Func ional Scale 2 Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) Mean Di e ence E ec Size (95% CI) Rela i e E iciency (95% CI) Global heal h s a us 47.7 58.4 −10.3 ** 0.95 (0.7; 1.3) −0.42 (−0.6; −0.2) Physical unc ioning 64.4 80.6 −16.2 ** 1.29(0.9; 1.8) −0.70 (−0.9; −0.4) Role unc ioning 53.9 74.7 −20.8 ** 1.25 (0.9; 1.7) −0.65 (−0.9; −0.4) Emo ional unc ioning 67.2 72.3 −5.1 0.94 (0.7; 1.3) −0.2 (−0.04; 0.1) Cogni i e unc ioning 81.7 84.4 −2.7 1.37 * (1.0; 1.9) −0.11 (−0.3; 0.1) Social unc ioning 62.2 74.1 −11.9 ** 1.35 (0.9; 1.8) −0.39 (−0.6; −0.1) EORTC QLQ-C30 symp oms scale 3 Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) Mean Di e ence E ec Size (95% CI) Rela i e E iciency (95% CI) Fa igue 48.4 33.7 +14.7 ** 1.27 (0.9; 1.7) 0.52 (0.3; 0.7) Nausea and omi ing 14.2 11.5 +2.7 0.98 (0.7; 1.3) 0.12 (−0.1;0.3) Pain 36.0 23.0 +13.0 ** 1.48 * (1.0; 2.0) 0.4 (0.2; 0.7) Dyspnea 23.5 13.0 +10.5 ** 1.5 ** (1.1; 2.0) 0.39 (0.2; 0.6) Insomnia 30.1 31.9 −1.8 0.97 (0.7; 1.3) −0.05 (−0.2;0.2) Appe i e loss 25.8 25.3 +0.5 1.0 (0.7; 1.4) 0.01 (−0.2;0.2) Cons ipa ion 26.7 22.1 +4.6 1.25 (0.9; 1.7) 0.1 (−0.1;0.4) Dia hea 15.1 16.5 +1.4 1.21 (0.9; 1.7) −0.05 (−0.3;0.2) Financial di icul ies 23.4 17.8 +5.6 1.35 (0.9; 1.9) 0.2 (−0.03;0.4) EQ-5D-3L 4Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) Mean Di e ence E ec Size (95% CI) Rela i e E iciency (95% CI) Index sco e 0.55 0.77 −0.22 ** 2.06 ** (1.5; 2.8) −0.7 (−0.9; −0.5) VEINES-QOL/Sym 5Cases (Cance wi h VTE) Con ols (Cance wi hou VTE) Mean Di e ence E ec Size (95% CI) Rela i e E iciency (95% CI) VEINES-QOL 42.7 51.7 −9.0 ** 0.82 (0.53; 1.20) 1.0 (0.79; 1.38) VEINES/Sym 43.8 51.4 −7.6 ** 0.80 (0.5–1.2) 0.8 (0.5–1.0) Abb e ia ions: VTE: enous h omboembolism; CI: con idence in e al. * p<0.05; ** p<0.001. 1 Pemb-QOL: Highe sco es e lec a lowe quali y o li e and he minimally clinically impo an di e ence is 15 poin s; 2 EORTC QLQ-C30 unc ional scale: Highe sco es e lec a be e heal h s a us and he minimally impo an di e ence a ies om 6 o 15 poin s; 3 EORTC QLQ-C30 symp oms scale: Highe sco es in he symp oms scale indica e a educ ion in quali y o li e; 4 EQ-5D-3L: Highe sco es e lec a be e heal h s a us and he minimally impo an di e ence on he EQ-5D ques ionnai e o pa ien s wi h malignancies is 0.06 − 0.08 UI; 5 VEINES-QOL/Sym: Highe sco es e lec a be e heal h s a us. Cases and con ols di e ed signi ican ly in e ms o PEmb-QoL esul s, and such di e ence was la ge han he MID wi h ega d o QoL (44.4 e sus 23, espec i ely; mean di e ence: − 21.4) and i e o he six measu ed dimensions. Simila ly, he VEINES-QOL/Sym ques ionnai e showed wo se QoL in cases han in con ols (42.7 e sus 51.7, espec i ely; mean di e ence: − 9), wi h he o me g oup ha ing mo e symp oms (43.8 e sus 51.4, espec i ely; mean di e ence: − 7.6). Figu e 1shows ou sec ions o he iolin plo indica ing di e ences in he median be ween cases and con ols (p<0.05). The e we e also ma ked di e ences in ke nel dis ibu ion. Speci ically, da a om con ols su ounded he median alues o he ou ques ionnai es, whe eas a wide dis ibu ion was obse ed o cases. Cance s 2020,12, 75 7 o 12 Cance s 2020, 12, x FOR PEER REVIEW 7 o 12 Figu e 1. Cases and con ols dis ibu ion o he da a and i s p obabili y densi y in di e en ques ionnai es. Violin plo s. (A) QLQ-c30 Global Heal h S a us, (B) Pemb-QOL, (C) EQ-5D-3L Index, and (D) VEINES QOL. The plo s show he ac ual dis ibu ion o he obse ed alues (do s in cases and iangles in con ols), ul ima ely allowing a ep esen a ion o he sco es used in he s udy. Boxplo s depic s he median (black line inside he box) and he in e qua ile ange ( he edges o he box). The ke nel densi y plo (g ey line) ep esen s he p obabili y densi y unc ion. La ge sec ions o he iolin plo indica e a highe p obabili y o obse a ion a a gi en alue, whe eas hinne sec ions co espond o a lowe p obabili y. 3.2. Subg oup Analysis No signi ican di e ences in e ms o EQ-5D-3L esul s we e ound be ween pa ien s wi h PE e sus DVT. Howe e , he wo g oups di e ed signi ican ly wi h ega d o dyspnea as measu ed by he EORTC QLQ-C30 ques ionnai e, and such di e ence was la ge han he MID (32.7 e sus 15.9; mean diffe ence: −16.8; Table S3). We subsequen ly pe o med an age- and sex-s a i ied analysis o he EORTC QLQ-C30 ques ionnai e in cases and con ols. Rega dless o sex, we ound s a is ically signi ican di e ences la ge han he MID in he g ea majo i y o he unc ioning scales (Table S4). Simila di e ences we e obse ed on he EQ-5D-3L ques ionnai e. As a as he PEmb-QoL ques ionnai e is conce ned, he p esence o PE was ound o a ec QoL (wi h he di e ence being la ge han he MCID) in women bu no in men (49.9 e sus 20.1, espec i ely; mean diffe ence: −29.8). Simila indings we e obse ed wi h ega d o all o he dimensions. Only wo k- ela ed p oblems and he in ensi y o complain s we e ound o be a ec ed in men. In con as , he VEINES-QOL/Sym ques ionnai e showed s a is ically signi ican di e ences in bo h sexes. When QoL was analyzed in ela ion o he cance si e, he unc ioning scales o he EORTC QLQ- C30 ques ionnai e showed s a is ically signi ican di e ences (la ge han he MID) in se e al dimensions among pa ien s wi h gynecologic and diges i e umo s. Pa ien s wi h gynecologic malignancies also showed di e ences in global heal h s a us, physical s a us, ole, and social unc ioning. Wi h ega d o diges i e umo s, signi ican di e ences we e obse ed in physical s a us, Figu e 1. Cases and con ols dis ibu ion o he da a and i s p obabili y densi y in di e en ques ionnai es. Violin plo s. ( A ) QLQ-c30 Global Heal h S a us, ( B ) Pemb-QOL, ( C ) EQ-5D-3L Index, and ( D ) VEINES QOL. The plo s show he ac ual dis ibu ion o he obse ed alues (do s in cases and iangles in con ols), ul ima ely allowing a ep esen a ion o he sco es used in he s udy. Boxplo s depic s he median (black line inside he box) and he in e qua ile ange ( he edges o he box). The ke nel densi y plo (g ey line) ep esen s he p obabili y densi y unc ion. La ge sec ions o he iolin plo indica e a highe p obabili y o obse a ion a a gi en alue, whe eas hinne sec ions co espond o a lowe p obabili y. 3.2. Subg oup Analysis No signi ican di e ences in e ms o EQ-5D-3L esul s we e ound be ween pa ien s wi h PE e sus DVT. Howe e , he wo g oups di e ed signi ican ly wi h ega d o dyspnea as measu ed by he EORTC QLQ-C30 ques ionnai e, and such di e ence was la ge han he MID (32.7 e sus 15.9; mean di e ence: −16.8; Table S3). We subsequen ly pe o med an age- and sex-s a i ied analysis o he EORTC QLQ-C30 ques ionnai e in cases and con ols. Rega dless o sex, we ound s a is ically signi ican di e ences la ge han he MID in he g ea majo i y o he unc ioning scales (Table S4). Simila di e ences we e obse ed on he EQ-5D-3L ques ionnai e. As a as he PEmb-QoL ques ionnai e is conce ned, he p esence o PE was ound o a ec QoL (wi h he di e ence being la ge han he MCID) in women bu no in men (49.9 e sus 20.1, espec i ely; mean di e ence: − 29.8). Simila indings we e obse ed wi h ega d o all o he dimensions. Only wo k- ela ed p oblems and he in ensi y o complain s we e ound o be a ec ed in men. In con as , he VEINES-QOL/Sym ques ionnai e showed s a is ically signi ican di e ences in bo h sexes. When QoL was analyzed in ela ion o he cance si e, he unc ioning scales o he EORTC QLQ-C30 ques ionnai e showed s a is ically signi ican di e ences (la ge han he MID) in se e al dimensions among pa ien s wi h gynecologic and diges i e umo s. Pa ien s wi h gynecologic malignancies also Cance s 2020,12, 75 8 o 12 showed di e ences in global heal h s a us, physical s a us, ole, and social unc ioning. Wi h ega d o diges i e umo s, signi ican di e ences we e obse ed in physical s a us, ole, emo ional, and cogni i e unc ioning (Table S5). An analysis o symp oms on he EORTC QLQ-C30 ques ionnai e is p o ided in Table S6. The EQ-5D-3L ques ionnai e yielded s a is ically signi ican di e ences (la ge han he MID) o all umo si es, he only excep ion being lung cance (Table S7). In he subg oup o pa ien s wi h DVT, he VEINES-QOL/Sym ques ionnai e iden i ied s a is ically signi ican di e ences in bo h QoL and symp oms o pa ien s wi h diges i e and pulmona y umo s (Table S8). The esul s on he PEmb-QoL ques ionnai e we e also ound o di e acco ding o he umo si e (Table S9). 4. Discussion The p esen case-con ol analysis demons a es a signi ican de imen al impac o acu e symp oma ic VTE on QoL o pa ien s wi h malignancies, wi h a wo se global heal h s a us being de ec ed by all o he ou ques ionnai es used in ou s udy. The e we e di e ences la ge han he MID on he EQ-5D-3L and he EORTC QLQ-C30 ques ionnai es and g ea e han he MCID on he PEmb-QoL ques ionnai e. Mo eo e , a s a is ically signi ican wo se QoL was iden i ied on he VEINES-QOL/Sym ques ionnai e. Using he EORTC QLQ-C30 ques ionnai e, we simila ly showed ha acu e symp oma ic VTE is associa ed wi h lowe physical unc ioning, ole unc ioning, social unc ioning, as well as highe a igue, pain, and dyspnea. A de imen al impac was also obse ed on i e o he six dimensions o he PEmb-QoL ques ionnai e. Ou indings ha e p ac ical implica ions. Owing o he nega i e impac o h ombosis on he quali y o li e o pa ien s wi h malignancies, heal hca e pe sonnel should be awa e o his aspec and pay adequa e a en ion o i s de ec ion. In addi ion, ou da a may pa e he way o u u e esea ch aimed a assessing he impac on quali y o li e o ea men s and in e en ions implemen ed in pa ien s wi h cance -associa ed h ombosis. Acco ding o he Wo ld Heal h O ganiza ion, QoL should be conside ed as a mul idimensional concep [ 28 ]. Gene ic QoL ques ionnai es allow compa ing o di e en diseases o p ocesses, whe eas disease-speci ic ques ionnai es can se e as mo e sensi i e ools o analyzing he epe cussions o a gi en disease on he pa ien . Recen yea s ha e wi nessed a moun ing in e es in QoL as a heal hca e ou come measu e—wi h inc easingly mo e s udies ocusing no only on he quan i y bu also on he quali y o li es li ed [29]. In a s udy conduc ed in 359 pa ien s wi h DVT, Kahn e al. [ 13 ] in es iga ed QoL by adminis e ing he 36-I em Sho -Fo m Heal h Su ey (SF-36) and he VEINES QOL/Sym ques ionnai es a baseline and a wo di e en ollow-up isi s (a 1 and 4 mon hs). The esul s o he VEINES QOL/Sym ques ionnai e demons a ed a sligh ly highe QoL in hei sample compa ed wi h ou s udy (50 e sus 42.7, espec i ely). This di e ence may be explained by he ac ha only 12.5% o hei s udy pa ien s had cance [ 13 ]. Ta oly e al. [ 14 ] pe o med a c oss-sec ional s udy o QoL in 213 pa ien s wi h PE—wi h hei esul s showing a highe EQ-5D index sco e han ha obse ed in ou s udy (0.8 e sus 0.55, espec i ely). Such di e ence may be a ibu ed o he ac ha only 7% o hei s udy pa icipan s had a diagnosis o cance . In addi ion, ques ionnai es we e adminis e ed a e 4 mon hs and 10 yea s om he index PE e en [ 14 ]. The p ospec i e, obse a ional, in e na ional PREFER s udy in es iga ed he QoL o 1399 pa ien s wi h PE using he EQ-5D-5L ques ionnai e‚—wi h a epo ed sco e o 0.71 ± 0.27 a he ime o e en [ 30 ]. Only 120 pa ien s (8.6%) in his s udy had a diagnosis o cance and disease-speci ic QoL ques ionnai es we e no u ilized. The QUAVITEC s udy was a p ospec i e, longi udinal s udy o pa ien s wi h cance and VTE [ 31 ] who we e adminis e ed h ee ques ionnai es on QoL (SF-36, EORTC QLQ-C30, and VEINES-QOL) a baseline and a wo ollow-up isi s (3 and 6 mon hs). Al hough a be e QoL was epo ed a 6 mon hs a e he index VTE e en , hese esul s should be in e p e ed cau iously because only 49% o he s udy pa ien s unde wen he 6-mon h assessmen . No ably, he global heal h s a us/QoL sco e on he EORTC QLQ-C30 ques ionnai e was simila o ha obse ed in ou cu en in es iga ion (47 e sus 47.7, espec i ely). A sub-analysis o he CATCH ial has been published in 2008 [ 32 ]. The s udy in es iga ed he u ili y o LMWH inzapa in in p e en ing ecu en VTE in pa ien s wi h di e en ypes o cance and he EQ-5D ques ionnai e was Cance s 2020,12, 75 9 o 12 adminis e ed o he pa icipan s. The au ho s ound ha ecu en VTE had a signi ican impac on EQ-5D sco es (dec ease: − 0.075). The s eng hs o his s udy included he la ge sample size (n =883) and he epea ed mon hly measu es o quali y o li e o 7 mon hs. Howe e , his esea ch also had some inhe en ca ea s, including he use o a gene ic—and no disease-speci ic—ques ionnai e and he compa ison wi h a p ede ined pa ien p o ile (male, om Wes e n Eu ope, wi hou dis an me as ases, wi h symp oma ic DVT as he quali ying e en , and an ECOG pe o mance s a us o 1 a baseline). Da a ob ained om quali y o li e ques ionnai es p o ide clinically ele an and ep oducible in o ma ion wi h espec o di e en pa ien dimensions. These esul s may be also complemen ed wi h quali a i e esea ch wo k. In his ega d, a p e ious s udy conduc ed semi-s uc u ed in e iews in 14 pa ien s wi h cance -associa ed h ombosis [ 33 ]. The esul s indica ed no only ha VTE had a majo ad e se impac on hei li e bu also ha h ombosis was conside ed a dis inc en i y— a he han a pa —o hei cance illness. The ollowing h ee a eas we e ound o be a ec ed by VTE: (1) symp om bu den; (2) impac in he con ex o hei cance jou ney; (3) impac on hei ac i i ies o daily li ing. Ou s udy has se e al s eng hs. Fi s , we speci ically ocused on he impac o acu e symp oma ic VTE on QoL in pa ien s wi h cance using di e en ques ionnai es. This app oach allowed us o compa e ou indings wi h hose ob ained in o he diseases (owing o he use o he gene ic EQ-5D-3L ques ionnai e), in o he cance -associa ed complica ions (owing o he use o he EORTC QLQ-C30 ques ionnai e), and in o he clinical popula ions wi h VTE (owing o he use o he PEmb-QoL and VEINES-QOL ques ionnai es). Second, ou case-con ol design allowed us ob aining di ec compa isons o QoL, wi hou eso ing o his o ical coho s cha ac e ized by di e en demog aphic and clinical cha ac e is ics. Thi d, he compa a i e analysis o QoL conduc ed in ou s udy ook in o accoun ei he MID o MCID. We we e he e o e able o iden i y clinically ele an di e ences ha we e no me ely s a is ically signi ican . Howe e , ou indings need o be in e p e ed in he con ex o some limi a ions. Fi s , al hough he design o ou wo k was a case-con ol s udy, he p ospec i e and mul icen e na u e o ou case-con ol s udy did no allow us ob aining a pe ec ma ching o all a iables ha may po en ially a ec quali y o li e. Fo example, umo loca ion was no well balanced be ween cases and con ols. In any case, h ombosis was ound o ha e a nega i e impac on quali y o li e ega dless o umo loca ion. In addi ion, mo e han hal o all cases (54.5%) and con ols (58.1%) we e included wi hin 6 mon hs om cance diagnosis. Also, he me as asis a e did no show signi ican in e g oup di e ences. Mo eo e , he e we e o he a iables ha could a ec o QoL ha we e no included in ou s udy (i.e., chemo he apy use, episodes o neu openic e e , in ec ions, ecen hospi aliza ions, i pa ien s ecei ed cu a i e o pallia i e ea men o 12-mon h su i al p obabili y in bo h g oups). Second, he numbe o pa icipan s was no su icien ly la ge o de ec s a is ically signi ican di e ences in ce ain ques ionnai e dimensions o speci ic subg oups. This ca ea despi e ha p ede e mined sample size was su icien ly la ge o demons a e an impac o acu e symp oma ic VTE on QoL o pa ien s wi h malignancies—a hypo hesis ha was ul ima ely con i med. Thi d, we did no pe o m se ial assessmen s o QoL in ou sample. Al hough his me hodological aspec may be essen ial in pa ien s wi h VTE and no malignancies, i s impo ance is less pa amoun in he oncology se ing. Acco dingly, he dismal p ognosis o pa ien s wi h me as a ic cance may lead o a bias simila o ha occu ing in he QUAVITEC s udy, which showed an imp o ed QoL a a 6-mon h ollow-up, albei a he expenses o a limi ed numbe o esponde s (less han 50% compa ed wi h baseline) [31]. 5. Conclusions In summa y, he esul s o ou s udy demons a e ha acu e symp oma ic VTE has an ad e se impac on he QoL o pa ien s wi h malignancies. Clinicians who ea cance -associa ed h ombosis should be awa e ha his e en is no me ely a complica ion bu has a b oade impac on he pa ien ’s quali y o li e, ul ima ely equi ing a comp ehensi e clinical managemen .