Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON)

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1 British Journl of Cncer (2010) 102, & 2010 Cncer Reserch UK All rights reserved /10 $ Short-term helth-relted qulity of life consequences in lung cncer CT screening tril (NELSON) KAM vn den Bergh*,1, ML Essink-Bot 2,1, GJJM Borsboom 1, E Th Scholten 3, M Prokop 4, HJ de Koning 1 nd RJ vn Klveren 5 1 Deprtment of Public Helth, Ersmus MC, University Medicl Centre Rotterdm, Rotterdm, The Netherlnds; 2 Deprtment of Socil Medicine, Acdemic Medicl Centre, University of Amsterdm, Amsterdm, The Netherlnds; 3 Deprtment of Rdiology, Kennemer Gsthuis Hrlem, Hrlem, The Netherlnds; 4 Deprtment of Rdiology, University Medicl Center Utrecht, Utrecht, The Netherlnds; 5 Deprtment of Pulmonology, Ersmus MC, University Medicl Centre Rotterdm, Rotterdm, The Netherlnds BACKGROUND: In lung cncer CT screening, prticipnts often hve n indeterminte screening result t bseline requiring follow-up CT. In subjects with either n indeterminte or negtive result fter screening, we investigted whether helth-relted qulity of life (HRQoL) chnged over time nd differed between groups in the short term. METHODS: A totl of 733 prticipnts in the NELSON tril received four questionnires: T0, before rndomistion; T1, 1 week before the bseline screening; T2, 1 dy fter the screening; nd T3, 2 months fter the screening results but before the 3-month follow-up CT. HRQoL ws mesured s generic HRQoL (the 12-item Short Form, SF-12; the EuroQol questionnire, EQ-5D), nxiety (the Spielberger Stte-Trit Anxiety Inventory, STAI-6), nd lung-cncer-specific distress (the Impct of Event Scle, IES). For nlyses, repeted-mesures nlysis of vrince ws used, djusted for covrites. RESULTS: Response to ech questionnire ws 88% or higher. Scores on SF-12, EQ-5D, nd STAI-6 showed no cliniclly relevnt chnges over time. At T3, IES scores tht were cliniclly relevnt incresed fter n indeterminte result, wheres these scores showed significnt decrese fter negtive result. At T3, differences in IES scores between the two bseline result groups were both significnt nd cliniclly relevnt (Po0.01). CONCLUSION: This longitudinl study mong prticipnts of lung cncer screening progrmme showed tht in the short term recipients of n indeterminte result experienced incresed lung-cncer-specific distress, wheres the HRQoL chnges fter negtive bseline screening result my be interpreted s relief. British Journl of Cncer (2010) 102, doi: /sj.bjc Published online 24 November 2009 & 2010 Cncer Reserch UK Keywords: lung neoplsms; mss screening; qulity of life; spirl computed tomogrphy Clinicl Studies Lung cncer is the min cuse of cncer-relted deths worldwide mong men nd women (Ferly et l, 2004; Americn Cncer Society, 2007). Although cncer cn be detected in n erly stge by computed tomogrphy (CT) screening (Henschke et l, 2006), results from rndomised controlled trils re needed before deciding whether CT screening will reduce lung cncer mortlity, nd whether implementtion of lrge-scle lung cncer CT screenings progrmmes should be recommended (Gohgn et l, 2004; Bch et l, 2007; vn Iersel et l, 2007; Field nd Duffy, 2008). Most CT screening studies report bseline rtes of 14 43% of non-clcified nodules (5 10 mm in dimeter); this reltively lrge rnge is ttributed to geogrphic differences in nodule prevlence nd the slice thickness used (Diederich et l, 2002; Wilson et l, 2008). Subjects with this type of nodule *Correspondence: KAM vn den Bergh, Deprtment of Public Helth, Ersmus MC, University Medicl Centre Rotterdm, P.O. Box 2040, 3000 CA Rotterdm, The Netherlnds; E-mil: k.vndenbergh@ersmusmc.nl Received 14 July 2009; revised 21 October 2009; ccepted 27 October 2009; published online 24 November 2009 usully receive recommendtion to undergo follow-up CT 3 4 months lter to ssess whether nodule hs grown, becuse nodule growth is ssocited with incresed cncer risk (Swensen et l, 2005). In the Dutch Belgin rndomised controlled tril for lung cncer screening in high-risk subjects (the NELSON tril), subjects could receive either negtive, n indeterminte, or positive scn result (Xu et l, 2006). Subjects receiving n indeterminte scn result t bseline were invited to undergo follow-up scn 3 months lter; however, receiving such result nd witing for this scn might hve n unfvourble effect on helth-relted qulity of life (HRQoL), compred with receiving negtive result. For exmple, in the PLuSS study, significnt increse of generic nxiety ws found 1 2 weeks fter communiction of n indeterminte bseline screening result (Byrne et l, 2008). However, Byrne et l (2008) used HRQoL instruments tht precluded detiled evlution of the psychologicl consequences of lung cncer screening; moreover, possible chnges in HRQoL between the bseline test result nd the 3-month follow-up scn result were not reported. Furthermore, study on brest cncer screening showed tht nxiety ws higher just before screening, compred to bsic HRQoL unrelted to

2 Clinicl Studies 28 screening (Rijnsburger et l, 2004). So, to determine the whole effect of screening, it is importnt to estblish whether HRQoL is lredy negtively ffected just before bseline screening. In this study we ssessed chnges in generic nd lung-cncerspecific HRQoL chnges over time mong prticipnts undergoing lung cncer screening in the short term. Therefore, we ddressed the following questions: (1) To wht extent does HRQoL decrese just before bseline screening? (2) Is there difference in HRQoL between those with n indeterminte bseline result nd those with negtive result? We hypothesised tht lung-cncer-specific distress scores just before bseline CT screening would be higher compred with scores cquired few months before screening (Rijnsburger et l, 2004). Also, in subjects who received n indeterminte bseline result we expected higher levels of lungcncer-specific distress 2 months fter screening (but before the 3-month follow-up scn) compred to those who received negtive result. MATERIALS AND METHODS NELSON study popultion A rndom smple of Dutch nd Belgin subjects (ged yers) registered in popultion registries received questionnire contining items bout helth nd smoking history. Current nd former smokers were sked to complete this first NELSON questionnire. Respondents who hd smoked 415 cigrettes per dy for 425 yers or 410 cigrettes per dy for 430 yers, those who still smoked, or those who hd quit 10 or less yers go were invited to prticipte in the tril (vn Iersel et l, 2007). Informed consent ws obtined from high-risk subjects who were subsequently rndomised (1 : 1) to either screening group, or control group tht received no screening. Prticipnts in the screening group could receive either positive, indeterminte, or negtive test result within 3 weeks fter the bseline CT scn ws performed (Xu et l, 2006). A positive test result required referrl to pulmonologist for work up nd dignosis. Prticipnts with n indeterminte result were scheduled to undergo follow-up CT scn 3 months lter to evlute whether the nodule hd grown. The letter to prticipnts with n indeterminte result stted: y we hve observed very smll bnormlity in your lung (5 to 10 mm long). Such smll bnormlity is often detected in mny persons nd it usully represents smll scr or minor inflmmtion. Therefore, t this moment there is no need for ny further investigtions. However, in order to see whether there hs been ny chnge in this bnormlity, new CT scn of the lungs will be mde fter 3 to 4 months. The letter lso explins the possible results nd relted work-up fter this follow-up CT scn: y prticipnts with n bnormlity showing no growth will receive negtive test result nd will be invited for CT scn 1 yer fter the bseline screening. Those with n bnormlity showing some growth will be referred to pulmonologist for further investigtions (Xu et l, 2006). The NELSON tril, including the current HRQoL study, ws pproved by the Dutch Ministry of Helth nd by the locl ethics committees of the prticipting centres. Informed consent ws obtined from ll prticipnts. The NELSON tril is registered t with number ISRCTN HRQoL study HRQoL in lung cncer CT screening KAM vn den Bergh et l A consecutive smple of 1466 prticipnts ws tken from the screening centres in Hrlem nd Utrecht, rndomised in August 2005 (n ¼ 977), September 2005 (n ¼ 390), nd November 2005 (n ¼ 99). All prticipnts received questionnire fter eligibility check, fter sending the informtion brochure, nd signing of the informed consent form, but before tril rndomistion (Time 0 (T0), bseline HRQoL ssessment). Subjects rndomised to the screen rm received second questionnire 1 week before the bseline scn (Time 1, T1); they were sked to complete the questionnire before the bseline scn ws performed. At 1 dy fter this bseline scn, they received third questionnire (Time 2, T2) nd were sked to complete this questionnire within 1 week. At T2, subjects did not receive the scn result of the bseline scn. Finlly, for subjects who hd negtive or n indeterminte test result, questionnire ws sent bout 2 months fter the bseline scn ws mde (Time 3, T3). For subjects with n indeterminte scn result this ws bout 1 month before the 3-month follow-up scn. In this study, the response of those who did not undergo bseline screening, or who hd positive test result, ws excluded from the nlyses. The questionnire responses of those who completed T1 fter the CT scn (n ¼ 12), who completed T2 before the CT scn (n ¼ 0) or fter the bseline test result (n ¼ 6), nd who completed T3 fter the result of the follow-up scn (n ¼ 1) were excluded. These were not counted s responses. Mesures Generic HRQoL The prticipnt s generic HRQoL ws mesured with the 12-item Short Form (SF-12) nd the EuroQol questionnire (EQ-5D) (Essink-Bot et l, 1993; Wre et l, 1996; Gndek et l, 1998; Kind et l, 2005). The SF-12 is shorter version of the SF-36 nd consists of physicl component summry (PCS) nd mentl component summry (MCS) (Wre et l, 1996). We used the cute (1-week recll) form of version 1. Ech prticipnt completed the SF-12 t T0 nd T3. A higher score indictes better HRQoL. Respondents were lso sked to rte their own helth on the visul nlogue scle (VAS) of the EQ-5D, rnging from 0 (worst imginble helth sttus) to 100 (best imginble helth sttus) (Essink-Bot et l, 1993; Kind et l, 2005). Prticipnts completed the EQ-5D VAS t ll four ssessment points (i.e. T0, T1, T2, nd T3). Generic nxiety Generic nxiety ws mesured using the short form of the Spielberger Stte-Trit Anxiety Inventory (STAI-6) (vn der Bij et l, 2003). Six items relted to nxiety (clm, tense, upset, relxed, content, nd worried) were rted on four-point scle. The totl summry score ws clculted in subjects with mximum of three missing vlues nd could rnge from 20 to 80, with higher scores indicting more nxiety (Missi et l, 2005). The STAI-6 is reported to hve good relibility nd vlidity, nd ws found useful to evlute the effectiveness of screening progrmmes on subjective nxiety levels (vn der Bij et l, 2003). The STAI-6 ws used t ll four ssessment points. Lung-cncer-specific distress Lung-cncer-specific distress ws mesured using the Impct of Event Scle (IES) (Horowitz et l, 1979; Brom nd Kleber, 1985). The 15 IES items were tilored to lung cncer s the specific stressors. Ech item ws scored on four-point scle: not t ll (score of 0), rrely (score of 1), sometimes (score of 3), nd often (score of 5). The totl score nd subscles (voidnce nd intrusion) were clculted for those who completed 75% of the questions on ech subscle, nd were corrected for the totl number of questions on the subscle. The totl summry score could rnge from 0 to 75 (intrusive scle 0 35, voidnce scle 0 40), with higher score indicting more lung-cncer-specific distress. The IES ws used t ll four ssessment points. Demogrphic nd other dt At T0, the questionnire hd items on mritl nd smoking sttus. Eductionl level nd smoking pck-yers were derived from the first NELSON questionnire. British Journl of Cncer (2010) 102(1), & 2010 Cncer Reserch UK

3 Sttisticl nlyses Differences in respondent chrcteristics between those with negtive or indeterminte bseline scn result were tested with Mnn Whitney U-tests (in cse of non-normlly distributed continuous vribles) nd w 2 -tests (for discrete vribles). Then, we first nlysed differences in HRQol over time, focusing on differences between the two bseline result groups. Second, the chnges in HRQoL before nd fter the bseline scn result were nlysed. For the ltter nlyses, we strted by using dt of the totl group in the period before the CT scn result (T0, T1, nd T2), becuse ll subjects were still unwre of the bseline CT result. After the CT scn result (T0 T3 nd T2 nd T3) the dt from the two result groups were nlysed seprtely. For ll nlyses repeted-mesures nlysis of vrince (ANOVA) ws pplied, using proc mixed from the SAS system version 9.1 (SAS Institute Inc., Cry, NC, USA); this llowed use of ll vilble dt, including the incomplete records. For the subjects, we used models with rndom intercept to llow for dependence between the repeted mesurements. Effect of bseline result on HRQoL over time Differences in HRQoL between the negtive nd indeterminte result groups were nlysed t the four ssessment points. The models included min effect for time, nd for n interction between group nd time. Time ws included s fctor with four levels (one for ech ssessment) to ccount for possible non-linerity in the chnge in HRQoL scores. The following fixed covrites were dded to the model: ge (becuse older people re reported to show less nxiety nd better mentl helth) (Tylor et l, 2004; Byrne et l, 2008), gender (becuse women re reported to show different fer of cncer nd hve worse generic HRQoL compred with men) (Tylor et l, 2004), eduction (becuse higher-educted lung cncer screening prticipnts re reported to be less nxious, hve less fer of cncer nd less distress) (Byrne et l, 2008), smoking sttus (becuse current smokers generlly hve worse HRQoL thn non-smokers, nd more nxiety nd fer of cncer) (Lksonen et l, 2006), nd smoking pck-yers (becuse we expected subjects with more pck-yers to be more nxious nd to hve worse helth). The IES scores were highly skewed. However, s logistic regression model using generlised liner mixed models pproch nlysis would limit the dt, nd becuse choosing cut-off point is rbitrry nd use of the model in fct produced the sme results s with the repeted-mesures ANOVA, we considered repeted-mesures ANOVA to be pproprite for the IES scores. Chnge in HRQoL before nd fter receipt of bseline scn result Before the receipt of the bseline result (T0, T1, nd T2), the sme repeted-mesures models s described bove (djusting for covrites) were used for the totl group, but this time including contrsts to test differences in scores of the totl group between specific ssessment points (ie T0 vs T1, nd T1 vs T2, nd model with T0 vs T2). In these models, the min effect for group, nd the interction between group nd time, ws no longer necessry nd ws thus excluded. After receipt of the bseline result (T3) chnges in HRQoL between T2 nd T3 nd between T0 nd T3 were nlysed seprtely for the groups with negtive nd with n indeterminte bseline result. The sme repeted-mesures model ws used s for the nlyses between T0, T1, nd T2. A P-vlue o0.05 ws considered sttisticlly significnt. To provide clue to the meningfulness of sttisticlly significnt differences between mens t two ssessments or between subgroups, we used the miniml importnt difference (MID), which is defined s hlf of stndrd devition (s.d.) of the men (Normn et l, 2003). The MID cn serve s defult vlue for HRQoL in lung cncer CT screening KAM vn den Bergh et l meningful chnges in HRQoL. For chnges over time the s.d. t the first ssessment of the two compred ssessment points ws used, nd for differences between groups the pooled s.d. of the two groups t specific time point ws used. RESULTS Response nd respondent chrcteristics In totl, 41 screen rm prticipnts (5.6%) were excluded from the HRQoL study becuse they either did not undergo bseline screening (n ¼ 30) or hd positive bseline result (n ¼ 11). In the screen group, the response to the questionnires ws 91.0% (630 out of 692) t T0, 93.6% (641 out of 685) t T1, 93.0% (620 out of 667) t T2, nd 87.7% (600 out of 684) t T3 (Figure 1). At lest one of the four questionnires ws returned by 99.6% (689 out of 692) of the subjects, nd 71.4% (494 out of 692) completed ll four questionnires. The T0 questionnire ws completed (s.d ) dys before bseline screening, nd the T1 questionnire 2.5 (s.d. 6.5) dys before bseline screening. The T2 questionnire ws completed 4.0 (s.d. 3.3) dys fter bseline screening, nd the T3 questionnire 80.2 (s.d. 20.1) dys fter bseline screening. The T3 questionnire ws completed 59.4 (s.d. 24.1) dys fter the bseline screening result. For subjects with n indeterminte result this ws 20.1 (s.d. 16.3) dys before the follow-up scn. Almost 50% of the respondents were men nd the men ge ws bout 58 yers (Tble 1). No sttisticlly significnt differences in bckground chrcteristics were found between subjects with negtive nd indeterminte bseline screening results. Effect of bseline result on HRQoL over time At ech ssessment, subjects with negtive test result hd better HRQoL scores on ll scles thn subjects with n indeterminte result (Tble 2; Figures 2A G). Results of the repeted-mesures nlysis (djusted for gender, ge, eduction, smoking sttus, nd smoking pck-yers) showed no sttisticlly significnt differences in the SF-12 scores (MCS nd PCS) between subjects with negtive nd n indeterminte result t the two ssessment points (Figures 2A nd B). Also, t T0, T1, nd T2 no sttisticlly significnt differences were found in EQ-5D-VAS nd STAI-6 scores between subjects with negtive nd n indeterminte test result (Figures 2C nd D). At T3, compred with subjects with negtive result, those with n indeterminte result hd sttisticlly significntly lower scores on the EQ-5D-VAS nd higher scores on the STAI-6 (i.e. both worse), but the difference ws not cliniclly relevnt (both P s o0.01). At T0, T1, nd T2 the IES totl score showed no sttisticlly significnt inter-group difference, wheres t T3 the IES scores in the indeterminte result group were sttisticlly significnt nd cliniclly relevnt higher (i.e. worse) thn in the negtive result group (Po0.01) (Figures 2E G). In women nd current smokers, scores on the PCS, EQ-5D VAS, STAI-6, nd IES showed sttisticlly significnt difference, but were not cliniclly relevnt worse (i.e. they did not exceed the MID), compred with men nd former smokers (dt not shown). Chnge in HRQoL before nd fter receipt of bseline scn result Before the receipt of the bseline scn result, HRQoL scores on the EQ-5D VAS, STAI-6, nd IES for the totl group of respondents were sttisticlly significntly worse t T1 (just before the bseline CT scn) compred with those t T0 (Po0.05 for EQ-5D, rest o 0.01) (Figures 2A G). Between T1 nd T2, there ws no sttisticlly significnt chnge in EQ-5D VAS scores. Averge scores on the STAI-6 nd IES were sttisticlly significntly better t T2 (just fter the CT scn) compred with T1 (ll Po0.01). 29 Clinicl Studies & 2010 Cncer Reserch UK British Journl of Cncer (2010) 102(1), 27 34

4 30 HRQoL in lung cncer CT screening KAM vn den Bergh et l Eligible subjects for the NELSON tril who signed the informd consent form T0 ssessment SF-12,EQ-5D,STAI-6, IES Response: 630/692 = 91.0% Rndomistion Clinicl Studies Control group Screen group Bseline CT scn T1 ssessment EQ-5D, STAI-6, IES Response: 641/685 = 93.6% T2 ssessment EQ-5D, STAI-6, IES Response: 620/667 = 93.0% Test result Positive result Indeterminte result Negtive result T3 ssessment SF-12,EQ-5D, STAI-6, IES 3 4-month follow-up scn Response: 600/684 = 87.7% Positive result Negtive result Second round CT scn Figure 1 Flow chrt of the HRQoL study. 41 subjects out of 733 of the screen group were excluded from the HRQoL study: 30 hd no bseline CT scn, nd 11 hd positive CT result t bseline. At T1, T2, nd T3 totl of 7, 25, nd 8 questionnires, respectively, were not sent due to dministrtive filures. Responses t T1, T2, nd T3 were excluded for 1, 2, nd 2 questionnires, respectively, due to more thn 50% missing items. Also excluded were T1 questionnires (n ¼ 10) completed fter the bseline CT scn, T2 questionnires (n ¼ 6) completed fter the bseline CT scn result, nd T3 questionnires (n ¼ 1) completed fter the follow-up scn result. IES totl scores nd the IES voidnce scores did not revert to bseline levels, s they were sttisticlly significntly worse t T2 compred with T0 (both P s o0.05). In the totl group, none of the sttisticlly significnt chnges over time exceeded the MID, thus none of them ws cliniclly relevnt. In the negtive result group, the EQ-5D VAS nd STAI-6 scores remined unchnged between T2 nd T3, nd between T0 nd T3. The IES scores were sttisticlly significntly lower (ie better) t T3 compred with T2 (ll Po0.01) nd lso compred with T0 (Po0.01). In the indeterminte result group, the EQ-5D nd the IES scores were worse t T3 compred with T2 (Po0.01), nd compred with T0 (Po0.01). The STAI-6 scores remined unchnged between T2 nd T3, but were worse t T3 compred with T0 (Po0.05). For ll sttisticlly significnt differences in HRQoL over time, only the chnges in IES scores between T0 nd T3 in the indeterminte result group were lso cliniclly relevnt. Impct of covrites on HRQoL In generl, the HRQoL scores were worse for women thn for men (Po0.05). Subjects with more pck-yers hd worse self-reported helth (EQ-5D VAS) nd hd worse physicl helth scores (PCS) thn subjects with less pck-yers (Po0.05). Current smokers hd worse HRQoL scores t ll scles (Po0.05) except for the mentl helth scores (MCS) thn former smokers. DISCUSSION Lung-cncer-specific distress incresed in cliniclly relevnt mnner 2 months fter receipt of n indeterminte result of bseline screening. After receiving the bseline CT result, subjects with n indeterminte screening result hd cliniclly relevnt higher lung-cncer-specific distress thn subjects with negtive result. In the groups with negtive or indeterminte result, British Journl of Cncer (2010) 102(1), & 2010 Cncer Reserch UK

5 HRQoL in lung cncer CT screening KAM vn den Bergh et l Tble 1 Chrcteristics of the respondents t T0 31 Bseline scn result Totl group (n ¼ 630) Negtive (n ¼ 489) Indeterminte (n ¼ 141) P differences Negtive/ Indeterminte result Sex: mle (%) Age in yers: men (s.d.), medin 57.8 (5.5), (5.5), (5.6), b Eduction Primry eduction (%) Lower voctionl or lower secondry generl eduction (%) Intermedite voctionl or higher secondry generl eduction (%) Higher voctionl eduction or university (%) Mritl sttus: Mrried/living with prtner (%) Smoking Current smokers (%) Pck-yers men (s.d.), medin 40.1 (17.8), (18.2), (16.3), b Abbrevition: s.d. ¼ stndrd devition. w 2 -test. b Mnn Whitney U-test. Clinicl Studies Tble 2 Undjusted men (s.d.) HRQoL scores t the four ssessment times, by bseline CT scn result (negtive or indeterminte) N T0 T1 T2 T Men (s.d.) Men (s.d.) Men (s.d.) Men (s.d.) SF-12 (PCS) Totl group 49.5 (8.7) 50.0 (8.2) Negtive 49.7 (8.4) 50.3 (8.3) Indeterminte 48.5 (9.6) 48.9 (7.8) SF-12 (MCS) Totl group 51.9 (10.3) 51.6 (11.1) Negtive 51.9 (10.2) 51.6 (11.1) Indeterminte 51.8 (10.6) 51.9 (11.0) EQ-5D, VAS Totl group 79.3 (13.7) 78.3 (12.9) 79.1 (12.3) 78.4 (13.7) Negtive 79.4 (13.8) 78.7 (12.6) 79.4 (12.2) 79.2 (13.4) Indeterminte 79.1 (13.4) 76.8 (13.8) 78.3 (12.5) 75.0 (14.5) STAI-6 Totl group 33.2 (8.6) 34.6 (8.6) 32.7 (8.8) 33.0 (9.2) Negtive 33.1 (8.4) 34.4 (8.5) 32.5 (8.8) 32.6 (9.2) Indeterminte 33.6 (9.3) 35.2 (8.9) 33.5 (8.9) 34.8 (9.2) IES totl score Totl group 4.2 (7.2) 5.9 (9.1) 4.5 (7.8) 3.6 (7.5) Negtive 4.1 (7.4) 5.8 (9.1) 4.5 (7.7) 2.4 (5.5) Indeterminte 4.5 (6.5) 6.3 (9.1) 4.9 (8.4) 8.3 (11.3) IES intrusive Totl group 1.8 (3.4) 2.5 (4.0) 1.8 (3.6) 1.4 (3.3) Negtive 1.7 (3.5) 2.4 (4.0) 1.8 (3.5) 0.8 (2.4) Indeterminte 2.0 (3.0) 2.7 (4.0) 2.0 (3.8) 3.5 (5.2) IES voidnce Totl group 2.4 (4.5) 3.5 (5.6) 2.7 (4.7) 2.2 (4.7) Negtive 2.4 (4.7) 3.4 (5.6) 2.7 (4.7) 1.5 (3.7) Indeterminte 2.5 (4.1) 3.6 (5.7) 2.9 (4.9) 4.8 (6.9) Abbrevitions: T0 ¼ before tril rndomistion, ie bseline HRQoL ssessment; T1¼ 1 week before the bseline CT scn; T2 ¼ 1 dy fter the bseline CT scn; T3 ¼ 2 months fter the bseline CT scn; s.d. ¼ stndrd devition; SF-12 ¼ Short Form 12 (generic HRQoL); PCS ¼ physicl component summry; MCS¼ mentl component summry; EQ-5D VAS ¼ EuroQol questionnire, visul nlogue scle; STAI-6 ¼ Spielberger Stte-Trit Anxiety Inventory 6, IES ¼ Impct of Event Scle. no cliniclly relevnt differences over time within or between groups were found for physicl/mentl/self-reported helth nd generic nxiety. In this study, the sttisticlly significntly worse HRQoL just before the CT scn, compred with HRQoL t neutrl point of time before screening (T0), is similr to n erlier report on brest cncer screening (Rijnsburger et l, 2004); however, in the ltter study it is unknown whether the self-reported helth chnge exceeded the MID of hlf n s.d. As result of slightly unfvourble effect of CT scnning on HRQoL, we did not find ny cliniclly relevnt chnges between the ssessment points (T0 to T1 to T2 to T3). Nevertheless, in the indeterminte result group there ws cliniclly relevnt increse in lung-cncer-specific distress when compring T0 with T3. This implies tht performing n HRQoL ssessment t neutrl point in time is importnt. In our indeterminte result group, the STAI nxiety scores showed sttisticlly significnt increse from the bseline HRQoL ssessment up to 2 months fter receipt of the bseline screening result. Byrne et l (2008) lso found sttisticlly significnt increse in nxiety 1 2 weeks fter n indeterminte bseline result compred with before the CT scn. However, the size of the chnge ws below our criterion for clinicl relevnce. Re-evlution of the reported undjusted mens in the study of Byrne et l reveled tht nxiety scores for indetermintes were not cliniclly relevntly worse, which is similr to our results. However, comprison of the results of the PLuSS study nd ours ws difficult becuse the detils of their result letter to the prticipnts were unknown, nd the follow-up time for the indeterminte results lso differed (Xu et l, 2006; Byrne et l, 2008; Wilson et l, 2008). Using more specific HRQoL instrument (i.e. the IES), we could show both sttisticlly significnt nd cliniclly relevnt chnge from the bseline HRQoL ssessment up to 2 months fter the receipt of the result, s well s difference between our two result groups. This implies tht n indeterminte test result hd t lest some negtive impct on HRQoL in the period between receipt of the test result nd the follow-up scn 3 4 months lter. Nevertheless, the effect ws smll becuse the verge IES totl score in the indeterminte group ws only 8.3 (s.d. 11.3) on scle with n upper limit of 75. The IES scles were lso highly skewed; even in the indeterminte result group 30% did not experience ny lungcncer-specific distress t 2 months fter screening (i.e. IES totl score ¼ 0). The HRQoL decrement should be very low in screening sitution, becuse even smll HRQoL decrement due to screening t the individul level will ccumulte to lrge burden t popu- & 2010 Cncer Reserch UK British Journl of Cncer (2010) 102(1), 27 34

6 Clinicl Studies 32 PCS (SF-12) EQ-5D VAS Negtive Indeterminte Negtive Indeterminte Physicl helth over time Self-reported helth over time MCS (SF-12) Negtive Indeterminte Negtive Indeterminte Mentl helth over time T0 T3 T0 T Tril rndomistion Tril rndomistion HRQoL in lung cncer CT screening KAM vn den Bergh et l T0 T1 T2 T3 CT scn CT scn CT scn result CT scn result 3-month follow-up CT scn 3-month follow-up CT scn STAI Tril rndomistion Tril rndomistion Generic nxiety over time T0 T1 T2 T3 CT scn CT scn CT scn result CT scn result 3-month follow-up CT scn 3-month follow-up CT scn IES totl Lung cncer-specific distress (totl) over time Tril rndomistion Negtive Indeterminte b Negtive Indeterminte IES voidnce over time Negtive Indeterminte IES intrusive over time 0 0 T0 T1 T2 T3 T0 T1 T2 T3 IES voidnce CT scn CT scn result 3-month follow-up CT scn IES intrusive T0 T1 T2 T3 Figure 2 (A G) Averge scle scores nd 95% confidence intervls per result group (negtive or indeterminte bseline result) djusted for gender, ge, eduction, smoking sttus, nd smoking pck-yers: SF-12 (PCS nd MCS) (A nd B); EQ-5D VAS (C), STAI-6 (D), nd IES (totl, intrusive, voidnce) (E G) T0, before tril rndomistion; T1, just before bseline CT scn; T2, 1 dy fter bseline CT scn; nd T3, bout 2 months fter bseline CT scn. Significnt difference. b Cliniclly relevnt difference. (A C) A higher score indictes better HRQoL. (D G) A lower score indictes better HRQoL. CT scn CT scn result Tril rndomistion b 3-month follow-up CT scn CT scn CT scn result b 3-month follow-up CT scn ltion level due to the lrge numbers of subjects involved. By using the MID criterion, we intended to provide clue to the meningfulness of sttisticlly significnt chnge in men scores. An dditionl reson for using the MID ws the fct tht this study included lrge numbers of subjects nd tht HRQoL scle scores do not hve n intuitive interprettion. It is sitution dependent whether sttisticlly significnt chnge in men scores from, for exmple 12.1 to 11.7 is to be regrded s meningful difference. Remrkbly, in the indeterminte result group, t ll ssessment points the HRQoL scores were worse thn those in the group with British Journl of Cncer (2010) 102(1), & 2010 Cncer Reserch UK

7 negtive results. This ws the cse before the screening result ws known, nd even before screening took plce; however, these differences were not sttisticlly significnt. Subjects who hd positive bseline CT scn who completed the T0 questionnire (n ¼ 8) reported even worse HRQoL scores before screening (dt not shown). Previous studies showed prognostic effect of HRQoL on survivl (of lung cncer) or disese onset (Montzeri et l, 2001). Our results suggest tht worse HRQoL scores before screening my serve s wek indictor of n indeterminte or positive bseline scn result. In the indeterminte group, we did not ssess HRQoL fter they hd received the result of the 3-month follow-up scn. This would hve provided dditionl informtion on the further evolution of the unfvourble HRQoL scores in test indetermintes, especilly becuse the mjority would hve received negtive result bsed on this follow-up scn. However, in our previous study on HRQoL we found no differences between subjects with negtive bseline CT scn nd subjects with n indeterminte follow-up scn tht hd negtive follow-up CT scn (vn den Bergh et l, 2008). It would hve been interesting to evlute the HRQoL effects in subjects who received positive test result; however, becuse only 11 subjects received positive result t bseline, this would not provide sufficient power to give relible results. Moreover, becuse this will be flse-positive result for some subjects, further studies re needed to determine the impct of such result on HRQoL. Implictions Following the bseline scn, this led to cliniclly relevnt increse in lung-cncer-specific distress in substntil number of persons who underwent bseline screening, lthough the letter to prticipnts clerly explined the mening of n indeterminte test result (i.e. very common smll bnormlity). Bsed on recent dt from the NELSON tril nd other lung cncer screening trils, the risk of lung cncer in this group is estimted to be o2.5% HRQoL in lung cncer CT screening KAM vn den Bergh et l (Gohgn et l, 2004). Becuse distress levels my remin elevted until the result of the follow-up CT scn is known (e.g. 3 months in the NELSON), we recommend tht the screening progrmme should be improved. For exmple, providing informtion bout the smll risk of hving lung cncer in the letter might led to reduction in the lung-cncer-specific distress. Another pproch could be to reduce the number of indeterminte test results by identifying certin subgroup of nodules with n incresed cncer risk, or by combintion of imging nd proteomic or genomic biomrkers. CONCLUSIONS This longitudinl study mong prticipnts of lung cncerscreening progrmme showed in the short term tht recipients of n indeterminte bseline screening result requiring follow-up CT experience n increse in lung-cncer-specific distress, wheres the scores of recipients of negtive bseline screening result my be interpreted s relief. ACKNOWLEDGEMENTS This study ws funded by the Netherlnds Orgnistion for Helth Reserch nd Development (ZonMw) Grnt numbers nd ; the Dutch Cncer Society (KWF) Grnt number EMCR , nd the Helth Insurnce Innovtion Foundtion (Innovtiefonds Zorgverzekerrs). The funding sources were not involved in ny of this work. We thnk R Fber, for estblishing the questionnire dtbse nd selecting the prticipnts; AC de Jongh (Artex BV, Cpelle n den IJssel), for ssistnce with the selection of prticipnts nd hndling of the milings; MA Quk, for sending the questionnires to the prticipnts; nd FJP Sntegoets, for ssistnce in linking the dtbses to dd in the bseline scn results. 33 Clinicl Studies REFERENCES Americn Cncer Society (2007) Cncer Fcts nd Figures Americn Cncer Society: Atlnt Bch PB, Jett JR, Pstorino U, Tockmn MS, Swensen SJ, Begg CB (2007) Computed tomogrphy screening nd lung cncer outcomes. JAMA 297: Brom D, Kleber RJ (1985) De Schok Verwerkings Lijst [The Dutch version of the Impct of Event Scle]. Nederlnds Tijdschrift voor de Psychologie 40: Byrne MM, Weissfeld J, Roberts MS (2008) Anxiety, fer of cncer, nd perceived risk of cncer following lung cncer screening. 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