Multidisciplinary treatment of rectal cancer. Medical oncology

Multidisciplinary treatment of rectal cancer. Medical oncology

Carlo AscheleE.O. Ospedali Galliera – Genova - Italy

Carlo AscheleE.O. Ospedali Galliera – Genova - Italy

ESMO CONFERENCE - LUGANO July 5-8 2007

Multidisciplinary treatment of rectal cancer

Multidisciplinary treatment of rectal cancer

extraperitoneal rectal cancer

locally advanced rectal cancer

extraperitoneal rectal cancer

locally advanced rectal cancer

Rigid rectoscopy - TRUS - CT scan - MRI

Standard treatment of locally advanced rectal cancer

Standard treatment of locally advanced rectal cancer

TME

45-50.4 Gy

CT

RT

Role of chemotherapyPRE-OP RT +/- CONCOMITANT CT

Role of chemotherapyPRE-OP RT +/- CONCOMITANT CT

pCR, %

RT RT + CT

EORTC 5 14

FFCD 3 10

Bosset, NEJM 2006; Gerard, JCO 2006

Role of chemotherapyPRE-OP RT +/- CONCOMITANT CT

Role of chemotherapyPRE-OP RT +/- CONCOMITANT CT

5-y LR, %

RT RT + CT

EORTC 17 8

FFCD 16 8

Bosset, NEJM 2006; Gerard, JCO 2006

Standard treatment of locally advanced rectal cancer

Standard treatment of locally advanced rectal cancer

TME

45-50.4 Gy

CT

RT

Dutch TME trial vs German trialDutch TME trial vs German trial5-year overall survival

Pre-op CMTPre-op CMT

Post-op CMTPost-op CMT

Years since surgeryYears since surgery

66 % vs 65 % 66 % vs 65 % p = 0.98p = 0.98

Marijnen et al, GIASCO 2005, Abstr 166; Sauer et al NEJM 2004

00 11 22 33 44 55 66 77 88 9900

0.20.2

0.60.6

1.01.0

00 11 22 33 44 55 66 77 88 9900

0.20.2

0.60.6

1.01.0

Years since surgeryYears since surgery

RT + TMERT + TME

TME aloneTME alone

76 % vs 74 %76 % vs 74 % p = 0.80p = 0.80

Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004

(NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791

ROLE OF CHEMOTHERAPY ROLE OF CHEMOTHERAPY POST-OP COMBINED-MODALITY POST-OP COMBINED-MODALITY

TREATMENTTREATMENT

CT

No CT

PRE-OP CHEMORADIATION: ORAL FP’s

PRE-OP CHEMORADIATION: ORAL FP’s

studies patients pCR(%)

g 3-4 tox(%)

Capecitabine 14 668 4-31 6-40

UFT 11 538 8-25 6-32

Eniluracile 1 22 6 nr

NSABP R-04NSABP R-04

RTRT + + CapecitabineCapecitabine +/- oxaliplatin +/- oxaliplatin

S

RT + RT + CI 5-FUCI 5-FU +/- oxaliplatin +/- oxaliplatin

R

N=1460

Norway NSABP-R01 GITSG-1 Mayo-NCCTGGITSG-2 INT-0114 NSABP-R02 INT-PVIDutch-TME Ulsan CAO/ARO/AIO

Decline in the rates of local failure: 1980s–2000sDecline in the rates of local failure: 1980s–2000s

35

30

25

20

15

10

5

0

Lo

cal

fail

ure

(%

)

sx only sx RT sx CTRT TME +RT/CTRT

NSABP-R02 INT-0114 Norway GITSG-1NSABP-R01 Mayo-NCCTG INT-PVI GITSG-2Dutch-TME Ulsan CAO/ARO/AIO

Proportion of patients with distant metastases: 1980s–2000sProportion of patients with distant metastases: 1980s–2000s

40

35

30

25

20

15

10

5

0

Dis

tan

t m

etas

tase

s (%

)

sx only sx RT sx CTRT TME +RT/CTRT

ONGOING STUDIES OF COMBINATION CHEMOTHERAPY IN LARC

ONGOING STUDIES OF COMBINATION CHEMOTHERAPY IN LARC

Post-op E3201E5204Chronicle

Pre-op STARNASBP R-04

Pre and post-op PETACC-6

Post-op E3201E5204Chronicle

Pre-op STARNASBP R-04

Pre and post-op PETACC-6

OXALIPLATIN + FP’s

% of patients

FU/RT FU/OXA/RT

Grade III-IV toxicity(mainly diarrhoea) 10 24

Ability to completeradiotherapy (> 80 %) 98 95

Ability to performsurgery 98 96

Preliminary safety findings:toxicity (n=313)

Aschele, ASCO GI & ASCO 2007

PRE-OP CHEMORADIATIONINCORPORATION OF BIOLOGICS

PRE-OP CHEMORADIATIONINCORPORATION OF BIOLOGICS

Cetuximab+ FU (1) pCR=12%+ cape (1) pCR=5%+ cape/ox (1) pCR=8%+ cape/iri (2)pCR=25-20%

??: adk=squamous - ras - arrest of cell cycle progression

Bevacizumab+ FU (1) no pCR at the RD / surrogate markers+ cape/oxa (1) pcR: 18%

??: toxicity - normalization vs antivascular effect - timing

Cetuximab+ FU (1) pCR=12%+ cape (1) pCR=5%+ cape/ox (1) pCR=8%+ cape/iri (2)pCR=25-20%

??: adk=squamous - ras - arrest of cell cycle progression

Bevacizumab+ FU (1) no pCR at the RD / surrogate markers+ cape/oxa (1) pcR: 18%

??: toxicity - normalization vs antivascular effect - timing

2004-2007

MULTIDISCIPLINARY TREATMENT OF RECTAL CANCER

MULTIDISCIPLINARY TREATMENT OF RECTAL CANCER

PRE-OP CHEMORADIATIONINCORPORATION OF BIOLOGICS

PRE-OP CHEMORADIATIONINCORPORATION OF BIOLOGICS

Better understanding of underlying biology

Definition of optimal timing and duration (induction vs concomitant or both)

Definition of an appropriate back-bone regimen

Patient selection

Better understanding of underlying biology

Definition of optimal timing and duration (induction vs concomitant or both)

Definition of an appropriate back-bone regimen

Patient selection

Studio Terapia Adiuvante Retto 2 (PAN-STAR)

Studio Terapia Adiuvante Retto 2 (PAN-STAR)

Oxa Oxa Oxa Oxa Oxa Oxa

5-FLUOROURACIL

RT RTRT RT RT RT

PAN PAN PAN PAN

- T4 and/or - T4 and/or - cN2 (> than 3 radiologically involved nodes) and/or- cN2 (> than 3 radiologically involved nodes) and/or- MRI prediction of +CRM - MRI prediction of +CRM

Phase IIn=70

INDUCTION CHEMOTHERAPYINDUCTION CHEMOTHERAPY

D1 D22

…x4

Patients with MRI defined poor-risk rectal cancer

T

M

E

RD1 D22

…x4

D1 D22

…x4

D1 D22

…x4

Oxa: 130 mg/m2/d

Cape: 2000 mg/m2/d

Cetuximab: 400 mg/m2 D1 than 250 mg/m2 weekly

Cape: 1650 mg/m2/d

RT:45 Gy+ 9Gy boost Oxa: 130 mg/m2/dCape: 2000 mg/m2/d

Phase IIn=164

EXPERT-C