Childhood Cancer Incidence and Survival in Sweden 1984-2010 - BLF

Childhood Cancer Incidence and Survival inSweden 1984-2010Report 2013From the Swedish Childhood Cancer RegistryEditors: G. Gustafsson, P. Kogner and M. Heyman

Financial support obtained fromThe Swedish Childhood Cancer Foundation2

FörordInnehållsförteckning1. Introduktion och Organisation 62. Material och metoder 123. Resultat 173.1 Översikter 17Diagnoser-procentuell fördelning 19Åldersfördelning- diagnoser 20Överlevnad över tiden 21Åldersfördelning vid Follow Up 22Årligt antal patienter över tiden 233.2 Alla maligniteter – 3 grupper 243.3 Detaljer3.3.1 Leukemier 30ALL 30AML 323.3.2 Lymfom 35Hodgkins lymfom 37Non-Hodgkin lymfom 38Burkitts lymfom 39Histiocytoser 403.3.3 Hjärntumörer 41Ependymom 43Astrocytom 44Embryonala tumörer 45Andra gliom 47Andra specificerade CNS tumörer 483.3.4 Sympatiska nervsystemstumörer 493.3.5 Retinoblastom 523.3.6 Njurtumörer 543.3.7 Levertumörer 573.3.8 Bentumörer 593.3.9 Mjukdelstumörer 623.3.10 Germcellstumörer 653.3.11 Carcinom 673.3.12 Andra och ospecificerade tumörer 674. Diskussion 695. Referenser 736. Publikationer 757. Appendix 1.1 841.2 884

ForewordContents1. Introduction and Organisation 62. Material and Methods 123. Results 173.1 Surveys 17Diagnoses - relative distribution 19Age distribution vs diagnoses 20Survival over time 21Age distribution at Follow Up 22All patients reported annually 233.2 All malignancies - 3 groups 243.3 Details3.3.1 Leukaemias 30ALL 30AML 323.3.2 Lymphomas 35Hodgkin´s disease 37Non-Hodgkin lymphomas 38Burkitt’s lymphoma 39Histiocytosis 403.3.3 Brain tumours 41Ependymomas 43Astrocytomas 44Embryonal tumours 45Other gliomas 47Other specified brain tumours 483.3.4 Sympathetic nervous system tumours 493.3.5 Retinoblastoma 523.3.6 Renal tumours 543.3.7 Hepatic tumours 573.3.8 Bone tumours 593.3.9 Soft tissue tumours 623.3.10 Germ cell tumours 653.3.11 Carcinomas 673.3.12 Others and unspecified tumours 674. Discussion 695. References 736. Publications 757. Appendix 1.1 841.2 885

1. Introduktion och organisationRapporten omfattar uppgifter på samtliga barnmed cancer diagnostiserade i Sverige åren1984 -2010.I kapitel 1 ges en presentation av nuvarandebarnonkologiska organisation med sektion,arbetsgrupper, barnonkologiska centra ochstaben vid Barncancerepidemiologiskaforskningsenheten vid Karolinska Institutet,som ansvarat för utgivningen av rapporten.Kapitel 2 redovisar materialet, metod förinsamling av data samt de statistiska metodersom använts vid analyserna.Resultaten presenteras i kapitel 3 med primärten översikt av de tre stora diagnosgrupperna(leukemier, solida tumörer och CNS- tumörer)följt av separata analyser för varjeunderdiagnos av barncancer.För att kunna presentera prognosutvecklingeninklusive tidsperioden innan uppgifter fanns ivår egen databas har data från SvenskaCancerregistret använts.Klassificeringen av diagnoserna baserasursprungligen på WHO:s ICD - koder (1) somhar anpassats till Birch-Marsdenklassifikationen för barncancer som förstpublicerades 1987 (2) senast reviderad 2005(3).I kapitel 4 diskuteras klassificering avsjukdomarna och prognosutvecklingen övertiden och resultaten i det aktuella materialetjämförs med andra internationella publiceradedata.Publikationslistan omfattar internationellaartiklar som helt eller delvis baseras på datafrån Svenska Barncancerregistret.I Appendix redovisas i detalj det basalapatientmaterialet.1. Introduction and organisationThis report contains information on allchildren with cancer diagnosed in Swedenbetween 1984 and 2010.Chapter 1 presents the childhood cancerorganisation in Sweden including section,working groups, regional centres and thestaff of the Childhood CancerEpidemiology Research Unit at KarolinskaInstitutet which has been responsible forthe report.In chapter 2 we report the material andmethods for collection of data and thestatistical methods used in the analyses.The results are presented in chapter 3 withan initial survey of the three maindiagnostic groups (leukaemias, solidtumours and CNS-tumours) followed byanalyses of the separate sub diagnoses inchildhood cancer.In order to present the development ofprognosis including the time period beforeour own database existed, we have useddata from the Swedish Cancer Registry.The classification of the diagnoses areoriginally based on WHO:s ICD – codes(1), which have been adjusted to the Birch– Marsden classification for childhoodcancer first published in 1987 (2), lastrevised 2005 (3).The classification of the diseases andsurvival over time is discussed in chapter 4and the results in the present material arecompared with international results.The list of publications includesinternational articles completely or partlybased on data from the Swedish ChildhoodCancer Registry.The appendix contains basic patient data.6

Barncancerepidemiologiska Forskningsgruppen vid Karolinska InstitutetChildhood Cancer Epidemiology Research Group at Karolinska InstitutetHead:Research secretary:Statistician:Developers:PhD student:Postdoc:Senior researcher:Mats HeymanJenny JuhlinMatteo Bottai (Karolinska Institutet core-facility for Biostatistics)Anders Larsson, Omid Mavadati, Mats NordströmTrausti ÓskarssonAnnaCarin HorneGöran GustafssonRegionala registrerareRegional registratorsEva FranzénCarina RinaldoGunnel HedblomAnna Schröder-HåkanssonCarina HallbergBirgitta HellströmIngrid HagelinIngrid ColbergerRut-Inger EnrydLotta Paulsson ÖdmarkCamilla ErnstssonBritt FällmanStockholmUppsala/StockholmUppsalaGöteborgGöteborgLinköpingLundLundUmeåUmeåUmeåUmeå8

Arbetsgrupper inom SektionenWorking groups within the SectionSBLG (Svenska Barnleukemigruppen)SBLG (Swedish Childhood Leukaemia and Lymphoma Group)Chair: Britt-Marie Frost UppsalaSecretary: Mikael Behrendtz LinköpingMembers: Jonas Abrahamsson GöteborgJohan ArvidsonUppsalaAnders CastorLundMats HeymanStockholmUlrika Noren-Nyström UmeåMargareta Stenmarker JönköpingArja Harila-SaariStockholmJacek WiniarskiHuddingeJohan MalmrosStockholmDominik Turkiewicz LundLene KarlssonSkövdeKarin MellgrenGöteborgAdjungerade: Erik ForestierStefan SöderhällJesper HeldrupUmeåStockholmLundVSTB (Vårdplaneringsgruppen för Solida Tumörer hos Barn i Sverige)Swedish Childhood Solid Tumours Working GroupChair: Gustaf Ljungman UppsalaSecretary: Niklas Pal StockholmMembers: Britt-Marie Holmqvist LinköpingTorbjörn BackmanLundTorben EkHalmstadKristina NilssonUppsalaUlf HjalmarsUmeåLars HjorthLundMats HeymanStockholmPer KognerStockholmOtte BrosjöStockholmBengt SandstedtStockholmGustaf ÖsterlundhGöteborgVladimir GatzinskyGöteborgPär-Johan SvenssonStockholmErik SköldenbergUppsalaZahra Taheri-Kadkhoda GöteborgMarie SandgrenLinköping9

VCTB (Vårdplaneringsgruppen för CNS Tumörer hos Barn i Sverige)Swedish Childhood CNS Tumours Working GroupChair: Stefan Holm StockholmSecretary: Magnus Sabel GöteborgMembers: Birgitta Lannering GöteborgHelena MörseLundIrene DevenneyLinköpingSusan PfeiferUppsalaFredrik HedborgUppsalaPer-Erik SandströmUmeåMattias MattssonUmeåNeurosurgery: Bengt Gustavsson StockholmPelle NilssonUppsalaPeter SiesjöLundJörgen ElfverssonGöteborgNeurology: Olof Rask LundPernilla GrillnerStockholmChristoffer EhrstedtUppsalaErik StenningerÖrebroRadiotherapy: Ulla Martinsson UppsalaGun Wickart-Johansson StockholmPer BergströmUmeåNeuropatohlogy: Irina Alafuzoff UppsalaOlivera Casar-Borota UppsalaJurate AsmundssonStockholmNeuroradiology: Daniel Martin Munoz StockholmEvaldas Laurencikas UppsalaRegistration: Mats Heyman StockholmConsultant nurse: Charlotte Castor Lund10

BMT-Gruppen (Benmärgstransplantationsgruppen)BMT Group (Bone Marrow Transplantation Group)Chair: Karin Mellgren GöteborgMembers: Johan Arvidson UppsalaNiklas PalStockholmJohan MalmrosStockholmUlrika Norén-Nyström UmeåJacek ToporskiLundJacek WiniarskiHuddingeSALUB (Svenska Arbetsgruppen för Långtidsuppföljning efter Barncancer)(Swedish Working Group for Long-term Follow-up after Childhood Cancer)Chair: Lars Hjorth LundSecretary: Mikael Behrendtz LinköpingMembers: Johan Arvidson UppsalaPer FriskUppsalaUlla MartinssonUppsalaMarianne JarfeltGöteborgBirgitta LanneringGöteborgUlrika Norén-Nyström UmeåPer-Erik SandströmUmeåStefan SöderhällStockholmCecilia PetersenUppsala/StockholmMats HeymanStockholmSvenska Radioterapigruppen för Barn med CancerSwedish Radiotherapy Group for Children with CancerChair: Kristina Nilsson UppsalaMembers: Jack Lind UmeåPer BergströmUmeåAnna-Maja SvärdUmeåUlla MartinssonUppsalaPetra Witt NyströmUppsalaGun Wickhart Johansson StockholmGunilla Frykholm Jansson StockholmTeresa Calero Herlestam StockholmClaes MerckeStockholmMåns AgrupLinköpingHedda HaugenGöteborgCharlotta FröjdGöteborgMalin BlomstrandGöteborgKarin BelfrageLundJacob EngelauLundSven Börje EwersLundIngrid KristensenLundPer NilssonLund11

2.2. Statistiska mått och metoder i dennarapportFör incidensberäkningar behövs en klardefinition av diagnosen. Detta innefattar bådedetektion av ursprungligt fall samt hur man skatackla pågående eller kroniska tillstånd där detkan finnas latens-, remissions-, bot/behandlings- samt återfallsproblematik. Det är viktigt attfullständigt besvara de till synes enkla frågorna’vad är en åkomma?’ och ’när är en åkomma?’före man beräknar dessa storheter.Incidenssiffror beräknas för fall som insjuknatmellan 1 januari, 1984 och 31 december, 2010bland barn (ej fyllda 15 år) boende i Sverigevid tiden för diagnos, diagnosticerade på någotbehandlande centra och räknas som insjuknadevid tidpunkten för diagnos. Incidenssiffrorpresenteras per 100 000.2.2.1 Incidens – Åldersspecifikt måttPrecis som hos vuxna varierarcancerincidensen hos barn med ålder och könpå barnet. ALL hos barn är till exempel tregånger så vanligt i åldersgruppen två till fyra årjämfört med övriga åldrar. Den åldersspecifikaincidensen för olika cancerformer är detobserverade antalet nya fall, vägda mot denobserverade riskpopulationen och sedanmultiplicerat med 100 000. Den åldersspecifikaincidensen för klass i ärdiri 100 000; därYiid är antalet fall i varje åldersklassY är observerat antal personår.i2.2.2 Incidens – ÅldersstandardiseratmåttDet är vanligt att rapportera incidens iåldersstandardiserade tal för att underlättajämförelser mellan riskgrupper eftersom måttetinte påverkas av skillnader i åldersfördelningmellan grupperna. Medan det åldersspecifikamåttet viktas enbart med riskpopulationen ärdet åldersstandardiserade måttet på incidens detåldersspecifika måttet viktat med ännu en gångmed användande av en standardpopulation. Påså vis blir det åldersstandardiserade måttet ettmer sammanfattande mått som underlättandejämförelse mellan många olika grupper. I2.2. Statistical methods used in thisreportIn incidence a clear definition is required forthe condition. This includes the detection aswell as how to deal with on-going or chronicconditions where there may be issues oflatency, remission, cure/treatment, andrecurrence.Answering the seemingly simple questions'What is a condition?' and 'When is a condition'before starting a study is important.Incidence figures are calculated on casesincluded between January 1, 1984 andDecember 31, 2010 among children (below 15years of age) living in Sweden at the time ofdiagnosis, diagnosed at one of the treatingcenters in Sweden and are counted as a case atthe time of diagnosis. Incidence figures arepresented per 100,000.2.2.1 Incidence - Age-specific ratesJust as among adults, cancer incidence indifferent types of cancers among childrenvaries with age and sex. ALL in childhood isi.e. three times more common in childrenbetween two and four years old compared toother ages. The age-specific rates for variouscancers are the observed number of new cases,weighted by the observed population at riskand multiplied by a factor of 100,000. The agespecificrate for class i isdiri 100,000 ; whereYd iY i13iis the number of events in each age classis the observed person-years.2.2.2 Incidence - Age-standardized ratesIt is common practice to report incidencefigures as age-standardized rates so as to enablecomparison of risk between different riskgroups, since it is not affected by age. Whereasthe age-specific incidence is weighted by thepopulation at risk, the age-standardized ratesare the age-specific rates weighted yet again bya standard population, making this a summarymeasure especially when it comes tocomparing many sets of incidence rates. In thisreport the so called world standard population,as it is presented by Doll et al., is used as astandard population. The world standardpopulation is presented in table 3.2.1. The

denna rapport används som standardpopulationden s.k. världsstandardpopulationen (the worldstandard population), såsom den presenteratsav Doll et al. Världsstandardpopulationenpresenteras i tabell 3.2.1. Den svenskabarnpopulationen återfinns i 3.2.2.Den åldersstandardiserade incidensen per100 000 invånare beräknas: riwiiASR 100 000; där wiär vikten i wiiden i :te åldersklassen. Graferna över incidensvisar ett 3-års glidande medelvärde för att slätaut kurvan. För år y kallas detta glidandemedelvärdeIMAy, vilket är medelvärdet avincidensen året före år y, incidensen år y samtincidensen året efter år y, således fås1iMA 1 iyI3I; där Iiär incidensen år i.Swedish child population can be found in table3.2.2.The age-standardized incidence per 100,000 iscalculated as:riwiiASR 100,000 ; where w iis the wiiweight in the i th age class. The graphedincidence shows a 3-year moving average ofthe incidence in order to smooth the curve. The3-year moving average value for year y,denoted, is the mean value of theincidence the year before year y, the incidenceat year y and the incidence the year after year y,thusi.MAI y1iMA 1 iyI3I; where Iiis the incidence at yearTabell 2.2.1 / Table 2.2.1Världsstandardpopulationen / The world standard population(Doll et al., 1966)Ålder/age Population(år/years) Män/males Kvinnor/females Totalt/total0 1,200 1,200 2,4001-4 4,800 4,800 9,6005-9 5,000 5,000 10,00010-14 4,500 4,500 9,000Totalt/total 15,500 15,500 31,000Tabell 2.2.2 / Table 2.2.2Den svenska barnpopulationen / The Swedish child population(Statistiska Centralbyrån (SCB) / Statistics Sweden (SCB))Ålder/age Medelpopulation över de studerade åren /Mean population during the years studied(år/years) Män/males Kvinnor/females Totalt/total0 53,013 50,219 103,2321-4 212,728 201,887 414,6155-9 270,994 257,413 528,40610-14 278,718 264,697 543,415Totalt/total 815,453 774,215 1,589,66814

2.2.3 ÖverlevnadsanalysMed användande av metoder inomöverlevnadsanalys är det möjligt att studera ochanalysera inte bara tid till en händelse (ettevent) utan även den förväntade kvarvarandelivstiden för en person vid en given tidpunkt.Metoder inom överlevnadsanalys tillämpasvanligen inom cancerforskning för att jämföratvå eller fler grupper med avseende påöverlevnad, med eller utan hänsyn taget tillandra kovariater som kan tänkas påverka (4).I denna rapport kommer främst så kallade Lifetables att presenteras. Skillnader mellangrupper testas med logrank-testet, ett test somsimultant tar hänsyn till skillnader över helaöverlevnadskurvan, inte enbart skillnader vidslutpunkten av överlevnadskurvan.2.2.4 The Kaplan-Meier product limitestimateAntag n oberoende observationer sombetecknas ( tj,j) för j = 1, … , n därt järtiden i studien för den j:te individen och jären händelseindikator. Multiplicerasöverlevnadstiderna över alla observationer fåsöverlevnadsfunktionenSˆ( t)tj1[( n j) /( n j 1)] ( j)där S ˆ(t ) är den skattade överlevnadsfunktionen;n är antalet fall ( j) , händelseindikatorn, är en konstant somantar värdet 1 om det j:te fallet är ocensurerat(har komplett uppföljningstid) och som antarvärdet 0 om värdet är censurerat (dvs. har fallitbort före uppföljningstiden är fullföljd) (5).;2.2.3 Survival analysisBy survival analysis methods it is possible tomeasure and estimate not only the time to eventbut also the expected remaining lifetime of aperson at a certain time. Survival analysismethods are commonly used in cancer researchto compare two or more groups with regard totheir survival pattern, with or without takingadditional covariates into account (4).In this report the main survival analysis methodused is Life tables. Differences between groupsare tested by the log rank test, whichsimultaneously takes differences over thewhole survival curve into account, not only thedifferences at the end point of the curve.2.2.4 The Kaplan-Meier product limitestimateAssume n independent observations denotedt , ) for j = 1, … , n where t is the time(j jon the study for the jth individual andis theevent indicator. Multiplying the survival timesover each single observation we get thesurvival functionSˆ( t)tj1[( n j) /( n j 1)]where S ˆ(t ) is the estimated survival functionn is the total number of cases ( j) , the event indicator, is a constant equal to1 if the jth case is uncensored (has completefollow-up time) and equal to 0 if it is censored(5).j ( j); j2.2.5 Logrank-testet (eller ’the Mantel-Haenszel test’ eller ’the Mantel-Coxtest’)Låt j = 1, ..., J vara distinkta tider förobserverade händelser i båda grupper. För varjetidpunkt j, låt N 1j och N 2j vara antalet individersom ännu ej haft ett event eller censurerats vidbörjan av period j i respektive grupp. Låt N j =N 1j + N 2j . Låt O 1j och O 2j vara observerat antalevents i respektive grupp vid tidpunkten j, ochsätt O j = O 1j + O 2j . Givet O j events sominträffat över båda grupperna vid tidpunkten j,under nollhypotesen att O 1j följer den2.2.5 The logrank test (or the Mantel-Haenszel test or the Mantel-Cox test)Let j = 1, ..., J be the distinct times ofobserved events in either group. For each timej, let N 1j and N 2j be the number of subjects "atrisk" (have not yet had an event or beencensored) at the start of period j in the groupsrespectively. Let N j = N 1j + N 2j . Let O 1j and O 2jbe the observed number of events in the groupsrespectively at time j, and define O j = O 1j + O 2j .Given that O j events happened across bothgroups at time j, under the null hypothesis O 1j15

hypergeometriska fördelningen med parametrarN j , N 1j , och O j . Den här fördelningen harförväntat värdeN1jEj Ojoch variansenNVjOj1 j1 j/ Nj1N1jN / N N O Nj1Logrank-teststatistikan jämför varje O 1j meddess förväntade värde E j under nollhypotesenoch definieras somZ Jj1O1 jJj1 EVjjOm båda grupper har sammaöverlevnadsfunktion så följer logrankteststatistikanapproximativt denstandardiserade normalfördelningen. Vid ettenkelsidigt test på α-nivån förkastasnollhypotesen om Z > den övre α:te quartilen iden standardiserade normalfördelningen.jjjfollows the hypergeometric distribution withparameters N j , N 1j , and O j . This distribution hasexpected valueN1jEj Ojand varianceNVjOj1 j1 j/ Nj1N1jN / N N O N1The logrank statistic compares each O 1j to itsexpectation E j under the null hypothesis and isdefined asZ Jj1O1 jJj1 EVjjIf the two groups have the same survivalfunction, the logrank statistic is approximatelystandard normal. A one-sided level α test willreject the null hypothesis if Z > the upper αquantile of the standard normal distribution.jjjj16

3.1 Resultat - översiktUnder tidsperioden 1.1.1984 – 31.12.2010diagnosticerades 7 065 barn (

ändra detta mönster.Figur 3.1.5 och Tabell 3.1.1 visarålderfördelningen vid uppföljningen föralla levande patienter totalt och uppdelatefter diagnosgrupper.Figure 3.1.1 and Table 3.1.1 show the agedistribution at follow up among survivingpatients in all and subdivided intodiagnostic subgroups.18

Distribution of childhood malignancies in Sweden diagnosed 1984-2010< 15 years of age at diagnosis (n= 7 065)Figure 3.1.1. The diagnoses are stratified according to the WHO ICCC3 classification from2005. Leukaemias, CNS-tumours and Lymphomas constitute 70% of the children and the othernine diagnoses account for 30%.19

Age distribution by diagnosis in childhood malignancies< 15 years of age at diagnosis (n= 7 065)Figure 3.1.2.90807060504030201000 1 2 3 4 5 6 7 8 9 10 11 12 13 14VIII-BonetumorsXI-OthercarcinomasIX-Soft tissuesarcomaX-Germ cellstumorsVII-LivertumoursFigure 3.1.3.Age at diagnosis20

Estimated5 yrs Survival (%)100HodgkinALL80NHLNephroblastomaCNS tumors60NeuroblastomaBone tumors40RhabdomyosarkomaAML200ChemotherapyIrradiationSurgeryFigure 3.1.4. The estimated prognosis (5-years survival) over time for selected diagnosticgroups. The prognosis improved considerably during time period 1970-1995. The resultsduring the last decades seem to have reached a plateau, although neuroblastoma and CNStumoursseem to have a continued improved 5-years survival.21

1200Leukemias Solid tumors CNS tumors10008006004002000< 10 years 10-

198419851986198719881989199019911992199319941995199619971998199920002001200220032004200520062007200820092010Number of patients diagnosed per year350300250200150100500Diagnosis -YearAge at diagnosis < 15 yearsAge at diagnosis >= 15 yearsFig 3.1.6. All reported patients annually 1984-201023

3.2.1 Alla maligniteterDen genomsnittliga årliga incidensen förall form av barncancer under tidsperioden1984-2010 var 16,0 fall/100 000 barn < 15år vid diagnos, 16,9 för pojkar och 15,0för flickor. (Appendix 1.1).Ingen signifikant incidensökning har skettunder tidsperioden.Könsfördelningen visar att fler pojkar änflickor insjuknar i cancer med ett M/FRatio = 1.17. Vidare framgår att cancer ärvanligast under de 5-6 första levnadsåren.Överlevnaden har ökat signifikant efter1990 vilket framgår av figur 3.2.1.1.Det är ingen skillnad i överlevnad mellanpojkar och flickor och prognosen för olikaåldersgrupper är lika med undantag avbarn>= 10 år vid diagnos som har sämreprognos än övriga ålders grupper.(Fig 3.2.1.2)Figur 3.2.1.3 visar motsvarandeanalysresultat för leukemier.Figur 3.2.1.4 visar översiktliga resultat försolida tumörer sammanslagna ochfigur 3.2.1.5 motsvarande för CNStumörer.3.2.1 All malignanciesThe mean annual incidence rate for thewhole group of childhood cancer diagnosed1984 through 2010 was 16,0 cases/100 000children < 15 years of age at diagnosis,16,9 for boys and 15,0 for girls. (Appendix1.1).No significant increase of incidence hasoccurred during the time period.The age-and sex-distribution shows thatcancer is more common among boys with aM/F Ratio = 1.17. Furthermore, cancer ismost common in children aged 5-6 yearsat diagnosis.The survival figures have increasedsignificantly after 1990 which is shown inadjoining life table in figure 3.2.1.1.There is no difference in prognosis betweenboys and girls and the prognosis is equalfor different age groups except for children>= 10 years of age who have an inferiorprognosis. (Fig 3.2.1.2).Fig 3.2.1.3 shows the correspondinganalyses for all leukemia.Figure 3.2.1.4 shows the survey analysesfor solid tumours and figure 3.2.1.5 thecorresponding results for CNS tumours.24

Fig 3.2.1.1.All Malignancies in Sweden 1984-2010.Selected criteria Total numbers of children: 7 065Number/Relative frequency 7 065= 100 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution.Number Alive Dead % Alive3 805 2 950 856 77,53 260 2 523 736 77,41.177762 5961 8161 877585 191 75,42 049 547 78,91 407 409 77,51 432 445 76,3Survival probability at 10 years by years of diagnosis.0.83 (n=1 296) 2006-2010 (5-yrs)0.79 (n=1 344) 2001-20050.79 (n=1 391) 1996-20000.79 (n=1 330) 1991-19950.72 (n=1 704) 1984-1990p< 0.01The prognosis has improved significantly after 1990. Nosignificant difference during later time periods.25

Fig 3.2.1.2.All Malignancies in Sweden 1984-2010 (continued).Total numbers of children: 7 065Survival probability at 10 and 20 years by genderSurvival probability at 20 years by age0.77 to 0.75 (n=3 260) Females0.78 to 0.75 (n=3 805) Males0.77 (n=2 596) 1-

Fig 3.2.1.3.All Leukemias diagnosed 1984-2010.Selected criteria Total number of children:2 109Relative frequency 2 109/7 065= 29.9 %Survival probability at 10 and 20 years. Subdiagnosis.SubdiagnosisALLANLLOthersBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution.Number1 741315531 1509591.201221 034545408Alive Dead % Alive1 422 319 81,7179 136 56,830 23 56,6897 253 78,0734 225 76,562 60 50,8863 171 83,5433 112 79,4273 135 66,90.81 to 0.79 (n=1 741) ALL0.56 to 0.54 (n= 315) AML0.54 to 0.39 (n= 53) Othersp overall

Fig 3.2.1.4.All Solid tumors diagnosed 1984-2010Selected criteria Total number of children: 3 011Relative frequency 3 011/7 065=42.6 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution.Number Alive Dead % Alive1 637 1 305 332 79,71 374 1 115 259 81,11.19542959637873455 87 83,9753 206 78,5517 120 81,2695 178 79,6Survival probability at 10 years0.84 (n=534) 2006-2010 (5-yrs)0.81 (n=568) 2001-20050.82 (n=597) 1996-20000.82 (n=583) 1991-19950.76 (n=729) 1984-1990p overall =0.0128

Fig 3.2.1.5.All CNS tumors diagnosed 1984-2010Selected criteria Total number of children: 1 945Relative frequency 1 945/7 065=27.5 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution.Number Alive Dead % Alive1 019 748 271 73,4926 674 252 72,81.1011260363459668 44 60,5433 170 71,8457 177 72,1464 132 77,9Survival probability at 10 years0.81 (n=359) 2006-2010 (5-yrs)0.76 (n=356) 2001-20050.73 (n=363) 1996-20000.76 (n=378) 1991-19950.68 (n=489) 1984-1990p=0.0329

3.3.1.1 Leukemi- ALLDen genomsnittliga årliga incidensen församtliga leukemier under tidsperioden1984-2010 var 5,0/100 000 barn < 15 årvid diagnos, 5,4 för pojkar och 4,6 förflickor.Motsvarande incidenssiffra för ALLpatienter var 4,2/100 000 barn.Incidensen har en topp i gruppen 1-

Fig 3.3.1.1I a. Acute lymphoblastic leukemia. Diagnosed 1984-2010Selected criteria Total number of children:1 741Relative frequency 1 741/7 065= 24.6 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsNumber Alive Dead % Alive974 798 176 81,9767 624 143 81,41.266689947030631 35 47,0786 113 87,4388 82 82,6217 89 70,9Survival probability at 10 years by years of diagnosis0.88 (n=320) 2006-2010 (at 5 years)0.82 (n=341) 2001-20050.85 (n= 49) 1996-20000.84 (n=311) 1991-19950.74 (n=420) 1984-1990p

3.3.1.2 Leukemi- AMLIncidensen för AML patienter var0,7/100 000 barn.Sjukdomen är vanligast under de tvåförsta levnadsåren med övervikt förflickor.Prognosförbättringen vid AML har somvid ALL varit dramatisk men inträffade ca10 år efter genombrottet vid ALL.AML hör fortfarande till gruppen av barnmed en allvarlig prognos.Förbättringen av prognosen sammanfallermed införande av gemensamma Nordiskabehandlingsprotokoll 1984. Dessa harsenare reviderats vid flertal tillfällen.Ett fynd som tidigt iakttogs vid AML varatt 10-15% av barnen som insjuknade varbarn med Mb Down som även visade sigha en mycket god prognos om debehandlades adekvat.AML resultaten på Nordisk nivå harpublicerats vid flertal tillfällen - seReferenser.3.3.1.2 Leukemia - AMLThe incidence rate for AML patients was0,7/100 000 children.The disease has the highest frequencyduring the first two years of life.The improved prognosis in AML has likein ALL has been dramatic but occurredsome 10 years later after the ALLbreakthrough. Children with AML stillbelong to the group of children with aserious prognosis.The improvement of prognosis coincideswith introduction of common Nordictreatment protocols in 1984. The protocolshave been modified at several time points.A special feature which was earlyrecognized in AML was that 10-15 % ofthe children were children with Mb Down.These children had an excellent prognosisif they received an adequately treatment.The Nordic AML results have beenpublished in several papers- SeeReferences.32

Fig 3.3.1.2I b.Acute non-lymphoblastic leukemiaDiagnosed 1984-2010.Selected criteria Total number of children: 315Relative frequency 315/7 065= 4.5 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsNumber Alive Dead % Alive144 84 60 58,3171 95 76 55,60.8549117698029 20 59,268 49 58,140 29 58,042 38 52,5Survival probability by diagnostic period0.60 (n=68) 2006-2010 (at 5 years)0.60 (n=65) 2001-2005 (at 10 years)0.60 (n=68) 1996-2000 (at 15 yrs)0.59 (n=49) 1991-1995 (at 20 years)0.33 (n=65) 1984-1990 (at 20 years)Age- and sexdistribution.33

3.3.1.3 Andra former av leukemi53 barn utgör en liten grupp medvarierande diagnoser (JMML, CMML,MDS).Dessa barn har en allvarlig prognos ochendast 23/53 (43 %) var i livet vid senasteuppföljningen.3.3.1.3 Other leukemias53 children constitute a small group withdifferent diagnoses (JMML, CMML,MDS).These children have a serious prognosisand only 23/53 (43%) were alive at lastfollow up.Fig 3.3.1.3Ic.Other mixed formsDiagnosed 1984-2010Selected criteria Total number of children: 53Relative frequency 53/7 065= < 0.1 %CML,JMMLMDSBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsNumber Alive Dead % Alive40 21 19 52,513 9 4 69,232211.571862215 17 46,915 6 71,42 5 28,69 9 50,05 1 83,314 8 63,6Age- and sexdistribution.34

3.3.2 LymfomDen genomsnittliga årliga incidensen förLymfom under tidsperioden 1984-2010var 2,0 fall/100 000 barn < 15 år viddiagnos, 2,6 för pojkar och 1,3 för flickor.(Appendix 1.1.)Motsvarande incidenser vid Hodgkinssjukdom var 0,5/100 000, vid Non-Hodgkins lymfom (NHL) 0,8 vidBurkitt’s lymfom 0,2 och för gruppenhistiocytoser 0,5/100 000 barn.Vid Hodgkins sjukdom ökar incidensenmed stigande ålder. På grund av de högaöverlevnadssiffrorna vid Hodgkinssjukdom (95 %) inriktas framtidaprotokoll på att reducerabehandlingsintensiteten för att reduceralångsiktiga biverkningar från framför alltstrålbehandlingen.Behandlingen av barn med NHL harframgångsrikt samordnats på Nordisk nivåmed gemensamma behandlingsrekommendationeroch uppföljningar avutfall. Prognosen har successivt förbättratsefter 1990. På senare år har Sverigeanslutit sig till fr a tyskabehandlingsstudier.Gruppen histiocytoser består av en mycketliten grupp patienter hemofagocyterandelymfhistiocytos (HLH) med mycketallvarlig prognos och en till antalet heltdominerande grupp av patienter medLangerhans cell histiocytos (LCH) - medmycket bättre prognos. Sistnämndapatientgrupp exkluderas i vissa rapporterom cancer och redovisas separat, men ärinkluderade i denna rapport.3.3.2 LymphomasThe mean annual incidence rate for alllymphomas diagnosed 1984 through 2010was 2,0 cases/100 000 children < 15 yearsof age at diagnosis, 2,6 for boys and 1,3for girls. (Appendix 1.1).Corresponding incidence rates were forHodgkin’s disease 0,4, for Non-Hodgkin’slymphoma 0,8 for Burkitt’s lymphoma 0,2and for the group histiocytosis 0,5/100000 children.The incidence rates for Hodgkin’s diseaseincrease with increasing ages. Due to thehigh survival figures for Hodgkin’sdisease (95 %), future protocols have theintention to reduce the treatment intensityin order to reduce long time side effectsespecially from irradiation.The treatment of children with NHL hasbeen coordinated with common Nordicprotocol recommendations and survivalanalyses. The prognosis in NHL hasimproved since 1990. In later years,Sweden has joined and treated the patientsaccording to German protocols.The histiocytoses consist of a smallergroup of patients: hemophagocytic lymphhistiocytosis (HLH) with a very seriousprognosis and the larger group of patientswith Langerhan’s cell histiocytosis (LCH)- with much better prognosis. Thesepatients are sometime excluded fromanalyses of cancer materials and arereported separately, but are included in thepresent compilation.35

Fig 3.3.2 Group II. Lymphomas and reticuloendothelialneoplasms. Diagnosed 1984-2010Selected criteria Total number of children: 848Relative frequency 848/7 065 = 12.0%Number Alive Dead % AliveDiagnosisHodgkin’sNon-Hodgkin’sBurkitt’sHistiocytosis (LCH/HLH)BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs218309702515652832.064196257331207 11 95,0242 67 78,364 6 91,4226 25 90,0488 77 86,4251 32 88,753 11 82,8164 32 83,7229 28 89,1293 38 88,5Survival probability at 20 years0.92 (n=218) Hodgkin’s0.89 (n= 70) Burkitt’s0.89 (n=251) Histiocytosis0.75 (n=309) NHLAge- and sex distribution36

Fig 3.3.2.1Group IIa. Hodgkin’s disease. Diagnosed 1984-2010Selected criteria Total number of children: 218Relative frequency 218/7 065 = 3.1 %Number Alive Dead % AliveBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs136821.701351154129 7 94,978 4 95,112 1 92,348 3 94,1147 7 95,5Survival probability at 20 years- PAD1.00 (n= 12) Hodgkin’s UNS0.96 (n= 35) Mixed cellularity0.94 (n= 37) Lymhocytic predominance0.90 (n=134) Nodular sclerosisAge- and sexdistributionSurvival probability at 10 years by diagnostic period1.00 (n= 38) 2006-2010 (at 5 years)0.97 (n= 33) 2001-20050.96 (n= 61) 1984-19900.96 (n= 37) 1991-19950.94 (n= 49) 1996-200037

Fig 3.3.2.2Group IIb.Non-Hodgkin’s diseaseDiagnosed 1984-2010Selected criteria Total number of children: 309Relative frequency 309/7 065= 4.4 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsNumber Alive Dead % Alive219 172 47 78,590 70 20 77,82.47711161153 4 42,954 17 76,195 21 81,990 25 78,3Survival probability at 10 years by diagnostic period0.87 (n= 55) 2006-2010 (at 5 years)0.80 (n= 50) 2001-20050.80 (n= 60) 1996-20000.80 (n= 67) 1991-19950.73 (n= 77) 1984-1990Age- and sexdistributionSurvival probability at 20 years by PAD1.00 (n= 5) Mature T/NK (at 10 years)0.84 (n= 14) Mature B-ALL (at 15 years)0.80 (n=105) Mature B-cell (except Burkitt)0.79 (n= 36) LCAL0.73 (n=115) Precursor cell0.55 (n= 34) NHL-UNS38

Fig 3.3.2.3Group IIc. Burkitt’s lymphomas diagnosed 1984-2010Selected criteria Total number of children: 70Relative frequency 70/7 065= 1.0 %Number Alive Dead % AliveBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs57134.4012362253 4 93,011 2 84,612 0 10035 1 97,217 5 77,3Survival probability at 10 years by diagnostic period0.97 (n= 26) 1991-20000.92 (n= 12) 1984-19900.88 (n= 32) 2001-2010Age- and sexdistributionp = 0.839

Fig 3.3.2.4Group IId. Histiocytosis. Diagnosed 1984-2010Selected criteria Total number of children: 251Relative frequency 251/7 065= 3,6 %Number Alive Dead % AliveLCH238 221 17 92,9HLHBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs13153981.65710054405 8 38,5134 19 87,692 6 93,950 7 87,786 14 86,051 3 94,439 1 97,5Survival probability at 5 and 20 years.0.93 (n=238) LCH0.38 (n= 13) HLHAge- and sexdistribution40

3.3.3 CNS tumörerDen genomsnittliga årliga incidensen förCNS-tumörer under tidsperioden 1984-2010 var 4,6 fall/100 000 barn < 15 år viddiagnos, 4,7 för pojkar och 4,5 för flickor.Incidensen har varit stabil under helatidsperioden vid analys av gruppen somhelhet. Åldersfördelningen vid CNStumörerär relativt jämnt fördelad utannågon påtaglig incidenstopp.(Appendix1.1)Figur 3.3.3 visar översiktligt alla CNStumörerindelade i undergrupper.Prognoserna skiljer sig avsevärt mellan deolika undergrupperna med skillnader iöverlevnadssiffror mellan 40-80 %. Vidareframkommer i överlevnadsfigurerna attsena dödsfall är relativt vanligtförekommande även 10-20 år efter diagnos.Detta skiljer sig från våra erfarenheter vidleukemier och merparten av solida tumörerdär en klar majoritet av dödsfallen skerinom 10 år efter diagnos.Prognosen över tiden har dock förbättratsöver hela tidsperioden.På följande sidor visas resultaten för barnmed CNS-tumörer.Fig. 3.3.3.2 visar de markant olikaöverlevnadsresultaten för undergruppernaav astrocytom.I fig. 3.3.3.3.2 framkommer att prognosenför barn med embryonala CNS-tumörerunder perioden 1984-1990 tycks vara bättreän under senare perioder vilket möjligenkan förklaras med att högre stråldoser gavsunder den tidigare tidsperioden. Flickornaär färre, men har bättre prognos vid dennatumörtyp.I fig. 3.3.3.4 ingår som undergruppoligodendrogliom och patienter medponsgliom med en i de flesta fall fatalutgång.Fig. 3.3.3.5 visar prognos för olika tumöreri denna grupp, bland annat kraniofaryngeom.3.3.3 CNS tumoursThe mean annual incidence rate for CNStumoursdiagnosed 1984 through 2010 was4,6 cases/100 000 children < 15 years ofage at diagnosis, 4,7 for boys and 4,5 forgirls. The incidence rates have been stabileduring the study period for the whole groupof patients. The age distribution in CNStumourshas a relatively even distributionwithout evident peaks (Appendix 1.1).Figure 3.3.3 shows an overview of allCNS-tumours classified into subgroups.The different diagnoses have markeddifferences in survival figures fluctuatingbetween 40-80%.Late deaths even after 10-20 years fromdiagnosis occur in a relative high frequencyamong CNS-tumour patients. This is incontrast with our experiences fromleukaemias and most solid tumours where aclear majority of the deaths occur within 10years after diagnosis.Anyhow, the prognosis over time hasimproved.The results for the different sub diagnosesof CNS-tumours are shown in thefollowing pages.Fig 3.3.3.2 shows the highly differentsurvival figures for the subgroups ofastrocytomas.Figure 3.3.3.3.2 shows that the prognosisfor children diagnosed with EmbryonalCNS-tumours during the time period 1984-1990 seems to be better compared to lateryears, which may be explained by higherradiation doses given during this earliertime period. Girls are fewer but have betterprognosis for this group of tumours.Figure 3.3.3.4 illustrates the survival forpatients with oligodendrogliomas andpatients with pontine gliomas who have adismal outcome in most cases.Figure 3.3.3.5 shows prognosis fordifferent types of tumours in this group,inter alia for craniopharyngeomas.41

Fig 3.3.3Group III. Intracranial/intraspinal neoplasms 1984-2010.Selected criteria Total number of children: 1 945/ 7 065Relative frequency 1 945/7 065 =27.5 %Subdiagnosisa. Ependymomab. Astrocytomac. Embryonal tumourd. Other gliomase. Others specifiedf. Others nonspec.BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistributionNumber1858533722032825010199261.1112603634596Alive Dead %Alive130 55 70,3702 151 82,3208 164 55,993 110 45,8252 30 89,437 13 74,0748 271 73,4674 252 72,868 44 60,7433 170 71,8457 177 72,1464 132 77,9Survival probability at 20 years- WHO group─ 0.86 (n=282) Other specified-- 0.80 (n=853) Astrocytoma─ 0.73 (n= 50) Others-not specified- -0.66 (n=185) Ependymoma- -0.52 (n=372) PNET/Medulloblastom─ 0.43 (n=203) Other gliomasSurvival probability at 10 years by diagnostic period0.81 (n=359) 2006-2010 (at 5 years)0.76 (n=356) 2001-20050.76 (n=378) 1991-19950.73 (n=363) 1996-20000.68 (n=489) 1984-199042

Fig 3.3.3.1Group IIIa. Ependymoma. Diagnosed 1984-2010Selected criteria Total number of children: 185Relative frequency 185/7 065 =2,6 %Number Alive Dead % AliveEpendymoma149 97 52 65,1Plexus choroideusBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution3695901.12471504033 3 91,767 28 70,563 27 70,018 6 75,039 32 54,938 12 76,035 5 87,5Survival probability at 20 years0.91 (n= 36) Plexus choroideus0.59 (n=149) Ependymomap

Fig 3.3.3.2Group IIIb. Astrocytoma. Diagnosed 1984-2010.Selected criteria Total number of children: 660Relative frequency 853/7 065 =12,1 %Number Alive Dead % AliveAstrocytoma-lowAstrocytoma-highOptic/hypothalamicBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs6011031494294241.0137268264284540 61 89,930 73 29,1132 17 88,6361 68 84,1341 83 80,423 14 62,2231 37 86,2219 45 83,0229 55 80,6Survival probability at 20 years0.85 (n=601) Astrocytoma-low0.83 (n=149) Optic/hypothalamic0.25 (n=103) Astrocytoma-highp

Fig 3.3.3.3.1Group IIIc.Embryonal tumours.Diagnosed 1984-2010.Selected criteria. Total number of children: 372Relative frequency 372/7 065 =5,3 %MedulloblastomaPNETAT/RTMedulloepitheliomaBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsInfratentoriellSupratentoriellBrain stemSpinalUnknown loc.Number Alive Dead % Alive296 174 122 58,863 27 36 42,99 4 5 44,44 3 1 75,02161561.3822149135662426912544112 104 51,996 60 61,58 14 36,484 65 56,480 55 59,336 30 54,5142 100 58,728 41 40,64 8 33,31 4 20,033 11 75,0Age- and sex distributionSurvival probability at 20 years0.75 (n= 44) Unknown loc.0.53 (n=242) Infratentoriell0.35 (n= 69) Supratentoriell0.31 (n= 12) Brain stem0.30-0.0 (n= 5 ) Spinal45

Fig 3.3.3.3.2Group IIIc. Embryonal tumours (continued)Survival probability at 10 years by diagnostic period0.63 (n=64) 2006-2010 (at 5 years)0.63 (n=99) 1984-19900.56 (n=78) 2001-20050.52 (n=67) 1991-19950.50 (n=64) 1996-2000Survival probability at 20 yrs - Gender0.58 (n=156) Females0.47 (n=216) Malesp = 0.0546

Fig 3.3.3.4Group IIId. Other gliomasDiagnosed 1984-2010.Selected criteria Total number of children: 203Relative frequency 203/7 065 =2,8 %OligodendrogliomMixed and unspec gliomasNeuroepitelial glialoruncertain originBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge-and sexdistributionNumber Alive Dead % Alive41 31 10 24,3102 51 51 50,060 11 49 18,31031001.01647845637 37 50,027 47 63,511 5 68,824 23 51,131 53 36,927 29 48,2Survival probability at 20 years0.74 (n= 41) Oligodendrogliom0.47 (n=102) Mixed and unspec. gliomas0.13 (n= 60) Neuroepitelial glial-or uncertain originp < 0.0147

Fig 3.3.3.5Group IIIe+f. Others specified and unspecified neoplasms.Selected criteria Total number of children: 332Relative frequency 332/7 065 =4,7 %Number Alive Dead %AlivePituitary adenomas/carcinomasCraniopharyngeomaPineal parenchymal tumoursNeuronal and mixed neuronglialMeningeomasOther specifiedUnspecified intracranial/spinalBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge-and sexdistribution.1610626942614501761561.1136810115016 0 10094 12 88,720 6 76,986 8 91,522 4 84,614 0 10037 13 74,0153 23 86,9136 20 87,28 5 66,655 13 84,289 12 91,2137 13 91,2Survival probability at 20 years1.0 (n= 16) Other spec and Pituitary tumours0.91 (n= 94) Neuronal and mixed neuroglial0.82 to 0.73 (n=106) Craniopharyngeom0.83 to 0.55 (n= 26) Meningeom0.74 (n= 26) Pineal parenchymal0.73 (n= 50) Unspecified48

3.3.4 NeuroblastomDen genomsnittliga årliga incidensen förbarn med neuroblastom under tidsperioden1984-2010 var 0,7 fall/100 000 barn < 15år vid diagnos. Incidensen är högst underförsta levnadsåret för att sedan successivtsjunka med stigande ålder.Neuroblastom är vanligare hos pojkar medett M/F ratio på 1,22.Den viktigaste kliniska prognostiskafaktorn vid neuroblastom är ålder viddiagnos vilket klart framgår av figur 3.3.4.1med bättre överlevnad för barn

Fig 3.3.4.1Group IV.Symphatetic nervous system tumors.Diagnosed 1984-2010Selected criteria Total number of children: 389Relative frequency 389/7 065 = 5.5 %Number Alive Dead % AliveDiagnosesa. Neuroblastomb. OthersBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistribution378112141751.221511834213241 137 63,810 1 90,9131 83 61,2120 55 68,6122 29 80,899 84 54,121 21 50,09 4 69,2Neuroblastoma. Different age at diagnosis.Total number of children: 3780.80 (n=151) =10 yrs0.50 (n=180 ) 1-

Fig 3.3.4.2 (continued)Survival probability at 10 years by diagnostic period – all ages0.77 (n=63) 2006-2010 (at 5 years)0.71 (n=70) 2001-20050.60 (n=79) 1991-19950.59 (n=75) 1996-20000.55 (n=91) 1984-1990p=0.04The prognosis has improved over time, most pronounced after2001.51

3.3.5 RetinoblastomDen genomsnittliga årliga incidensen förretinoblastom under tidsperioden 1984-2010 var 0,25 fall/100 000 barn < 15 årvid diagnos. Sjukdomen är vanligastunder första levnadsåret för att däreftersnabbt sjunka i frekvens och är ovanlighos barn över 5 års ålder (5/153).Det är en svag övervikt av flickor med ettM/F Ratio=0.7.Av 153 barn hade 33 barn tumör i bådaögonen, hos 76 var ett öga engagerat och i44 fall saknades denna uppgift.Behandlingen av denna sjukdom harsedan många år varit centraliserad till ettsjukhus i Sverige.Prognosen för dessa barn är mycket godoch endast tre av barnen har hittillsrapporterats som avlidna.3.3.5 RetinoblastomaThe mean annual incidence rate forchildren with retinoblastoma diagnosed1984 through 2010 was 0,25 cases/100 000children < 15 years of age at diagnosis. Theincidence rate is highest during the firstyear of life with decreasing incidence withincreasing age and is a rarity in childrenmore than 5 years of age. (5/153).There is a slight overweight of girls with aM/F Ratio = 0.7.Of 153 children the disease was bilateral in33 children, unilateral in 76 children and in44 this information was missing.The treatment of this disease has sincemany years been centralized to one hospitalin Sweden.The prognosis for these children is verygood and only three children have so farbeen reported as deceased.52

Fig 3.3.5Group V. Retinoblastoma. Diagnosed 1984-2010.Selected criteria Total number of children: 153Relative frequency 153/7065= 2,2 %BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsUnilateralBilateralUnknownNumber62910.7697941763344Alive Dead % Alive61 1 98,489 2 97,867 2 97,178 1 98,74 0 1001 0 10075 1 98,732 1 97,043 1 97,7Survival probability at 20 years0.97 (n=153)Age- and sexdistribution53

3.3.6 NjurtumörerDen genomsnittliga årliga incidensen förnjurtumörer under tidsperioden 1984-2010var 0,9 fall/100 000 barn < 15 år viddiagnos med högst incidens < 5 års åldervid diagnos. (Appendix 1.1).Åldern är en prognostisk faktor vid dennatumörform med sämre prognos för äldrebarn. (Fig 3.3.6.2).Gruppen utgörs till största delen av Wilmstumörer med en historiskt sett godprognos. Dessa barn har under många årmed stor framgång behandlats enligtprotokoll i SIOP:s regi. Tidigt uppnåddeshöga överlevnadssiffror vilket ledde till attman under strikt kontrollerade former harkunnat reducera behandlingen.Detta kan vara anledningen till de någotlägre överlevnadskurvorna under senaretidsperioder.(Fig 3.3.6.2).3.3.6 Renal tumoursThe mean annual incidence rate forchildren with renal tumours diagnosed1984 through 2010 was 0,9 cases/100 000children < 15 years of age at diagnosis.(Appendix 1.1).Age is a prognostic factor among thesechildren with worse prognosis for olderchildren (Fig 3.3.6.2).The group of patients consists mainly ofpatients with Wilms’ tumour who have hada good prognosis. The children have sincemany years been treated according to SIOP– protocols. Good survival figures wereestablished early which has led to asuccessive reduction of treatment durationand intensity in the protocols under strictlycontrolled forms. This may explain theslight decrease in the survival during latertime periods. (Fig 3.3.6.2).54

Fig 3.3.6.1Group VI. Renal tumours. Diagnosed 1984-2010Selected criteria Number of children: 407Relative frequency 407/7 065= 5,8 %Number Alive Dead %AliveDiagnosis:Wilms’400 338 62 84,5Renal Carcinoma7 6 1 86,0BoysGirlsRatio boys/girls0 < 1 year1-4 yrs5-9 yrs10-14 yrs2002070.9792456914171 29 85,5173 34 83,668 11 86,1213 32 86,953 16 76,810 4 71,4The tumors were further sub classified into 4 groups in 35patients.Alive Dead TotalVIa1. Nephroblastoma-UNS 314 51 365VIa2. Rhabdoid renal tumors 1 7 8VIa3. Kidney sarcomas (CCSK) 8 2 10VIa4. pPNET of kidney 2 2 4VIa5. Mesoblastiskt nephrom (GG) 13 0 13VIb. Renal carcinomas 6 1 7Total 344 63 407Age- and sexdistribution.55

Fig 3.3.6.2 (continued)Survival probability at 10 years by diagnostic period0.90 (n=84) 1991-19950.89 (n=65) 1996-20000.81 (n=102) 1984-19900.80 (n=76) 2001-20050.85 (n=80) 2006-2010 ( at 5 yrs)Survival probability at 20 years- Age at diagnosis0.87 (n=245) 1-

3.3.6 LevertumörerDen genomsnittliga årliga incidensen förlevertumörer under tidsperioden 1984-2010 var 0,2 fall/100 000 barn < 15 år viddiagnos. Denna ovanliga tumör ärvanligast förekommande under de förstatvå levnadsåren.Hepatoblastom utgör flertalet inom dennatumörgrupp och bland dessa barn har detskett en signifikant prognosförbättringöver tiden. (Figur 3.3.7)Orsaker till förbättringen står att finna iförbättrade och standardiseradestadieindelnings och handläggningskriterier, förfinade kirurgiska metoderkombinerat med effektivarecytostatikabehandling.3.3.7 Hepatic tumoursThe mean annual incidence rate forchildren with hepatic tumours diagnosed1984 through 2010 was 0,2 cases/100 000children < 15 years of age at diagnosis. Theincidence rate is highest during the firsttwo years of life with decreasing incidencewith increasing age.Hepatoblastoma constitute the majority ofpatients within this diagnostic group andthe prognosis among these children hasimproved significantly over time.(Fig 3.3.7)The reasons for the improved results arestandardized staging and management ofthese patients, refined surgical techniquesin combination with more effectivechemotherapeutic treatment.57

Fig 3.3.7Group VII. Hepatic tumours. Diagnosed 1984-2010Selected criteria Total number of children: 91Relative frequency 91/7 065= 0,1 %Diagnosesa. Hepatoblastomab. Hepatic carcinomac. OthersBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sex-distributionNumber789456351.63343105Alive Dead % Alive64 14 82,14 5 44,42 2 50,042 14 75,028 7 80,027 6 81,832 11 74,47 3 70,04 1 80,0Survival probability at 10 years by diagnostic period.0.88 (n=34) 2001-20100.74 (n=34) 1991-20000.70 (n=23) 1984-1990p overall=0.1Survival probability at 20 years- Age at diagnosis0.81 (n=33) < 12 months0.80 (n=10) 12 - < 18 months0.35 (n=33) 18 months - < 5 years0.65 (n=15) ≥ 5 years58

3.3.8 BentumörerDen genomsnittliga årliga incidensen förbarn med bentumörer under tidsperioden1984-2010 var 0,6 fall/100 000 barn < 15år vid diagnos. Incidensen ökar medstigande ålder och bland barnen ärbentumörer vanligast i tonåren. Gruppenbestår av två huvudgrupper - osteosarkomoch Ewings sarkom. Särskilt osteosarkomblir mycket vanligare under pubertetenstillväxtspurt än i de yngre åldrarna (Fig3.3.8.1).Behandlingen består ofta av enkombination av kirurgi och kemoterapimed hög intensitet samt ibland strålning fra för Ewings sarkom. Prognosen har intesignifikant förbättrats sedan 1990, men entendens till fortsatt förbättring kan skönjasfr a för Ewings sarkom (Fig 3.3.8.2).3.3.8 Bone tumoursThe mean annual incidence rate forchildren with bone tumours diagnosed1984 through 2010 was 0,6 cases/100 000children < 15 years of age at diagnosis. Theincidence rate increases with increasing ageand is most common among teenagers.The diagnostic group consists of two maindiagnoses- osteosarcoma and Ewing’ssarcoma. In particular osteosarcomabecomes much more common during thegrowth velocity peak of puberty comparedto younger ages (Fig 3.3.8.1).The children are mostly treated with acombination of surgery and intensivechemotherapy and sometimes radiation,particularly for Ewing’s sarcoma. Theprognosis has not improved significantlysince 1990, but a slight improvement maybe seen in Ewing’s sarcoma (Fig 3.3.8.2).59

Fig 3.3.8.1Group VIII. Malignant bone tumors. Diagnosed 1984-2010Selected criteria Total number of children:257Relative frequency 257/7 065= 3,6 %Number Alive Dead %AliveAge- and sex distribution- Ewing’sDiagnosesOsteosarcomaChondrosarcomaEwing’s sarcomaOthersBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrs1327107111291281.04217315987 45 65,96 1 85,767 32 62,69 2 81,880 49 62,089 39 69,54 0 10014 7 66,752 21 71,299 60 62,3Age- and sex distribution- OsteosarcomasMale/Female Ratio – Osteosarcoma 69/63 (Ratio 1.1)-“- Ewing’s 50/57 (Ratio 0.9)60

Fig 3.3.8.2 (continued)Survival probability at 10 years by diagnostic period.OsteosarcomaSurvival probability at 10 years- Years of diagnosisEwing’s0.70 (n=53) 1991-20000.63 (n=50) 2001-20100.48 (n=29) 1984-1990p=0.10.72 (n=49) 2001-20100.59 (n=34) 1991-20000.50 (n=24) 1984-1990p=0.3Survival probability at 10 years- GenderOsteosarcoma Diagnosed 2001-2010No difference between males-females among the Ewing’s.Older patients ≥ 10 years of age at diagnosis (both osteosarcomasand Ewing’s) have an inferior prognosis compared to youngerchildren. (See table)0.79 (n=23) Females0.51 (n=27) MalesThe difference in prognosis between genders has become moreevident during the last diagnostic period (figure to the left).p=0.0361

3.3.9 MjukdelstumörerDen genomsnittliga årliga incidensen förmjukdelstumörer under tidsperioden1984-2010 var 0,9 fall/100 000 barn < 15år vid diagnos.Gruppen består av tre större undergruppervarav majoriteten utgörs avrhabdomyosarkom. I denna diagnosgrupphar pojkarna en signifikant bättre prognosjämfört med flickor vilket är ett ovanligtfynd vid barncancer.Prognosen för hela gruppen har inteförbättrats under senare tidsperioder.Snarare tycks en viss försämring avprognosen ha inträffat. (Fig 3.3.9.2)En djupare analys av denna diagnosgruppoch prognosförändringen övertiden kommer att utföras av VSTBgruppen.3.3.9 Soft Tissue TumoursThe mean annual incidence rate forchildren with soft tissue tumours diagnosed1984 through 2010 was 0,9 cases/100 000children < 15 years of age at diagnosis.The diagnostic group consists of threemajor sub groups, the majority of whichare rhabdomyosarcoma. Boys have asuperior prognosis compared to girls in thisdiagnostic subgroup, which is an unusualfinding among childhood cancer patients.The prognosis has not improved during thelast time periods.Instead, a decrease in prognosis seems tohave occurred during the last decades (Fig3.3.9.2).A deeper analysis of this diagnostic groupand the change of prognosis will beperformed of the VSTB-group.62

Fig 3.3.9.1Group IX. Soft tissue sarcomas. Diagnosed 1984-2010Selected criteria Total number of children: 406Relative frequency 406/ 7 605= 5.7 %Diagnosesa. Rhabdomyosarcomab. Fibrosarcomasc. Kaposi sarcomad. Other soft tissue sarc.e. Unspec. soft tissue sarc.BoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsNumber2189119062291771.351117106132Alive Dead %Alive154 9 61,277 7 78,10 1 -62 28 68,95 1 ,3177 52 7,3121 56 68,433 18 64,785 32 72,686 20 81,294 38 71,2Sub - Diagnosesb1. Fibroblastic tumors2. Nerve sheet tumors3. Other fibromatous neo4. Acusticusneurinomd1. Ewing and Askim2. pPNET of soft tissue3. Extra renal4. Liposarcoma5. Fibrohistocytic6. Leiomyosarcoma7. Synovial sarcoma8. Blodd vessel tumors9. Misc soft tissue sarc.10. OthersNumber Alive Dead %Alive244313115211310421222122 2 91,733 10 76,711 2 84,611 0 1003 2 60,011 10 52,41 0 1002 1 66,79 1 90,03 1 75,017 4 81,02 0 10014 8 63,60 1 10063

Fig 3.3.9.2 (continued)Survival probability at 10 years by diagnostic period.Survival probability at 20 years. Sub-diagnoses.0.80 (n=75) 1996-20000.78 (n=76) 1991-19950.71 (n=83) 2001-20050.69 (n=90) 1984-19900.69 (n=82) 2006-2010 (at 5 yrs)0.82 (n= 91) Fibrosarcoma0.69 (n=218) Rhabdomyosarcoma0.61 (n= 90) Other soft tissue sarcomap= 0.01Survival probability at 20 years by gender.Children with fibrosarcomas have the best prognosis. The group –“other soft tissue sarcoma” is a very heterogeneous group withdifferent prognosis for different sub diagnoses.0.75 (n=229) Males0.64 (n=177) Femalesp< 0.01There is a significant difference in prognosis betweenmales and females. This is the case for the whole group and forthe three main subgroups.(left figure)For all Soft tissue tumours: The prognosis seems to have decreasedduring the last decade.64

3.3.10 GermcellstumörerDen genomsnittliga årliga incidensen förgermcellstumörer under tidsperioden1984-2010 var 0,6 fall/100 000 barn < 15år vid diagnos. De flesta barnen är < 1 årvid diagnos. M/F Ratio= 0.7.Gruppen är heterogen med tre störrehuvudgrupper:intrakraniella/intraspinala, non-gonadalaoch gonadala GC.Överlevnaden vid dessa tumörer äröverlag hög och överstiger 80 % medundantag av de intrakraniella/intraspinalaGC med en långtidsöverlevnad på drygt60 %.Barnen behandlas oftast efterinternationella protokoll.3.3.10 Germ cell tumoursThe mean annual incidence rate forchildren with germ cell tumoursdiagnosed 1984 through 2010 was 0,6cases/100 000 children < 15 years of ageat diagnosis. Most children are < 1 year ofage at diagnosis. M/F Ratio=0.7.This is a heterogeneous group with threemain sub groups: intracranial/intraspinal,non-gonadal and gonadal GC.The survival figures for these patients aregood and exceed 80 % except for theintracranial/intraspinal GC with a longterm survival rate of 60%.The children are mostly treated accordingto international protocols.65

Fig 3.3.10Group X. Germ cell tumors. Diagnosed 1984-2010Selected criteria Total number of children: 312Relative frequency 312/7 065= 4.4 %a.Intracran./intraspin. GCb.Non-gonadal GCc.Gonadal GCd.Gonadal carcinomae.Other and unspec GCBoysGirlsRatio boys/girls< 1 year1-4 yrs5-9 yrs10-14 yrsAge- and sexdistributionNumber50791712101331790.7856256109Alive Dead %Alive34 16 68,071 8 89,9160 11 93,61 1 50,09 1 90,0116 17 87,2159 20 91,376 9 89,457 5 91,946 10 82,196 13 88,7Survival probability at 10 years0.96 (n=52) 2006-2010 ( at 5 yrs)0.96 (n=47) 2001-20050.89 (n=66) 1991-19950.88 (n=69) 1996-20000.82 (n=78) 1984-1990Survival probability at 20 yearsp= 0.080.93 (n=171 Gonadal GC tumors0.88 (n=79) Non-gonadal GC tumors0.62 (n=50) Intracranial/intraspinal GC tumorsp

3.3.11 CarcinomDen genomsnittliga årliga incidensen förgruppen carcinom under tidsperioden1984-2010 var 0,3 fall/100 000 barn < 15år vid diagnos. Sjukdomen drabbarfrämst barn över 10 år och är vanligarebland flickor.Gruppen är en till antalet liten gruppbestående av 137 patienter med skiftandelokalisation av tumörerna.Prognosen för patienterna i denna gruppligger på drygt 80 % och har inteförändrats över tiden.3.3.11 CarcinomaThe mean annual incidence rate forchildren with soft tissue tumours diagnosed1984 through 2005 was 0,2 cases/100 000children < 15 years of age at diagnosis andmore often girls. Most children are morethan 10 years of age at diagnosisThis diagnostic group is small and containsonly 72 patients with different localizationsof the tumours.The children in this group have a goodprognosis exceeding 80 % which has notchanged over time.3.3.12 Andra och ospecificerademaligniteterGruppen utgörs av 11 barn med tumörerdär närmare klassifikation av tumöreninte varit möjlig eller saknas.8 av de 11 barnen levde vid uppföljning.3.3.12 Others and unspecified malignantneoplasmsThis group consists of 11 children withtumours where detailed classification of thetumours has not been possible or ismissing.8 out of 11 children were alive at followup.67

5. DiskussionCancer hos barn motsvarar mindre än 2 %av all cancer, men består av ett stort antalolika sjukdomar som signifikant skiljer sigfrån cancer hos unga och äldre vuxna (6).Cancer är fortfarande den sjukdom somorsakar flest dödsfall bland barn >1år iden rika delen av världen (7).Under de senaste 10 åren har ett flertalpublikationer redovisat incidens- ochöverlevnadssiffror avseende barn medcancer (< 15 år) från ett flertal länder.EUROCARE-3 har sammanställt data frånpopulationsbaserade cancer register i 20europeiska länder (8, 9) ochACCI (Automated Childhood CancerInformation) presenterade i septembernumret 2006 av Eur J Cancer ett flertalartiklar angående incidens- och översiffrorvid barncancer från 35 europeiska länderomfattande 50 000 barn med cancer(10, 11, 12).Svenska Cancerregistret har deltagit meddata till vissa av studierna. Genomgåenderesultat från dessa arbeten visar att det harskett en årlig incidensökning avbarncancer på cirka 1 % under de senaste4-5 decennierna vilket även gällt under detvå senaste decennierena (10, 11)Incidenssiffrorna varierar kraftigt mellanländer från 1,3/100 000 barn till 16,0 /100000 barn < 15 års ålder, den senare siffranhärrör från de Nordiska länderna. Medelincidensen ligger på 13,8 fall/100 000.Flera studier har visat en incidensökningunder senaste 30-40 åren (10, 11, 13, 14)vilket har förklarats med förbättraderegistreringar och känsligare diagnostiskametoder såsom immun histokemiskaanalyser, ultraljud, CT och MRI.I en publicerad studie från Japan fann manen stadigt ökande incidens från 1970-taletfram till slutet av 1980-talet varefter enminskning av incidensen inträffade (5).Detta fenomen förklarades inte av5. DiscussionAlthough childhood cancer represents lessthan 2% of human cancers, they arehistologically very diverse and differs intypes and distributions from those found inyoung and old adults (6). Cancer is still themost common cause of death from diseasein children older than 1 year (7).Several publications from various countrieshave reported incidence and survival forchildren

införandet av neuroblastom screening dåsamma trender observerades även efterexklusion av neuroblastomgruppen.Sammanställning av data ur det SvenskaBarn Cancer Registret visar att vi har enhög incidensen av barncancer i Sverigesom legat stabilt under hela tidsperioden1984 till 2010.Det har skett en successiv förbättring avprognosen av samtliga diagnoser avcancer sedan 1970-talet. (7, 8, 9, 12, 13,15). Det mest påtagliga genombrottet ägderum under 70-och 80 talen då behandlingintensifierades med kombinationer avkirurgi, strålning och cytostatika somalltmer kom att dominera de nyabehandlingsprotokollen. Den så kallade”Total Therapy” som infördes vidleukemibehandlingen under 70-talet leddetill snabbt ökade överlevnadssiffror fördenna tidigare undantagslöst fatalasjukdom.I en studie som redovisar barn med cancerfrån 20 europeiska länder diagnostiserade1990-94, visas att resultaten i de Nordiskaländerna har de högstaöverlevnadssiffrorna överlag samt i fyraav sju diagnoser som analyserats mer idetalj (njurtumörer, ALL, AML och CNStumörer)(7). Slutsatsen i artikeln blir att:”The Nordic countries represent a survivalgold standard to which other countries canaspire”. Även om ökad överlevnad oftakan kopplas till introduktion av nyaspecifika behandlingar betonas i en annaninternationell jämförelse just betydelsenav registrering och uppföljning avbehandlingsresultat så som det tidigtinfördes i det nordiska samarbetet (9).Behandlingsresultaten i Sverige har följtde internationella trenderna. Den mestpåtagliga prognosförbättringen skeddeunder 1970- och 1980 talen med enökning av 5-års överlevnaden från ca 40incidence from the 1970s to the end of the1980s and then a decline (13). This findingwas not explained by the introduction ofscreening for neuroblastoma, since thesame pattern was observed even when thecases of neuroblastoma were excludedfrom the analysis.The compilation of data from the SwedishChildhood Cancer Registry shows thatSweden has a high incidence of childhoodcancer, which has been stable from 1984 to2010.There has been a gradual improvement ofthe outcome for all diagnoses of childhoodcancer since the 1970s (7, 8, 9, 12, 13, 15).The most prominent breakthrough occurredin the 1970sand 1980s, when the therapy wasintensified with combinations of surgery,irradiation and chemotherapy as a part ofthe new treatment protocols. The “TotalTherapy” developed during the 1970s forthe treatment of Leukaemia led to quicklyincreasing survival for this until thenuniformly fatal disease.A study reporting results from thetreatment of children with cancerdiagnosed 1990-1994 from 20 Europeancountries showed the highest survival inthe Nordic countries, both overall and infour out of seven diagnoses analysed inmore detail (kidney tumours, ALL, AMLand CNS-tumours) (7). The conclusion ofthe paper was that: ”The Nordic countriesrepresent a survival gold standard to whichother countries can aspire”. Althoughimproved cancer survival often can belinked to the introduction of novel moreeffective treatments another internationalevaluation emphasised the importance ofregistration and evaluation of treatmentresults as it was early introduced in theNordic collaboration (9).70

% till ca 80 % med fortfarande relativtstora variationer mellan olikadiagnosgrupper (Fig 3.1.4).Sedan 1990 verkar prognosutvecklingenha planar ut och legat relativt konstant ilikhet med andra länder i västvärlden (7,16) men med några undantag. Prognosenför barn med neuroblastom har klartförbättrats sedan början av 2000-talet, ochdå särskilt för barn med den svårasteformen, högrisk-neuroblastom. Dettatorde kunna förklaras både med en ökadbiologisk förståelse av sjukdomens olikaformer och därigenom bättrehandläggning av patienterna, men ocksåmed en påtaglig intensifiering avbehandlingen, framförallt för barn medhögrisk form av sjukdomen där även nyabehandlingsmöjligheter introducerats.Prognosen för barn med hjärntumörer harockså fortsatt förbättrats de senastedecennierna troligen beroende på enkombination av förbättrad diagnostik ochbehandling inom ramen för ettmultidisciplinärt samarbete.Prognosen för barn med mjukdelssarkomvisar en trend till försämring under detsenaste decenniet. Orsakerna till dennaförändring är oklar varför en noggranngenomgång av denna patientgruppsdiagnostik och behandling har inletts.Den stora utmaningen för framtiden bliratt utarbeta nya behandlingsmetoder föratt bota fler barn men samtidigt reducerade toxiska långtidseffekterna av givenbehandling. Just utprövandet av nyabehandlingsformer kräver stora resurseroch ett nära samarbete mellan klinisk ochtranslationell forskning ofta i ett brettinternationellt samarbete (17).Nya strålbehandlingsmetoder kommer attbli tillgängliga inom en snar framtid,vilket kommer att medföra mer skonsambehandling särskilt vid behandling av barnmed CNS-tumörer.The treatment results in Sweden havemirrored the international trends. The mostpronounced improvement of the prognosisoccurred in the 1970s and 1980s with anincrease in the 5-year survival from about40% to around 80% with still relativelypronounced variation between differentdiagnostic groups (Fig 3.1.4).Since 1990 the prognosis has beenrelatively stable seemingly reaching aplateau similar to other countries (7, 16)but with a few exceptions. The outlook forchildren with neuroblastoma has improvedmarkedly from the beginning of the 21 stcentury, and then in particular for the worstsubset, with high-risk neuroblastoma. Thisis likely due to significant advances in thebiological understanding of the differentforms of neuroblastoma leading to a bettermanagement and stratification of thepatients, but also a substantialintensification of the treatment, mostly forchildren with high-risk disease andintroduction of several new treatmentmodalities.The prognosis for children with braintumours has also improved over the lastdecades, which probably is the result of acombination of improved diagnosticmeasures and treatment within theframework of a multi-disciplinarycollaboration.The outcome for children with soft tissuesarcomas shows a trend towards worseresults during the last ten years. The reasonfor this decline in prognosis is unclear anda thorough survey of the clinicalcharacteristics and treatment of this patientgroup has been started.The greatest challenge for the future will bethe preparation and implementation of newtreatment methods to cure more childrenwhile at the same time reducing the toxiclong-term side effects of the treatment. Thedevelopment of novel therapies requires71

Pågående långtidsuppföljningar somkartlägger livskvaliteten hos vuxna som ibarndomen genomgått behandling ochöverlevt en cancersjukdom får allt störrebetydelse. Drygt 850 av patienterna i BarnCancer Registret är idag 30 år eller äldre(Fig 3.1.6). Information från dessa studierkommer att utgöra viktiga komponentervid utarbetande av framtidabehandlingsprotokoll.Genom mer sofistikerade diagnostiskaanalysmetoder kommer behandlingen iframtiden att bli mer stratifierad ochanpassad till väl definierade grupper avpatienter och mer individualiserad förvissa patienter.Denna sammanställning presenterar detaktuella nuläget vid behandling av barnmed cancer i Sverige. Den framtidautvecklingen måste följas noggrant medåterkommande uppföljningar, men medfokus även inriktat på livskvalitet hos debarn som behandlats för cancer.extended resources and a close interplaybetween clinical and translational researchoften in extensive internationalcollaborative efforts (17).New methods for irradiation will beavailable soon, which will result in lesstoxic treatment, particularly for thetreatment of children with CNS-tumours.Ongoing long-term follow-up studiesfocusing on the quality of life of adultswho have survived treatment for cancerduring childhood will gain in importance.Slightly more than 850 patients in theSwedish Childhood Cancer Registry aremore than 30 years old today (fig 3.1.6).Information from these studies will addimportant components to the developmentof future treatment protocols. With the useof more sophisticated analytical methodsthe treatment will become more stratifiedand adapted to well defined sub-groups ofpatients and possibly even individualisedfor some patients. This compilationpresents the current situation for thetreatment of childhood cancer in Sweden.The future development must be followedclosely with repeated surveys, but with thefocus also directed towards quality of lifeof children treated for cancer.72

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Palle J, Frost BM, Forestier E, Gustafsson G, Nygren P, Hellebostad M, Jonsson OG, Kanerva J,Schmiegelow K, Larsson R, Lonnerholm G; on behalf of the Nordic Society for PaediatricHaematology and Oncology. Cellular drug sensitivity in MLL-rearranged childhood acuteleukaemia is correlated to partner genes and cell lineage.Br J Haematol. 2005 Apr;129(2):189-98.Schmiegelow K, Gustafsson G. Acute lymphoblastic leukemias. In: Cancer in children, clinicalmanagement, 5th edn. (ed. Voute PA, Barrett A, Stevens M, Caron H). Oxford University Press,London, 2005138-170.Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, Jonmundsson G, Mellander L,Siimes MA, Yssing M, Zeller B, Gustafsson G. Long-term results in children with AML:NOPHO-AML study group – report of three consecutive trials. Leukemia 2005; 19:2090-2100.Saarinen-Pihkala UM, Gustafsson G, Carlsen N, Flaegstad T, Glomstein A, Kristinsson J,Lanning M, Schroeder H, Mellander L on behalf of NOPHO. Outcome of children with high-riskacute lymphoblastic leukemia (HR-ALL): Nordic results on an intensive regimen with restrictedcentral nervous system irradiation. Ped Blood Cancer 2004; 1: 16-26.Frost BM, Forestier E, Gustafsson G, Nygren P, Hellebostad M, Jonsson OG, Kanerva J,Schmiegelow K, Larsson R, Lonnerholm G. Translocation t(12;21) is related to in vitro cellulardrug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia. Blood2004 Oct 15;104(8):2452-7.Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A,Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R. Intensification ofmercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse forsome children with acute lymphoblastic leukemia. J Clin Oncol 2003 Apr 1;21(7):1332Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, Jonmundsson G, Mellander Land Gustafsson G. Treatment stratification based on initial in vivo response in acute myeloidleukaemia in children without Down's syndrome: results of NOPHO-AML trials.Br J Haematol.2003 Jul; 122(2): 217-Frost BM, Nygren P, Gustafsson G, Forestier E, Jonsson OG, Kanerva J, Nygaard R,Schmiegelow K, Larsson R, Lönnerholm G. On behalf of NOPHO. Increased in vitro cellulardrug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia.Br J Haematol. 2003 Aug; 122(3): 376-85.Hjalgrim LL, Rostgaard K, Schmiegelow K, Soderhall S, Kolmannskog S, Vettenranta K,Kristinsson J, Clausen N, Melbye M, Hjalgrim H, Gustafsson G. Age- and sex-specific incidenceof childhood leukemia by immunophenotype in the Nordic countries. J Natl Cancer Inst. 2003Oct 15; 95(20): 1539-44.T M Calero Moreno, G Gustafsson, S Garwicz, D Grandér, G K Jonmundsson, B-M Frost,A Mäkipernaa, O Rasool, E-R Savolainen, K Schmiegelow, S Söderhäll, K Vettenranta,F Wesenberg, S Einhorn, M Heyman. Deletion of the ink4-locus (the p16ink4a, p14ARF and NDp15ink4b genes) predicts relapse in children with ALL treated according to the Nordic ProtocolsNOPHO-86 and NOPHO-92. Leukemia, 2002, 16, 2037-2045.80

Frost B-M, Eksborg S, Björk O, Abrahamsson J, Behrendz M, Castor A, Forestier E, Lönnerholm G.Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutionalcollaborative study. Med Pediatr Oncol, 2002; 38:329-337.Lie SO, Clausen N, Jonmundsson G, Mellander L, Siimes MA, Gustafsson G, on behalf of theNordic Society for Pediatric Hematology and Oncology (NOPHO). Early response to therapy isthe strongest prognostic factor in childhood AML. Acute Leukemias VIII. Prognostic andTreatment Strategies, Springer 2001; 499-507Saarinen-Pihkala UM, Gustafsson G, Ringdén O. et al. No disadvantage in outcome of usingmatched unrelated donors as compared with matched sibling donors for bone marrow transplantationin children with acute lymphoblastic leukemia in second remission. J Clin Oncol;19:3406-3414, 2001.Forestier E, Johansson B, Borgstrom G, Kerndrup G, Johansson J, Heim S. Cytogenetic findingsin a population-based series of 787 childhood acute lymphoblastic leukemias from the Nordiccountries. The NOPHO Leukemia Cytogenetic Study Group. Eur J Haematol. 2000 Mars;64(3):194-200.Forestier E, Johansson B, Gustafsson G, Borgstrom G, Kerndrup G, Johannsson J, Heim S.Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordicseries comparing two treatment periods. For Nordic Society of Paediatric Haematology andOncology and Leukaemia Cytogenetic Study Group. Br J Haematol. 2000 Jul;110(1):147-53.Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G, MellanderL, Mäkipernaa A, Nygaard R, Saarinen-Pihkala U-M. Improving outcome through two decades inchildhood ALL in the Nordic countries: the impacr of high-dose methotrexate in the reduction ofCNS irradiation. Leukemia, 2000, 14: 2267-2275.Frost B-M, Gustafsson G, Larsson R, Nygren P, Lönnerholm G. Cellular cytotoxic drug sensitivity inchildren with acute leukemia and Down´s syndrome: an explanation to differences in clinicaloutcome? Leukemia, 2000, 14: 943-944.Schroeder H, Gustafsson G, Saarinen-Pihkala U, Glomstein A, Jonmundsson G, Nysom K,Ringden O and Mellander L. Allogeneic bone marrow transplantation in second remission ofchildhood acute lymphoblastic leukemia: a population-based case control study from the Nordiccountries. Bone Marrow Transplant, 1999,Mar;23(6):555-560Gustafsson G, Lie SO. Acute leukemias. In: Cancer in children, clinical management, 4th edn. (edPA Voute, C Kalifa, A Barrett). Oxford University Press, London, 1998, 99-118.Gustafsson G, Kreuger A, Clausen N, Garwicz S, Kristinsson J, Lie SO, Moe PJ, Perkkiö M,Yssing M and Saarinen-Pihkala U. Intensified treatment of acute childhood lymphoblasticleukemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of2648 patients diagnosed between 1981 and 1996. Acta Paediatr, 1998;87:1151-61.Jahnukainen K, Salmi TT, Kristinsson J, Müller J, Madsen B, Gustafsson G. The clinicalindications for identical pathogenesis of isolated and non-isolated testicular relapse in acutelymphoblastic leukemia. Acta Paediatr,1998,87:638-64381

Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O. Impact of morningversus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children withacute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). JPed Hematol Oncol, 1997;19(2):102-9.Lie SO, Jonmundsson GK, Mellander L, Siimes MA, Yssing M, Gustafsson G. Chemotherapy ofacute myelocytic leukemia in children. Ann N Y Acad Sci.1997;824:84-90. Review.Saarinen U, Mellander L, Nyström K, Ringden O, Schroeder H, Glomstein A and Gustafsson Gfor NOPHO. Allogeneic bone marrow transplantation in first remission for children with veryhigh risk acute lymphoblastic leukemia: A retrospective case-control study in the Nordiccountries. Bone Marrow Transplantation; 17 (3):357-363 1996.Lie S, Jonmundsson G, Mellander L, Siimes MA, Yssing M and Gustafsson G on behalf of NOPHO.A population based study of 272 children with acute myeloid leukemia treated on two consecutiveprotocols with different intensity: Best outcome in girls, infants and in children with Down´ssyndrom. Br Journal of Hematology 1996; 94:82-88Schröder H, Garwicz S, Gustafsson G, Kristinsson J, Siiemes MA and Wesenberg F on behalf ofNOPHO. Outcome after relapse in children with acute lymphoblastic leukemia. Med Ped Onc1995; 25:372-378.Schmiegelow K, Schröder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, and Wranne L forNOPHO. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexateand mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for PediatricHematology and Oncology. Journal Clin Oncol 1995; 13:345-351.Marky I, Jonsson O, Kreuger A, Gustafsson G, Perkkio M, Schmiegelow K, Storm-Mathiesen Iand Langmark F. Childhood Non-Hodgkin´s Lymphoma (NHL) in the five Nordic countries.A five year population based study. Am Journal Pediatr Hem/Onc.; 17(2): 163-166, 1995.Siimes MA, Lie SO, Andersen O, Marky I, Rautonen J, Hertz H. Prophylactic cranial irradiationincreases the risk of testicular damage in adult males surviving ALL in childhood. Med PedOncol 1993;21:117-121.Lanning M, Garwitz S, Hertz H, Jonmundsson G, Kreuger A, Lie SO, Moe PJ, Salmi TT,Schröder H, Siimes M, Wesenberg F, Yssing M, Åhström L and Gustafsson G for NOPHO.Superior treatment results in girls with high risk acute lymphoblastic leukemia compared to boys.Acta Paediatr Scand 1992; 81:66-68.Lie Sverre and Gustafsson Göran on behalf of the Nordic Society for Pediatric Hematology andOncology (NOPHO). Progress in the treatment of childhood leukemias. Review article Annals ofMedicin 1992; 24:319-323.Kreuger A, Garwitz S, Hertz H, Jonmundsson G, Lanning M, Lie SO, Moe PJ, Salmi TT,Schroeder H, Siimes MA, Wesenberg F, Yssing M, Åhström L and Gustafsson G for NOPHO.CNS disease in childhood acute lymphoblastic leukemia. Prognostic factors and treatment results.Pediatr Hem Oncol 1991; 8:291-299.82

Nygaard R, Clausen N, Siimes MA, Marky I, Skjeldestad FE, Kristinsson JR, Vuoristo A, WegeliusR, Moe PJ. Reproduction following treatment for childhood leukemia: A population-basedprospective cohort study of fertility and offspring. Med Ped Oncol 1991;19:459-466.Nygaard R, Garwicz S, Haldorsen T, Hertz H, Jonmundsson GK, Lanning M, Moe PJ. Secondmalignant neoplasms in patients treated for childhood leukemia. A population-based cohort studyfrom the Nordic countries. Acta Pædiatr Scand 1991;80:1220-1228.Jacobsen BB, Garwicz S, Glomstein A, Jonmundsson G, Kruus S, Yssing M. Medulloblastoma inNordic children. III. Long term growth and endocrine sequelae. Acta Pædiatr Scand 1990;271:20-27.Lie S, Berglund G, Gustafsson G, Jonmundsson G, Siimes M, Yssing M for NOPHO. High doseARA-C as a single agent consolidation therapy in childhood AML. In: Haematology and BloodTransfusion. Acute Leukemia II. pp 215-221. Springer Verlag, 1990.Yssing M, Garwicz S, Glomstein A, Jonmundsson G, Kruus S. Medulloblastoma in Nordic children.II. Neurologic and social prognosis in long term survivors. Acta Pædiatr Scand 1990, suppl.371:12-19.Gustafsson G, Berglund G, Garwicz S, Hertz H, Jonmundsson G, Moe PJ, Salmi TT, Seip M,Siimes MA, Yssing M for NOPHO. A population-based study of children with stanard risk acutelymphoblastic leukemia in the five Nordic countries. Acta Paediatr Scand 1989; 78: 104-109Gustafsson G, Kreuger A. Behandlingsresultat för barn med akut lymfatisk leukemi 1973-1985 - enöversikt. Läkartidningen 84: 623- 626, 1987.Gustafsson G, Garwicz S, Hertz H, Jonmundsson G, Johanesson G, Moe PJ, Salmi T, Seip M,Siimes MA, Yssing M and Åhström L for NOPHO. A Population-based study of childhood acutelymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordiccountries. Acta Paediatr Scand 1987; 76: 781-788.Gustafsson G, Kreuger A. Akut lymfatisk leukemi hos barn- en översikt. Medicinsk kommentar.Läkartidningen 80: 2719-2720, 1983.Gustafsson G, Kreuger A for SCLG. Sex as a prognostic factor in acute lymphoblastic leukemia inchildhood. Am J Hematol Oncol 3: 243-250, 1983.Gustafsson G, Kreuger A for SCLG. Incidence of childhood leukemia in Sweden 1975-1980. ActaPaedriatr Scand 71: 887-892, 1982.Gustafsson G, Kreuger A, Dohlwitz A for SCLG. Acute lymfoblastic leukemia in Swedish children1973-1978. Acta Paedriatr Scand 70: 609-614, 1981.Dohlwitz A, Gustafsson G, Kreuger A. Resultat av behandlingsprogram III för akut lymfatisk leukemi(1973-1976). Läkartidningen 76: 3069-72, 1979.83

7. AppendixTable Appendix 1.1 Numbers and incidence vs age for different diagnoses. (1984-20010)Diagnoses Sex Age - Number of cases Number of cases Incidence rates/100 000

Diagnoses Sex Age - Number of cases Number of cases

Diagnoses Sex Age - Number of cases Number of cases

Diagnoses Sex Age - Number of cases Number of cases

Table Appendix 1.2 Numbers, relative frequencies and survival figures for different diagnoses. (1984-2010)Diagnoses Sex Number Relative Group Ratio Age Survival% % M/F Mean/Md 5-yrs 10-yrs 20 yrsAll malignancies Total 7065 100 100 1.17 5.9/5 79±1 77±1 75±1Males 3805 53.8 53.8 6.0/5 79±1 77±1 75±1Females 3260 46.2 46.2 5.7/5 80±1 77±1 75±1I Leukemias Total 2109 29.9 100 1.20 5.2/4 79±1 76±1 74±1Males 1149 16.3 54.5 5.6/4 79±1 77±1 75±1Females 960 13.6 45.5 4.8/4 78±1 75±1 73±2ALL Total 1741 24.6 82.6 5.2/4 84±1 81±1 79±1AML Total 315 4.6 15.7 5.5/4 59±3 55±3 53±3JMML,CMML,MDS Total 53 0.6 1.7 5,6/4 59±9 45±13 37±11II Lymphomas Total 848 12.0 100 2.00 7.5/8 89±1 88±1 85±1Males 565 8.0 66.6 7.6/8 88±2 88±1 84±2Females 283 4.0 33.3 7.5/8 91±2 89±2 87±2Hodgkin´s disease Total 216 3.1 25.5 10.8/12 98±1 96±1 92±2Non-Hodgkin Lymphoma Total 309 4.4 36.4 7.8/8 81±2 79±2 75±3Burkitt's lymphoma Total 70 1.0 8.3 7.9/8 94±3 92±3 90±4LCH Total 236 3.5 29.6 4.2/3 92±2 91±2 89±2HLH Total 13Other Total 2 1.5/188

Diagnoses Sex Number Relative Group Ratio Age Survival% % M/F Mean/Md 5-yrs 10-yrs 20 yrsIII CNS tumours Total 1945 27.5 100 1.10 6.7/6 76±1 73±1 70±1Males 1019 14.4 52.4 6.7/6 76±1 73±1 70±2Females 926 13.1 47.6 6.8/7 76±1 73±2 70±2Ependymom Total 185 2.6 9.5 5.2/4 75±3 70±4 66±4Astrocytom Total 853 12.1 43.9 7.0/7 85±1 83±1 80±2Medulloblastoma/PNET Total 372 5.3 19.1 5.6/5 62±3 55±3 52±3Other gliomas Total 203 2.9 10.4 6.9/7 45±4 44±4 43±4Other specified Total 282 4.0 14.5 8.4/9 92±2 89±2 86±3CNS-Unspecified Total 50 0.7 2.5 7.1/6 73±6 73±6 73±6IV Symphatetic nervous systemtumours Total 389 5.5 100 1.22 2.1/1 66±2 64±3 62±3Males 214 3.0 55.0 2.2/1 61±3 60±3 60±3Females 175 2.5 45.0 1.9/1 71±3 68±4 65±4Neuroblastoma Total 378 5.4 97.2 1.9/1 65±2 63±3 62±3Other symp nervous system tumors Total 11 0.2 2.8 8.9/11V-Retinoblastomas Total 153 2.2 100 0.68 1.2/1 98±1 98±1 98±1Males 62 0.9 40.5 1.3/1 98±2 98±2 98±2Females 91 1.3 59.5 1.1/1 98±2 98±2 98±2Retinoblastoma, unilateral Total 76 1.1 49.7 1.2/1Retinoblastoma, bilateral Total 33 0.5 21.5Retinoblastoma, unspec Total 44 0.6 28.9VI Renal tumours Total 407 5.8 100 0.97 2.8/2 85±2 84±2 83±2Males 200 2.8 49.1 2.9/2 86±3 86±3 85±3Females 207 3.0 50.9 2.7/2 85±3 83±3 82±3Nephroblastom Total 400 5.7 98.2 2.7/2 85±2 84±2 83±2Renal carcinoma (1/7 dead) Total 7 0.1 1.8 8.1/989

Diagnoses Sex Number Relative Group Ratio Age Survival% % M/F Mean/Md 5-yrs 10-yrs 20 yrsVII Hepatic tumours Total 91 1.3 100 1.60 2.3/1 78±4 78±4 75±5Males 56 0.8 61.5 2.5/1 74±6 74±6 74±6Females 35 0.5 38.5 1.9/1 83±6 83±6 77±8Hepatoblastom Total 78 1.1 85.7 1.7/1 83±4 83±4 80±5Hepatocellular carcinoma (5/9 dead) Total 9 0.1 9.8 7.2/6Other and unspec. (2/4 dead) Total 4 0.1 4.3 3.0/3VIII Bone tumours Total 257 3.6 100 1.00 10.0/11 66±3 63±3 62±3Males 129 1.8 50.1 9.7/11 64±4 61±4 59±5Females 128 1.8 49.9 10.2/11 69±4 66±4 66±4Osteosarcoma Total 132 1.9 51.4 10.8/12 65±4 64±4 64±4Chondrosarcoma (1 dead) Total 7 0.1 2.7 12.6/13Ewings Total 107 1.5 41.6 8.8/9 64±5 61±5 58±6Other and unspec. Total 11 0.2 4.3 9.2/11IXSoft tissue tumours Total 406 5.7 100 1.29 6.5/6 74±2 74±2 70±3Males 229 3.2 56.4 6.6/6 78±3 77±3 75±3Females 177 2.5 43.6 6.4/5 70±4 69±4 64±4Rhabdomyosarkoma,embr. sarc. softtis Total 218 3.1 53.7 5.3/4 70±3 69±3 69±3Fibrosarkoma,neurofibrosarkoma,other Total 91 1.3 22.4 7.7/10 86±4 86±4 82±4Kaposi's sarkom Total 1

Diagnoses Sex Number Relative Group Ratio Age Survival% % M/F Mean/Md 5-yrs 10-yrs 20 yrsX Germ cells tumours Total 312 4.4 100 0.74 6.0/5 89±2 89±2 86±6Males 133 1.9 42.6 5.8/3 89±3 89±3 85±3Females 179 2.5 57.4 6.1/6 90±2 89±2 86±3Intracranial/intraspinal germ cells Total 50 0.7 16.0 9.8/10 76±6 73±6 62±8Non-gonadal germ-cell and trophoblast Total 79 1.1 25.3 2.3/2 90±4 90±4 87±5Gonadal germ-cell and trophoblastic n Total 171 2.4 54.8 6.4/6 93±2 93±2 93±2Gonadal carcinoma Total 2