p53 adapted neoadjuvant therapy for esophageal cancer: pilot study
DESCRIPTION
p53 adapted neoadjuvant therapy for esophageal cancer: Pilot study. Gastrointestinal (Non colorectal) cancer Poster discussion session Sat, June 2, 2007. The two largest trials produced conflicting results. Therapy. #. median survival. OVS 2y. p. CIS/5FU +SURGERY. 233. 15. 35%. - PowerPoint PPT PresentationTRANSCRIPT
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p53 adapted neoadjuvant therapy for esophageal cancer: Pilot study
Gastrointestinal (Non colorectal) cancer
Poster discussion session
Sat, June 2, 2007
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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
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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%
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Esophageal Cancer - Neoadjuvant Therapy:
…Overall failure rate = p53 mutation rate (60%)…
60%40%
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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
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The presence of p53 mutations must not be assessed by immunohistochemistry
…sequence analysis is the golden standard
immunohistochemistrysequence analysis
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Neoadjuvant treatment 1: CIS/5FU
Response
CR, PR
Failure
SD, PD
p53 normal 12 2
p53 mutant 0 16
p=0,0001
30 patients
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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
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p53 mutation by histology
p53 normal
p53 mutant
adeno 9 9 50%
squamous 7 13 65%
42% 58%
p53 mutation
frequency
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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
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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
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…Selection of the appropriate therapy based on the p53 genotype
FailureBenefit
side
effe
cts
costs
… could significantly improve likelihood of response
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PANCHO: P53 Adapted Neoadjuvant Chemotherapy for Oesophageal cancer
Prospective, randomized controlled,
PREDICTIVE MARKER TRIAL
…designed to test the p53 predictive factor question
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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
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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)