c. schuhmacher, p.m. schlag, f. lordick, w. hohenberger, j. heise, c. haag, s. gretschel, m. mauer,...
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C. Schuhmacher, P.M. Schlag, F. Lordick,
W. Hohenberger, J. Heise, C. Haag, S. Gretschel,
M. Mauer, M.P. Lutz, J.R. Siewert
Neoadjuvant chemotherapy versus surgery alone
for locally advanced adenocarcinoma of the stomach and cardia
Final results of the EORTC phase III randomized trial 40954
Rational for the EORTC Trial
Remarkable response rates in clinical trials of locally advanced and metastatic gastric cancer
Phase II trials were always criticized for an incomplete pretreatment staging
Postoperative chemotherapy (adjuvant trials) could not demonstrate significant benefit
Adjuvant therapy had to be often delayed:postoperative deterioration of performance status and complications
…at the time of protocol preparation (1998)
Background
Multimodal therapy in Gastric Cancer:
Trials performed at a comparable point in time in
The Netherlands, Great Britain, Switzerland, Italy, France, USA
Staging
Prospective phase II trial with endoscopic ultrasound and extended
diagnostic laparoscopy: Exact cT-category and detection of peritoneal
carcinosis or occult visceral metastases
Regimen
EORTC 40953: Combination of cisplatinum, folinic acid, and infusional
5-FU (good activity and well tolerated) J Clin Oncol. 2007;25(18):2580-5.
!
Background
EORTC 40954
2 cycles (d1 – d49)
• Cisplatin (50 mg/m²) q 2 wks x 3 • 5FU (2000 mg/m²) q week x 6• FA (500 mg/m²) q week x 6
+ surgery
Does a purely neoadjuvant chemotherapy yield an overall survival benefit in the treatment of locally
advanced gastric cancer?
Design
Randomize
CS S
1 cycle (d1 – d49)
Cisplatin/5FU/FA
Restaging
within 3 days before cycle 2
Resection
If no PD/tox/WHO 2
Cycle 2
Resection
<= 4 weeks
<= 4 weeks
<= 14 days
Resection if possible
Follow-up
Endpoints
Primary: • Overall Survival
Secondary• R0 resection rate• Time to progression• Toxicity during preoperative chemo• Postoperative morbidity• Effect of chemo on lymph node metastasis
Main eligibility criteria
Histologically proven adenocarcinoma of the stomach (∑ AEG Type II and III)
cT3/4 NX M0 (only exception M1lymph)
No histological confirmation of suspicious peritoneal lesions at diagnostic laparoscopy
No prior chemotherapy and/or radiotherapy
WHO PS 0-1; 18 ≤ age ≤ 70; adequate organ function
Randomization stratified by:
- institution - primary tumor cT3 vs. cT4- localization of the tumor (upper vs. middle - lower 1/3)- gender - histological subtype (intestinal vs. non intestinal)
Statistical considerations
Primary end-point: overall survival
282 events required to detect an improvement in median overall survival from 17 months to 24 months (HR=0.708) with a power of 80%, using a two-sided logrank test with a significance level of 4%
- initially planned to perform a first analysis on patients who had an extended D2 resection
- next to perform a second analysis on all randomized patients with a significance level of 2%
N=360 patients (180:180)
4 years accrual
2 year additional follow-up
Recruitment
Date of activation: July 15th, 1999
Date of closure: February 10th, 2004
Study was closed early at 144 pts (72:72) because of poor accrual.
N=144/360 (40%)
!
Patient characteristics (N=144)
CS(N=72)
S(N=72)
Age Median (years) 56 (38 - 70) 58 (26 - 69)Sex Male 50 (69.4%) 50 (69.4%) WHO performance PS 0 48 (66.7%) 55 (76.4%)
PS 1 24 (33.3%) 17 (23.6%) Clinical T stage T3 68 (94.4%) 67 (93.1%)
T4 4 (5.6%) 5 (6.9%) Histological subtype intestinal 33 (45.8%) 33 (45.8%)
non-intestinal 39 (54.2%) 39 (54.2%) Tumor localization upper third + cardia II, III 37 (51.4%) 39 (54.2%)
middle third 20 (27.8%) 18 (25.0%) lower third 15 (20.8%) 15 (20.8%)
!
!
Treatment
CS (N=72) S (N=72)
Started chemotherapy n=69 (96%)
1 patient refusal but had surgery 2 patients with
no records
Completed chemotherapy
n=45 (63%)
Discontinued n=24 (37%)
Underwent resection
n=70 (96%)
Underwent resection n=68 (94%)
2 patients with unresectable tumors, 1 patient with liver mets discovered intraoperatively,1 patient without record
!Toxicity (n=8),
Patient refusal (n=5),
Other (n=7) PD (n=4)
Reason for discontinuing chemotherapy
Major reason for protocol discontinuation CS (N=69)
normal completion 45 (65.2%)
PD 4 (5.8%)
toxicity renal toxicity (max G2) 2 pts cardiac toxicity (G3) 1 pt nausea and vomiting (max G3) 4 pts
neutropenia (max G2) 1 pt
8 (11.6%)
refusal
other worsening of symptoms (not PD): 2 pts non-compliance: 1 pt judgment of investigator: 3 pts infarction of the pons cerebri 1 pt (unrelated)
5 (7.2%)
7 (10.1%)
Surgery
Resection consisted of a subtotal or total gastrectomy with extension depending on the localization of the primary tumor with either a D1 lymphadenectomy (7 patients) or preferably a D2 lymphadenectomy (130 patients).
CS(N=70)
S(N=68)
D2 lymphadenectomy 67 (95.7%) 63 (92.6%)
+ transhiatal resection 31 (44.3%) 35 (51.5%)
+ hepatoduodenal lig. & rt. retroperitoneal excision 20 (28.6%) 22 (32.4%)
Subtotal distal resection w/ systemic LN resection 1 (1.4%) 2 (2.9%)
Multivisceral resection 6 (8.6%) 12 (17.6%)
Type of reconstruction Roux-en-Y Pouch
48 (68.6%)17 (24.3%)
50 (73.5%)12 (17.6%)
Postoperative complications
CS S
Postoperative 3/70 1/68 deaths (4.3%) (1.5%)
2 sepsis 1 sepsis1 cardiac arrest
+ PE
Postoperative 19/70 11/68complications (27.1%) (16.2%)
Response to chemotherapy
CR 4/69 (5.8%)
PR 21/69 (30.4%)
CR+PR 25/69 (36.2%) (95% CI: 25.0% - 48.7%)
Pathology
CS(N=72)
S(N=72)
R0 59 (81.9%) 48 (66.7%)
R1 9 (12.5%) 15 (20.8%)
R2 2 (2.8%) 5 (6.9%)
Not operated 2 (2.8%) 4 (5.6%)
• R0 resection rate was significantly higher in the CS arm (P=0.036)
(according to the pathology report)
• By intraoperative assessment, R0 resection was achieved for 63
patients in each arm (87.5%)
!
Pathology
CS(N=70)
S(N=68) P-value
Median tumor thickness (mm) 11.0 13.0
Median tumor length (mm) 50.0 57.5
Median tumor width (mm) 40.0 45.0
Extent of tumor*T0/1/2T3/4
46 (65.7%)24 (34.3%)
34 (50.0%) 31 (45.6%)
0.113
Nodal status*N0N1-3
27 (38.6%)43 (61.4%)
13 (19.1%)52 (76.5%)
0.018
no lymphangiosis 41 (58.6%) 23 (33.8%) 0.011
*2 unknown, 1 missing
!
!
Survival
(years)
0 1 2 3 4 5 6 7
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment35 72 58 48 34 20 11 4
32 72 61 49 41 29 15 6
S
CS
Overall Logrank test: p=0.466
!
Survival
TreatmentPatients
(N)
ObservedEvents
(O)Hazard Ratio
(95% CI)P-Value
(Log-Rank)% at 2 Year(s)
(95% CI)
CS 72 32 0.84 (0.52,1.35)
0.466 72.75 (60.66, 81.67)
S 72 35 1.00 69.92 (57.68, 79.24)
CS(N=72)
S(N=72) P-value
Follow-up 4.7 years
4.1 years 0.637
67 events: power of 25%!
Progression-free survival
(years)
0 1 2 3 4 5 6 7
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment44 72 44 34 28 16 11 4
40 72 56 41 31 24 13 5
S
CS
Overall Logrank test: p=0.200
Progression free survival
TreatmentPatients
(N)
ObservedEvents
(O)Hazard Ratio
(95% CI)P-Value
(Log-Rank)% at 2 Year(s)
(95% CI)
CS 72 40 0.76 (0.49,1.16)
0.2003 58.57 (46.16,69.07)
S 72 44 1.00 47.89 (35.93,58.88)
CS(N=72)
S(N=72)
Progression documented
34 (47.2%)
43 (59.7%)
Time to progression: HR=0.66 (95% CI:0.42-1.03), p=0.065 but two more deaths due to postoperative complications in the CS arm
Discussion based on the results
Accrual unexpectedly low Competing trials on the market
High number of proximal tumors Epidemiological evolution
Unexpectedly high cT-category staging error
Cardia is covered with fat, not serosa (“T2b”)
Chemotherapy with only 63% complete courses
Toxicity of PLF still too high
Pathological findings as expected New effect on lymphangiosis
Surgery arm with a median survival of at least 36 months (better than expected)
Effect of D2-Lymphadenectomy?
Result of “overestimation” of primary tumor category
Result of center-oriented accrual (70% patients from two centers)
Discussion with regard to literature
Neoadjuvant chemotherapy has an effect on gastric cancer• Who benefits the most?• nCtx appropriate for all patients or only a subgroup?• Will we be able to predict response in the future? • Are there predicitive molecular tools or imaging tools available?• Are there new and active regimen including biologicals?• What is the role of radiochemotherapy?
Neoadjuvant Chemotherapy has a relevant toxicity• Which is the least toxic but most effective regimen?
Influence of surgeon’s experience on survival• Japanese training and expertise as one of our important aims
International cooperation in gastric research• Support joint trials (MRC ST03, CRITICS, etc) • Cooperation for future trials
Acknowledgements
Ulrich Fink Professor emeritus Medical Oncologist Visionary Physician Empathetic Personality
Thanks to Patients and Participating Centers
W. Bechstein, Frankfurt; P. Reichardt, Bad Saarow;
CF. Eisenberger, Düsseldorf; A. Hoelscher, Koeln;
H. Wilke, Essen;
Munich Center : Katja Ott, Sonja Gillen,
Maria Leibl and Rana Tabash;
EORTC Headquarters
M.A. Lentz, B. Meulemans, M.L. Couvreur, U. Bethe,
J Welch, B. Hasan, M. Mauer, L. Collette