p53 adapted neoadjuvant therapy for esophageal cancer: Pilot study

Gastrointestinal (Non colorectal) cancer

Poster discussion session

Sat, June 2, 2007

2002

MRCLancet

1988

INTNEJ

The two largest trials The two largest trials produced conflicting resultsproduced conflicting results

34%13402SURGERY

0.00443%17400CIS/5FU+SURGERY

37%16234SURGERY

ns35%15233CIS/5FU +SURGERY

pOVS 2y

mediansurvival

# Therapy

vs

vs

…indicating moderate efficiency of standard neoadjuvant therapy

Pathologic response to neoadjuvant Pathologic response to neoadjuvant therapy improves overall survival therapy improves overall survival

significantysignificanty

neoadjuvant therapy

allOVS 3 ys pCR

OVS 3 ys

Urba, JCO 2001

CIS/5FU, VBL, 45 Gy + Surg 30% 28% 64%

Esophageal Cancer - Neoadjuvant Therapy:

…Overall failure rate = p53 mutation rate (60%)…

60%40%

PILOT STUDY:Prospective evaluation of hypothesis

38 operable esophageal cancer patients,prospectively recruited between 2004-2006

Neoadjuvant therapy:

30 patients CIS/5FU Cisplatin 80mg/m2 d1, 5FU 1000mg/m2 d1-52 cycles q21d

8 patients Docetaxel off label Docetaxel 75mg/m2

2 cycles q21d

The presence of p53 mutations must not be assessed by immunohistochemistry

…sequence analysis is the golden standard

immunohistochemistrysequence analysis

Neoadjuvant treatment 1: CIS/5FU

Response

CR, PR

Failure

SD, PD

p53 normal 12 2

p53 mutant 0 16

p=0,0001

30 patients

Neoadjuvant treatment 2 : Docetaxel

Response

CR, PR

Failure

SD, PD

p53 normal 0 2

p53 mutant 6* 0

8 patients off label

*including 4 CR

p53 mutation by histology

p53 normal

p53 mutant

adeno 9 9 50%

squamous 7 13 65%

42% 58%

p53 mutation

frequency

Correct response prediction in 36/38 patients (95%).

CR, PR SD, PD

CIS/5FU

p53 normal 12 2

p53 mutant 0 16

Docetaxel

p53 normal 0 2

p53 mutant 6 0

p53 adjusted versus non adjusted therapy

p=0,027

Überlebensfunktionen

MONTH

403020100

Ku

m.

Üb

erl

eb

en

1,0

,8

,6

,4

,2

0,0

P53

2

2-zensiert

1

1-zensiert

p53 adjusted

p53 not adjusted

p=0,042

months

median follow up: 15,4 months

Ove

rall

surv

ival

…Selection of the appropriate therapy based on the p53 genotype

FailureBenefit

side

effe

cts

costs

… could significantly improve likelihood of response

PANCHO: P53 Adapted Neoadjuvant Chemotherapy for Oesophageal cancer

Prospective, randomized controlled,

PREDICTIVE MARKER TRIAL

…designed to test the p53 predictive factor question

Pancho : trial design

randomize

p53 mutant

randomize

stratify *

stratify *

p53 normal

p53gene

analysis

Patients with resectableesophageal cancer

S

U

R

G

E

R

Y

Cisplatin 80 mg/m², day 1, 3 cycles

5-FU 1000 mg/m² days 1-5; q 21,3 cycles

Docetaxel 75 mg/m², day 1, q 21, 3 cycles

Cisplatin 80 mg/m², day 1, 3 cycles

5-FU 1000 mg/m² days 1-5; q 21,3 cycles

Docetaxel 75 mg/m², day 1, q 21, 3 cycles

* Stratification for adeno- and squamous cell cancer

Primary endpoint: RESPONSE to neaoadjuvant therapy

PANCHO

• Start: Mai 2007 • 84 patients to be randomized within 18 months

• Intended by www.p53.at

• Sponsored by the ASSO

(Austrian Society for Surgical Oncology)