Koc atcp c TIp Dcrgi si (~l l to.i ). I . ·D · :17 Th e Medi cal Journal of Koc.ucp e 2{J03, Afyon Kocatepe Universitesi

EFFECT OF PACLITAXEL ADMJNISTRATION ON ELECTROCARDIOGRAPHIC PARAME IERS REFLECTING VENTRICULAR HETEROGENITY

Irfan BAR UT<X I , Alpay Turan SEZGIN3, Hakan GULLU2, Ergun TOPAL2

,

Nurzen SEZGIN4, Ramazan OZDEMIR2

'A fyo n Koc.ucpe University. School or Medicine, Department or Cardiology. AFYON ' Inonu University, School or Medicinc'Turgut Ozal Medical Center Department or Cardiology. MALATYA ·' Baskent University, School cf Medicine Adana Hospital Deparuneut or Card iology, ADAI\A "Buskcnt University. School or Medicine A;[,1I:a Hospital Department or Biochemistry, ADANA

()ZET: Son birkac dek r.ddir tubulin dinarn iklerin i bozarak e tki ede n ve prototip bir taksan bilesig i ol au pakl ita xel , kuc uk hu creli o lmay an akciger kan seri , over ve merne kan seri , ba s ve boyun kanserl eri dahil olrna k t.zerc bir col: so lid rnali gniteniu tedavisinde yaygm olarak kullarulrn aktadir. Ancak paklitaxel infuzyonu srras mda pekcok kardiya k yan etki rapor edilrni stir . Bu ned enl e , bu cahsmadu paklit axel infuzyonunun elektrokar diyografi (E '<.G) uzerine etkisi arasunldi . Cuhsrnaya rneme (6 vaka), over (3 vaka) ve ku cuk hucreli o lmaya n ak ciger kan seri (3 vaka) nedeni yle paklitaxel kemoterapi si a l:1I1 toplarn 12 hasta (7 kadm, 5 erkek ortalarna 55±9 yas) almdi. TUm hastalard a paklit axel infuzyonun dan hemen o nce ve infuzyondan I saat so nra E KG kaydedildi . Tum kayrtlar 12 de rivasyonlu yuzey elektrokardiyograrm nda almdi. Ventrikuler heteroj en iteyi goste ren e lektro ka rdiyografik pa rame tre ler manuel o larak he sapl andi . Ortalarn a kalp luzi , maksimum QT, duzeltil rnis QT ve QRS inte rval suresi infuzyon so mas I degisrnedi . (O rtalarn a kalp luzi; 85±5 ve 79 ±4 anm/ dakika, maksimum QT 414±22 ve 4 20±24 ms, QTc 41 2± 25 424±15 ms, ortalarna Q RS int er val suresi 93±4 ve 95 ±5 ms p>0.005 ). An cak duzeltilmis QT di spersiy onu infu zyon so nras i belirgin olarak artu (duze ltilmis QT d isper siyonu 41±9 ve 70 ± 11 rns p< 0 .005). Sonne olarak pakl ita xel in fuzyonu sonras i artrrus QT di sper siyonu , o tono mik di sfonksiyonu yansiur ve ayru za ma nd a bu ilacian kaynaklanan c idd i potansiyel aritmi risk in i de gos tere bilir. Ancak, paklit axel infiizyonun a baglr kardi yak yan etkiler in alua yatan mekanizmasmi aydmlatmak icin daha fuzla ca lrsmaya ihtiyac vardir. [Anahtar kelimeler : QT di sper siy onu , paklita xel , aritmi]

ABSTRACT: During past sev e ra l decad es the protot ypi c taxane pacli taxel , whi ch di srupt tubu lin dyn am ics, has been wid el y used in trea tment of so lide mal ign anc ies, incl ud ing non-sm all cell lun g ca rc inoma, ovarian and breast . head and neck ca nce r. Ho wever , a vari ety of cardiac adv e rse effec ts have be en rep orted during paclit axel therap y. Th erefor e , in thi s s tudy e ffec t o f the paclitaxel infu sion o n e lec trocard iog ram was investi gated , Twelve pati ent s (7 female,S male mean 55±9 years) recei vin g pacl itaxel che mo the rapy becau se o f bre ast ( in 6 ca ses ), ovarian (in 3 cases) , non­sma ll cell lun g (in 3 ca ses) cars inornas were included to study . Fo r all pati ents just be fore infusion and 1 hour afte r the e nd of infu sion e lec troc ardiogra m were recorded. All records were obta ined o n a ro utine 12 lead sur face e lec trocard iog ra m. Electrocardi og raphi c paramet ers suggesting ventricular heterogen eit y were ca lculated manu all y. M ean heart rate , QT max, co rrec ted QT (QTc) and QR S interval durati on d id not c hange after infu sion . (Mean heart rate ; 85±5 vs . 79±4 beats/rnin ., QT ma x. 4 14±2 2 vs . 42 0±24 ms, QTc 41 2±25 424±15 rns, mean QRS inte rva l durat ion 93±4 vs, 9S±S I11S p>0.005 ). However, co rrec ted QT di sper sion (QTc d) sig nifica ntly inc rease d a fte r infu sion (Q'Tcd 41±9 vs. 70±11 ms p< 0 .00 5) . In co ncl us ion, incr eased QT disp er sion after paclitaxel in fusion refl ect s autono mic dysfunc tion and it may also suggest the risk o f pot en tia l se rious arrhy thm ias ar is ing fro m thi s drug . Ho wever furth er st ud ies are wa rra nted to e luc idate the und erl yin g mechani sm o f ca rdiac adve rse e ffec ts relevant to paclitaxel. [Key wo rds: QT d isp er sion , paclitaxel , arrhythmia]

43

INTRODUCTION

Paclitaxel , an antimicrotu bul e age nt that dis rupts tub ulin dynami cs , has been use d in treatme nt of ma ny common types of solid malignancies including methastat ic breast ca rc inoma, advance d ovaria n carci noma and non -sm all ce ll lung carci no mas (1-3) . Ca rdiac side effects incl udi ng ventric ular tach ycard ia, at ria l ar rhy thm ias, isc hemic events and sudden deat h have been rep orted associated with paclitaxel the rapy (4, 5). How ever, the factors that inc rease the risk for ca rd io tox ic ity, and rhythm di sturban ces ha ve no t been ident ified in pati ents recei vin g paclita xel . Measurem ent o f the va riabi lity in QT inter val duration am ong the 12- lead s o f the standard e lec trocardiogram (E CG ), call ed QT di spersion , has been prop osed as a practical meth od for the eva lua tio n o f the nonhomogen ity of ve ntric ular recover y time (6). Th er efor e, th is study was design ed to test whe the r the paclita xel therapy inc reases in suscept ibi lity to ve ntricular arrhy thm ias .

MATERIALS AND METHODS

T wel ve pat ients (7 female, S male , mean

55 ±9 yea rs) recervi ng pnclitaxe l chemotheraphy because of breast (in 6 cases), ovarian (in 3 cases) and non-small-cell lung (in 3 cases),' cars ino mas were included to study . For a ll mem ber s pacl itaxel was the sing le therapeut ic agent and study was don e during firs t co urse of ther apy. No one had previ ou s recei ved che mo therapy . Three of 12 pat ient s had the histor y of pr ior radi other ap y and two o f them had pri orl y ex perienced surgica l interventi on . Befor e admini stration o f paclit axel , a history was tak en and complete physical examination was performed and co mp lete blood co unt, ro utine bioc he mical and e lec tro lyte pro files, urine ana lysis, ches t radiograph and e lectrocardiogram was obtai ned. Blood sample was taken to excl ude e lec tro lyte abnormalities that co uld be affec t on e lec trocardiogra m (ECG). Pacl itaxel was infused at a dose of 175- 200 rng/n r' ove r one

44

hou r with recommended anti histamine prem edi cati on .

Just before the firs t course of the ra py an d I h after the - end of infu sion ECG was recorded . Before and after infusion echocard iog raphic evaluat ion was done . Pat ien ts wit h cardiac d isease and those o n medicatio ns known to alte r ca rd iac conduct ion were exc lude d fro m the study . The QT interva l was measured fro m the beginning of the QRS complex to the end of the T wave . QT disp ersion , defined as the max im um m inus mi nimu m QT intervals, and co rrec ted QT

. (QTc) was measu red accord ing to Bazeu 's formul a to adj us t heart rate . (7) QT ma ximum and QT di sper sion wer e mea sured in a ll lead s of a 12-lead ECG recorde d at a spee d o f 50 mm/s for 2 co nsecutive cyc les. None o f the 12 study subjects had a U wav e supe rimposed o n the terminal porti on o f the T wa ve. If the T wa ve co uld not be rel iabl y det ermined or if it had very low amplitude, QT mea surement s were not obtai ned and these leads wer e excl ude d from the ana lys is. T wo ind ependent ex pe rienced observe rs who were unaware of the cli nical de tai ls examined QT dispersio n measu rements . Th e third obse rver verified d isagreement betwee n observe rs.

STATISTICAL ANALYSIS

Data are ex pressed as the mean va lues. Compar ison o f date was performed with the Student t test and for co mpariso n of QT interval be fore and afte r infu sion Mann Whitney U test was used . A p-value <0 .05 was co nside red to indi cate statistica l significan ce.

RESULTS

All patient s well tolerated the therap y. Du ring admini str ati on Was not see n an y rhythm di sturbances inc luding ve ntricular tach yarrh ythmi as, co nd uc tio n defects, S-T seg me nt changes and hemod ynami c ch ange. Befor e and after adm inis tra tio n hemod ynamic change and e lec tro lyte abn ormalities we re no t de tected (Table-I), EC G pa ra me ters are listed

in Table-II. During echocardiographic analysis p>0.005) . Mean QRS interval durations, valvular disorders, left ventricular hypertrophy Q'Tmax , and corrected QT (QTc) did not and wall motion abnormalities and clinically change after infusion (mean QRS interval significant valvular regurgitation were not duration 93±4 vs . 95±5 ms, QTmax . 414±22 detected . All members had sinus rhythm. There vs . 420±24, and QTc : 412±25 vs . 424±15 was no any record with low-amplitude and p>0.05). However, corrected QT dispersion with U waves . The number of the leads in (QTcd) significantly increased after infusion. which QT intervals could be measured was (QTcd 41±9 vs . 70±11 p< 0.005). There was similar before and after infusion (range 8 to no association between the dose of paclitaxel 12) . There was no statistical differences with and QTd, QTcd. regard to mean heart rate before and after infusion (Mean heart rate; 85±5 vs . 79±4

Table-I: Hemodynamic and biochemical values Variable Before infusion After infusion

Mean blood pressure (mmHg) Blood glucose level (g/dl) Na (mrnol/L) K + (rnmol/L) Ca++(rnrnol/L) Cl (mmol/L) Ejection Fraction (%)

87 ±7 80 ±6 140 ±4 4.4 ± 0.2 9 .3 ±0.3 105 ± 0.9 64 ±5

84 ± 5 82 ± 5

139 ± 4 4.4 ± 0.3 9.4 ± 0 .2 104 ± 1.0

63 ±4

Table-II: Comparison of ECG parameters Variable Before infusion After infusion

Mean Heart Rate (beat/min) 85 ± 5 79 ±4 Mean QRS duration, ms 93 ±4 95 ± 5 QTmax 414 ± 22 420 ± 24 QTc, ms 412 ± 25 424 ± 15 QTcd*, ms 41 ± 9 70 ± 11

>< p< 0.005 Statistically significant

DISCUSSION

In the present study we found that administration of the paclitaxel increased QTc dispersion . It is known that increased QTcd is associated with increased susceptibility to ventricular arrhythmias and reflects the regional variation in ventricular repolarization, .. hich may increase the risk of sudden death caused by malignant arrhythmias (8,9) .

Although cardiac rhythm disturbances have been widely observed during paclitaxel therapy, their importance and exact mechanism are not known. Until today, no previous studies have examined electrocardiographic changes observed in patients receiving paclitaxel and their relation to susceptibility to arrhythmias . Thus, our study is the first showing increased QTcd during paclitaxel infusion. From this point of view, we hypothesized that paclitaxel exhibits increased ventricular susceptibility,

45

ev en during asymptomatic phase and this may pred ispose the pat ien t receivi ng paclitaxel therapy to the devel opment o f mal ign ant ventric ular ar rhythm ias. Sin ce QT d ispe rs ion reflects ve ntricular hete rogen eit y, it may pro vide import ant cl in ical ben efits, part icul arl y in the assessme nt the risk of arrhy tmogenic d rug. The prol on ged QT interv a l is regarded as a marker of im ba lance d d istribition of sympa thet ic ner vou s sys tem ac tiv ity o n the heart, indi cating that the auto no mic neural ton e is an imp o rtant determinant of QT inter va l dura tio n and disp er sion (10-12). Previou s stud ies ha ve sho wn tha t QT di sp ersion is abn ormall y inc reased in pati ents with primary auto no mic failure (10). It has a lso bee n sho wn tha t importa nt infuen ce o f auto nom ic ne rvou s systems on QT interval in d iabeti c pat ien ts with auto no mic neu ro pathy (12) in cardiac tran splant recipients with auto no mica lly den er vated hearts (13 ) and by usin g phar macologic ace rus that b lock e ithe r limb o f au tono mic ner vou s system (14). Sever al car d iac side e ffec ts such as mob itz types 1 (Wenckebach sy ndrome), II and th ird -degree hea rt bloc k, myocardi al ischemia , myocard ial infarcti on , atria l arrh ythmias and ventricular tach ycardi a have been not ed during pacl itaxel ther ap y (4,5, 16). Furthe rmore , ca rdiac death res ulting from paclitaxel therapy has been report ed (15) . Ou r find ing with increased QT di spersion suggest that paclitaxel may pred isp ose the patients to arr hythmic event and may incr eases the risk of sudde n death . It is likely tha t rhy thm disturbances ca use d by pac litaxe l are re la ted ca rd iac automat icit y and cond ucti on ch an ges. T his hypothesis has been suppo rted by so me cl ues, for example, similar disturbances ha ve occurred in huma ns and anima ls after the ingest ion of yew plant s whic h are the basic substa nces of pacli tax el (16 ). Th us, we attr ibuted the inc rease in QT duration to imp aired card iac autonornia afte r pacli taxel infu sion . Previously, Ekh olm e t a l. (17) rep orted that pacl itaxel cha nges sy mpathe tic co ntro l o f bloo d pressure examined with a battery o f auto no mic functi on tests. Ek ho lm e t al, (18) also rep ort ed reduced lo w freque ncy/h igh freq uency ra tio and a tten uated

c irca dian rhyhm :)1 heart rate variab ility and claime d tha t autonomi c ca rdiac modulati on is impaired afte r the co urse of pacl itaxe l. Our findings a re in accorda nce with the hypoth esis that auto no mic cardiac modulati on is impai red during paclitaxel ther ap y as rep orted by Ekholm et a l (18). O n the o the r hand , it has been re ported that paclitaxel induces mot or and autono mic dys functio n es pec ia lly a t high doses and in pa tients with preexisting neurop ath ies caused by di abetes mell itu s and alc oh o lism (19) . These findings sugges t that pacl itaxel not only imp air card iac auto no my but a lso e ffects peripheric and santral aut on omic functi on . If the measurement e rro rs and poor reprod ucibility o f QTc di spersio n method are g iven, reported risk estimates are like ly to be substantia lly d iluted . However, we be lieve that this simple and cheap met hod is a strong and independent predic tor o f ventricu lar heterogeni ty and ca rd iac morta lity. Hen ce, it can be eas ily used to es tima te arrhythmia risk duri ng paclitaxe l admi nistra tion. In co ncl us ion, increased QT disp ersion aft er paclitaxel in fusion re flec ts that cardiac auto no mic modulati on is impaired and it may also sugges t the risk of potenti al se rious arrhyt hm ias a risi ng fro m thi s dru g. However further studies are wa rranted to e luc ida te the underl ying mech an ism o f ca rd iac adverse effec ts relevant to paclitax el .

REFER ENCES

1­ McGu ire WE, Hoskins WJ , Br ad y MF, et a l. Cycl op hosphamide and c isplatin compared with paclitaxel in pati ents with stage III and stage IV ovarian cancer. N Eng J Med , 334: 1-6, 1996.

2­ Clemons M , Leahy M , Valle J et a l. Review o f rec e nt trial s of ch em otherap y for adv ance d brea st cancer:the Taxa nes . Eur J Canc er , 33: 2183-2193, 1997.

3- Schiller JH. Role of taxan es in lun g .unce r che mo the rapy. Cancer Inv est , 16: 47 1­477, 1998.

4- Hoch ster H, Wa sserheit C, Sp eyer Cardiot oxicit y and cardiopro tec tion in

46

and

I.::l in .., ith

);

chemotherapy. Cur r Opin Oncol, 7: 304­309, 1995.

5­ McGuire WP ,Rowin sky EK, Rosenshein NB. Taxol: a new antineop lastic agent with significant activity in advan ced ovaria n epithelial neopl asms. Ann Int Med, Ill: 273 -279, 1989.

6­ Day CP, McComb J\1 , Campbell RWF. QT dispersion : an indication of arrhythmia risk in patient s with long QT intervals. Br Heart J, 63 : 342-344, 1990 .

7­ Ahnve S. Co rrection of QT interval for heart rate. Review of different formula s and the use of Bazzets formula in myocardial infarct ion. Am Heart J, 109: 568-574, 1985.

8­ Algra A, Tijssen JOP, Roel and JR ere, QTc prolongation measu red by standard 12-lead elect rocardiog rap hy is an independent risk factor ;';)1' sudden death due to cardiac arrest. Circ ul .nion, 83: 188­194, 1991.

9­ Glancy JM , Garra tt CJ, Woods KL QT dispersion and mortality after myocard ial infarction. Lancet, 345: 945-948 , 1995.

10- Loo SSS, Mathia s CJ, Sutton 1\11. QT inter val and dispersion 111 primary autonomic failure. Heart , 75: 498-50 I , 1996.

11- Capatto R, Alboni P, Pedroni P, Sympathetic and vagal influences on rate dependent changes of QT interval in healthy subjec ts. Am J Cardiel, 68: 1188­11 93,1991.

, "I._- Ewing OJ, Nei lson JMM . QT interval length and diab etic autonomic neuropathy. Diabeti c Med , 7: 23-6, 1990 .

: 3- G::xton RS, Vallin HO, Carnm AJ. Diurnal \ ariation of the QT interval influence of the automatic nervous system. Br Heart J, ~ :; : 253-8, 1986.

1"+- A hnve S, V allin H, Influence of heart rate and inhibiti on of autonomi c tone on the QT interval. Circulation, 65: 435 -9, 1982.

15- Alagaratnam TT. Sudden death 7 days after paclitaxel infusion for breast cancer. Lancet, 342: 1232-1233, 1993.

16- Arbuck SG, Strauss H, Rowinsky E. Assess ment of the cardiac toxicity associa ted with taxol. J Natl Cancer Inst Monogr, IS : 117-132, 1993.

17- Ekholm EM, Antila KJ, Salmi TA, Pacl itaxel changes sympathetic control of blood pressure. Eur J Cancer, 33 : 1419­1424,1 997.

18- Ekholm EM, Salminen EK, Huikuri HV. Impairment of heart rate variability during paclitaxel therapy. Cancer, 88: 2 149­2 153,2000.

19- Rowinsky EK. The development and clinical utility of the taxane class of antimicrotubul e chemotherapy agents. Annu Rev Med, 48: 353-374, 1997.

AUTHORS: i. BARUTCU, M.D., Afyon Kocatepe University, School of Medicine, Department of Cardiology A.T. SEZGi N, M.D., Buskent University, Adana Hospital Departm ent of Cardiology H. GOLLO, M.D., lnonu Universi ty, Turgut azal Medical Center Department of Cardio logy E. TOP AL, M.D., lnonu University, Turgut a zal Medical Center Department of Cardiology N. SEZGiN, M.D., Baskent Univers ity. Adana Hospital Departm ent of Biochemistry R. aZDEMiR. M.D., inonU University , Turgut Ozal Medical Center Department of Cardiology

ADDRESS FOR CORRESPOl'lDE~CE:

lrfan BARUTClJ, MD Afyon Kocaiepe Unive rsi te.' , Ahrnet Necdet Seze r Uygularna ve Arasn rrna Hastanesi, Kardiyoloji Anabilim Dah, Tel: 0272 2 1 453 1~- 121, AFY =.. :-.J E-mail:irfanbarutcu oryahoo.co m

47