Nuovi dati Colon - media.aiom. · PDF fileNuovi dati Colon Roma, 7 Ottobre 2017 Alain Gelibter...
date post
22-Feb-2019Category
Documents
view
216download
0
Embed Size (px)
Transcript of Nuovi dati Colon - media.aiom. · PDF fileNuovi dati Colon Roma, 7 Ottobre 2017 Alain Gelibter...
Nuovi dati Colon
Roma, 7 Ottobre 2017
Alain Gelibter
Policlinico Umberto I
UOC Oncologia B
1
NEOADJUVANT FOLFOX 4 VERSUS FOLFOX 4 PLUS CETUXIMAB VERSUS IMMEDIATE SURGERY FOR HIGH-
RISK STAGE II AND III COLON CANCERS: A PHASE II MULTICENTRE RANDOMISED CONTROLLED TRIAL
(PRODIGE 22) KAROUI Mehdi, RULLIER Anne, MARIETTE Christophe, MAILLARD Emilie, BARDIER Armelle, POIZAT Flora, LUCIANI
Alain, SARRAN Anthony, LEGOUX Jean-Louis, DE CHAISEMARTIN Ccile, LECAILLE Cdric, BOUCHE Olivier, MAUVAIS Franois, BRUNETTI Francesco, PRUDHOMME Michel, SEITZ Jean-Franois, LEPAGE Cme, TAIEB Julien
esmo.org
However recurrence rates at 3 years (95%CI)
IDEA (2017) PETACC8 (2014)
pT1-T3, N1 Capox 3m 15% (13.1-16.9) -
pT4/ or N2 Folfox 6m 35.3% (32.7-37.8) Folfox + Cetuximab 6m 43.1% (32.5-55.4)
Qian Shi et al., ASCO 2017; Taieb J et al., Lancet Oncol 2014
BACKGROUND AND RATIONALE (2)
Reasons for this relative failure
- Delayed start of chemotherapy
- Growth factors stimulation / immunosuppression induced by surgery
Van der Bij G et al., Ann Surg 2009;249
PRODIGE 22 STUDY DESIGN
Multicenter randomized phase II trial
FOLFOX (4 cycles)
High risk T3
T4
N2
SURGERY
SURGERY
FOLFOX (12 cycles)
Stage III ou II (investig)
FOLFOX (8 cycles)
FOLFOX + Cetuximab
(4 cycles) SURGERY
FOLFOX + Cetuximab
(8 cycles)
R
RAS WT
esmo.org Challenge: to make decisions on small numbers, dropping of cetuximab arm based upon lack
of TRG from 13 pts. Morbidity the same as in the surgery only arm: IDMC decision
esmo.org
120 patients
Surgery (52) ITT population
Folfox-Cetuximab (3) : TRG 1 = 0
Folfox preop (52)
Interim analysis Folfox
(n = 13)
Folfox-Cetuximab
(n = 13)
Surgery
(n = 13)
TRG 1 3 0 0
Severe morbidity (Dindo > 3) 1 (7.7%) 2 (15.3%) 2 (15.3%)
Colectomy (51)
Protocol deviation (1) Metastatic disease (1)
PT related complication (1)
Disease progression under CT (1) Surgery (49)
Unresectable PT (1)
Colectomy (48)
esmo.org
PRODIGE 22 ENDPOINTS (1)
Primary endpoint: Tumor response
(Ryan simplified Tumor Regression Grade)
double central
independent
and blinded review
esmo.org
PRODIGE 22 ENDPOINTS (2)
Secondary outcome measures
- Chemotherapy toxicity
- Primary tumor (PT) complications under chemotherapy
- Postoperative morbidity
- Quality of surgery
- Radiological staging
- 3 years DFS
- Quality of life
BASELINE CHARACTERISTICS
FOLFOX
(n = 52)
Surgery
(n = 52)
Total
(n = 104)
Age (years, median) 64.6 62.2 62.6
Males (n, %) 30 (58%) 33 (63%) 63 (60.5%)
BMI (kg/m, median) 24.3 26.4 25.3
Tumor location (n, %)
Right / transverse
Left / sigmoid
27 (52%)
25 (48%)
21 (40%)
31 (60%)
48 (46%)
56 (54%)
CEA level > 2.5N (n, %) 10 (19%) 10 (19%) 20 (19%)
Small numbers and lack of stratification potentially can have Large consequences.
FOLFOX PREOP: ADVERSE EVENTS
FOLFOX
(n = 50)
Pts who completed 4 cycles 48 (96%)
Pts with grade > 3 AE (n, %) 19 (38%)
Pts who discontinued study drug for AE
Primary tumor complication
2 (4%)
0
Time to surgery (median, days) 31 (20 - 62)
Grade > 3 AE, n (%)
Anemia 1 (2%)
Thrombocytopenia 1 (2%)
Neutropenia 5 (10%)
Diarrhea 2 (4%)
Nausea 4 (8%)
Fatigue 2 (4%)
Fever 2 (4%)
Deep venous thrombosis 1 (2%)
Acute coronary
syndrome
1 (2%)
esmo.org
POST-OPERATIVE RESULTS
FOLFOX
(n = 49)
Surgery
(n = 51)
Total
(n = 100 )
PT resection 48 51 99%
Mortality 0 1 (2%) 1%
Overall morbidity 17 (34.5%) 18 (35%) 35%
Severe morbidity (> Dindo III) 4 (8%) 4 (8%) 8%
Surgical complications
Anastomotic leak
11
1
14
1
25%
2%
R0 resection 46 (94%) 48 (98%) 94%
Complete mesocolic excision 95% 91% 93%
PATHOLOGICAL RESULTS
Surgery
(n = 51)
FOLFOX
(n = 48) p
Stage
I
II
III
0.019
0
20 (39%)
31 (61%)
4 (8%)
25 (52%)
19 (40%)
pT4 and/ or N2 30 (59%) 18 (37.5%) 0.033
Vascular emboli, lymphatic and/
or perineural invasion 25 (49%) 9 (19%) 0.001
Number of harvested LN (mean) 25.2 +/- 11.2 26.6 +/- 11.3 0.529
Number of positive LN (mean) 2.5 +/- 3.9 1.65 +/- 2.9 0.215
Radiological
concordance
awaited.
Up to 40% of
patients
receiving
Oxaliplatin
unnecessarily.
How many would
not have
required chemo
at all
esmo.org
PRIMARY ENDPOINT: TUMOR RESPONSE
FOLFOX
(n = 52)
Surgery
(n = 52) p
TRG 1 4 (8%) 0 0.118
TRG 2 19 (36%) 4 (8%)
TRG 3 25 (48%) 45 (86%)
Non available 4 (8%) 3 (6%)
Significant tumor
regression (TRG 1 + 2) 23 (44%) 4 (8%)
esmo.org
PRODIGE 22 : CONCLUSION
Neoadjuvant FOLFOX chemotherapy (4 cycles) in a perioperative
setting in patients with locally advanced colon cancer :
- is well tolerated
- does not increase surgical morbidity
- is not associated with major histological response (TRG1)
- is associated with significant tumor regression as compared
to upfront surgery (TRG 1+2 : 44% vs. 8% p
VOLFI:
mFOLFOXIRI + PANITUMUMAB VERSUS FOLFOXIRI
esmo.org
Abstract 475O
AS FIRST-LINE TREATMENT IN PATIENTS WITH RAS WILD-TYPE
METASTATIC COLORECTAL CANCER (mCRC):
A RANDOMIZED PHASE II TRIAL OF THE AIO (AIO-KRK-0109)
M. Geissler (Esslingen, Germany), U. M. Martens (Heilbronn, Germany),
J. R. Knorrenschield (Marburg, Germany), J. Greeve (Paderborn, Germany),
A. Florschuetz (Dessau, Germany), A. Tannapfel (Bochum, Germany),
S. Wessendorf (Esslingen, Germany), P. Bchner-Steudel (Halle, Germany), T. J. Ettrich (Ulm, Germany), S. Kanzler (Schweinfurt, Germany), V. Heinemann (Munich, Germany),
S. Held (Leverkusen, Germany), A. Reinacher-Schick (Bochum, Germany)
Presented by Michael Geissler at the ESMO congress 2017.
Slides are property of the author. Permission required for reuse.
The study was sponsored by AIO-Studien-gGmbH (Berlin, Germany)
The study was financially supported by an unrestricted grant from Amgen. NCT01328171
EudraCT 2009-017731-17
RATIONALE
1
7
FOLFOXIRI is an active and intensive chemotherapeutic regimen in mCRC
(Falcone et al. 2007)
FOLFOXIRI+bevacizumab (TRIBE, STEAM, OLIVIA) and FOLFOXIRI + anti-
EGFR mAb (TRIP, MACBETH) resulted in high RR and long OS
However, there is no randomized trial demonstrating superiority of FOLFOXIRI
plus an anti-EGFR or anti-VEGF mAb compared to FOLFOXIRI alone
Therefore, the VOLFI trial compared the FOLFOXIRI Falcone protocol with
modified FOLFOXIRI + panitumumab
PHASE II TRIAL DESIGN
mCRC
Unresectable
1st-line
WT RAS**
Age 18yrs
ECOG PS 0-1
(n=96)
Randomization:
6/2011 - 1/2017
R
Treatment until PD, resectability,
or to maximum 12 cycles
mFOLFOXIRI +
panitumumab 6 mg/kg
Q2W
N=63 Irinotecan 150 mg/m2***, oxaliplatin 85 mg/m2,
LV 200 mg/m2, 5-FU 3000 mg/m2 CIV;
Planned safety analysis after 10 patients
treated in panitumumab arm
FOLFOXIRI Q2W
N=33
2:1
If resectable:
Surgery, then
protocol treatment to
maximum 12 cycles
If CR/PR/SD after 12 cycles:
re-induction
(same combination)
recommended on PD
Strata:
Cohort 1: histologically confirmed and definitively inoperable or unresectable
Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumor biopsy)
*
*
21 active centers in Germany **amendment in 11/2013 to include all RAS wild-type only
***Trial started with irinotecan 165 mg/m2 (n=2), first amendment to 130 mg/m2
(n=9) and final amendment to 150 mg/m2 (n=52)
1 cycle FOLFOXIRI
prior R was allowed
1
8
HYPOTHESIS AND ENDPOINTS
Secondary endpoints Secondary tumor resection rate
Time to relapse
Progression free survival (PFS)
Overall survival (OS)
Pathological response and liver toxicity in resected tumor
specimens
Toxicity
QoL (QLQ-C30)
Statistical hypothesis ORR Arm A >75% vs. Arm B 60%
N=62 patients arm A RAS wt; 2-sided Fisher exact test, type I
RAS mutations