Cancerele colorectale

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 CANCER
incidenta globala
Western Europe Eastern Europe Japan Australia/ New Zealand South Central Asia Northern Africa

M F

39.8 29.0

M F
M F M F M F M F M F M F M F

25.3 18.5
39.5 24.6 45.8 34.8 5.0 3.8 6.0 4.2 11.2 8.5 8.8 7.9 44.3 32.8

Southern Africa
Central America North America
*Incidenta per 100,000

Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64.

COLORECTAL CANCER
1930-1997 decese, barbati, USA
80

Rate per 100,000 Male Population

70 60 50 40 30 20 10

Prostate Lung & Bronchus Colon & Rectum

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

0
1930 1940 1950 1960

Year

1970

1980

1990 1997

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

COLORECTAL CANCER
1930-1997 decese, femei, USA
80

Rate per 100,000 Female Population

70 60 50 40 30 20 10 0 1930 1940

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

1950

1960

Year

1970

1980

1990

1997

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

COLON Anatomie si vascularizatie

Colon transvers Splenic flexure Hepatic flexure
Mid colic a. Sup. mes a. and v. Inf. mes. v.

R. colic a.

Ascending colon
small intestine Sup. hemorrhoidal a. and v.

L. colic a. Inf. mes. a. Aorta

Descending colon

Cecum

Sigmoid colon

RIGHT
Rectum

LEFT
Artera rusinoasa interna

a.hemoroidala medie

Artera hemoroidala inferioara

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

RECTUM
Anatomie
Portion of Rectum upper 1/3 cm from anal verge Left upper valve of Houston Right middle valve of Houston 15 Peritoneum

middle 1/3

11

Ampulla of Rectum

Left lower valve of Houston

lower 1/3

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

COLORECTAL ADENOMA
adenom pediculat
Adenocarcinoma

Adenomatous epithelium

Normal colonic mucosa Muscularis mucosae

Submucosa Muscularis propria

Subserosal connective tissue

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

COLORECTAL ADENOMA
Adenomul sesil
Adenocarcinoma

Adenomatous epithelium Normal colonic mucosa Muscularis mucosae

Submucosa

Muscularis propria

Subserosal connective tissue

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

COLORECTAL CANCER

Mucoasa Musculara mucoasei Submucoasa

Musculara proprie

Subseroasa Seroasa

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.
iii. iv.

Oldfield (+ chiste sebacee multiple)

iii. Turcot (+ tumori SNC) 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 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 (!!!!!)

dieta :

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 testare si consiliere genetica sigmoidoscopie 1/ an, de la pubertate testare + consiliere genetica examinare intreg colon : 20-39 la 1-2 ani ; > 40 ani , 1/an initial , la 3 ani daca normal , la 5 ani daca normal colonoscopie 1-2ani , > 8 ani (de la debutul pancolitei) ; la 15 ani daca doar colon sting
18

istoric de FAP

istoric de HNPCC

Istori personal de polipi adenomatosi

istoric boala inflamatorie

Histologie
adenocc 98% macro : vegetanta , ulcerativa, infiltrativa G1-G4

adenocc mucipare (coloide) 17%, mucina extracelulara adenocc in inel cu pecete - mucina intracelulara

Prog rezervat

rar : carcinoide cec, rect limfoame, sarcoame (leio..) canal anal : epidermoide (trat., istoric diferite)
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%) dureri abdominale (72%) singerare (53%) constipatie (42%) scaderea calibrului scaunului + obstructie rectoragii (85%) constipatie (46%) tenesme (30%) diaree (30%) dureri abdominale

colon sting

recto-sigmoidiene

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

diseminare limfatica

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 CANCER
Sistem 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 maligna a unui adenom

Histologie:

Villous: Tubular villous: Tubular:

+++ ++ +

Sessile, > pedunculated

Morphologie:

marime:

< 1 cm: Risc = 1% 1 2 cm: Risc = 510%

> 2 cm: Risc = 2050%

Numar: Displazie:

RR* creste cu numarul Risc de transformare maligna: Low grade: 6% High grade: 35%

*Relative Risk.

Hamilton JM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;156. OBrien MJ, et al. Gastroenterology. 1990;98:370-379.

26

Diagnostic
Stadiu la diagnostic
Stadiu I Stadiu II Stadiu III Stadiu IV 15% 20%30% 30%40% 20%25%

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

27

COLORECTAL CANCER Definire T

Tis
Mucosa Muscularis mucosa

T1

T2 T3

T4

Submucosa

Muscularis propria

Subserosa
Serosa

Extensie la organele adiacente

28

Clasificare TNM

Definire N No N1 = 1-3 ganglioni pozitivi N2 = >4 ganglioni pozitivi N3 gaglioni centrali (emergenta) Definire M : M0, M1

29

Localizare si frecventa metastazelor

Ficat
Ganglioni abd. Plamin Peritoneu Ovar Suprarenale Pleura Os Cerebral

38-60%
39% 38% 28% 18% 14% 11% 10% 8%

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

30

Clasificare. Supravietuire
AC A

Definire Astler-Coller
Tumora limitata la mucoasa

TNM
T1NoMo

Stadiu
I

S5
mediana
90-100 %

B1
B2

Perete interresat pina la musculara T2NoMo

Invazie seroasa, subseroasa, organe adiacente
T3-4NoMo

65-85%

II

55-65%

C1 C2
D

Musculara + N+ Seroasa, organe + N+

Meta la distanta

T1-2 N1-3 Mo

III

40-50%

T3-4 N1-3 Mo

III

0-35%

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
sediul tumorii (rect, rectosigma) debut prin ocluzie sau perforatie aspect macro infiltrativ

factori legati de tumora

factori anatomopatologici postoperatori

G3,G4 mucipar (coloid) sau celule in inel cu pecete / nediferentiat invazie capilara venoasa, limfatica, perineurala prezenta de relicvat tumoral
33

nivel crescut al ACE preoperator

Profilaxie

Dieta

fumat predispozitie pentru polipi fibre , calciu pot intirzia progresia polipilor profilaxie primara identificare / indepartare leziuni premaligne profilaxie secundara studii reducerea formarii, numerica si dimensionala a polipilor si a incidentei CCR , familiale si sporadice Aspirina , Sulindac
34

sigmoidoscopia / colonoscopia

AINS

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 colorectala 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
Examen clinic (ficat, ggl. TR)

2 an
La 3 luni

3-lea an 4 si 5
La 6 luni

ACE, Eco abd. Colonoscopie

Ecoendoscopie (rect) Rgr pulmonar

3 luni

6 luni

La 3 ani dupa 2 colonoscopii normale facute la1 an interval 6 luni Annual anual anual
42

WHERE HAVE WE COME FROM ? WITH CAMPTO

1972 1987-1991 1995 1998 2000

Phase II Camptothecin trial associated with high incidence of adverse events

CPT-II semi synthetic Camptothecin Derivative shows activity in preclinical models

CAMPTO : benefit in 2nd line CRC: registration

CAMPTO is the new Reference in MCRC 2nd-line

CAMPTO

+ 5FU/FA Standard Therapy MCRC 1st-line

Lancet 1998

Lancet 2000; NEJM 2000 43

Raspuns la chimioterapie
Pacient 1

Pacient 2

44

Epidermal growth factor receptor (EGFr)

New Molecular Targets

EGF-Receptor

C225 mAb

EGF

Extracellular

Intracellular Tyrosine kinase

ZD1839
Signal transduction
45