Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
w w w . r b h h . o r g
Original
article
Trends
in
mortality
of
adult
patients
diagnosed
with
myeloid
leukemia
from
1994
to
2011
in
southeastern
Brazil
Fernando
Callera
∗,
Alexandra
Fernandes
Callera,
Evandro
Secchi
Rosa
CentrodeHematologiadoVale,SãoJosédosCampos,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received8May2014
Accepted11July2014
Availableonline21November2014
Keywords:
Myeloidleukemia
Acutemyeloidleukemia
Chronicmyelogenousleukemia
BCR-ABLpositive
Mortalityrate
a
b
s
t
r
a
c
t
Objective:ToevaluatetrendsinmortalityamongadultswithmyeloidleukemiaintheVale
doParaíba,StateofSãoPaulo.
Methods:DatafromtheBrazilianNationalHealthServicedatabaseDATASUSprovidedthe
numberofdeathscausedbymyeloidleukemiaandthenumberofinhabitantsperyearin
theRegionalHealthDivisionXVIIfrom1994to2011.Registrieswerecategorizedaccordingto
genderintofourageranges(over20years,20–49,50–69andover70years)foranestimation
oftheannualpercentchangeforage-adjustedmortalityrates.Thepercentchangeswere
calculatedusingtheJoinpointregressionanalysismodel.
Results:Overall,asignificantdeclineperyearwasdemonstratedfortheentiresample(over
20years)acrossthe18-yearperiodstudied(annualpercentchange:−5.59%;95%CI:−8.5to
−2.5%formales;p-value<0.05and−7.02%;95%CI−11.2to−2.8%forfemales;p-value<0.05)
withnosignificantdifferencebetweengenders.InananalysisusingtwoJoinpoints,
sig-nificant dropswereobservedfrom1994to2001(annual percentchange:−21.22%; 95%
confidenceinterval:−27.9to−13.9%;p-value<0.05)andfrom1994to2003(annual
per-centchange:−12.86%;95%confidenceinterval−22.2to−2.5%;p-value<0.05)formenand
women,respectively.Thedecliningtrendsweregreatestforpatientsagedover70years
withtheage-adjustedmortalityratesinyoungergroupsdecliningnon-significantlyexcept
formalesaged50–69yearsold.
Conclusion: Ourdatasuggestasignificantdeclineperyearinage-adjustedmortalityratesof
adultpatientsdiagnosedwithmyeloidleukemiafrom1994to2011intheValedoParaíba,
StateofSãoPaulo.
©2014Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published
byElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthorat:CentrodeHematologiadoVale,RuaEuclidesMiragaia,700,Sala75,Centro,12245-820SãoJosédosCampos,
SP,Brazil.
E-mailaddress:fcallera@centrodehematologiadovale.com.br(F.Callera).
http://dx.doi.org/10.1016/j.bjhh.2014.11.011
1516-8484/©2014Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Allrights
Introduction
Itiswidelyacceptedthattheassessmentofmortalitydatais
ausefultoolformonitoringoutcomesinpatientswith
hema-tologicmalignancies,particularlyincountrieswheresurvival
estimatesfromcancerregistriesarenotbroadlyavailable.1,2
Thisinformationmayberelevanttothestrategicplanningof
healthmanagersandenabletheimplementationofmeasures
toimproveservicesthattreatthesekindsofdiseases.
Myeloid leukemia is a group of hematologic
malignan-ciesdividedintoacuteandchronicsubtypes,someofwhich
requireexpensivetreatmentregimenswhileothersare
poten-tiallylethal.InBrazil,theMinistryofHealthhasdemonstrated
the mortality rates for leukemia in general3 but there are
insufficientdatatosupportdiscussionsregardingdeathrates
frommyeloidleukemia.
Therefore,inordertoprovidecomprehensiveand
region-alizedinformationwhichreflectthecharacteristicsandneeds
ofthelocalpopulation,anexploratoryanalysisofthe
mortal-itytrendsduetomyeloidleukemiawasperformedintheVale
doParaíba,StateofSãoPaulo.
Methods
ThisstudywascarriedoutintheCentrodeHematologiado
Vale (CHV). TheCHV consistsof medical
oncohematologi-calprofessionalsfromthefollowingservices:PioXIIHospital
in São José dos Camposand the Regional Hospital of the
ValedoParaíba,locatedinthe city ofTaubaté.These
non-teachinghospitalsarereferralcentersoftheRegionalHealth
DivisionXVII,composedof39municipalitiesintheValedo
Paraíba.Theyhavetreatedpatientswithhematologic
malig-nancies under the Brazilian National Health Service (SUS)
sinceearly1999.Together,theservicesthatcomprisetheCHV
attendalladultSUSpatientsdiagnosedwithacutemyeloid
leukemia (AML) and more than 110 patients with chronic
myeloidleukemia(CML).
Datafrom the SUSdatabase, DATASUS(Health
Informa-tion, TABNET, statistical data), available on the Brazilian
Ministry of Health website4 were considered for inclusion
intheanalysis.RegistriesfromtheRegionalHealthDivision
XVII (Valedo Paraíba),provided the number of deathsper
yearduetomyeloidleukemia(categorizedasC92according
to the International Classification of Diseases 10 [ICD-10]
from1996to2011andas205accordingtoICD-9from1994
to1995).Thisclassificationcomprisesthefollowingdiseases:
AML,CML,subacutemyeloidleukemia,acutepromyelocytic
leukemia (APL), acute myelomonocytic leukemia, myeloid
leukemia otherwise specified and myeloid leukemia not
otherwisespecified.Toobtainasetofdatawithadequately
specified characteristics, registries were grouped according
togenderintosevenageranges: 20–29,30–39,40–49,50–59,
60–69,70–79andmorethan80years.Registries(Health
Infor-mation,TABNET,demographicandsocioeconomicdata)also
providedthenumberofresidentsperyearaccordingtothe
above-mentionedagerangesandthe2000standardmillion
population; thus the death rates per 100,000 inhabitants
were calculated (crude mortality rate). These groups were
comparedusingtheone-wayanalysisofvariance(ANOVA),
and Kruskal–Wallis test withDunn’s multiplecomparisons
test.p-valueslessthan0.05wereconsideredstatistically
sig-nificant.Theannualpercentchange(APC)oftheage-adjusted
mortalityratesbasedonthe2000standardmillionpopulation
wasalsoestimatedbyfittingastraight-lineregressiontothe
naturallogarithmoftherates,withcalendaryearusedasa
regressorvariableinJoinpointregressionanalysis5usingthe
JoinpointRegressionProgram(version4.0.4).6TheAPCwere
considered significant when the 95% confidence intervals
(95%CI)excludedzero(p-value<0.05).Inordertocomparethe
data,thesamemethodwasadaptedtoperformAPCanalysis
ofage-adjustedmortalityratesamongpatientswithmyeloid
leukemiafromallregionsofBrazil.
Results
Thecrudemortalityrateroseastheageincreasedwiththis
phenomenon being observed equally in men and women;
similarcrudemortalityrateswerefoundbetween20and49
years,50and69yearsandover70years(Figure1).Basedon
theseinitialfindings,datawerecategorizedaccordingto
gen-der into fourageranges (over20,20–49,50–69andover 70
years)fortheAPCestimationofage-adjustedmortalityrates.
Overall,significantdeclinesperyearintheage-adjusted
mor-talityratesweredemonstratedfortheentiresample(over20
years)acrossthe18-yearperiodstudied(APC:−5.59%;95%CI:
−8.5to−2.5%formales;p-value<0.05andAPC:−7.02%;95%
CI:−11.2to−2.8%forfemales;p-value<0.05);nosignificant
difference wasfoundbetweenthe genders(Figure2).Inan
analysisperformedwithtwoJoinpoints,significantdeclines
wereobservedfrom1994to2001(APC:−21.22%;95%CI:−27.9
to−13.9%)andfrom1994to2003(APC:−12.86%;95%CI:−22.2
to −2.5%) for menand women respectively(Figure 3).The
decliningtrendsweregreatestforpatientsagedover70years
oldwiththeage-adjustedmortalityratesinyoungergroups
Male Female 50
45
30
35
30
25
20
15
10
5
0
20-29 30-39 40-49 50-59 60-69 70-79 >80
Age range (years)
Crude mortality rate
40.00
35.00
30.00
25.00
20.00
15.00
10.00
5.00
0.00
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Year
Age-adjusted mor
tality r
a
te
Male Female
1994-2011 APC = –5.59%a 1994-2011 APC = –7.02%a
a p-value < 0.05
Figure2–Trendsinage-adjustedmortalityrateforover 20-year-oldmalesandfemalesfrom1994to2011.
40.00
35.00
30.00
25.00
20.00
15.00
10.00
5.00
0.00
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Year
Age-adjusted mor
tality r
a
te
Male Female
1994-2001 APC = –21.22%a 1994-2003 APC = –12.86%a
2001-2004 APC = 25.08
2004-2011 APC = –5.04
2003-2006 APC = 16.81%
2006-2011 APC = 14.59
a
p-value < 0.05
Figure3–Significantchangesoversuccessivetime segments(Joinpoints)forover20-year-oldmalesand femalesfrom1994to2011.
Table1–Estimatedannualpercentchangeofthe age-adjustedmortalityratesofpatientswithmyeloid leukemiaaccordingtoagerangeandgenderintheVale doParaíbafrom1994to2011.
Agerange(years) Male Female
Over20 −5.59(−8.5to−2.5)a −7.02(−11.2to−2.8)a
20–49 −2.40(−5.8to1.1) −3.60(−7.3to0.1) 50–69 −3.90(−7.2to−0.5)a −0.30(−3.7to3.3) Over70 −6.52(−10.3to−2.6)a −8.01(−13.2to−2.5)a
Dataareexpressedasmeanrateofchange(%)and(95%confidence interval).
a p-value<0.05.
Table2–Estimatedannualpercentchangeofthe age-adjustedmortalityratesofpatientswithmyeloid leukemiaaccordingtoagerangeinBrazilfrom1994to 2011.
Agerange(years) Meanannual
percentchange
95%confidence
interval
Over20 +1.4a +0.6to+2.2
20–49 −1.2a −1.9to−0.6 50–69 +0.3 −0.4to+1.0 Over70 +2.3a +1.4to+3.1
a p-value<0.05.
decliningalbeitnotsignificantlyexceptformalesaged50–69
yearsold(Table1).WithregardtoBrazilasawhole,a
signifi-cantupwardtrendwasobservedforboththeentiresample
(over 20 years) and forpatients aged over 70 years. There
wasasignificantdeclineforpatientsaged20–49yearsandan
insignificantincreaseforpatientsaged50–69years(Table2).
Discussion
SUSisavailabletoallBraziliancitizensalthoughroughly25%
ofthepopulationhasprivatehealthinsurance7;wetherefore
believe thatdata extrapolatedfrom the DATASUS database
areusefulforclinicalandepidemiologicalstudies.However,
animportantlimitationofthisstudy regardsthequalityof
data.RegistrationoferroneousICDcodesresultsin
misclassi-ficationandcouldberesponsiblefordifferencesinmortality
ratesobservedinthisseries.Itshouldalsobestressedthat,
inmany areas,accesstotimelycancercareisimpairedby
theinadequateinfrastructureofthehealthcaresystem,
espe-ciallyinlow-incomeandgeographicallyisolatedpopulations
withthesecasesbeingmorelikelytoremainunreportedthan
casestreatedinhospitals.Inaddition,deathsfrompatients
witheitheracuteorchronicmyeloidleukemiaareregistered
intheDATASUSdatabaseasmyeloidleukemiawhichis
unsa-tisfactory because mortality rates vary between acute and
chronicmyeloidleukemia.Thiscomplicatescomparisonsand
in particular makes it difficult to interpret regional
differ-ences.Furthermore,thestudywasbasedonacross-sectional
structureandregistriesdidnotstatewhetherdeathsoccurred
duringorafterspecifictreatments, thereforeacause-effect
relationshipcould notbeestablished.Thus,an exploratory
ratesandtheresultsgainedoveraperiodoftimeintheVale
doParaíba.
Thediagnosis ofAMLmayexplain, atleastinpart, the
increasedcrudemortalityratesobservedintheelderlygroup.
AMLpresents atall ages, but its incidence increases with
ageandoutcomesarestronglyageandperformancestatus
dependent. Older patients have more comorbidities and a
higherincidenceofpoorprognosticfactors,suchassecondary
leukemia andhigh-risk cytogenetics.Moreover,early death
ratesof15%to55%havebeenreportedamongtheelderlyand
evenincasesofAPL,alowersurvivalratehasbeendescribed
inolderpatients.8,9
Overall,ourseriessuggeststhatmortalitydropped
signif-icantlyovertheyearsinthisregion.Thepossiblereasonsfor
thisfindingarebasedontheimprovementsinthequalityof
carewhichwasintroducedbyourteamintheValedoParaíba
sinceearly1999;thepracticeguidelinesfortheuseof
antimi-crobialagentsinneutropenicpatientswithcancer,hospital
environmental precautions, more intensive chemotherapy
followed byautologoushematopoietic stem cell
transplan-tation(whichhasbeen usedinthisregion since2004)and
allogeneic bone marrow transplant from related or
unre-lateddonorsprobablyledtobettersurvivalofthesepatients.
Besides,newtreatmentoptionssuchastheuseofall-trans
retinoicacid(ATRA)pluschemotherapy,whichwasassociated
withahighcompleteremissionrateinnewlydiagnosedAPL,
andtheuseofanti-tyrosinekinasetargetedtherapyspecific
fortheBCR-ABLrearrangementinCML(authorizedinBrazil
sinceOctober,2001)couldalsoexplaintheobserveddecrease
inmortality.Ontheother hand,ourfindingscontrast with
theupwardtrendinmortalityseeninBrazilasawhole.We
believethatdifferentBrazilianregionsalsohaveexperienced
improvementshowever, thereisstill abiasedallocation of
resources,underinvestmentinequipmentandinfrastructure
andinequitiesincancercareacrosspopulationgroups;some
institutionsprovideallaspectsofhealthcaretospecific
popu-lationswhileothersareexcludedwhichconsequentlyreflects
onthemortalityratesobservedinBrazil.
The age-adjusted mortality rates in younger groups
declinedinsignificantlyoverthelastfewyears.Furthermore,
astrikingfinding ofthepresent study isthatthe decrease
wasthegreatestforover70-year-oldpatientscontrastingwith
those observedforthe sameage groupin Brazil.This
sce-narioisdifficultto explain.Ithas beendemonstrated that
patientswhowerediagnosedwithAMLatyoungerageshave
highersurvivalrates,10andCMLisexpectedinthisagerange.
Basedonthesereasonsandconsideringtheaforementioned
improvementsinthequalityofcareinthisregion,weexpected
tofind amoresignificant dropacross timein theyounger
groups. It is possible that a significant decline could not
bedemonstrated for youngerpatients because deathrates
were consistentlylow overthe years.Moreover,inanother
studyregardingdemographiccharacteristicsofhematological
malignanciesintheValedoParaíba,11 itwasdemonstrated
that the periodbetween the first symptomsand definitive
diagnosisofthediseaseinthisagerangewas greaterthan
twomonthsin65%ofthecases;adelayinreceivingaproper
diagnosiswhich consequentlyworsensthechancesof
suc-cessfulchemotherapymayexplainthesefindings.Withregard
toolderpatients,improvementsinearlydeathratesandlong
termsurvivalweredemonstratedeveninolderpatientswith
AML9;thefallinmortalityrateswithadvancingagepointsto
anincreaseinthequalityofcare,suggestingthatoldpatients
maybereceivingoptimaltreatmentfortheirconditionsinthis
region.
Finally,thedropincancermortalityisnotsurprising.The
AmericanCancerSocietyrecentlydemonstratedthatcancer
deathrateshavedeclined20% overthelast20yearsinthe
UnitedStates.2 Inaddition, authorshavereportedan
asso-ciation betweensocioeconomic statusand mortalitydueto
cancerindifferentregionsoftheworld.12–15Inthiscontext,
theValedoParaíbahasmadegreatstridesduetotheeconomic
andsocialdevelopmentofthepopulation,includingterritorial
expansionandindustrialization.Thepresentworksuggests
thatourcombinedandcontinuouseffortstomakebetterand
sustained improvementsinthequality ofcancercare
con-tributedtothedecreaseinmyeloidleukemiamortalityrates
acrossthe18-yearperiodstudied.
Conclusion
Despitethemethodologicallimitations,thedataofthisstudy
suggestasignificantdeclineinage-adjustedmortalityratesof
patientsdiagnosedwithmyeloidleukemiafrom1994to2011
intheValedoParaíba,StateofSãoPaulo.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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