Colorectal tumors 950.000 new patients in the world 13% of all tumors The incidence of colorectal tumor is increasing 8000 new patients in Hungary/year.

Colorectal tumors

950.000 new patients in the world

13% of all tumors

The incidence of colorectal tumor is

increasing

8000 new patients in Hungary/year

5000 patients die from colorectal cancer

1. Occurence of colorectal tumors

Their number increases worldwide. Represents the third cause of tumorous deaths both in male and females. In man the first two are lung and prostatic cancer in women lung and breast cancer. Geographical differencies are also to be observed, is more frequent in developed countries. In Hungary is the second most frequent cause of death after lung cancer. Yearly are discovered 8500-9000 new cases yearly in both sexes, death is 5000 yearly. Incidence is 43/100 000 people.

1. Occurence of colorectal tumors

Both sexes are equally involved, rate is 1,2:1. The rectal malignancies are more rare than the upper colon malignomas. Below 40 is rare but after this age the frequency increases, the majority of patients are between 60-70 years of age.

Colorectal cancer stage

II IIII IIIIII IVIV

Bowel wallBowel wall Invades bowel Invades bowel wallwall Lymph node Lymph node

involmentinvolment Distant Distant metastasesmetastases

The stage of colon cancer at time of diagnosis

Stage I. : 10-15%

Stage II.: 20–30%Stage III. : 30–40%

Stage IV: 25-30%

5-years survival: 5–40%

2. Risk faktors of colorectal cancer

• Environmental factors : After 1-2 generation the higher tumor incidence of the adopting country develops in the low risk asian, african, and south american populations• Nutrition : high fat, protein and alcohol consumption• High calcium intake, fruits, legumes, fibers lower its incidence•Genetical factors : Inherited non-adenomatous polyposis and adenomatous polyposis syndromes, chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease)•Positive tumorous anamnesis : in women breast, uterus, adnex tumors and in men colo-rectal cancer presents higher risk • Previous operations : cholecystectomy

Colorectal cancer symptoms

rectal bleeding change in bowell defecation habits signs of ileus, abdominal pain, meteorism, tenesms when the tumor is located in the left bowell the right bowel tumors often are asymptomatic anemia, fatigue, loss of weight, loss of appetite, icterus

Colorectal cancer –screening and chemoprevention

• Rectal digital examination , and haemmocult test is used for detection of hidden rectal bleeding. In case of positivity endoscopic examinations are proposed.• With the detection of colon adenomas, and polipectomy the incidence of cancer decreased with 76-90 %.•The role of chemoprevention is to block the carcinogenesis, before the tumor developed : Beta carotin, vitamin-C, vitamin-E, calcium, non-steroidal antiinflamatory drugs.

Colorectal cancer-examinations

Laboratory: •Total blood count, liver function, renal function, proteins, ions, clotting factors. •Tumor markers: CEA and CA 19-9 Imaging modalities:•. Endoscopy, irrigoscopy. The benefit of endoscopy is that biopsy can be taken and polips can be remowed •The irrigoscopy could complete the endoscopy, when because of stricure the bowell can not be examined with endoscopy and before operation the examination of all the bowell is needed. •Abdominal sonography, abdominal CT, MRI, thoracal X-ray, CT, PET

The treatment of colorectal cancerThe treatment of colorectal cancer

• Surgical treatment• Irradiation - for rectal cancer• Chemotherapy• Biological treatment– like Avastin®

(bevacizumab) and Erbitux ( EGFR inhibitor)

Adjuvant treatmentAdjuvant treatment

Neoadjuvant treatmentNeoadjuvant treatment

Treatment of metastasesTreatment of metastases

The treatment of colorectal cancerThe treatment of colorectal cancer

• Chemotherapy• Adjuvant treatmentAdjuvant treatment

administrated after operation, to administrated after operation, to prevent recidive of cancerprevent recidive of cancer

Adjuvant treatment of colorectal cancerAdjuvant treatment of colorectal cancer

Chemotherapy

1. fluoropyrimidines ( 5FU, capecitabine)

2. oxaliplatin ( platinum compound) is given in combination with other anticancer drugs (fluorouracil and leucovorin)=FOLFOX

Adjuvant treatment( hystory)

1990: 5-FU/levamisole (LEV) is better than surgical treatment1994: 5-FU/LV is better, than surgical treatment 1998: 5-FU/LV is better, than 5-FU/LEV1998: 6 month treatment = 12 month treatment1998 LEV has side effects (neurotoxicity!)1998 weekly treatment = monthly treatment2002 5-FU/LV = monthyl bolus2003 5-FU infusion is better, than 5-FU bolus2003 FOLFOX is better, than 5-FU/LV (MOSAIC)

5-FU basical treatments in colon cancer adjuvant treatmentstudy Study arms 3 year DFS

QUASAR (4 927pts)

(Chau I. Ann Oncol 2006)

5FU/LV fix dose

5FU/LV fix dose hetente 5FULV/LEV H/L dose monthly

5FU/LVplac H/L dose

36.0%

35.8%

37.0%

34.9%

X-ACT (1 987 beteg)

(Twelves et al. NEJM 2005)

5FULV (bolus)

Xeloda

60.6%

64.2%

PETACC 3 (2 094 st.III pts)

(Cutsem et al. ASCO 2005 Abstr. 8)

LV5FU2

LV5FU2+Irinotecan

59.9%

62.9%

NSABP C07 (2 407 pts)

(Wolmark et al. ASCO 2005 Abstr. 3500)

5FULV weekly bolus

FLOX (Oxali+5FU/FV)

71.6%

76.5% s.

MOSAIC (2 246 pts)

(André et al.NEJM 2004)

5FULV

FOLFOX 4

72.9%

78.2% s.

MOSAIC: 5 year DFSMOSAIC: 5 year DFS

3 years

(2003 April)

5 years (2006 June)

FOLFOX4(n=1123)

LV5FU2(n=1123)

FOLFOX4(n=1123)

LV5FU2(n=1123)

Median follow up months

37.9 37.8 73.5 73.4

Cases (%) 21.1 26.1 27.1 32.1

DFS (%) 78.2 72.9 78.5 75.8

HR 0.77 0.80

[95% CI] [0.65–0.91] [0.68–0.93]

p-value 0.002 0.003

De Gramont et al. ASCO 2007. Abstract 4007.

MOSAIC: sensorMOSAIC: sensoryy neuropathy neuropathy

Grade 0 –

Grade 1 –

Grade 2 –

Grade 3 –

Sub treatment

1. month 6 months 12 months 18 months

Pat

ien

ts (

%)

100

90

80

70

60

50

40

30

20

10

0

André T et al. N Engl J Med 2004; 350:2343-51

Survival Colorectal carcinoma stage II., III. and IV

•Stadium n T&N 5 years survival

•II 34 261 T3-T4 N0 82.5 %•IIa 28 635 T3-N0 84.7 %•IIb 5 826 T4 N0 72.2 %

•III 26 249 Tx, N1 ,2 59,5 %•IIIa 1 989 T1-2, N1 83.4 %•IIIb 15 940 T3-4, N1 64.1 %•IIIc 8 600 Tx, N2 44.3 %•IV Tx, NX, M1 30%

High risc stage II. patients

• pT4• ileus • perforation • ulceration• low differentiated tumors• vascular invasion• lymph nodes examinated - 13. • inflamatory bowell diseases • younger than 40 years • CEA (increased 4ng/ml )• Molecular prognostic factors:TS, LOH/ 18Q loss of heterozigozity negatív prognostic factor., MSI

The influence of number of removed lymph nodes to survival

35787 patients stage T3N0

Removed lymph. nodes: 5 year survival

1-7 lymph nodes. 49,8 %

8-12 lymph nodes 56,2 %

more than 13 lymph nodes 63,4 %

P o,ooo1

Swanson RS, Ann Surg onc. 2003

Treatment of rectal tumorsTreatment of rectal tumors

Neoadjuvant chemotherapy+irradiation therapy The chemotherapy has a role to sensitisate the tumor cells to irradiation

fluoropyrimidines ( 5FU)+ irradiation to prevent the local recidive

After operation we can continue the treatment with adjuvant chemotherapy

Treatment of metastatic colorectal cancerTreatment of metastatic colorectal cancer

1. Chemotherapy1. fluoropyrimidines ( 5FU, capecitabine)2. oxaliplatin ( platinum compound) is

given in combination with other anticancer drugs (fluorouracil and leucovorin)=FOLFOX

3. irinotecan is given in combination with other anticancer drugs (fluorouracil and leucovorin)=FOLFIRI

2. Biological treatmentbevacizumab ( VEGF inhibitor)cetuximab and panitumumab ( EGFR

inhibitor)

00 66 1212 1818 2424

1990- 5-FU/LV

IFL

FOLFOX

FOLFOX/FOLFIRI szekvenciális

IFL + bevacizumab

1960- Best supportive care

1970–1980 5-FU

Overall survival (months)3030

Oxaliplatinfluoropyrimidin+ bevacizumab

Treatment of metastatic colorectal

Can be improved with VEGF + EGFR inhibitors?

Hochster et al. ASCO 2006 Abstr. 3510.

The treatment of metastatic colorectal cancer

•I. CIFUFA, capecitabine ,than: FOLFIRI

•

irinotecan+cetuximabFOLFOX

FOLFOXirinotecan+cetuxim.

II. FOLFIRI than*: FOLFOX

irinotecan-cetuximab

FOLFIRI-cetuximab

FOLFOX

III. FOLFOX than*: FOLFIRI irinotecan-cetuximab

IV. irinotecan-bevacizumab than:FOLFOXirinotecan-cetuximab

irinotecan-cetuximabFOLFOX

SurvivalSurvivalSurvivalSurvival

Probability

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 36 42 months

p = 0.9

FOLFIRI / FOLFOX

FOLFOX / FOLFIRI

FOLFIRI/FOLFOX FOLFOX/FOLFIRI

months 21.5 [16.9-25.2] 20,6 [17.7-24.6]

65/10967/111

Follow-up

18.6 months

30

•FOLFOX

•n = 111

•35

•4

•FOLFIRIn = 69

B

•79

•56 (3)

•FOLFIRI

•n = 109

•0.68

•p valu

e

•63

•15

•FOLFOX

•n = 81

•ORR + SD %

•ORR (CR) %

A

TOURNIGAND study- EfficacyTOURNIGAND study- EfficacyTOURNIGAND study- EfficacyTOURNIGAND study- Efficacy

•81

•54 (5)

The biological targets of tumor treatment (regulation of tumor cell proliferation and groth)

1

2

3

4

5

Nucleus

1. Groth factors (GF) and ther receptors (GFR) HER/EGFR, C-kit, PDGF

2. Extracellular matrix – angiogenesis ways VEGF, intergrins, MMP

3. Signal transduction ways Ras, raf, MAPK, MEK, PKC

4. Cell survival ways CDK, mTOR, cGMP, COX-2, p53, Bcl-25. Proteosoma

ErbB signal transduction ways

Grb2 Sos

Shc Grb2Sos

PI3KAkt

Ras

Raf

MEK1/2

MAPKBAD

Survival Proliferation

PTEN

mTOR

Progression of cell cycle

FKHRGSK3p27

Cyclin D1, E

Treatment of metastatic colorectal cancerTreatment of metastatic colorectal cancer

2. Biological treatmentcetuximab and panitumumab ( EGFR

inhibitors) can be used only in

K-RAS wild tumors

usually are given in combination with other anticancer drugs -FOLFOX or FOLFIRI

CRYSTAL study: PFS

Progression-free survival time (months)

PF

S e

stim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

HR = 0.851; 95% CI = [0.726-0.998]

Stratified log-rank p-value = 0.0479

8.9 months8.0

months

FOLFIRI, n=599

Cetuximab + FOLFIRI, n=599

1-year PFS rate23% vs 34%

Subjects at risk

FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI

599 499 392 298 196 103 58 29 12 5 1

CRYSTAL trial:Sub group analysis PFS depending on skin reactions :

cetuximab + FOLFIRI

Skin reaction grade 0 or 1, n=244

*No grade 4 skin reaction

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Progression-free survival time (months)

1.00

0.75

0.50

0.25

0.00

PF

S e

stim

ate

Skin reaction grade 2, n=243

Skin reaction grade 3*, n=112

11.3 mo5.4 mo 9.4 mo

The role of angiogenesis in tumor growth

Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

Tumor progression, with central role of angiogenesis

Premalignant status

Malignanttumor

Tumorgrowth

Vascularinvasion

Micrometastasis Metastasis

(Avasculartumor)

(Angiogenswitch)

(Vascularisedtumor)

(Tumor cell invasion))

(metastases) (Secunder angiogenesis)

Antivascular treatment results in decrease of the Antivascular treatment results in decrease of the vessels in the tumorvessels in the tumor

Changes the structure of the vessels, Changes the structure of the vessels, decreases the fenestration, the permeability,decreases the fenestration, the permeability, increases the pericitic cover and so the efficacy increases the pericitic cover and so the efficacy

of the chemotherapyof the chemotherapy

Biological treatment: VEGF inhibition

IFL ± Avastin phase III study in metastatic CRC /Hurwitz/ : total survival

Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001

CI = confidenciaintervallum

Like

lihood o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + bevacizumab

IFL + placebo

15.6 20.3

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

+30%

IFL ± Avastin phase III study in MCRC /Hurwitz/ : survival without progression

Median survival without progression (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0)HR=0.54 (95% CI: 0.45–0.66) p<0.001

Like

lihod

of

lack

of

pro

gre

ssio

n

1.0

0.8

0.6

0.4

0.2

00 10 20 30

Median survival without progression (months)

6.2 10.6

IFL + bevacizumab

IFL + placebo

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

+71%

Side effects related to Avastin

• They are different from the usual citotoxic side effects!

• Hipertension (most frequent)

• Proteinuria

• Arterial thrombosis

• Effect on scar formation

• Bleeding complication

• GI perforation

Kabbinavar F, et al. J Clin Oncol 2003;21:60–5Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Giantonio BJ, et al. J Clin Oncol 2004;22 (July 15 Suppl.): Abstract 3017

Vascular effects

It is to suppose that treatment should be continued also after pogression

Start of new vasculature development after stopping of anti-VEGF therapy1–3

1Kamba, et al. Am J Physiol Heart Circ Physiol 20062Vosseler, et al. Cancer Res 2005

3Mancuso, et al, J Clin Invest 20064Hu-Lowe, et al. Proc Am Assoc Cancer Res 2002

Untreated Anti-VEGF, 7 days Withdrawal, 2 days Withdrawal, 7 days

*AG-013736; terminal half-life of 6–7 hours4