Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer

ORIGINAL ARTICLE Quali y o li e wi h biweekly doce axel and capeci abine in ad anced gas o-oesophageal cance E. A. Ko keila 1 &T. Salminen 2 &R. Kallio 3 &M. Mikkola 4 &P. Au inen 5 &S. Py hönen 1 & R. Ris amäki 1 Recei ed: 15 June 2016 /Accep ed: 31 Ma ch 2017 /Published online: 20 Ap il 2017 #The Au ho (s) 2017. This a icle is an open access publica ion Abs ac Pu pose This s udy aimed o e alua e he easibili y and ol- e abili y o biweekly doce axel wi h capeci abine as i s -line ea men in ad anced gas o-oesophageal cance . Me hods Fi y- h ee pa ien s a median age o 61 yea s wi h ad anced gas ic cance we e included in his p ospec i e, non- andomized, mul icen e phase II ial o ecei e in a e- nous doce axel 50 mg/m 2 on days 1 and 15, and o al capeci - abine 1250 mg/m 2 e e y 12 h, on days 1–7and15–21 o each 28-day cycle. QOL was assessed using EORTC QLQ-C30, oge he wi h he gas ic module (QLQ-STO 22). Resul s Fo y-six pa ien s we e e aluable o QOL analyses. No de e io a ion in global heal h s a us was ound. Social unc ioning sco es imp o ed, and ea ing di icul ies and pain we e alle ia ed du ing ea men . The mos common g ade 3 o 4 oxici y was neu openia (47%), whe eas neu openic e e was uncommon (6%). The clinical bene i a e was 60%, including comple e and pa ial esponses as well as s a- bilized disease. Median o e all su i al was 8.8 mon hs (95% CI 5.8–11.9 mon hs), and median ime o p og ession was 6.2 mon hs (95% CI 4.9–7.5 mon hs). Conclusions Biweekly doce axel wi h capeci abine is a easi- ble ea men in AGC, deli e ed on an ou pa ien basis, wi h no need o cen al enous access de ice. No de e io a ion o global heal h s a us was epo ed. In addi ion, pain and ea ing di icul ies we e alle ia ed du ing s udy ea men . This ial is egis e ed a ClinicalT ials.go , numbe NCT00669370. Keywo ds Quali y o li e .Ad anced gas o-oesophageal cance .Chemo he apy .Pallia i e ea men In oduc ion The incidence o dis al gas ic cance is dec easing, whe eas cance s o he dis al oesophagus and gas o-oesophageal junc- ion end o inc ease in he Wes e n wo ld [1]. Wo ldwide, hese cance s cause subs an ial mo bidi y and mo ali y. Nea ly one million new cases and mo e han 700,000 dea hs due o gas ic cance we e es ima ed o ha e occu ed in 2012, se ing gas ic cance he i h mos common cance and he hi d mos common cause o cance dea h [2]. The p ognosis o ad anced gas o-oesophageal cance (AGC) emains poo [1,2]. A subs an ial p opo ion o pa ien s p esen s wi h o ends up ha ing me as a ic disease a e ini ial ea men [3,4]. Sys emic chemo he apy is shown o imp o e disease ou - come in AGC, as compa ed o bes suppo i e ca e, wi h me- dian su i al a es eaching 6–9mon hs[5–7]. Du ing he pas decade, se e al new-gene a ion cy o oxic agen s, including capeci abine, i ino ecan, oxalipla in and doce axel, ha e been in es iga ed in he ea men o me as a ic gas ic cance [7–10]. Two p e ious la ge phase III ials demons a ed an o al luo opy imidine capeci abine no o be in e io o 5-FU in he se ing o a pla inum-con aining double o iple o *E. A. Ko keila eija.ko keila@ yks. i 1 Depa men o Oncology, Uni e si y o Tu ku and Tu ku Uni e si y Hospi al, Hämeen ie 11, PB 52, FI-20521 Tu ku, Finland 2 Depa men o Oncology, Tampe e Uni e si y and Tampe e Uni e si y Hospi al, Tampe e, Finland 3 Depa men o Oncology and Haema ology, Oulu Uni e si y and Oulu Uni e si y Hospi al, Oulu, Finland 4 Depa men o Oncology, Vaasa Cen al Hospi al, Vaasa, Finland 5 Facul y o Medicine and Cance Cen e and Depa men o Oncology, Uni e si y o Eas e n Finland, Kuopio Uni e si y Hospi al, Kuopio, Finland Suppo Ca e Cance (2017) 25:2771–2777 DOI 10.1007/s00520-017-3689-5 AGC [8,9]. Adding doce axel in o he combina ion o cispla - in and luo ou acil (DCF) was s udied in a andomized phase III ial in i s -line he apy o AGC. The inal esul s showed imp o ed su i al, esponse a e, and heal h- ela ed QOL, al- bei inc eased oxici y wi h DCF [10]. Fu he , in a phase III open-label, andomized con olled ial in HER2-posi i e AGC, as uzumab in combina ion wi h chemo he apy signi - ican ly imp o ed median o e all su i al as compa ed o che- mo he apy alone [11]. Recen ly, VEGFR-2 an agonis amuci umab was ound o imp o e su i al as mono he apy o in combina ion wi h pacli axel in AGC a e i s -line ea - men [12,13]. Howe e , so a , no su i al bene i has been epo ed in he i s -line se ing wi h o he no el a ge ed agen s in AGC, in addi ion o as uzumab. In ad anced cance , he p ima y ea men goals a e o p o- long su i al, elie e symp oms and sus ain o imp o e he quali y o li e. The eby, chemo he apy- ela ed oxici y is an impo an issue when de e mining he ue alue o ea men . Pa ien s wi h AGC a e gene ally elde ly and exhibi poo gen- e al pe o mance s a us, which emphasizes he need o e ec- i e ea men op ions and imp o ed con ol o side e ec s. On he basis o hese conside a ions, we conduc ed a phase II ial o de e mine he easibili y and ole abili y o biweekly doce- axel in combina ion wi h capeci abine as i s -line ea men o pa ien s wi h AGC. Pa ien s and me hods S udy design and pa ien popula ion This p ospec i e, non- andomized, mul icen e phase II ial included pa ien s o e 18 yea s o age wi h his ologically con- i med, locally ad anced (inope able) o me as a ic adenoca - cinoma o he s omach o gas o-oesophageal junc ion. Disease lesions could be ei he e aluable o measu able. No p e ious chemo he apy o ad anced o me as a ic disease was allowed, and a ime in e al o ≥6 mon hs a e adju an chemo he apy was impe a i e. Pa ien s we e equi ed o ha e adequa e haema ological (neu ophils >1.5 × 10 9 /l, haemoglobin ≥100 g/l a e ans usion when needed and pla ele s ≥100 × 10 9 /l), enal (se um c ea inine ≤1.25 × uppe no mal limi ) and li e unc ion ( o al se um bili ubin ≤1.25 × uppe no mal limi o alanine amino ans e ase ≤3 × uppe no mal limi , alkaline phospha ase ≤2.5 × uppe no mal limi , unless bone me as ases; in case o li e me as asis o al se um bili ubin ≤1.5 × uppe no mal limi and alanine amino ans- e ase ≤5 × uppe no mal limi ). P ophylac ic use o g anulo- cy e colony-s imula ing ac o (G-CSF) was no allowed. Exclusion c i e ia included p egnancy o b eas eeding, me as a ic disease o he cen al ne ous sys em, un esol ed bowel obs uc ion o dysmo ili y, ch onic dia hoea, clinically signi ican malabso p ion synd ome, inabili y o swallow able s, known dihyd opy imidine dehyd ogenase de iciency, pe iphe al neu opa hy ≥g ade 2, concu en se e e and/o un- con olled co-mo bid medical condi ion such as uncon olled in ec ion, hype ension, ischemic hea disease, myoca dial in a c ion wi hin p e ious 6 mon hs o conges i e hea dis- ease. Pa ien s wi h p e ious se ious hype sensi i e eac ions, his o y o alle gy o d ugs con aining he excipien TWEEN 80® o 5- luo ou acil, majo su ge y wi hin 4 weeks p io o s udy ea men o passage diso de we e also excluded om he pa icipa ion in he s udy. S udy ea men Pa ien s ecei ed in a enous doce axel 50 mg/m 2 on days 1 and 15 and o al capeci abine 1250 mg/m 2 e e y 12 h, s a ing on days 1 and 15 in he e ening and con inuing on days 2–7 and 16–21. One cycle consis ed o 28 days. P emedica ion wi h 7.5 mg o o al dexame hasone o me hylp ednisolone 40 mg was gi en he e ening p io o doce axel in usion and con inuing he ea e e e y 12 h h ee imes. Dose educ ion was based on he mos se e e g ade o oxici y in he p e ious cycle. A planned cycle could be delayed up o 21 days due o oxici y. I a pa ien had no eco e ed om oxici ies wi hin 21 days, he/she was wi hd awn om he s udy. In case ei he Table 1 Pa ien cha ac e is ics (n=53) Median age ( ange) (yea s) 61 (28–79) Sex, n(%) Male 36 (68) Female 17 (32) ECOG pe o mance s a us, n(%) 0 10 (19) 1 39 (74) 24(7) Loca ion o p ima y umou , n(%) Oesophagogas ic junc ion 21 (40) Gas ic 32 (60) Resec ion o p ima y umou , n(%) Yes 19 (36) No 34 (64) P e ious adju an chemo he apy, n(%) 10 (19) P e ious adio he apy, n(%) 8 (15) O gan in ol emen , n(%) S omach 34 (64%) Lymph nodes 25 (47%) Li e 12 (33%) Pe i oneum 11 (21%) Numbe o disease si es, n(%) 1 20 (38) 2 26 (49) ≥37(13) 2772 Suppo Ca e Cance (2017) 25:2771–2777 o he es doce axel o capeci abine was discon inued due o an ad e se e en , he pa ien could con inue in he s udy aking only one es d ug. E icacy and sa e y assessmen s Be o e s udy inclusion, pa ien s unde wen comple e physical examina ion, blood analysis (haema ology and biochemis y), elec oca diog am and compu e ized omog aphy (CT) scan o he abdomen and pel is as well as CT o he ho ax o ches x- ay. Blood samples we e aken o haema ology es s p io o each ea men on days 1 and 15 o each cycle. Biochemis y es s we e pe o med be o e he s a o each cycle. Du ing ea men , imaging o a ge and non- a ge le- sions was epea ed e e y h ee cycles (e e y 12 weeks) o as clinically indica ed. Tumou esponse was classi ied acco d- ing o RECIST [14].Toxici y was e alua ed be o e e e y cycle using Na ional Cance Ins i u e-Common Te minology C i e ia o Ad e se E en s [15]. Quali y o li e assessmen s Quali y o li e (QOL) was assessed using 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) [16], oge he wi h he gas ic module (QLQ-STO 22) [17]. QLQ assessmen was pe o med a baseline, on day 1 o he second and subsequen cycles (p io o he in usion), a he end-o -s udy isi , du ing ollow-up un il p og ession o he s a o second-line ea - men o dea h. P e equisi es o inclusion in he analyses o (a change in) physical unc ioning sco e consis ed o a leas one gi en ea men cycle as well as QLQ-ques ionnai e illed a baseline and a e he i s ea men cycle. The physical unc- ioning sco e was measu ed using he EORTC QLQ-C30 and QLQ-STO 22 [16,17]. S a is ical analysis The p ima y end poin o he s udy was physical unc ioning sco e, measu ed by he EORTC QLQ-C30 and QLQ-STO 22 ins umen s, compa ing he sco es ecei ed a baseline wi h hose ob ained a e one ea men cycle, using a pai ed es . Seconda y end poin s we e ime o p og ession (TTP), o e all esponse a e (ORR) and o e all su i al (OS). Summa y measu emen s a e p esen ed as mean and s an- da d de ia ion (SD) o as median wi h 25 h–75 h pe cen ile, unless o he wise s a ed. The change om baseline o con in- uous a iables was analysed by pai ed samples es . The Kaplan-Meie cu e was c ea ed o show o e all su i al om ec ui men o he end o ollow-up (i.e. dea h o end o he s udy). All analyses we e pe o med using SPSS o Windows (IBM Co p. Released 2011. IBM SPSS S a is ics o Windows, e sion 20.0. A monk, NY: IBM Co p.) Table 2 The main esul s o QoL-C30 and STO-22 ques ionnai es Va iable Baseline n= 46 Cycle 1 n= 45 Cycle 2 n= 37 Cycle 3 n=30 Cycle4n=27 Cycle5n=20 Global heal h s a us 62 (SD19) 64 (SD19) 67 (SD18) 66 (SD17) 62 (SD16) 62 (SD16) p=0.002 p=0.018 Physical unc ioning 77 (SD18) 76 (SD17) 78 (SD17) 77 (SD16) 77 (SD17) 77 (SD18) p=0.012 Social unc ioning 83 (SD20) 82 (SD19) 84 (SD22) 87 (SD18) 91 (SD15) 87 (SD16) p=0.005 Emo ional unc ioning 76 (SD20) 84 (SD17) 86 (SD14) 87 (SD12) 85 (SD20) 84 (SD17) p=0.004 p=0.011 p=0.004 p=0.025 Cogni i e unc ioning 87 (SD14) 89 (SD14) 90 (SD13) 86 (SD16) 88 (SD14) 89 (SD17) Role unc ioning 68 (SD31) 74 (SD24) 79 (SD25) 80 (SD23) 80 (SD16) 77 (SD29) Fa igue 33 (SD19) 32 (SD17) 31 (SD20) 30 (SD20) 30 (SD18) 28 (SD20) Pain 26 (SD16) 20 (SD15) 15 (SD11) 14 (SD12) 13 (SD14) 1 (SD12) p=0.01 p<0.001 p=0.001 p=0.001 p=0.002 Ea ing es ic ions 29 (SD23) 22 (SD20) 15 (SD17) 19 (SD18) 16 (SD19) 15 (SD12) p=0.001 p=0.005 Dysphagia 31 (SD31) 26 (SD24) 21 (SD25) 20 (SD23) 18 (SD16) 22 (SD29) Tas e 16 (SD25) 27 (SD28) 37 (SD28) 36 (SD33) 30 (SD21) 38 (SD25) p=0.004 p<0.001 p=0.007 p=0.003 p=0.030 Anxie y 46 (SD23) 38 (SD21) 34 (SD19) 33 (SD31) 31 (SD21) 32 (SD18) p=0.001 p=0.006 p=0.001 p=0.002 p=0.011 The alues a e p esen ed as mean wi h s anda d de ia ion (SD). The sco es o each cycle as compa ed o he baseline sco e Suppo Ca e Cance (2017) 25:2771–2777 2773 Resul s Pa ien s and ea men This p ospec i e phase II ial was conduc ed a ou uni e - si y hospi als and one cen al hospi al in Finland. A o al o 53 pa ien s we e egis e ed be ween June 2006 and Decembe 2009. One pa ien was wi hd awn om he s udy a e he i s cycle due o de ec ed HER2-posi i i y, necessi a ing he s a o as uzumab ea men . Al oge he , 46 pa ien s we e eligible o he QOL analyses. The pa ien cha ac e is ics a e summa- ized in Table 1. The o al numbe o chemo he apy cycles adminis e ed was 220. The median numbe o ea men cycles pe pa ien was 4 ( ange, 0.5–16), and he median ime on s udy ea men was 4.8 mon hs ( ange, 0.1–17.6 mon hs). The main easons o ea men discon inua ion we e p og essi e disease o de- e io a ing gene al condi ion (n= 31, 58%). Al oge he , 26 pa ien s (49%) ecei ed second-line chemo he apy. E ec o ea men on quali y o li e The numbe o pa ien s wi h assessable QOL ques ionnai es a baseline was 46 (45 o global heal h s a us and STO 22 ques- ionnai es), a e he i s and subsequen ou cycles, he num- be o pa ien s was 45, 37, 30, 27 and 20, espec i ely. De ailed esul s QOL analyses a e shown in Table 2. Pain and ea ing es ic ions we e common a baseline (Fig. 1a). Du ing ea men , clinically ele an alle ia ion was de ec ed bo h in pain and in ea ing es ic ions. No de e io a ion in global heal h s a us o in social o physical unc ioning oc- cu ed (Fig. 1a–c). Clinical bene i One o he 53 pa ien s (2%) achie ed comple e esponse (CR), and 8 pa ien s (15%) had pa ial esponse (PR). O he pa- ien s, 23 (43%) showed s able disease (SD) and 5 (9%) had p og essi e disease (PD). The clinical bene i a e was 60%. The esponse was no e aluable among 18 pa ien s (30%), due o ea ly discon inua ion o he s udy ea men . Median ime o p og ession was 6.2 mon hs (95% CI 4.9–7.5 mon hs) and median o e all su i al 8.8 mon hs (95% CI 5.8–11.9 mon hs) (Fig. 2a, b). Sa e y Du ing s udy ea men , 25 (47%) pa ien s we e hospi- alized. Fi y pe cen o he hospi aliza ions we e caused by a ea men - ela ed ad e se e en . The mos common g ade 3 o 4 oxici y was neu openia, de ec - ed in 25 pa ien s (47%). Howe e , only h ee pa ien s (6%) expe ienced neu openic e e . One pa ien had a g ade 3 alle gic eac ion du ing doce axel in usion, p ecluding u he ea men . The e we e no di ec ea men - ela ed dea hs. One sudden dea h occu ed du ing he i s ea men cycle. Acco ding o he au opsy epo , he cause o dea h was me as a ic gas ic cance and no e idence o ca diac- ela ed dea h could be de ec ed. The common ad e se e en s a e lis ed in Table 3. 0 20 40 60 80 100 Mean Cycle Global heal h s a us n = 45 45 37 30 27 20 0 20 40 60 80 100 Mean Cycle Social unc ion Physical unc ion 0 20 40 60 80 100 Mean Cycle STO22 Pain STO22 Ea ing es ic ion 012345 012345 n = 46 45 37 30 27 20 012345 n = 45 45 37 30 27 20 a b c Fig. 1 E ec o ea men on quali y o li e: aglobal heal h s a us, b social and physical unc ion, and cpain and ea ing es ic ions p esen ed as mean alues pe cycle 2774 Suppo Ca e Cance (2017) 25:2771–2777 Discussion This p ospec i e phase II ial wi h a combina ion o biweekly doce axel and capeci abine in AGC showed no de e io a ion o global heal h s a us o ei he physical o social unc ioning. Impo an ly, he pa ien s’quali y o li e was no comp omised du ing ea men . Mo eo e , disease-associa ed symp oms, in- cluding ea ing es ic ions and dysphagia, as well as pain and anxie y, we e alle ia ed du ing s udy ea men . The egimen was also con enien ly deli e ed on an ou pa ien se ing wi h- ou a need o cen al enous access de ice. Doce axel in a ious combina ions has p e iously been s udied in he ea men in AGC, also including QOL assess- men s [18–21]. A ecen p os a e cance ial epo ed be e ime o ea men ailu e and ewe se ious ad e se e en s wi h wo weekly han wi h h ee weekly dosing o doce axel [22]. Fig. 2 a Median ime o p og ession. bMedian o e all su i al Suppo Ca e Cance (2017) 25:2771–2777 2775 In AGC, doce axel combined o cispla in and luo ou acil e- sul ed in be e symp om pallia ion and imp o ed QOL, as compa ed o ea men wi h epi ubicin, cispla in and luo o- u acil. Un o una ely, ea men oxici y da a o his combina- ion we e no eadily p o ided [19]. P e ious ials ha e gen- e ally demons a ed imp o ed QOL accompanied wi h im- p o ed e icacy in AGC, despi e inc eased oxici y wi h doce- axel iple combina ions [10,18,19,21], i.e. ea men e i- cacy a he han oxici y ends o a ec QOL [23]. Impo an ly, in he cu en s udy, he pa ien s’QOL was no comp omised du ing ea men . Ea ing di icul ies we e alle- ia ed du ing chemo he apy bu s a ed de e io a ing along wi h disease p og ession. Simila ly, a e commencing he a- py, pain was expe ienced o elie e bu in ensi y again as cance p og essed. Physical unc ioning emained s able du - ing chemo he apy, while social unc ioning imp o ed, e en despi e disease p og ession. The global heal h s a us was main ained o sligh ly imp o ed du ing he apy. Gubanski and colleagues in es iga ed he e ec o sequen ial ea men on QOL. Pa ien s we e andomized o s a ea men wi h ei he doce axel o i ino ecan combined o luo ou acil and leuco o in. A e ou cycles, he ea men was swi ched. Chemo he apy was no ound o a ec he a e age QOL sco es. Ins ead, pa ien s wi h a adiological esponse we e able o sus- ain be e QOL as compa ed o pa ien s wi h no adiological esponse [24]. A pa ien ’s pe cep ion o expec ed ea men e i- cacy migh also in luence on QOL sco es: a subs an ial p opo ion o pa ien s may no comp ehend hei disease unlike- ly o be cu able [25]. Thus, hey may be eady o ole a e e en se ious side e ec s and ye expe ience QOL o be main ained. The esul s o his s udy showed he clinical bene i a e o be 60%, including comple e (CR) and pa ial (PR) esponses and s abilized disease (SD), and median o e all su i al o 8.8 mon hs. These indings a e pa allel o a p e ious ial o weekly doce axel oge he wi h capeci abine on days 1–14 o a 21-day cycle, showing a compa able esponse a e o 29%, s able disease o 44% and o e all su i al eaching 10.7 mon hs [26]. Ano he s udy in es iga ing dose-dependen e icacy o doce axel and capeci abine esul ed in imp o ed o e all e- sponse a es wi h ull dosing o hese agen s. Howe e , wo pa ien s in each coho expe ienced g ade 3–4 ca diac a hy h- mia, one pa ien pulmona y oedema, and h ee pa ien s g ade 3– 4 h ombosis/pulmona y embolism, one o hem leading o dea h [27]. In he cu en s udy, no dea h was di ec ly associa ed o s udy ea men . One pa ien died a e he e y i s in usion o chemo he apy due o apidly p og essing cance , wi hou any signs o ca diac complica ions in he au opsy. Howe e , en- icula ib illa ion canno en i ely be uled ou , despi e o a nega i e au opsy epo . In he cu en s udy, only one pa ien expe ienced g ade 3–4 ca diac a hy hmia. Ou s udy shows a mode a e incidence o g ade 3–4neu o- penia, esul ing only a ely in neu openic e e . Ne e heless, in ec ion was he main eason o ea men - ela ed hospi aliza- ion. These esul s a e compa able wi h ea lie s udies, epo ing e en highe a es o g ade 3–4neu openia,inup o23–80% o pa ien s, eb ile neu openia among 2–12% and g ade 3–4non- neu openic e e among 2–41% o pa ien s, while hospi aliza- ion da a a e no eadily a ailable [19,26,27]. The incidence o mild palmo-plan a dyses hesia o hand- oo synd ome (HFS) was p e iously epo ed o be 9–42% and ha o se e e HFS 3– 20% [19,26,27]. E en hough he incidence o HFS in he cu en s udy was 45%, no g ade 3–4 symp oms we e de ec ed. Likewise, mild dia hoea was equen bu se e e dia hoea a a e e en . On he whole, haema ologic and non-haema ologic oxici ies we e conside ed ole able. In conclusion, no ea men combina ion has been p o en supe io as compa ed o o he s in AGC in he pallia i e se - ing. Biweekly doce axel, oge he wi h capeci abine is a ea- sible, ou pa ien -based, well- ole a ed ea men ha enables sus aining QOL and alle ia ing disease-associa ed symp oms. Acknowledgemen s This s udy was pa ly suppo ed by a g an om Sano i Genzyme. We a e hank ul o Au a A ola, M.D, o collec ing da a, Pasi Oh onen M.A, Bios a is ician, o his help wi h he s a is ical analyses and Kaisa-Ma i Paananen, Key Accoun Manage , Sano i Genzyme, o he con inuous suppo and encou agemen du ing his s udy. Compliance wi h e hical s anda ds E hical app o al This s udy was conduc ed in acco dance wi h he e hical s anda ds o he ins i u ional and/o na ional esea ch commi ee Table 3 Ad e se e en s, acco ding o g ade G ades 1 and 2 G ades 3 and 4 n(%) n(%) Non-haema ological oxici y As henia 26 (49) 11 (21) Alopecia 42 (79) 0 (0) Ano exia 31 (59) 6 (11) Nausea 31 (59) 4 (8) Vomi ing 12 (23) 2 (4) Dia hoea 20 (38) 3 (6) Hand- oo synd ome 24 (45) 0 (0) Nail changes 29 (55) 0 (0) Pa aes hesia 18 (34) 0 (0) Fluid e en ion 14 (26) 0 (0) Ca diac a hy hmia 8 (15) 1 (2) Non-neu openic e e 13 (24) 10 (19) Haema ological oxici y Anaemia 28 (72) 1 (2) Leukopenia 18 (34) 8 (15) Neu openia 11 (21) 25 (47) Th ombocy openia 4 (8) 0 (0) Neu openic e e 0 (0) 3 (6) 2776 Suppo Ca e Cance (2017) 25:2771–2777 and wi h he 1964 Decla a ion o Helsinki and i s la e amendmen s o compa able e hical s anda ds. 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