Radiation therapy (RT) for cancer that involves the thorax

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1 Originl Article Prospective Explortory Anlysis of Crdic Biomrkers nd Electrocrdiogrm Abnormlities in Ptients Receiving Thorcic Rdition Therpy with High-Dose Hert Exposure Dniel R. Gomez, MD,* Syed Wmique Yusuf, MD, Mrk F. Munsell, MS, Jmes W. Welsh, MD,* Zhongxing Lio, MD,* Steven H. Lin, MD, PhD,* Hubert Y. Pn, MD,* Joe Y. Chng, MD, PhD,* Ritsuko Komki, MD,* Jmes D. Cox, MD,* Mry Frnces McAleer, MD, PhD,* nd Dvid R. Grosshns, MD, PhD* Introduction: Acute effects of incidentl crdic irrdition in ptients treted for thorcic cncer re not well chrcterized. We evluted longitudinl chnges in crdic biomrkers for ptients undergoing conforml rdition therpy (RT) with thorcic mlignncies with high-dose crdic exposure. Methods: Twenty-five ptients enrolled in prospective tril (Februry 2009 December 2012) received more thn or equl to 45 Gy to the thorx, with pretretment estimtes of more thn or equl to 20 Gy to the hert. Chemotherpy ws llowed except for doxorubicin or fluorourcil. Electrocrdiogrphic (ECG), troponin-i (TnI), nd brin ntriuretic peptide (BNP) mesurements were obtined before RT, within 24 hours of the first frction, t the end of RT, nd t first follow-up (1 2 months). These biomrkers were quntified t specific times nd chnges from bseline were evluted with pired t tests. Results: The medin hert dose ws 25.9 Gy (rnge Gy). After the first RT frction, no chnges were noted in ECG or medin TnI or BNP levels; t the end of RT, two ptients hd elevted TnI nd BNP, but neither difference ws sttisticlly significnt. At first followup, TnI hd returned to norml but the medin BNP remined elevted (p = 0.042). BNP did not increse over time in the 18 ptients who received only RT. Twelve ptients experienced cute ECG chnges during RT, which resolved in seven ptients by the next mesurement. No ptients experienced cliniclly significnt RT-relted events. Conclusion: Increses in BNP nd ECG chnges were observed during high doses of rdition to the hert. The findings of this pilot study wrrnt further investigtion nd vlidtion. Key Words: Crdic toxicity, Rdition therpy, Lung cncer, Brin ntriuretic peptide. (J Thorc Oncol. 2014;9: ) *Deprtment of Rdition Oncology; Deprtment of Crdiology; nd Deprtment of Biosttistics, The University of Texs MD Anderson Cncer Center, Houston, TX. Supported, in prt, by Cncer Center Support (Core) Grnt CA to The University of Texs MD Anderson Cncer Center. Disclosure: The uthors declre no conflicts of interest. Address for correspondence: Dniel Gomez, MD, Deprtment of Rdition Oncology, Unit 1150, The University of Texs MD Anderson Cncer Center, 1840 Old Spnish Tril, Houston, TX E-mil: dgomez@mdnderson.org DOI: /JTO Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer ISSN: /14/ Rdition therpy (RT) for cncer tht involves the thorx sometimes involves unvoidble exposure of the hert to high rdition doses, even when dvnced RT technologies re used. Although the long-term effects of low-dose crdic exposure re reltively well known, the cute effects, if ny, re not. Moreover, most prior studies hve focused on the long-term effects of rdition mong survivors of Hodgkin s lymphom or ptients receiving rdition for left-sided brest cncer, nd most involved exposure of lrge portions of the hert to low rdition doses. 1 5 The conclusions from these studies cnnot be extrpolted to ptients being treted for thorcic mlignncies such s lung cncer for severl resons. First, with the dvent of incresingly conforml RT techniques, the dose distributions cross the hert cn differ substntilly, with focl regions receiving high doses but other portions spred lmost completely. Second, ptients being treted for lung cncer often differ from those treted for brest cncer or Hodgkin s lymphom in tht they tend to be older nd to hve underlying crdiopulmonry conditions such s coronry rtery disese or chronic obstructive pulmonry disese. For these resons, hert exposure for ptients being treted for thorcic mlignncies, with modern techniques, should be studied seprtely from tht for ptients with other forms of cncer. The purpose of this study ws to prospectively evlute biomrkers of crdic function mong ptients receiving highdose conforml RT for thorcic mlignncies. Specificlly, we quntified brin ntriuretic peptide (BNP) nd troponin- I (TnI) levels, nd electrocrdiogrphic (ECG) differences, before, during, nd fter RT, nd we ssessed whether crdic dose ws ssocited with chnges in these vlues over time. We lso documented clinicl events to determine whether the occurrence of such events correlted with chnges in these biomrkers. PATIENTS AND METHODS Ptient Selection This study ws pproved by the pproprite institutionl review bord t The University of Texs MD Anderson Cncer Center. Ptients were enrolled from Februry 2009 to December Inclusion criteri were hving (1) primry 1554 Journl of Thorcic Oncology Volume 9, Number 10, October 2014

2 Journl of Thorcic Oncology Volume 9, Number 10, October 2014 Crdic Biomrkers fter High-Dose Rdition Exposure thorcic mlignncy (lung cncer, esophgel cncer, thymom, or mlignnt mesotheliom) nd (2) n estimted men crdic dose of more thn or equl to 20 Gy t tretment simultion (ssessed by the treting physicin). Our institution trets pproximtely 200 ptients per yer definitively for lung cncer, nd s such the study ws initilly designed to include ptients who received only RT. However, initilly there were difficulties with enrollment becuse mny ptients who hd men hert dose more thn 20 Gy received chemotherpy or hd other histologies (e.g., mesotheliom). At tht point, in lte 2011, the enrollment criteri were expnded to include ptients with other histologies nd ptients treted with concurrent chemotherpy s long s the chemotherpy regimen did not include doxorubicin or fluorourcil owing to the potentil crdiotoxicity of those drugs. Enrollment then incresed substntilly nd the tril ws closed in the next yer. Exclusion criteri of the study were recent (within 3 months) history of crdic events (myocrdil infrction, decompensted hert filure, or myocrditis/pericrditis) or renl filure (serum cretinine 2.0), or hving pulmonry embolus during the month before RT. Ptients with remote history of these events were not excluded becuse we sought to evlute cute chnges regrdless of crdic history. Study Evlutions All ptients underwent complete history nd physicl exmintion nd ECG, BNP, nd troponin level mesurements before study entry. ECG mesurements were obtined with 12-led devices, nd blood smples were drwn for BNP nd TnI ssessment fter the first RT frction, on the lst dy of rdition or chemordition, nd t the first follow-up visit (1 2 months fter completing RT). These mesurement points were chosen to ddress the primry study im, tht is, determine whether high rdition doses led to cute chnges in these crdic biomrkers or ECG findings; future im ws to determine whether such chnges could be ssocited with subsequent long-term events. Hert Contouring For ll ptients, the hert ws contoured by using model-bsed segmenttion method tht ws then djusted mnully to ensure tht the entire structure ws encompssed. For the purposes of tretment plnning, the hert ws defined superiorly s directly inferior to the ortic rch through the pex, nd included both tri nd ventricles. The pericrdium ws lso encompssed within the hert contour. Crdic Biomrkers For the crdic biomrker nlysis, we chose to ssess TnI becuse it is more sensitive mesure of myocrdil injury thn is cretine kinse-myocrdil bnd (CK-MB) or troponin T (TnT). We chose to ssess BNP s n indictor of left ventriculr function nd congestive hert filure. TnI levels were mesured with the Unicel Dxl Access Immunossy System (Beckmn Coulter, Bre, CA), in which concentrtions of the nlyte re determined from stored, multipoint clibrtion curve. The detection limit of this ssy for TnI is 0.03 ng/ml (norml rnge ng/ml, reportble rnge ng/ml). BNP ws mesured by using the Trige Method with Beckmn Coulter UniCel Dxl 600 Access Immunossy system (norml rnge pg/ ml; reportble rnge pg/ml). The sensitivity, specificity, nd negtive predictive vlue of troponin for myocrdil infrction hs been shown in previous studies to be 85% or higher, wheres the positive predictive vlue rnges from 65% to lmost 90%. 6,7 Blinded Anlysis of Electrocrdiogrms All ECGs were nlyzed fter cquisition by crdiologist (W.Y.) in blinded mnner for the following chrcteristics: norml ECG, sinus tchycrdi/brdycrdi, conduction bnormlities (e.g., bundle brnch block, tril fibrilltion), nd ischemic chnges. Subsequent ECGs were then nlyzed to determine whether ny cute chnges hd resolved. Sttisticl Methods Our primry objective ws to investigte (1) the reltionship between crdic rdition dose nd crdic biomrker levels nd (2) the temporl reltionship between RT delivery nd nticipted elevtion of crdic biomrkers. The distribution of BNP levels ws reported s bseline (i.e., before RT) nd chnge over time. Pired t tests were used to ssess whether BNP levels chnged over time, specificlly if the chnge in men levels ws different thn 0. Repeted mesures regression nlysis ws then used to determine the effect of hert dose nd time since bseline on BNP level. Ninetyfive percent confidence intervls (CIs) were determined for the men chnge in BNP from bseline to dy 1 of RT, to the end of RT, nd to the first follow-up visit. Repeted mesures regression nlysis ws used to ssess the time since bseline on BNP level nd to identify ny sttisticlly significnt increses in BNP level over time. We lso included n interction term for MHD nd time in our model to llow for the possibility tht the effect of MHD on chnge in BNP vried with time. Becuse of the repeted mesures nlysis, we hd 40 degrees of freedom for testing the interction term nd the term for time, becuse ptients contribute dt t ech time point. Finlly, we used the Spermn correltion to determine the correltion between men hert rdition dose nd chnge in BNP, both t the end of RT nd t the 1- to 2-month follow-up period. These nlyses were then repeted for the 18 ptients who received only RT to identify trends without the potentil confounding effect of chemotherpy. A Bonferroni correction ws used in the smple-size justifiction bsed on tests of the correltion between rdition dose nd the chnge from bseline t three different time points for ll ptients nd for ptients who received RT lone, for totl of six tests. With 25 ptients, we hd 80% power to detect correltion of 0.60 or greter, with one-sided significnce level of RESULTS Ptient Chrcteristics Chrcteristics of the 25 ptients enrolled in this study re listed in Tble 1. Most ptients (72%) were mle nd hd Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 1555

3 Gomez et l. Journl of Thorcic Oncology Volume 9, Number 10, October 2014 TABLE 1. Ptient Chrcteristics (n = 25) Chrcteristic Vlue or No. of Ptients (% or Rnge) Age t dignosis, yr Medin (rnge) 63 (31 75) Sex Mle 18 (72) Femle 7 (28) Tumor type Mesotheliom 16 (64) NSCLC 5 (20) Thymom 2 (8) Other 2 (8) Prescription rdition dose, Gy Medin (rnge) 50 (45 70) Rdition frction size, Gy Medin (rnge) 2 (1.8 3) Crdic comorbid conditions Hypertension 13 (52) Hyperlipidemi 7 (28) Dibetes mellitus 6 (24) Arrhythmi 2 (8) Myocrdil infrction 1 (4) Men hert dose, Gy Medin (rnge) 26.5 ( ) Hert volume receiving t lest 40 Gy (V 40 ), % Medin (rnge) 23.4 ( ) Men lung dose, Gy Medin (rnge) 18.1 ( ) Concurrent chemotherpy Yes 7 (26) No 18 (72) Other histologies were smll cell lung cncer, typicl crcinoid. NSCLC, non smll-cell lung cncer. received RT in conventionlly frctionted regimens, with prescribed doses rnging from 45 to 50 Gy (to trget microscopic disese fter surgery) to 66 to 70 Gy s definitive RT. Most ptients hd preexisting crdic conditions, primrily hypertension (52%) nd hyperlipidemi (28%), with 48% of ptients hving more thn one preexisting condition. Chnges in Troponin-I nd Brin Ntriuretic Peptide All ptients hd undetectble TnI levels t bseline (before RT). Two of the 25 ptients experienced increses in TnI levels during RT. One ptient hd history of thymic crcinom but no preexisting crdic conditions nd ws treted with 66 Gy in 2-Gy frctions to the nterior medistinum; the men hert dose ws 20.2 Gy nd the V 40 ws 28%. This ptient s TnI level incresed from undetectble (<0.03 ng/ml) before RT to 0.07 ng/ml t the end of RT, nd hd returned to n undetectble level t the first follow-up visit. The other ptient hd history of hypertension nd dibetes mellitus nd received RT for mlignnt pleurl mesotheliom to 60 Gy in 2.4-Gy frctions to the gross tumor volume. This ptient lso experienced n increse in TnI from undetectble before RT to 0.03 ng/ml t the end of RT, with TnI returning to undetectble levels t the first follow-up visit. Becuse chnges in BNP were found to not be correlted with men hert dose on dy 1 (Spermn correltion r = 0.15, p = 0.51), t the end of RT (r = 0.23, p = 0.27), or t the first follow-up visit (r = 0.18, p = 0.46), we then exmined BNP chnges over time in n explortory nlysis. All ptients hd BNP mesurements t the end of RT, nd 19 of the 25 ptients hd BNP mesurements t the first follow-up period. Chnges in BNP over the course of tretment for the entire group re shown in Figure 1A nd Tble 2, with tbultion of the correltion coefficients in Tble 2. One ptient hd gretly incresed BNP level fter one frction (684 pg/ml) tht then decresed nd remined t pproximtely norml levels therefter; tht ptient hd received concurrent chemotherpy with cispltin nd etoposide. Among the entire group, the men chnge in BNP from bseline to the end of RT ws sttisticlly significnt (95% CI 3.39 to 46.53, p = 0.025), nd the men chnge in BNP from bseline to first follow-up ws lso sttisticlly significnt (95% CI 6.96 to 79.77, p = 0.022). No difference ws found in men chnge in BNP from bseline to fter one frction of RT (95% CI to , p = 0.227). Repeted mesures regression nlysis reveled no effect of men hert dose (p = 0.167) or time since bseline on chnge from bseline for BNP levels (p = 0.104). These nlyses were then repeted for the 18 ptients who did not receive concurrent chemotherpy. Agin, neither men hert dose (p = 0.19) nor time since bseline (p = 0.92) ffected chnge from bseline in BNP level. Moreover, no interction effect ws found between men hert dose nd time becuse of bseline. Chnges in BNP levels over time for ptients who received only RT re lso shown in Tble 3. Figure 1B, C nd Tble 4 compre chnges in BNP t different time points in those ptients receiving chemordition (Figure 1B) nd those receiving RT lone (Figure 1C). It is evident tht the mgnitude of chnges ws incresed in those ptients receiving chemotherpy, lthough the differences were not sttisticlly significnt (p > for ll timepoints). Electrocrdiogrm Chnges Associted with Rdition Therpy Twelve ptients were found to hve chnges in ECG redings fter inititing RT (Tble 5), with the two most common being T-wve chnges nd poor R-wve progression. The effects occurred t vrious times in reltion to RT, nd in seven of these 12 ptients (58%), the ECG chnges hd resolved on subsequent studies nd were symptomtic. In no ptient ws intervention deemed to be required s result of these ECG bnormlities. Clinicl Events Relted to Rdition Therpy No ptient experienced crdic event relted to RT t ny time during the study Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer

4 Journl of Thorcic Oncology Volume 9, Number 10, October 2014 Crdic Biomrkers fter High-Dose Rdition Exposure FIGURE 1. Chnge in the level of brin ntriuretic peptide (BNP) with time in (A) ll ptients (n = 25), (B) ptients receiving concurrent chemordition (n = 7), nd (C) ptients receiving only rdition therpy (n = 18). The box represents the interqurtile rnge (IQR), nd the shded region is 95% CI for the medin. The whiskers re drwn to the nerest vlue nd not beyond 1.5 IQR from the top (qurtile 3) or bottom (qurtile 1) of the box. Outliers re those vlues beyond the whiskers. TABLE 2. Correltion Coefficients nd p Vlues of Chnges of BNP with Time fter High-Dose Crdic Rdition All Ptients Ptients with Rdition Only Ptients with Chemotherpy Correltion p Vlue 1 Correltion p vlue Correltion p vlue Dy End of RT Month p Vlues should be compred with significnce level of to ccount for multiple testing (p = 0.05/9 = ). RT, rdition therpy. DISCUSSION In this prospective study of blood-bsed crdic function biomrkers nd ECG chnges mong ptients receiving high rdition doses to the hert from conforml techniques, our pertinent findings re s follows. First, most ptients did not experience ny discernible chnges in TnI, either fter exposure to single frction of RT or t long-term follow-up (t the end of RT, 1 2 months fter the completion of RT). Second, we found trend towrd incresed BNP t the end of RT nd t the 1- to 2-month follow-up period reltive to bseline levels. However, the quntittive chnges from bseline were modest nd were not ssocited with ny cliniclly meningful events. Furthermore, we did not find n ssocition between hert dose nd crdic biomrkers, though cknowledging tht ll the ptients received reltively high hert doses in this nlysis. Third, the correltion of BNP levels with time ws substntilly ttenuted for ptients receiving only RT, suggesting tht concurrent chemotherpy increses ny cute RT effects on the hert. Finlly, slightly less thn hlf of ll ptients hd ECG chnges t vrious times fter RT, but most Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 1557

5 Gomez et l. Journl of Thorcic Oncology Volume 9, Number 10, October 2014 TABLE 3. Brin Ntriuretic Peptide Levels (in pg/ml) t Ech Study Visit Mesurement Time No. of Ptients Men Stndrd Devition Minimum Medin Mximum All ptients Bseline Dy End of RT Month Ptients receiving only RT Bseline Dy End of RT Month RT, rdition therpy. TABLE 4. Comprison of Chnges in Brin Ntriuretic Peptide (BNP) Among Those Ptients tht Received Rdition Therpy Alone vs. Those with Chemordition Men Chnge in BNP Dy 1 RT lone: 8.81 ChemoRT: End of RT RT lone: ChemoRT: Month 1 2 RT lone: ChemoRT: p Vlue of Mens (Chemotherpy vs. RT Alone) Medin Chnge in BNP p = 0.12 RT lone: 2.5 ChemoRT: 42.0 p = 0.51 RT lone: 2.5 ChemoRT: 41.0 p = 0.81 RT lone: 15.0 ChemoRT: 30.0 p Vlue of Medins (Chemotherpy vs. RT Alone) p = p = 0.12 p = 0.47 It is cler tht the chnges re lwys greter in the ptients receiving chemotherpy, though not sttisticlly significnt, possibly secondry to smll numbers of ptients. The differences between the two groups re lso more substntil during the erlier time periods. p Vlues should be compred with due to multiple testing (0.05/6 = 0.008). RT, rdition therpy. TABLE 5. Summry of Electrocrdiogrphic Chnges During nd After Rdition Therpy Ptient Men Hert Dose, Gy Concurrent Chemotherpy Mesurement Time Description of Chnge Chnge Resolved on Next ECG Yes Follow-up Septl T-wve chnges Unknown No After first frction Septl T-wve chnges No No Follow-up Extensive T-wve chnges No No Follow-up Anterior/lterl T-wve chnges No No End of RT Septl nd lterl T-wve chnges No Yes End of RT Prolonged QT intervl Yes No End of RT Prolonged QT intervl Yes No End of RT Septl ST chnges Yes Yes Follow-up Poor R-wve progression Yes No After first frction Poor R-wve progression Yes No After first frction Poor R-wve progression Yes No After first Frction/end of RT Septl T-wve chnges/st Junction depression Yes/No This ptient did not undergo subsequent ECG testing. ECG, electrocrdiogrm; RT, rdition therpy. of these bnormlities were nonspecific, most hd resolved upon subsequent evlution, nd none required intervention. Although some studies hve ssessed short-term chnges in crdic biomrker levels fter RT, 8,9 few hve nlyzed such chnges fter high-dose RT delivered vi modern, highly conforml techniques. To our knowledge, the tril most similr to ours ws conducted by investigtors t Msschusetts Generl Hospitl, who ssessed the effect of RT on TnT, CK-MB, nd minoterminl pro-brin ntriuretic peptide (NT-proBNP) levels in 30 ptients who received either three-dimensionl 1558 Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer

6 Journl of Thorcic Oncology Volume 9, Number 10, October 2014 Crdic Biomrkers fter High-Dose Rdition Exposure conforml therpy or intensity-modulted rdition therpy, most (24 ptients) with concurrent chemotherpy; 18 of these ptients hd lung cncer. Those investigtors found tht TnT remined undetectble in 29 ptients, nd none of the other biomrkers chnged significntly fter RT, with or without chemotherpy. 10 However, tht study differed from ours in tht the crdic RT doses were pproximtely hlf of those in the current study. Moreover, the minimum men hert dose in the Mss Generl study ws 0.6 Gy, nd lmost no ptients received doses bove 50 Gy (medin V 50 = 0%). At doses such s these, one could surmise tht no chnges in crdic biomrkers were observed becuse the hert dose ws insufficient to cuse ny differences, t lest during the cute period. Even with the substntilly higher hert dose in the current study, our findings showed tht troponin levels did not chnge in most ptients. However, two ptients in this study did hve temporrily detectble TnI levels t the end of tretment. Crdic troponin is biomrker of crdic injury tht is undetectble in helthy subjects. 11 However, even very smll elevtions in troponin levels cn hve importnt prognostic significnce. For exmple, t lest one study showed tht ptients with troponin levels exceeding more thn 0.01 ng/ml hd worse crdic outcomes nd significntly incresed mortlity compred with ptients with troponin levels less thn 0.01 ng/ml. 12 Notbly, the ptients with smll elevtions in troponin in our study hd no other risk fctors tht would precipitte troponin lek. Therefore, these chnges could represent trnsient membrne lek from crdic myocytes due to direct rdition dmge. Alterntively, the lekge could be relted to other fctors, s hs been observed in endurnce thletes with elevted troponin levels but no evidence of myocrdil necrosis on mgnetic resonnce imging (MRI). 13 We lso found tht high hert doses led to increses in BNP levels t the end of RT nd t the first follow-up visit, gin suggesting tht the higher rdition dose used here led to more mrked chnges thn previously reported for low-dose RT. The chnges in BNP seem to hve been more pronounced for ptients who received chemotherpy. Interestingly, bseline BNP levels were lso slightly elevted in this study, for resons tht re not pprent when exmining the dt. However, fctors such s tchycrdi cn lso increse BNP nd were not ssessed in this nlysis. An increse in BNP level my represent direct myocyte inflmmtion nd potentil residul distolic dysfunction relted to RT. One ptient receiving concurrent chemordition hd shrp increse in BNP fter one RT frction tht quickly declined therefter. The reson for this observtion is uncler but could be relted to temporry crdic overlod with the dministrtion of chemotherpy. Prior nlyses hve shown tht both smll elevtions in troponin nd ny elevtion in BNP levels predict worse outcomes mong ptients with stble congestive hert filure. 12 Although no lrge-scle trils hve been published with long-term follow-up of biomrkers in ptients receiving RT, incresed BNP levels in ptients with cncer hve been linked with poor survivl even in the bsence of ventriculr dysfunction or volume overlod. 14 Indeed, longer follow-up of the ptients in the current study who experienced chnges in biomrkers will determine the clinicl relevnce of short-term increses in such cses. We lso found tht RT led to ECG chnges in lmost hlf of the ptients in our tril. Although severl studies hve ssessed the effect of systemic therpy regimens such s fluorourcil on crdic rhythms, 15 nd the effect of RT on crdic devices, 16,17 studies of high-dose RT nd cute chnges in ECG findings hve been sprse nd primrily limited to cse reports. 18 The most common ltertions in ECG in the current study were septl T-wve chnges nd poor R-wve progression. Septl T-wve chnges re nonspecific nd cn represent severl cute nd chronic processes, including electrolyte bnormlities, nemi, nd ph chnges, s well s cute crdic processes such s myocrditis, pericrditis, crdiomyopthy, pulmonry emboli, nd lung disese. The differentil dignosis of poor R-wve progression is lso reltively brod nd includes body hbitus, ventriculr hypertrophy, nd myocrdil infrction. 19 In ddition, both these chnges cn represent norml vrints, lthough given the timing of these observtions during nd fter RT, nd the fct tht most ptients did not receive chemotherpy, it is resonble to hypothesize tht rdition to the hert cused these cute chnges. We cknowledge tht the overll clinicl significnce of cute chnges in ECG ptterns for ptients receiving RT will need to be determined with long-term follow-up for the occurrence of subsequent clinicl events. This study did hve limittions tht constrin interprettion of the results. The primry limittions were the smll number of ptients nd the inbility to detect cuslity using this study design, which were functions of the pilot nture of this prospective nlysis. Indeed, our gol ws not to provide definitive conclusions regrding the effect of high-dose RT on crdic biomrkers in thorcic mlignncies, but rther to observe if short-term trends could be observed in the cute setting. A second restriction is the limited bility to detect increses in TnI nd BNP levels, which ws function of the sensitivity of the ssys used. However, one could rgue tht the utility of detecting smller chnges in these mrkers is low, given the lck of cler clinicl significnce of smller elevtions. Another limittion ws tht crdic events my be difficult to ssess in ptients with lung cncer nd mesotheliom becuse such ptients my lso hve other crdiopulmonry comorbidities. However, becuse the incidence of crdic events ws so low, ny influence of this confounding fctor ws likely miniml in this study. Fourth ws our inclusion of ptient who turned out to hve substntilly smller hert dose (10 Gy) thn our intended minimum predicted during tretment plnning (20 Gy). We ultimtely chose to include this ptient in the nlysis becuse 10 Gy cn be considered moderte hert dose nd becuse we wnted to mximize the mount of prospective dt for nlysis. We do not believe tht including this ptient hd ny mjor influence on our results or conclusions. We further included ptients with vriety of tumor types, most notbly mesotheliom. We re unwre of ny findings suggesting tht tumor histology would ffect crdic toxicity, nd thus the rtionle for including these ptients ws the presumption tht cute crdic chnges in troponin nd ECG would depend primrily on RT dose in ptients receiving high doses. Notbly, however, no ptients with mesotheliom were given concurrent chemotherpy with the RT, the use of Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 1559

7 Gomez et l. Journl of Thorcic Oncology Volume 9, Number 10, October 2014 which seemed to hve enhnced the crdic chnges observed in this study. Finlly, this study ws designed with short-term follow-up period nd limited rnge of doses, thus restricting the cpcity to detect dose response, becuse our focus ws on cute chnges tht my be ssocited with high crdic dose. A more complete clinicl nlysis would entil followup for t lest 2 or 3 yers nd with n incresed dose rnge; such design presumbly would revel the impct of dose on both cute nd lte RT-relted toxicity nd thereby strengthen the ssocitions observed in this nlysis of cute effects. We re continuing to follow these ptients nd intend to pool the results of this study with those involving other ptients with loclly dvnced disese to determine whether further toxicity rises tht wrrnts longer follow-up with these metrics. In conclusion, this prospective nlysis of cute chnges in crdic biomrkers nd ECG findings in ptients receiving high crdic rdition doses reveled differences in BNP levels t the end of RT nd t the first follow-up period. Nerly hlf of the ptients studied lso experienced ECG chnges fter RT, lthough these ltertions my not be directly relted to the RT. Finlly, no ptients experienced cliniclly significnt crdic event, implying either tht the vst mjority of such events re subclinicl or tht dditionl events could be identified in ptients experiencing detectble vritions in biomrkers with long-term follow-up. This distinction should be nswered in future studies tht focus on cncer survivors who receive nlogous dose distributions. Combining these studies with novel imging techniques is lso expected to help nswer this question. ACKNOWLEDGMENT We sincerely thnk Christine Wogn, MS, ELS, of MD Anderson s Division of Rdition Oncology, for her work in reviewing nd editing this mnuscript. REFERENCES 1. Boivin JF, Hutchison GB, Lubin JH, Much P. Coronry rtery disese mortlity in ptients treted for Hodgkin s disese. Cncer 1992;69: Clrke M, Collins R, Drby S, et l. Effects of rdiotherpy nd of differences in the extent of surgery for erly brest cncer on locl recurrence nd 15-yer survivl: n overview of the rndomised trils. Lncet. 2005;366: Hncock SL, Tucker MA, Hoppe RT. Fctors ffecting lte mortlity from hert disese fter tretment of Hodgkin s disese. JAMA 1993;270: Lund MB, Ihlen H, Voss BM, et l. Incresed risk of hert vlve regurgittion fter medistinl rdition for Hodgkin s disese: n echocrdiogrphic study. Hert 1996;75: Drby SC, Ewertz M, McGle P, et l. Risk of ischemic hert disese in women fter rdiotherpy for brest cncer. N Engl J Med 2013;368: Keller T, Zeller T, Peetz D, et l. Sensitive troponin I ssy in erly dignosis of cute myocrdil infrction. N Engl J Med 2009;361: Reichlin T, Irfn A, Twerenbold R, et l. Utility of bsolute nd reltive chnges in crdic troponin concentrtions in the erly dignosis of cute myocrdil infrction. Circultion 2011;124: D Errico MP, Grimldi L, Petruzzelli MF, et l. N-terminl pro-b-type ntriuretic peptide plsm levels s potentil biomrker for crdic dmge fter rdiotherpy in ptients with left-sided brest cncer. Int J Rdit Oncol Biol Phys 2012;82:e239 e Hughes-Dvies L, Scks D, Rescigno J, Howrd S, Hrris J. Serum crdic troponin T levels during tretment of erly-stge brest cncer. J Clin Oncol 1995;13: Kozk KR, Hong TS, Sluss PM, et l. Crdic blood biomrkers in ptients receiving thorcic (chemo)rdition. Lung Cncer 2008;62: Wllce TW, Abdullh SM, Drzner MH, et l. Prevlence nd determinnts of troponin T elevtion in the generl popultion. Circultion 2006;113: Ltini R, Msson S, Annd IS, et l.; Vl-HeFT Investigtors. Prognostic vlue of very low plsm concentrtions of troponin T in ptients with stble chronic hert filure. Circultion 2007;116: Schrhg J, Urhusen A, Schneider G, et l. Reproducibility nd clinicl significnce of exercise-induced increses in crdic troponins nd N-terminl pro brin ntriuretic peptide in endurnce thletes. Eur J Crdiovsc Prev Rehbil 2006;13: Burjonropp SC, Tong AT, Xio LC, Johnson MM, Yusuf SW, Lenihn DJ. Cncer ptients with mrkedly elevted B-type ntriuretic peptide my not hve volume overlod. Am J Clin Oncol 2007;30: Sif MW, Shh MM, Shh AR. Fluoropyrimidine-ssocited crdiotoxicity: revisited. Expert Opin Drug Sf 2009;8: Gomez DR, Poenisch F, Pinnix CC, et l. Mlfunctions of implntble crdic devices in ptients receiving proton bem therpy: incidence nd predictors. Int J Rdit Oncol Biol Phys 2013;87: Oshiro Y, Sughr S, Nom M, et l. Proton bem therpy interference with implnted crdic pcemkers. Int J Rdit Oncol Biol Phys 2008;72: Vsic N, Stevic R, Pesut D, Jovnovic D. Acute left bundle brnch block s compliction of brchytherpy for lung cncer. Respir Med 2011;105(Suppl 1):S78 S McKenzie R. Poor R-wve progression. J Insur Med 2005;37: Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer