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