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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)