Cancerele colorectale

1

Epidemiologie

15% din cancere frecventa crescuta : nivel de viata crescut scazuta : Asia, Africa Ro : frecventa < gastric B : F = 1 : 3 3% < 40 ani incidenta incepe sa creasca rapid > 45

an ; se dubleaza cu fiecare deceniu

2

COLORECTAL CANCERCOLORECTAL CANCERincidenta globalaincidenta globala

*Incidenta per 100,000 Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64.

MM39.839.8

FF29.029.0

MM25.325.3

FF18.518.5

MM39.539.5

FF24.624.6

MM45.845.8

FF34.834.8

MM5.05.0

FF3.83.8

MM6.06.0

FF4.24.2

MM11.211.2

FF 8.58.5

MM8.88.8

FF7.97.9

MM44.344.3

FF32.832.8

Eastern Eastern EuropeEurope

JapanJapan

Australia/Australia/New ZealandNew Zealand

South CentralSouth CentralAsiaAsia

Northern Northern AfricaAfrica

Southern Southern AfricaAfrica

Central Central AmericaAmerica

WesternWestern Europe Europe

NorthNorthAmericaAmerica

3

COLORECTAL CANCERCOLORECTAL CANCER1930-1997 decese, barbati, USA1930-1997 decese, barbati, USA

80

70

60

50

40

30

20

10

0

YearYear

Lung & BronchusProstate

Colon & Rectum

1930 1940 1950 1960 1970 1980 1990 1997

Rat

e p

er 1

00,0

00 M

ale

Po

pu

lati

on

Rat

e p

er 1

00,0

00 M

ale

Po

pu

lati

on

Estimated incidence (% of all cancers in men):Prostate=31%; Lung & Bronchus=14%; Colon and rectum=10%

Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.4

COLORECTAL CANCERCOLORECTAL CANCER1930-1997 decese, femei, USA1930-1997 decese, femei, USA

YearYear

80

70

60

50

40

30

20

10

0

Lung & BronchusColon & Rectum

Breast

1930 1940 1950 1960 1970 1980 1990 1997

Rat

e p

er 1

00,0

00 F

emal

e P

op

ula

tio

nR

ate

per

100

,000

Fem

ale

Po

pu

lati

on

Estimated 2001 incidence (% of all cancers in women):Breast=31%; Lung=13%;Colon and rectum=11%

Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36. 5

COLONCOLONAAnatomie si vascularizatie natomie si vascularizatie

RIGHTRIGHT LEFTLEFT

Ascendingcolon

Descendingcolon

Hepaticflexure

Colon transvers

Splenicflexure

Sigmoidcolon

Cecum

Sup.hemorrhoidal

a. and v.

Sigmoid a.

Ileoco

lic a

.

R. colic a.

Midcolic a.

Sup. mesa. and v.

Inf.mes. v.

L. colic a.Inf.mes. a.

Aortasmall

intestine

Artera rusinoasa internaa.hemoroidala medie

Artera hemoroidala inferioara

Rectum

Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271. 6

RECTUMRECTUMAnatomieAnatomie

Left upper valve of HoustonLeft upper valve of Houston

Right middle valve of HoustonRight middle valve of Houston

PeritoneumPeritoneum

Left lower valve Left lower valve of Houstonof Houston

Anal vergeAnal verge

AmpullaAmpullaof of

RectumRectum

22

77

1111

1515upper 1/3upper 1/3

middle 1/3middle 1/3

lower 1/3lower 1/3

PortionPortionofof

RectumRectum

cm fromcm fromanal vergeanal verge

Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1271-1319. 7

COLORECTAL ADENOMACOLORECTAL ADENOMAadenom pediculat adenom pediculat

AdenocarcinomaAdenocarcinoma

AdenomatousAdenomatousepitheliumepithelium

Normal colonicNormal colonicmucosamucosa

MuscularisMuscularismucosaemucosae SubmucosaSubmucosa

MuscularisMuscularispropriapropria

Subserosal connective tissueSubserosal connective tissue

Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271. 8

COLORECTAL ADENOMACOLORECTAL ADENOMAAdenomul sesil Adenomul sesil

AdenocarcinomaAdenocarcinoma

AdenomatousAdenomatousepitheliumepithelium

Normal colonicNormal colonicmucosamucosa

MuscularisMuscularismucosaemucosae SubmucosaSubmucosa

MuscularisMuscularispropriapropria

Subserosal connective tissueSubserosal connective tissue

Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271. 9

COLORECTAL CANCERCOLORECTAL CANCER

MucoasaMucoasaMusculara mucoaseiMusculara mucoasei

SubmucoasaSubmucoasa

Musculara proprieMusculara proprie

SubseroasaSubseroasa

SeroasaSeroasa

Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1155. 10

Etiologie

factori de mediu factori genetici

POLIPII ADENOMATOSI:- 90% din CCR- mai ales pe stinga- risc de malignizare :

- polipii cu displazie severa- vilosi / tubulovilosi- > 1 cm

- profilaxie : depistare + eradicarea polipilor voluminosi

11

Model multistadial (multistep)

mutatii punctiforme K-ras hipometilarea AND care determina activare

genica si amplificarea myc del 5q21 cu pierdere alelica de ADN la nivelul

genei supresoare APC (gena adenomatozei polipoide a colonului)

del 18q cu pierderea alelica a AND la nivelul genei supresoare DCC (gena deletata in cancerul colorectal)

mutatii in gena supresoare p53

12

Etiologie

Factori genetici - 15%-25% dintre CCR au AHC ruda grad I 1. Sindroamele de polipoza familiala - cel mai importanta : polipoza adenomatoasa rectocolica familiala

(FAP) (AD ; dezvoltare pina la adolescenta a > 100

polipi ; CCR predilect stg. , exereza preventiva ) - modificare genetica = 5q21 - urmasii au 50% risc de a mosteni boala

13

Etiologie

Variante : i. Gardner (polipoza colorectala + intestin subtire +

tumori mezenchimale)

ii. Oldfield (+ chiste sebacee multiple)

iii. iii. Turcot (+ tumori SNC)

iv. iv. Sindromul Peutz – Jeghers (+ leziuni mucocutanate) – risc scazut de malignizare

14

Etiologie

Sindroamele de cancer colic familial - AD, - tineri, colon drept FARA polipoza (HNPCC) - 2 variante

= Lynch I – ccr multiple la virste tinere ( cu 2-3 decade mai repede)

= Lynch II – adenocarcinomatoza familiala (adenocc : sin, ovar, pancreas, cai biliare, endometru, stomac)

- modificari in genele de reparare a AND : “DNA mismatch repair genes)

15

Etiologie sindromul adenomului sesil ereditar – tineri , colon

drept, < 100 polipi bolile inflamatorii

RCUH si boala Crohn > 10 ani evolutie colonoscopie > 8 ani ; daca displazie - colectomie

dieta : hiperlipidica, hipercalorica, saraca in fibre cancerogeneza : fecapentanii (produsi de flora

intestinala) , 3-cetosteroizii (metabolismul colesterolului) , benzpirenul (piloliza carnii), acizii biliari , pH-ul alcalin,

protectie : calciu, retinoizii , vitamina C, E si seleniu, AINS (!!!!!)

fumat , colitele granulomatoase, iradierea pelvina ureterosigmoidostomia

16

Screening (risc mediu)

B , F > 50 ani , fara factori de risc :

– test singerari oculte + colonoscopie : la 5 ani– test singerare oculta– sigmoidoscopia 3-5 ani +/- tuseu rectal – colonoscopie la 5 ani– irigografie in dublu contrast la 5 ani– valoare Hemocult : controversata

17

Screening (risc crescut)

la 40 ani , AHC grad I / polip adenomatos: la fel ca la risc mediu

istoric de FAP testare si consiliere genetica sigmoidoscopie 1/ an, de la pubertate

istoric de HNPCC testare + consiliere genetica examinare intreg colon : 20-39 – la 1-2 ani ; > 40 ani ,

1/an

Istori personal de polipi adenomatosi initial , la 3 ani daca normal , la 5 ani daca normal

istoric boala inflamatorie colonoscopie 1-2ani , > 8 ani (de la debutul pancolitei)

; la 15 ani daca doar colon sting 18

Histologie

adenocc – 98% macro : vegetanta , ulcerativa, infiltrativa G1-G4 adenocc mucipare (coloide) – 17%, mucina extracelulara adenocc in inel cu pecete - mucina intracelulara

rar : carcinoide cec, rect limfoame, sarcoame (leio..) canal anal : epidermoide (trat., istoric

diferite)

Prog rezervat

19

Localizare

2/3 – colon sting 1/3 – colon drept cancere sincrone – 4% polipi adenomatosi asociati – 25% incidenta CCR – crescuta - colon > rect

20

Prezentare clinica lipsa de specificitate : dureri abdominale, tulburari de tranzit, hemoragii digestive -- benigne

colon drept : dureri abdominale (74%) astenie (29%) singerare oculta cu anemie secundara (27%) masa abdominala palpabila (23%)

colon sting dureri abdominale (72%) singerare (53%) constipatie (42%) scaderea calibrului scaunului + obstructie

recto-sigmoidiene rectoragii (85%) constipatie (46%) tenesme (30%) diaree (30%) dureri abdominale

21

Cai de extindere

invazie directa circulara, longitudinala, in profunzime invazia capilarelor limfatice, venoase si perineurala interesarea peretelui intestinal seroasa peritoneala,

grasime perirectala organe vecine

diseminare limfatica adenopatii perirectale : 40-70% la diagnostic ulterior – de-a lungul axelor arteriale majore

diseminare hematogena sistem port – meta hepatice – electie exceptie – rect inferior si canal anal – plaminul ale sedii : ovare, os, SR, SNC

diseminare transperitoneala – carcinomatoza peritoneala

diseminare intraoperatorie – evitare

22

Bilant preterapeutic

anameza : AHC , cautarea formelor familiale , polipi ….

examen clinic general : hepatomegalie, ascita la femei : examen sin , ovar

tuseu rectal + examen gine (F) colon : confirmare prin colonoscopie + biopsie rect : confirmare prin rectoscopie + biopsie + colonoscopie :

tumori sincrone eco hepatica + abdomino-pelvina ; rect – endorectala / CT pelvin

Rx pulmonar : PA + profil

markeri : ACE (antigenul carcino-embrionar)

hemoleucograma , bilant hepaticc, creatinina….

23

Bilant preterapeutic

optional :

clisma baritata (dificultati la colonoscopie / tumora ce nu poate fi depasita

CT abdomino-pelvin (incertitudine ecografica / se are in vedere chirurgia hepatica)

dozare CA 19.9 – daca ACE negativ dozare CA 125 – DD ovar

24

COLORECTAL CANCERCOLORECTAL CANCERSistem de clasificareSistem de clasificare

1932 Dukes 1954 Astler & Coller 1975 Gastrointestinal Tumor

Study Group (GITSG)

1978 Gunderson & Sosin(Modified Astler & Coller)

1987 AJCC/UICC

Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271. 25

Factori predictivi pentru transformarea Factori predictivi pentru transformarea maligna a unui adenommaligna a unui adenom

*Relative Risk. Hamilton JM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;156. O’Brien MJ, et al. Gastroenterology. 1990;98:370-379.

Numar:Numar:

Displazie:Displazie:

Histologie:Histologie:

Morphologie:Morphologie:

marime:marime:

Villous: +++

Tubular villous: ++

Tubular: +

Sessile, > pedunculated

< 1 cm: Risc = 1%

1 – 2 cm: Risc = 5–10%

> 2 cm: Risc = 20–50%

RR* creste cu numarul

Risc de transformare maligna:

— Low grade: 6% — High grade: 35%

26

Diagnostic Diagnostic

Hamilton IM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;157.

Stadiu I 15%

Stadiu II 20%–30%

Stadiu III 30%–40%

Stadiu IV 20%–25%

Stadiu la diagnostic Stadiu la diagnostic

27

COLORECTAL CANCERCOLORECTAL CANCERDDefinire Tefinire T

TisTis TT11 TT22 TT33 T T44

MucosaMucosaMuscularis mucosaMuscularis mucosa

SubmucosaSubmucosa

Muscularis propriaMuscularis propria

SubserosaSubserosa

SerosaSerosa

Extensie la organele adiacenteExtensie la organele adiacente28

Clasificare TNM

Definire N No N1 = 1-3 ganglioni pozitivi N2 = >4 ganglioni pozitivi N3 – gaglioni centrali (emergenta)

Definire M : M0, M1

29

LLocalizare si frecventa metastazelorocalizare si frecventa metastazelor

Adapted from Kemeny N, Seiter K. Handbook of chemotherapy in clinical oncology. SCI ed.1993;589-594.

FicatFicat 38-60%

Ganglioni abd. 39%

PlaminPlamin 38%

PeritoneuPeritoneu 28%

OvarOvar 18%

SuprarenaleSuprarenale 14%

PleuraPleura 11%

OsOs 10%

CerebralCerebral 8%

30

Clasificare. Supravietuire

AC Definire Astler-Coller TNM Stadiu S5 mediana

A Tumora limitata la mucoasa T1NoMo I 90-100 %

B1 Perete interresat pina la musculara T2NoMo I 65-85%

B2 Invazie seroasa, subseroasa, organe adiacente

T3-4NoMo II 55-65%

C1 Musculara + N+ T1-2 N1-3 Mo III 40-50%

C2 Seroasa, organe + N+ T3-4 N1-3 Mo III 0-35%

D Meta la distanta M1 IV 6-12 luni

31

Factori de prognostic

cel mai important :stadiu TNM si Dukes in definirea caruia intra :

gradul de invazie transparietala invazia prin contiguitate a organelor vecine invazia ganglionara numarul ggl.invadati prezenta metastazelor hematogene

32

Alti factori factori legati de pacient

sex masculin virsta < 40 ani transfuzii in perioada perioperatorie durata scurta a simptomatologiei pina la diagnostic

factori legati de tumora sediul tumorii (rect, rectosigma) debut prin ocluzie sau perforatie aspect macro infiltrativ

factori anatomopatologici postoperatori G3,G4 mucipar (coloid) sau celule in inel cu pecete / nediferentiat invazie capilara venoasa, limfatica, perineurala prezenta de relicvat tumoral

nivel crescut al ACE preoperator

33

Profilaxie

Dieta fumat – predispozitie pentru polipi fibre , calciu – pot intirzia progresia polipilor –

profilaxie primara

sigmoidoscopia / colonoscopia identificare / indepartare leziuni premaligne –

profilaxie secundara

AINS studii reducerea formarii, numerica si

dimensionala a polipilor si a incidentei CCR , familiale si sporadice

Aspirina , Sulindac 34

Tratament

TUMORA LOCALIZATA , OPERABILA chirurgie radicala

– scop : excizie cu margini de siguranta + LA regionala cu prezervarea functiei

– examinare : ficat, pelvis, ovare– colon : hemicolectomie …..; in CCR complicate (ocluzie,

perforatie) – interventie in 2 timpi – rect :

< 2 cm – amputatie abdominoperineala 2-4 cm : de discutat > 4 cm rezectie anterioara cu anastomoza colo-rectala joasa

sau anatomoza colo-anala +/- rezervor

tratamente adjuvante– CT adjuvanta– RTE

35

Tratament

TUMORA LOCALIZATA , OPERABILA chirurgie

tratament adjuvante prognostic la cei tratati EXCLUSIV chirurgical S5 – 50% ; de ce ? :

boala meta subclinica meta + recidiva locala (25-50%) CT adjuvanta : FU-FOL (6 , sau 24 sapt.) Dukes C (S5 – 50 62%) ,

probabil B2 rect :

CT + RTE (45-55 Gy) ; risc de recidiva fara = 50% (abordare chirurgicala dificila)

Organele pelvine tolerreaza mai bine iradierea CT : debut z7-14, RTE la 4 saptamini postoperator ; plaga nevindecata – 8

saptamini studii europene :

RTE neoadjuvanta (T3-4 No) 45 Gy (+ CT pre si post) refuz nejustificat al multor chirurgi de a opera pe un teren iradiat

36

Tratament

TUMORA PRIMARA INOPERABILA CT = pentru colon RTE (60 Gy) + CT concomitenta FU-FOL pentru

rect

REZECTIA COMPLETA A TUMORII PRIMARE DAR EXISTA META HEPATICE

<4 meta si rezecabile ; chirurgia metastazelor > 4 : chimioterapie

37

Tratament

TUMORA PRIMARA INOPERABILA SI/SAU METASTAZE

colon – CT ; rect – CT +/- RTE paleativa beneficiu CT paleative vs BSC :

supravietuire beneficiu clinic

putin chimiosensibile (20-35%) DAR incidenta crescuta a stabilizarilor (9 luni, dar si ani)

beneficiu clinic : ameliorarea calitatii vietii reducerea simptomelor legate de boala consumul de analgetice cistig ponderal ameliorare IP

38

Tratament

5 Fluorouracilul : 1956 RR > 15% in monoterapie > 40 ani biomodulare cu acid folinic Mayo lunar, Mayo saptaminal , De Gramont

(dose dense) > 25%

’90 : CPT-11 , Oxaliplatin , raltitrexat (tomudex)

analogi 5 FU cu administrare orala – UFT, Xeloda (capecitabina)

rolul acestora : dupa inchiderea trialurilor randomizate

39

Tratamente de salvare

esec prin recidiva locala reinterventie daca este posibil chimioterapie dara reinterventia nu este posibila chimioradioterapie pentru tumori rectale neiradiate

esec prin metastaze– metastazectomie (rezectii pulmonare, hepatice) daca:

boala este controlata local interval > 6 luni de la tratamentul primar exsita premisele eradicarii complete a bolii metastatice

decelabile (unice, multiple rezecabile in totalitate) – CT daca nu este posibila chirurgia

esec locoregional si metastaze CT

40

Chimioterapia . Nota

indicatie : IP 0-2 ; la cei cu IP 3-4 BSC

chimioterapia este intrerupta in caz de BE

fara CT anteriora / DF > 6 luni de la CT adjuvanta = FU-FOL

< 6 luni CT de linia II-a : CPT-QQ, Oxaliplatin ,…

41

Umarire postterapeutica si evaluare

1 an 2 an 3-lea an 4 si 5

Examen clinic (ficat, ggl. TR)

La 3 luni La 6 luni

ACE, Eco abd. 3 luni 6 luni

Colonoscopie La 3 ani dupa 2 colonoscopii normale facute la1 an interval

Ecoendoscopie (rect)

6 luni anual

Rgr pulmonar Annual anual

42

WHERE HAVE WE COME FROMWHERE HAVE WE COME FROM WWITH CAMPTOITH CAMPTO®® ? ?

Lancet 1998

Lancet 2000; NEJM 2000

1972 1972 1987-1991 19919955 19919988 20002000

Phase IICamptothecin trial associatedwith high incidence of adverse events

CAMPTO®CAMPTO®

+ + 5FU5FU/FA/FAStStandarandarddTTherapyherapyMCRC MCRC 1st1st-line-line

CPT-II CPT-II semi syntheticCamptothecin Derivativeshowsactivity in pre-clinical models

CAMPTO ®: CAMPTO ®: benefit benefit in 2nd line CRC: registration

CAMPTO CAMPTO ®®is the new Reference in MCRCMCRC 2nd2nd-line-line

43

Raspuns la chimioterapie

Pacient 1

Pacient 2

44

New Molecular TargetsEpidermal growth factor receptor (EGFr)

Signal transduction

EGF

P P

Intracellular

C225 mAb

Extracellular

Tyrosine kinase

EGF-Receptor

ZD1839

45