Med ca beh PMc - cancerakademin.se€¦ · Docetaxel 75 mg/m2 vs 100 mg/m2 ... Anvisningar för regimen Anvisningar för ordination G-CSF bör ges till alla patienter, f örslagsvis

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MedicinskcancerbehandlingVerkningsmekanismer och biverkningar

MikaelJohanssonDocent,ÖverläkareCancercentrum/Instför Strålningsvetenskaper,Umeå [email protected]

Medicinskcancerbehandlingärintebaracytostatikabehandling…

• Cytostatika

• Hormonellbehandling• Antikroppar• Proteinkinashämmare• Immunterapi

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19591942 1978 1992 20011948

mustin

mtx

cyklofosfamid

cisplatin

paklitaxel

imatinib

Efter Chabner &RobertsNatRevCancer2005

1963

vinkristin

Några milstolpar

2011

ipilimumab

rituximab

1997

5FU

1957

Tidigaresponser1950t

Bot?1960t

Kombinationer,adjuvant beh1970t

Biologiskabeh2000t

Varför ger vicytostatika idag?

• Kurativa behandlingar– Primärt kurativbehandling

– Adjuvant– Neo-Adjuvant

• Öka chansen tillbot

• Palliativ behandling– Olika cykellängd– Kontinuerligt ellerintermittent

• Förlängd överlevnad• Symtomkontroll• Förbättrad QoL

Linje 1 Linje 2 Linje 3Paus

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Hurgescytostatika?

• Intravenöst– Periferinfart– Centralinfart

• CVK• Venport• PICCline

• Peroralt• Monoterapi• Kombination• Olikacykellängd

Dosering av cytostatika

• Ofta mktsmalt

terapeutiskt fönster

• Ges vanligen sommaximalt tolererad dos

med2-4(6)veckorsintervall

• Ingensteadystate…• Doseras medhjälp av

– Kroppsyta (BSA)(m2)– Vikt (kg)– Njurfunktion (GFR)

C

t

veckor

mg/mL

BSA=M0.425xH0.725 x71.84

DuBois&DuBois1916

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Det är svårt att dosera cytostatika…

Felici EJC2002

Docetaxel75mg/m2 vs100mg/m2

Cytostatikahämmarcelldelning

• Oändligdelningsförmåga

• Minskadapoptos

• Invasivitet• Metastasering• Tillväxtfaktorstimulering• Kärlnybildning

Hanahan&Weinberg Cell 2000, 2011

Dennaskillnadgerettterapeutisktfönsterförklassiskkemoterapi

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2000 2017

Indelning av cytostatika

• L01AAlkylerande medel 9 10• L01BAntimetaboliter 8 17• L01CVäxtalkaloider 8 10• L01DCytotoxiska antibiotika 8 8• L01XÖvriga cytostatika 12 72

Klassifikation enlATCsystemet (FASS)

IaAlkylerare

Mustin

Cyclofosfamid

Ifosfamid

Melfalan

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Verkningsmekanismer alkylerare

ReagerarmedbasernaiDNAochbildarkovalentakorsbindningarvilketinterfererarmedsåvältranskriptionsomreplikation.

• Intersträngochintrasträng korskopplingar(G-X-C/C-G-X)• Basmodifiering (Guanin O6)

Alkylering ochmodifieringavproteiner

Verkningsmekanismeralkylerare

Vanliga kvävesenapsgasderivat

Cyklofosfamid (Sendoxan®)

Denvanligaste alkyleraren.Metaboliseras tillaktiv kvävesenap i levern.Mycket brett

användningsområde.Mesna ges vid doseröver 1000mg/m2för att undvika hemorragiskcytstit.

Ifosfamid (Holoxan®)

Enisomerav cyklofosfamid medliknandemetabolism.Används vid lymfom och

sarkom.Kräver samtidig administrering avMesna för att undvika hemorragisk cystit.

De Vita 2001

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CHOP 21 Oversikt Sida 1(2)

Antitumoral regim - Lymfom Behandlingsavsikt: Remissionssyftande

CHOP 21 (Cyklofosfamid-Doxorubicin-Vinkristin)Indikation: Lymfom C81-C86

Kurintervall: 21 dagar Oversikt

Lakemedel

Substans Administrering Spadning InfusionstidGrunddos/admtillfalle

Beraknings-satt

Maxdos/admtillfalle

Max ack.dos

1. Cyklofosfamid(monohydrat)

Intravenos infusion250 ml Natriumklorid9 mg/ml infusion

30 min. 750 mg/m2 kroppsyta

2. Doxorubicin Intravenos infusion250 ml Natriumklorid9 mg/ml infusion

30 min. 50 mg/m2 kroppsyta 550 mg/m2

3. Vinkristin Intravenos infusion100 ml Natriumklorid9 mg/ml infusion

5 min. 1,4 mg/m2 kroppsyta 2 mg

4. Prednison Per oral tablett 50 mg/m2 kroppsyta

Regimbeskrivning

Dag 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Ny kur dag

22

1. Cyklofosfamid (monohydrat) x1

2. Doxorubicin x1

3. Vinkristin x1

4. Prednison x1 x1 x1 x1 x1

Emetogenicitet: Hog

Anvisningar for regimen

Anvisningar for ordinationG-CSF bor ges till alla patienter, forslagsvis dag 4-11 (8 doser).Dosen for prednison avrundas med fordel till hela eller halva tabletter (styrka 50 mg).

Ovrig informationInbordes ordning av de olika substanserna ar valfri.Doxorubicin och vinkristin ar blandbara i samma infusion.Urinen kan fargas rod av doxorubicin.

Utfardad av: regim0fyanUppdaterad datum: 2016-10-14

Version: 1Vardprogramsgruppen for Lymfom

Faststalld av: regim0wabjFaststalld datum: 2014-11-06

www.regimbiblioteket.cancercentrum.se

Biverkningar Alkylerare

Vanligtvis dendosberoende toxiciteten.Cyklofosfamid har enkort periodochnitrosureapreparat enlång periodavbenmärgshämning.

Illamående och kräkningarmycket vanligt.Mellan30-90%beroende på drog och dos.

Lungfibros framför allt vid busulfanmenäven efternitrosurepreparat och cyklofosfamid

Sekundära leukemier (upp till5%incidensrapporterad)och sekundära solida tumörer.

Benmärg

Mage&tarm

Lungtoxicitet

Cancer….

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Ib.Platinaföreningar

www.3dchem.com www.jonthanpmiller.comCoste et al NRA 1999

Cisplatin Cisplatin DNA addukt

PlatinaföreningarCisplatin

Bildar starkt reaktiv jon efter administrering.Njurtoxisktoch neurotoxiskt.Kräver omfattande prehydrering.Brettanvändningsområde.

Karboplatin

Omvandlas tillsamma aktiva substans som cisplatin.Mindre njur och neurotoxicitet.Mer benmärgstoxiskt.

Inte samma behov av prehydrering

Oxaliplatin (Eloxatin®)

Används framför allt vid gastrointestinalcancertillsammans med5FU.Neurotoxiskt.

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Biverkningar Platinaföreningar

Cisplatin

Neurotoxiskt. Kumulativ neurotoxicitet viddoser över300mg/m2.Ofta irreversibelt.Hörselskador.

Nefrotoxiskt. Kräver prehydreringmed2000mLNaCl ivsamt övervakad diures efter administration.

Illamående. Starkt illamåendeframkallande

Karboplatin

Benmärg Riskför neutropeni och trombocytopeni

Övrigt Mindre riskför neuro/nefrotox än vidcisplatin-behandling.Inget krav på prehydrering.Utsöndrasvianjurarna och doseras vanligen efter GFR.

Oxaliplatin

Neurotox Akut neurotxicitet som förvärras av kyla.Kumulativ neurotox viddoser över 800mg/m2.

Cisplatin-Fluorouracil 5-dygnsinfusion Oversikt Sida 1(2)

Antitumoral regim - Matstrups- och magsackscancer Behandlingsavsikt: Kurativ, Neoadjuvant, Palliativ

Cisplatin-Fluorouracil 5-dygnsinfusion (PF)C15.9Kurintervall: 21 dagar Oversikt

Lakemedel


Beraknings-satt

Maxdos/admtillfalle

Max ack.dos

1. Cisplatin Intravenos infusion1000 mlNatriumklorid 9mg/ml infusion

1 tim. 100 mg/m2 kroppsyta

2. Fluorouracil Barbarinfusionspump

Intravenos infusion 5 dygn 3750 mg/m2 kroppsyta

Regimbeskrivning

Dag 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Ny kur dag

22

1. Cisplatin x1

2. Fluorouracil Barbarinfusionspump

x1 æ æ æ æ

Emetogenicitet: Hog


Villkor for start av regimenKontroll av blod-, lever och elektrolytstatus med clearance (Cystatin C, Iohexol, kreatininclearance eller motsvarande).EKG vid anamnes pa hjartsjukdom. Horselkontroll enligt lokal rutin.Vid patologiskt kreatinin eller da gynnsammare biverkningsprofil onskas gors byte till Karboplatin-Fluorouracil.

Villkor och kontroller for administrationVikt eller diureskontroll.

Anvisningar for ordinationKontroll av blod- och elektrolytstatus inklusive kreatinin. Kontroll av neurotoxicitet inklusive horselnedsattning.Om S-kreatinin over normalvarde gors kontroll av njurfunktion med clearancebestamning enlig lokal metod (Cystatin C, Iohexol,kreatininclearance eller motsvarande).Neutrofila >1,5 och TPK >75 for behandlingsstart.Vid samtidig stralbehandling ges filgrastim 0,5 ME/kg dag 7-15 eller pegfilgrastim 6 mg, dag 7. Start tidigast 24 timmar efter avslutadbehandling med Fluorouracil.Cisplatin - under behandlingsdygnet ges minst 4 liter vatska. Intravenos posthydrering kan bytas mot dryck.

Dosreduktion rekommendationVid genomgangen neutropen feber och kurativ behandlingsintention overvag att komplettera med G-CSF under efterfoljande kurer.

Ovrig informationDygnsdos Fluorouracil 750 mg/m2. Barbar infusionspump avsedd for anvandning under 5 dygn anvands, t.ex Baxter Infusor eller Homepump.

Utfardad av: regim0bakaUppdaterad datum: 2017-02-10

Version: 1Vardprogramsgruppen for Matstrups- och magsackscancer

Faststalld av: regim0bodaFaststalld datum: 2016-03-08


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II.Indirekt påverkan av DNA

• Topoisomerashämmare

Hämmartoposiomeras ochförhindrarnormaltunderhållavkromsomens DNA

• Antimetaboliter

InterfererarmedolikafaseravDNAsyntesenochförhindrarreplikation.

• Övriga

Induktionavfriasyreradikaler

IIa.topoisomerashämmare

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Topoisomeras 1hämmareIrinotekan (Campto®)

Används framförallt vidkolorektalcancermenäven vidventrikelcancer och småcelliglungcancer.

Ges vanligen i kombination med5FUochkalciumfolinat

Topotekan (Hycamtin®)

Används framförallt vid ovarialcancer ochsmåcellig lungcancer

Trettio minuters infusiondagligen i 5dagar.Finnsäven för peroral behandling. Camptotheca acuminata

Topoisomeras 2hämmareAntracykliner

Doxorubicin,epirubicin medflera hämmartopoisomeras 2medalkylerar även DNAochinducerar bildning av fria syreradikaler.Mycket brett användningsområde.

Antracendioner,aza-antracendioner

Mitoxantron (Novantrone®).Inducerar ingafria syreradikaler. Fungerar annars somantracyklinerna.Pixantron (Pixuvri®)alkylerar DNAmenär ensvag topo-2hämmare och inducerar inte friasyreradikaler

Podofyllotoxinderivat

Etoposid (Vepesid®)hämmar enbart

topoisomeras 2. Kanges peroralt.

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Biverkningar topoisomerashämmare

Deflesta topoisomeras hämmare ger dosberoendeneutropeni som dosbegränsande toxicitet.

Illamående och kräkningar vanligt.Irinotecan(Campto®)kan ge svåra diarrébesvär

Antracykliner ger dosberoende kardiotoxicet tillföljd av bildning av fria radikaler.

Antracykliner är starkt vävnadsretande och ger storaskador vid extravasering.

Benmärg

Mageoch tarm

Cirkulation

Vävnadstoxicitet

Karboplatin-Etoposid Oversikt Sida 1(2)

Antitumoral regim - Lungcancer Behandlingsavsikt: Kurativ

Karboplatin-EtoposidIndikation: Smacellig lungcancer C34


Lakemedel


Beraknings-satt

Maxdos/admtillfalle

Max ack.dos

1. Karboplatin Intravenos infusion500 ml Natriumklorid9 mg/ml infusion

30 min.5 x (GFR+25)mg

njurfunktion(AUC Calvert)

1000 mg

2. Etoposid Intravenos infusion500 ml Natriumklorid9 mg/ml infusion

60 min. 100 mg/m2 kroppsyta

Regimbeskrivning

Dag 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Ny kur dag

22

1. Karboplatin x1

2. Etoposid x1 x1 x1

Emetogenicitet: Medel

Behandlingsoversikt: Standardbehandling ar 4 kurer och darefter utvardering.


Villkor for start av regimenKontroll av blod-, lever och elektrolytstatus med clearance (Cystatin C, Iohexol, kreatininclearance eller motsvarande).

Anvisningar for ordinationKarboplatin - Calverts formel: Dos = AUC x (GFR+25). AUC=5 mg/ml x min; GFR=.... ml/min, okorrigerat varde; Dos=....mg, totaldos.Kontroll av blod inkl. neutrofila och elektrolytstatus inklusive kreatinin. For behandlingsstart neutrofila >1,5 och TPK >75.Om S-kreatinin over normalvarde gors kontroll av njurfunktion med clearancebestamning enligt lokal metod (Cystatin C, Iohexol,kreatininclearance eller motsvarande).

Dosreduktion rekommendationHematologisk toxicitetNADIR-varde for leukocyter < 2,0 och/eller neutrofila < 1,0 - ge nasta kur med 80 % av doserna for bada lakemedlen.Om NADIR-varden efter dosreduktion fortsatt ar leukocyter < 2,0 och/eller neutrofila < 1,0 - dosreducera ytterligare 10-15 % eller byt regim.

AlbuminVid P/S albumin < 30 g/L reduceras dosen Etoposid till 75 % pga hogre biotillganglighet.


Version: 1Vardprogramsgruppen for Lungcancer

Faststalld av: regim0ohroFaststalld datum: 2017-06-08


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IIb.Antimetaboliter

www.ericharshbarger.org/lego/mini_dna.html

Folsyraantagonister

Metotrexat

Binderdihydrofolatreduktas och hämmarfolsyracykeln.Kalciumfolinat används

som antidot vid höga dosermetotrexat.

Används vid sarkom,blåscancer ochlymfom bla.

Pemetrexed (Alimta®)

Enny multitarget antimetabolit somhämmar tre olika enzymer i pyrimidinoch purinsyntesen.

Används vid lungcancer ochmesotheliom

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Pyrimidinanaloger

5-Flourouracil

Enkonstgjord uracilmolekyl som binderoch hämmartymidylatsyntetas och stoppar därmed DNAsyntesen.Används tillsammans medkalciumfolinat som

förstärker effekten av 5FU.

Bryts ner av enzymet dihydropyrimidindehydrogenas(DPD).2-3%av befolkningen har medfött låg DPDaktivitet.Dessa får betydande biverkningar av 5FU.

Capecitabin (Xeloda®)och Tegafur (Teysuno®)ärprodroger som metaboliseras till5FUIlevern

5FUanvänds framför allt vid gastrointestinal cancer.

X

Pyrimidin analoger

Gemcitabin (Gemzar®)

Bindsinsom enfelaktig basi DNAoch stoppardärmed DNAreplikationen.Brettanvändningsområde.Används vid lungcancer,pankreascancer,blåscancermm.

Cytarabin (Cytosar®)

Bindsinsom enfelaktig basi DNAoch stoppardärmed DNAreplikationen.Smaltanvändningsområde.Används vidleukemier

och maligna lymfom.Kan ges intratekalt

Gemcitabin

CytarabinTrifluridin (Lonsurf®)

Bindsinsom en felaktig tymidinbas.Preparateten kombination av pyrimidinanalog och Tpashämmare.Används vidkolorektalcancer.

Trifluridin

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Biverkningar antimetaboliterBesvärliga slemhinnebiverkningarmedsår imunhålan,diarréer och sväljningsbesvär vidmetotrexat och 5FUbehandling.

Hand-fot syndrommederytem vidlångtidstillförsel av 5FU

Övergående feber efter cytarabin ellergemcitabintillförsel

Högre doser metotrexat gerbenmärgspåveran medneutropenier.

Benmärg

Feber

Hud

Slemhinnor

FLV Oversikt Sida 1(2)

Antitumoral regim - Tjock- och andtarmscancer Behandlingsavsikt: Palliativ

FLV (Fluorouracil-Kalciumfolinat)C18-C20Kurintervall: 14 dagar Oversikt

Lakemedel


Beraknings-satt

Maxdos/admtillfalle

Max ack.dos

1. Fluorouracil Intravenos injektion 3 min. 500 mg/m2 kroppsyta2. Kalciumfolinat(vattenfritt)

Intravenos injektion 3 min. 60 mg/m2 kroppsyta

Regimbeskrivning

Dag 1 2 3 4 5 6 7 8 9 10 11 12 13 14Ny kur dag

15

1. Fluorouracil x1 x1

2. Kalciumfolinat (vattenfritt) x1 x1

Emetogenicitet: Lag


Villkor for start av regimenKontroll av blod-, lever- och elektrolytstatus med kreatinin. EKG vid anamnes pa hjartsjukdom.

Villkor och kontroller for administrationPaustiden mellan Fluorouracil och Kalciumfolinat ar ungefarlig.

Anvisningar for ordinationBlodstatus inkl. neutrofila. Behandlingen uppskjutes till neutrofila >= 1,5 och TPK >= 75.Vid samtidig stralbehandling bor Fluorouracil reduceras till 80%.

Dosreduktion rekommendationVid genomgangen neutropen feber eller icke aceptabla biverkningar dosreduktion till 75%.

Utfardad av: regim0ulfevUppdaterad datum: 2017-04-18

Version: 1Vardprogramsgruppen for Tjock- och andtarmscancer

Faststalld av: regim0bodaFaststalld datum: 2017-02-27


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III.Mitoshämmare

Mikrotubuli

De Vita 2001

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IIIa.Vinkaalkaloider

Vinkaalkaloider

Förhindrar uppbyggnad av mikrotubuli.

• Vinkristin

• Vindesin• Vinblastin• Vinorelbin• Vinflunin

Växtalkaloider fån Vinca Rosea.Ingår ikombinationer vidmånga olika maligniteter.Vinorelbin (Navelbine®)används ofta vidlungcancer och bröstcancer.Vinkristin(Onkovin®)ingår i många regimer (lymfom,CNSmfl).Vinflunin används Iandra linjenvidurotelcellscancer.

Vinca Rosea

Vinkristin

IIIb Taxaner

Paklitaxel (Taxol®)

Docetaxel (Taxotere®)

Cabazitaxel (Jevtana®)

nab-paklitaxel (Abraxane®)

Förhindrar nedbrytning av mikrotubuli.

Utvanns ursprungligen ur barken frånidegran (amerikans resp europeisk).

Används vidovarialcancer,bröstcancer,lungcancer och prostatacancer.

Monoterapi eller i kombination medframförallt platinumpreparat

docetaxel

Taxus Baccata

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Biverkningar mitoshämmare

Perifera neuropatier vanligt.Dosbegränsande vidvinkristin och paklitaxel.

Muskelvärk och ledsmärtor ffa vid taxol.

Ovanligt frånsett vid Taxoterebehandling därneutropenier vanligen är dosbegränsande.

Trötthet och vätskeretention vid taxaner,ffataxotere.

Benmärg

Rörelseapparaten

Neurotoxicitet

Allmänna symtom

Karboplatin-Paklitaxel Oversikt Sida 1(2)

Antitumoral regim - Lungcancer Behandlingsavsikt: Palliativ

Karboplatin-PaklitaxelIndikation: Icke-smacellig lungcancer C34


Lakemedel


Beraknings-satt

Maxdos/admtillfalle

Max ack.dos

1. Paklitaxel Intravenos infusion1000 mlNatriumklorid 9mg/ml infusion

3 tim. 200 mg/m2 kroppsyta

2. Karboplatin Intravenos infusion500 ml Glukos 50mg/ml infusion

30 min.6 x (GFR+25)mg

njurfunktion(AUC Calvert)

1000 mg

Regimbeskrivning

Dag 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Ny kur dag

22

1. Paklitaxel x1

2. Karboplatin x1

Emetogenicitet: Medel


Villkor for start av regimenKontroll av blod-, lever och elektrolytstatus med clearance (Cystatin C, Iohexol, kreatininclearance eller motsvarande).

Villkor och kontroller for administrationPaklitaxel - Okad beredskap for anafylaktisk reaktion. Overkanslighetsreaktioner ar vanliga, sarskilt kur 1 och 2.Blodtryck och puls.

Anvisningar for ordinationKarboplatin - Calverts formel: Dos = AUC x (GFR+25). AUC=6 mg/ml x min; GFR=.... ml/min, okorrigerat varde; Dos=....mg, totaldos.Kontroll av blod inkl. neutrofila och elektrolytstatus inklusive kreatinin. For behandlingsstart neutrofila >1,5 och TPK >75.Om S-kreatinin over normalvarde gors kontroll av njurfunktion med clearancebestamning enligt lokal metod (Cystatin C, Iohexol,kreatininclearance eller motsvarande).Paklitaxel - Premedicinering med kortison, antihistaminer och H2- blockare t.ex. peroral behandling med Betametason 8 mg, Cetirizin 10 mg,Ranitidin 150 mg.Kontroll av perifer neuropati.

Dosreduktion rekommendationHematologisk toxicitetNADIR-varde for leukocyter < 2,0 och/eller neutrofila < 1,0 - ge nasta kur med 80 % av doserna for bada lakemedlen.Om NADIR-varden efter dosreduktion fortsatt ar leukocyter < 2,0 och/eller neutrofila < 1,0 - dosreducera ytterligare 10-15 % eller byt regim.


Version: 1Vardprogramsgruppen for Lungcancer

Faststalld av: regim0ohroFaststalld datum: 2017-06-08


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Sammanfattningsvis…

Mekanism Typ Exempel

Direkt DNApåverkan

Alkylerarecyklofosfamid,ifosfamid,prokarbazin,DTIC,temozolomid,CCNU, klorambucil,tiotepa,mitomycin C,busulfan,bendamustin

Platinumprep cisplatin,karboplatin,oxaliplatin

IndirektDNApåverkan

Topoisomeras-hämmare

doxorubicin,epirubicin, daunorubicin,idarubicin,mitoxantron,pixantron,etoposid,irinotekan,topotekan

Antimetabolitermetotrexat,5FU, capecitabin,tegafur,gemcitabin,cytarabin,trifluridin,fludarabin,kladribin,trabectidin

Mitos-hämmare

Vinka-alkaloider vinkristin,vinorelbin, vindesin,vinblastin

Taxaner paklitaxel, docetaxel,cabazitaxel

Halikondriner eribulin

Övrigacytostatika

bleomycin,sstramustinmfl

IV.Nya cancerläkemedel!

• Signaltransduktions-hämmare– Proteinkinashämmare

• Tyrosinkinashämmare• Andra kinashämmare

• Antikroppar– Okonjugerade– Konjugerade

• Immunterapi– Vacciner– Immunstimulerande

behandlingar• Övriga

– Proteasomhämmare

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Läkemedel Antikropp Antigen Användning Biverkningar

Mabthera rituximab CD20 Lymfom Frossa,anafylaxi

Herceptin trastuzumab HER2 Bröstcancer Hjärtsvikt

Perjeta pertuzumab EGFR/HER2 Bröstcancer Hjärtsvikt

Erbitux cetuximab EGFR KoloncancerH&Ncancer

hudbiverkningar

Vectibix Panitumumab EGFR Koloncancer hudbiverkningar

Avastin bevacizumab VEGF KoloncancerLungcancerBröstcancerNjurcancer

BlödningarHypertoniTromboserSårläkn problem

Antikroppar i vardagsonkologin

Målstyrd cytostatikabehandling

Senter,NatBiotech2012

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T-DM1(trastuzumab emtansine)

Målstyrd bröstcancerbehandling

• Trastuzumab (T)kopplat tillmertansine (DM1),enmikrotubulihämmare.

• DM1frigörs efterinternalisering

• Nyligen registrerat föranvändning vidmetHer2+bröstcancer

• Lite biverkningar

Tyrosinkinashämmare

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Tyrosinkinashämmarna ärmånga

Läkemedel Substans Target(s) Användning Biverkningar

Glivec imatinib bcr-abl,C-KIT, PDGFR KML,GIST Illam,ödem,värk,diarrér

Sprycel dasatinib bcr-abl,C-KIT, PDGFR KML Benmärgshämn,ödem

Tasigna nilotinib bcr-abl KML Illamående, ödem,

TarcevaIressa

erlotinib,gefitinib

EGFR Lungcancer Hudbiverkningar,diarrér

Sutent sunitinib VEGFR,c-kit,PDGFR NjurcancerGIST

Trötthet,illam,tromboser,neutrop,hypertoni, stomatit,blödn

Nexavar sorafenib VEGFR,c-kit,PDGFR,RAF NjurcancerLevercancer

Diarré,hudbesvär

Votrient pazopanib VEGFR,c-kit,PDGFR, Njurcancer Diarré,hypertoni,stomatit

Inlyta axitinib VEGFR1,2,3 Njurcancer Diarré,Trötthet,illam,tromboser,hypertoni, stomatit,blödn

Tyverb lapatinib EGFR,HER2 Bröstcancer Hudbesvär,diarrér

Xalkori crizotinib ALK Lungcancer Diarrér,synstörningar

Zelboraf vemurafenib BRAFV600E Melanom Artralgi,alopeci,fotosens,diarrér,scc,

EGFRTKi vidlungcancersomexempelGefitinib or Chemother apy for Non–Small-Cell Lung Cancer

n engl j med 362;25 nejm.org june 24, 2010 2385

as that obtained with the use of carboplatin–pacli-taxel in patients with mutated-EGFR non–small-cell lung cancer, with a tolerable toxicity profile, including less hematologic toxicity and neurotox-icity than is seen with chemotherapy.

The IPASS, which was conducted in Asia, com-pared gefitinib with carboplatin–paclitaxel as the first-line treatment for advanced non–small-cell lung cancer in patients selected on the basis of clinical characteristics that included a history of no smoking or light smoking as well as histologic evidence of adenocarcinoma.7 Although IPASS showed the overall superiority of gefitinib (rate of 1-year progression-free survival, 24.9%, vs. 6.7% with chemotherapy; hazard ratio for death or dis-ease progression, 0.74; P<0.001), the most impres-sive result emerged from subgroup analysis: as compared with chemotherapy, gefitinib was effec-tive in patients with mutant EGFR (hazard ratio for death or disease progression, 0.48) but was ineffective in those with wild-type EGFR (haz-ard ratio, 2.85). This finding suggested that the presence of EGFR mutations is the best criterion for selection of patients who benefit from gefi-tinib, an idea that is validated by the present study.20 Recently, another Japanese phase 3 study (WJTOG3405; University Hospital Medical In-formation Network Clinical Trials Registry [UMIN-CTR] number, UMIN000000539) com-pared gefitinib to cisplatin–docetaxel as the first-line treatment for advanced non–small-cell lung cancer with EGFR mutations.21 Although this study also showed the superiority of gefitinib over standard chemotherapy with respect to progres-sion-free survival, the magnitude of the benefit was somewhat smaller than in our study, possibly because of differences in the characteristics of the patients (since 41% of patients in WJTOG3405 had had surgery, vs. only 9% in our study) and the duration of follow-up (median, 81 days in WJTOG3405 vs. 527 days in our study).

The standard end point of phase 3 trials of treatments for advanced non–small-cell lung can-cer has been overall survival. However, when our trial was begun in 2006, we had data only on

Figure 2. Progression-free Survival and Overall Survival among the Study Patients.

Kaplan–Meier curves for progression-free survival are shown for the progression-free–survival population (Panel A) and for the 107 patients in the gefitinib group with either of the two most common types of epidermal growth factor receptor (EGFR) mutation (Panel B). Kaplan–Meier curves for overall survival in the intention-to-treat population are shown in Panel C. In Panels B and C, tick marks indicate patients for whom data were censored at the data cutoff point (early December 2009).

The New England Journal of Medicine Downloaded from nejm.org on January 7, 2011. For personal use only. No other uses without permission.

Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Maemondo et al NEJM 2010

Articles

738 www.thelancet.com/oncology Vol 12 August 2011

progression-free survival. The sample size was set at 152 patients (with 103 events needed) on the basis of several assumptions: a median progression-free survival of 11 months with erlotinib, on the basis of data from the Spanish Lung Cancer Group (SLCG),7 compared with 6 months for chemotherapy; a 10% dropout rate; 80% power to detect a hazard ratio (HR) of 0·54 with an overall α level of 2·5% (α-spending for a fi nal analysis

of 0·025); and a 12-month enrolment period and 24-month follow-up, with a projected overall study period of 47 months. The software used for statistical analyses was SAS version 9.1.3.

The primary cutoff date for progression-free survival data was July 16, 2010; however, because an additional ten events occurred after this cutoff , an updated analysis was done on Aug 16, 2010, after a median follow-up of 15·6 months. These updated data are reported here. Survival was estimated with Kaplan-Meier methodology and was summarised as a median value with range and a two-sided 95% CI. A two-sided log-rank test was the main method used to compare survival between the two treatment groups. Estimates of the treatment eff ect were expressed as an HR for erlotinib versus chemotherapy, with a two-sided 95% CI. Exploratory and preplanned subgroup analyses of progression-free survival were done with the Cox proportional hazards model and included the stratifi cation factors from randomisation.

This study is registered at ClinicalTrials.gov, NCT00874419.

Role of the funding sourceThis study was supported by partial research grants from F Hoff mann-La Roche (China) and a grant from the Science and Technology Commission of Shanghai Municipality (No 06DZ19502). F Hoff mann-La Roche had no input into the design of the study or the collection of data, although they provided fi nancial assistance and input towards the analysis and interpretation of results, and also reviewed the study report and the Article. All authors had access to the raw data and the corresponding author had full access to all data and the fi nal responsibility to submit for publication.

ResultsFigure 1 shows the trial profi le. 549 patients were screened for EGFR mutations and 165 were randomly assigned to treatment groups between Aug 24, 2008, and July 17, 2009. Of these patients, 154 had measurable disease and received at least one dose of study drug (82 erlotinib, 72 chemotherapy; fi gure 1). Both treatment groups were generally well matched with respect to baseline characteristics (table 1). Median duration of treatment was 55·5 weeks (range 3·1–93·0) for erlotinib and 10·4 weeks (range 1·0–18·9) for carboplatin plus gemcitabine. The median number of treatment cycles for the chemotherapy group was four (range 1–6). Dose reduction was necessary in fi ve (6%) erlotinib-treated patients and 40 (56%) chemotherapy-treated patients; treatment discontinuation was needed in one (1%) patient on erlotinib and seven (10%) on chemotherapy. Dose reductions or treatment discontinuations were attributable to adverse events, except for fi ve patients in the chemotherapy group who discontinued for personal reasons (n=3), intolerable toxic eff ects (n=1), or at the judgment of the investigator (n=1).

Prog

ress

ion-

free s

urvi

val (

%)

Number at riskErlotinib 82 70 51 20 2

Gemcitabine plus 72 26 4 0 0carboplatin

100

80

60

40

20

00 5 10 15 20

Time (months)

Erlotinib (N=82)Gemcitabine plus carboplatin (N=72)

HR 0·16 (95% CI 0·10–0·26)Log-rank p<0·0001

4·6 13·1

Figure 2: Progression-free survival in both treatment groups PFS=progression-free survival. HR=hazard ratio.

OverallStage IV IIIBSex Female MaleAge ≥65 years <65 yearsECOG PS 0–1 2Smoking status Never-smoker Present or former smokerHistology Adenocarcinoma Non-adenocarcinomaEGFR mutation type Exon 19 mutation Exon 21 mutation

0·16 (0·10–0·26) 154

0·18 (0·11–0·28) 1380·27 (0·06–1·16) 16

0·13 (0·07–0·24) 910·26 (0·14–0·50) 63

0·17 (0·07–0·43) 380·19 (0·11–0·31) 116

0·16 (0·10–0·26) 1440·21 (0·04–1·28) 10

0·14 (0·08–0·25) 1090·21 (0·09–0·49) 45

0·17 (0·11–0·28) 1340·22 (0·06–0·73) 20

0·13 (0·07–0·25) 820·26 (0·14–0·49) 72

HR (95% Cl) n

Favours erlotinib

0·05 0·1 0·2 0·4 0·8 1·0 2·01·5

Favours gemcitabine plus carboplatin

Figure 3: Subgroup analyses of progression-free survival, by clinical characteristics ECOG=Eastern Cooperative Oncology Group. PS=performance status. HR=hazard ratio.

Zhou et al Lancet Onc 2011

Gefitinib

Erlotinib

and consisted primarily of rash, diarrhea, stomatitis, and paronychia,as expected from EGFR inhibition.2-6 Despite higher frequencies ofsuch AEs in our trial, these AEs rarely led to drug discontinuation,indicating that proactive supportive treatment and dose modificationwere an adequate strategy to properly manage the expected classeffects associated with EGFR inhibition. In addition, the results of thepharmacokinetic analysis indicate that afatinib dose modificationbased on individual tolerability optimized the exposure to afatinib andmaintained efficacious plasma levels.

Cisplatin plus pemetrexed is widely considered the optimalchemotherapy doublet for patients with nonsquamous NSCLC.The efficacy of this regimen is supported by the PFS observed inour control arm, which exceeded the results observed in other

studies comparing EGFR TKIs with first-line chemotherapy.2-6

One of the limitations of our study is that the chemotherapy armwas devoid of maintenance pemetrexed and/or bevacizumab.However, at the time of study design, cisplatin plus pemetrexedwithout maintenance was considered an efficacious treatmentchoice for patients with adenocarcinoma.31a The prevailing treat-ment standard changed after LUX-Lung 3 accrual was completed,when the results of a trial of maintenance pemetrexed after cispla-tin plus pemetrexed showed significant improvement comparedwith placebo, with a median PFS of 6.9 months.32 Another limita-tion is that bevacizumab treatment was not included in thecomparator arm of this study. There were two reasons for this: first,although addition of bevacizumab to paclitaxel plus carboplatin is

Factors HR 95% CI P InteractionNo. of

Patients

0.49345Total

SexMaleFemale

121

61414/161/1

Favors afatinib Favors cisplatin plus pemetrexed

Hazard Ratio

2240.450.51

.61

Age at baseline, years< 65≥ 65

211134

0.430.63

.40

Race stratification factorNon‐AsianAsian

96249

0.620.45

.62

EGFR mutation categoryDel19/L858R (common)Del19L858R

308170138

0.410.270.60

.02

Baseline ECOG score01

133211

0.470.53

.64

Smoking historyNever smoked< 15 packet years + stop > 1 yearOther current/ex‐smoker

2363079

0.480.340.54

0.37 to 0.65

0.28 to 0.700.36 to 0.72

0.30 to 0.610.40 to 0.98

0.36 to 1.060.33 to 0.62

0.31 to 0.550.18 to 0.410.39 to 0.93

0.30 to 0.750.38 to 0.75

0.34 to 0.690.14 to 0.850.33 to 0.91

.64

A

B

No. at riskAfatinibCisplatin/pemetrexed

AfatinibCisplatin/pemetrexed

HR, 0.49; 95% CI, 0.37 to 0.65; P < .001

Events, n (%)Median (months)

155 (67)11.07

83 (72)6.70

Afatinib(n = 230)

Cisplatin/pemetrexed(n = 115)

230115

0.2

0.4

0.6

0.8

1.0

30 6 9 12 15 18 21 24 27

18779

15947

13427

8812

Time (months)

Prog

ress

ion-

Free

Sur

viva

l (p

roba

bilit

y)

588

383

162

40

00

Fig 3. (A) Progression-free survival (PFS) by investigator review for all randomly assigned patients. (B) Forest plot of subgroups of patients showing PFS by investigatorreview. HR, hazard ratio; ECOG, Eastern Cooperative Oncology Group.

Sequist et al

3332 © 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

130.239.20.174Information downloaded from jco.ascopubs.org and provided by at Umea university library on January 18, 2014 from

Copyright © 2013 American Society of Clinical Oncology. All rights reserved.

Afatinib

Sequist et al JCO 2013

28/01/2018

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mTOR inhibitorer

Temsirolimus (Torisel®)

Everolimus (Afinitor®)

Hämmar det intracelluläraproteinkinaset mTOR.

Används vidmetastaseradnjurcancer och vidmantelcellslymfom(temsirolimus)

Proteasomhämmare

Bortezomib (Velcade®)

Hämmar proteasomkomplexet vilketleder tillstörning i nedbrytning avproteiner och slutligen tillcelldöd

Används vid behandling avmyelom

28/01/2018

24

Immunterapi

• Cytokiner– Interferon– Interleukin

• Monoklonala antikroppar• Vacciner

– Helaceller/lysat– Proteiner– DNA

• Adaptivimmunterapi• Immunstimulerande

antikroppar– Checkpointinhibitorer

Ribas NEJM2015

TABLE 1. CTLA-4 and PD-1 Pathway Inhibitors Approved or in Phase II and/or III Clinical Trial Stage of Development41–44

Target Name Status* Company

CTLA-4 Ipilimumab Approved for the treatment of unresectable or metastatic melanomaPhase III: lung cancer, kidney cancer, and prostate cancerPhase II: cervical cancer, colorectal cancer, gastric cancer, pancreatic cancer, ovarian cancer, and

urothelial cancer

Bristol-MyersSquibb

CTLA-4 Tremelimumab Phase II studies in lung cancer MedImmune/AstraZeneca

PD-1 Pembrolizumab Approved in the United States for treatment of unresectable or metastatic melanomawPhase III: gastric/GEJ cancer, lung cancer, head and neck cancer, and urothelial cancerPhase II: colorectal cancer, glioblastoma, Merkel cell cancer, pancreatic cancer, and hematologic

malignancies

Merck

PD-1 Nivolumab Approved in the United States for second-line/third-line treatment of unresectable or metastaticmelanomaw and for the treatment of metastatic non–small cell lung cancerz

Phase III: gastric cancer, glioblastoma, head and neck cancer, kidney cancer, and lung cancer(nonsquamous)

Phase II: cervical cancer, colorectal cancer, pancreatic cancer, and hematologic malignancies

Bristol-MyersSquibb

PD-1 Pidilizumab Phase II: kidney cancer and hematologic malignancies CureTech/Medivation

PD-L1 Durvalumab Phase III: head and neck cancer and lung cancerPhase II: colorectal cancer and glioblastoma

MedImmune/AstraZeneca

PD-L1 Atezolimab Phase III: bladder cancer and lung cancerPhase II: kidney cancer

Roche

*Only most advanced phase of development for any tumor type is listed; phase I or phase I/II indications are not listed. Includes both monotherapy and combinationtrials. Information from clinicaltrials.gov.

wWith disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Or in combination with ipilimumab in BRAF WTpatients.zWith disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on

FDA-approved therapy for these aberrations prior to receiving pembrolizumab or nivolumab.CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; GEJ, gastroesophageal junction; PD-1, programmed death 1; PD-L1, programmed death ligand 1.

FIGURE 4. CTLA-4 and PD-1 pathway blockade. CTLA-4 blockade allows for activation and proliferation of more T-cell clones, andreduces Treg-mediated immunosuppression. PD-1 pathway blockade restores the activity of antitumor T cells that have becomequiescent. A dual pathway blockade could have a synergistic effect, resulting in a larger and longer lasting antitumor immune response.CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; MHC, major histocompatibility complex; PD-1, programmed death 1;PD-L1, programmed death ligand 1; TCR, T-cell receptor; Treg, regulatory T cell.

Buchbinder and Desai American Journal of Clinical Oncology ! Volume 39, Number 1, February 2016

102 | www.amjclinicaloncology.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Buchbinder &Desai AJCO2016

28/01/2018

25

Goda erfarenheter från melanom!

• Nya typer avbiverkningar– kolit– dermatit– tyreoidit– encefalit

• Används idag för– Metmelanom– Lungcancer– Njurcancer– Urotelcellscancer– Lymfom– HoN cancer

• Långtidsöverlevare!

PetersetalNEJM2015

Nivolumab in Untreated Melanoma without BR AF Mutation

n engl j med 372;4 nejm.org january 22, 2015 325

0.60]; unadjusted hazard ratio for death among those with PD-L1 negative or indeterminate PD-L1 status, 0.48 [95% CI, 0.32 to 0.71]) (Fig. S2 in the Supplementary Appendix). In the nivolumab group, the median overall survival was not reached in either PD-L1 subgroup. In the dacar-bazine group, the median overall survival was slightly longer in the subgroup with positive PD-L1 status than in the subgroup with negative or indeterminate PD-L1 status (12.4 vs. 10.2 months) (Fig. S3 in the Supplementary Appendix).

In the two PD-L1 subgroups, nivolumab-treated patients had improved rates of objective response, as compared with dacarbazine-treated patients. In the subgroup with positive PD-L1 status, the objective response rate was 52.7% (95% CI, 40.8 to 64.3) in the nivolumab group versus 10.8% (95% CI, 4.8 to 20.2) in the dacar-bazine group. In the subgroup with negative or indeterminate PD-L1 status, the objective re-sponse rate was 33.1% (95% CI, 25.2 to 41.7) in the nivolumab group versus 15.7% (95% CI, 10.0 to 23.0) in the dacarbazine group. The survival benefit with nivolumab versus dacarbazine was also observed across prespecified subgroups based on age, sex, metastasis stage, ECOG per-formance-status score, status with respect to a history of brain metastases, baseline lactate de-hydrogenase level, and geographic region (Fig. S2 in the Supplementary Appendix).

ADVERSE EVENTSThe incidence of treatment-related adverse events of any grade was similar in the nivolumab group and the dacarbazine group (74.3% and 75.6%, respectively). However, treatment-related adverse events of grade 3 or 4 were reported less fre-quently in the nivolumab group than in the da-carbazine group (11.7% vs. 17.6%) (Table 3, and Table S3 in the Supplementary Appendix). The most common adverse events related to nivolu-mab treatment were fatigue (in 19.9% of pa-tients), pruritus (in 17.0%), and nausea (in 16.5%). In the dacarbazine group, common treat-ment-related adverse events were consistent with those in previous reports and included gastroin-testinal and hematologic toxic events. The fre-quency of treatment-related serious adverse events of grade 3 or 4 was similar in the two groups (5.8% in the nivolumab group and 5.9% in the dacarbazine group). The percentage of pa-tients who discontinued the study treatment ow-

ing to adverse events was 6.8% in the nivolumab group and 11.7% in the dacarbazine group. No deaths were attributed to study-drug toxicity in either group.

Selected adverse events — defined as those with a potential immunologic cause — were analyzed according to organ category. Grade 3

NivolumabDacarbazine

50/21096/208

Not reached10.8 (9.3–12.1)

Patients Who Diedno./total no.

Median Survivalmo (95% CI)

Patie

nts

Surv

ivin

g (%

)

100

80

90

70

60

40

30

10

50

20

00 3 6 9 12 15 18

Months

B Progression-free Survival

A Overall SurvivalHazard ratio for death, 0.42 (99.79% CI, 0.25–0.73)P<0.001

No. at RiskNivolumabDacarbazine

210208

185177

150123

10582

4522

83

00

Nivolumab

Dacarbazine

Patie

nts

with

out P

rogr

essi

on (%

)

100

80

90

70

60

40

30

10

50

20

00 3 6 9 12 15 18

Months

Hazard ratio for death or diseaseprogression, 0.43 (95% CI, 0.34–0.56); P<0.001

No. at RiskNivolumabDacarbazine

210208

11674

8228

5712

120

10

00

Nivolumab

Dacarbazine

NivolumabDacarbazine

108/210163/208

5.1 (3.5–10.8)2.2 (2.1–2.4)

Patients Who Diedor Had Disease

Progressionno./total no.

MedianProgression-free

Survivalmo (95% CI)

Figure 1. Survival End Points.

Panel A shows the Kaplan–Meier curves for overall survival. The median follow-up for overall survival was 8.9 months in the nivolumab group and 6.8 months in the dacarbazine group. Panel B shows the Kaplan–Meier curves for progression-free survival.

The New England Journal of Medicine Downloaded from nejm.org at UMEA UNIVERSITY LIBRARY on November 4, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Biverkningarvidimmunterapi

• Immunrelateradebiverkningarärvanliga– Allvarligabiverkningar

dockmindrevanliga• Andratyperav

biverkningar• Vanligendebut3- 6

månaderefterstart• Sendebutinteovanligt• Viktigtmedtidig

intervention

– Steroider!

display elevated (>10 mIU/l) thyroid-stimulating hor-mone (TSH) levels, an additional assay for free T4 and T3is required, and hormone replacement therapy (e.g. levo-thyroxine) should be initiated [26,27]. A few cases of hy-perthyroidism have been reported; in this setting, non-selective beta-blockers (e.g. propranolol) are suggested asthe initial treatment. Hyperthyroidism resolves spontane-ously in almost all cases, with the subsequent appearanceof hypothyroidism [24].

6.3.2. HypophysitisHypophysitis is mainly observed with anti-CTLA-4therapy and can affect up to 10% of patients [41].Hypophysitis results in low release of all or some of thefollowing pituitary gland hormones: adrenocorticotro-pic hormone (ACTH), TSH, follicle-stimulating hor-mone (FSH), luteinising hormone (LH), growthhormone or prolactin. Hypophysitis is difficult to di-agnose because its symptoms are non-specific: head-aches, fatigue and muscle weakness, paleness orconstipation, weight loss, anorexia, nausea. Additionalsymptoms reflecting specific hormonal deficiency couldbe helpful for the diagnosis: weight gain, constipation,bradycardia, attention or cognitive difficulties for thethyrotropin axis; erectile dysfunction or amenorrhoeafor the gonadotropin axis defect (LH/FSH); orthostatichypotension and hypoglycaemia/hyponatraemia for thecorticotrophin deficiency (ACTH) [41]. The central hy-pothyroidism appears to be the most frequent hormonedeficiency [41]. Serum pituitary auto-antibodies could bepresent [25]. Pituitary magnetic resonance imaging im-aging with gadolinium and selective slides should be

considered, searching enlargement or heterogeneity ofthe gland [40]. Treatment is based on the replacement ofappropriate hormones deficiency (e.g. levothyroxine andhydrocortisone) is required [25,41].

6.4. Liver disorders

Immune-relatedhepatitismust be consideredwhenever thephysician is confronted with an unexplained elevation ofserum levels of hepatic alanine aminotransferase oraspartate aminotransferase enzymes, which occurs in lessthan 5% of patients [4,31,33]. Most patients are asymp-tomatic and present with abnormal laboratory test results[34]. Viral infection with hepatitis A (primary infection), Bor C (primary or chronic infection) and emergent hepatitisE should be ruled out. A CT scan or an ultrasound of theliver and biliary tract may help to rule out liver metastasesor cholelithiasis. Some patients with IRAE hepatitis mayhave mild hepatomegaly, periportal oedema or lympha-denomegaly [34]. Serum assays for ANAs, anti-smoothmuscle antibodies, anti-liver kidney microsomal antibodytype 1 and anti-liver cytosol type 1 are often negative [23].The formal diagnosis of autoimmune hepatitis requires aliver biopsy showing a diffuse T-cell infiltrate in all lobes,prominent sinusoidal histiocytic infiltrates and central veindamagewith endothelialitis [23]. Patients should be treatedwith corticosteroids [23], and in steroid-refractory cases,adding the azathioprine orMMF is in accordance with themanagement of autoimmune hepatitis [35].

6.5. Lung disorders

Immune-related pneumonitis (including sarcoidosis [36,37]and organising inflammatory pneumonitis [38]) occurs inaround1%ofpatients takinganti-PD-1/PDL-1orCTLA-4antibodies [11,33,39]. This condition can be severe and lifethreatening, and thus requires the physician to pay partic-ular attention to respiratory symptoms [22]. Alertingsymptoms are dry cough, progressive shortness of breathandfine inspiratorycrackles. In casesof suspected immune-related pneumonitis, a chest CT scan and spirometry (withmeasurement of the carbon monoxide diffusing capacity)are useful. Immune-related pneumonitis shows ground-glass lesions and/or disseminated nodular infiltrates, pre-dominantly in the lower lobes [22,38]. Cardiac abnormal-ities with left ventricular dysfunction must be ruled out inthis setting. A bronchoscopy with bronchoalveolar lavageshould be considered to search infectious agents such asPneumocystis jirovecii and respiratory virus as influenza,metapneumovirus or the syncytial virus. Other atypical in-fectious agents, such as Legionella pneumophilia, Chla-mydia and Mycoplasma pneumoniae, should be alsoscreened. The treatment of immune-related pneumonitis isbasedon the systemic steroids [26,27]. If a courseof steroidsdoes not reduce the severity of the initial symptoms, addi-tional immunosuppression with infliximab could beconsidered [22].

Fig. 3. The clinical spectrum of IRAEs. IRAEs: immune-related

adverse events.

J.M. Michot et al. / European Journal of Cancer 54 (2016) 139e148144

Michot etalEJC2016

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26

therapies. For example, the deployment of apoptosis-inducingdrugs may induce cancer cells to hyperactivate mitogenicsignaling, enabling them to compensate for the initial attritiontriggered by such treatments. Such considerations suggestthat drug development and the design of treatment protocolswill benefit from incorporating the concepts of functionallydiscrete hallmark capabilities and of the multiple biochemicalpathways involved in supporting each of them. Thus, in partic-ular, we can envisage that selective cotargeting of multiplecore and emerging hallmark capabilities and enabling character-istics (Figure 6) in mechanism-guided combinations will result inmore effective and durable therapies for human cancer.

CONCLUSION AND FUTURE VISION

We have sought here to revisit, refine, and extend the concept ofcancer hallmarks, which has provided a useful conceptualframework for understanding the complex biology of cancer.

The six acquired capabilities—the hallmarks of cancer—havestood the test of time as being integral components of mostforms of cancer. Further refinement of these organizing princi-ples will surely come in the foreseeable future, continuing theremarkable conceptual progress of the last decade.Looking ahead, we envision significant advances during the

coming decade in our understanding of invasion andmetastasis.Similarly, the role of aerobic glycolysis in malignant growth willbe elucidated, including a resolution of whether this metabolicreprogramming is a discrete capability separable from the corehallmark of chronically sustained proliferation. We remainperplexed as to whether immune surveillance is a barrier thatvirtually all tumors must circumvent, or only an idiosyncrasy ofan especially immunogenic subset of them; this issue too willbe resolved in one way or another.Yet other areas are currently in rapid flux. In recent years, elab-

orate molecular mechanisms controlling transcription throughchromatin modifications have been uncovered, and there are

Figure 6. Therapeutic Targeting of the Hallmarks of CancerDrugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in somecases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of theenabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrativeexamples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.

668 Cell 144, March 4, 2011 ª2011 Elsevier Inc.

Hanahan&Weinberg Cell2011

CytostatikaStrålbehandling

Sammanfattningsvis

• Cytostatikahämmarcelldelningmenharolikaverkningsmekanismerocholikabiverkningar

• Målstyrdbehandlingfinnsförmångapatientgrupper.Kanhastoreffektidenpalliativasituationenförvissagrupper

• Immunterapikange(mycket)långöverlevnadsvinstförenmindregrupppatienter

• Nyabehandlingargernyabiverkningar…

Med ca beh PMc - cancerakademin.se€¦ · Docetaxel 75 mg/m2 vs 100 mg/m2 ... Anvisningar för regimen Anvisningar för ordination G-CSF bör ges till alla patienter, f örslagsvis

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