Table 1 Phase III* clinical trials evaluating perioperative therapy for gastroesophageal adenocarcinoma

i. Neoadjuvant CRT versus surgery alone

Walsh et al.[12], 1996

Locally advanced RT: 40 Gy

A: CRT (PF) → S: 58

100

NR

A: 25

NR

NR

Esophagus (16 middle 1/3^rd; 51 lower 1/3^rd; 34 cardia)

0

A: 32

Irish Trial

B: S: 55

B: 0

B: 6

p = 0.01

Burmeister et al.[13], 2005

T1-3, N0-1

A: CRT (PF) → S: 128

62/37

A: 80

A: 12

A: 45

A: 11

Esophagus (21, upper and middle 1/3; 79 distal 1/3)

0

A: 32

RT: 35 Gy

B: S: 128

B: 59

B: 0

B: 41

B: 14

B: 29

p = 0.83

Tepper et al.[14], 2008

T1-3, Nx

A: CRT (PF) → S: 30

75/25

NR

A: 40

A: 27

A: 3

Thoracic esophagus & EGJ

0

A: 39 (5-year)

CALGB 9781

RT: 50.4 Gy

B: S: 26

B: 0

B: 38

B: 11

B: 16

p < 0.002

Urba et al.[15], 2001

Locally advanced

A: CRT (PFV) → S: 50

NR

A: 28

A: 65

A: 19

0

A: 30

RT: 45 Gy

B: S: 50

75/25

B: 0

B: 60

B: 42

Esophagus (8 upper 1/3rd; 92 mid and distal 1/3rd)

B: 16

p = 0.15

van Hagen et al.[18], 2012

T1N1 or T2-T3N0-1

A: CRT (TP) → S: 175

75/25

92 vs. 69

A: 29

A: NR

A: NR

49

26

0

0

A: 58

‘CROSS’ Trial

Ib-IIIb

B: S: 188

AC: 23%

B: NR

B: NR

B: 44

RT: 41.4 Gy

B: 0

HR 0.65 (0.49-0.87)

p = 0.003

Subgroup analysis for AC only: HR 0.74 (0.53-1.02)

p = 0.07

ii. Adjuvant CRT versus surgery alone

Macdonald et al.[19], 2001

T1 – 4 N +  Ib – IV

A: S: → CRT 281

100/0

NA

NA

A: 33

A: 19

0

0

20

80

A: 50

Intergroup 0116

RT: 45 Gy

C(5FU) – CRT(5FU) – C(5FU)

B: 18

B: 29

B: 41

B: S: 275

HR 0.76 (0.62-0.96)

p = 0.005

iii. Neoadjuvant chemotherapy versus surgery alone

MRC OEO-2[27], 2002

Resectable cancer

A: C (CF) → S: 400

66/31

A: 60

NR

A: 12

A: 8

64

10

0

A: 43 (2 year)

B: S: 402

B: 54

B: 10

B: 8

(26 SCC)

B: 34

HR 0.78 (0.67-0.93)

p = 0.004

Schuhmacher et al.[28], 2010

T3 – T4, N0 – N + (Locally Advanced)

A: C (CF) → S: 72

100/0

A: 84

A: 7

NR

NR

53

47

A: 72.7 (2 year)

EORTC 40954

B: S: 72

B: 72

B: 0

B: 69.9

p = 0.46

iv. Adjuvant chemotherapy versus surgery alone

Sakuramoto et al.[31], 2007

T1 – 4 N +  II (excluding T1) – IIIB

A: S → C (S1) 529

100/0

NA

NA

A: 21.4

A: 2.8

0

0

0

100

A: 80

ACTS-GS Trial

B: S: 530

B: 27.1

B: 1.3

B: 70

HR 0.68 (0.5-0.87)

p = 0.003

Bang et al.[34], 2012

T – 4 N + or II-IIIB

A: S → C (CapeOx): 520

100/0

NA

NA

A: 18

A: 4

0

0

2.5

97.5

A: 74 (3-year DFS)

‘CLASSIC’ Trial

B: S: 515

B: 26

B: 8

B: 59

HR 0.56 (0.44-0.72)

p < 0.0001

v. Perioperative chemotherapy versus surgery alone

Kelsen et al.[36, 37], 1998, 2007

I-III

A: C (CF) → S → CF 233

51/44

A: 62

A: 2.5

A: 49

A: 19

51

0

A: 26

RTOG 8911

Any N +

B: S: 234

B: 59

B: 0

B: 51

B: 21

B: 23

p = 0.53

Cunningham et al.[38], 2006

T1-4 N + or II-IV

A: C (ECF) → S → C (ECF): 250

100/0

A: 69

4

A: 24

A: 14

14

12

74

A: 36 (5-year)

‘MAGIC Trial’

B: S: 253

B: 66

B: 37

B: 21

B: 23

HR 0.75 (0.6-0.9)

p = 0.009

Ychou et al.[39], 2011

T1-4 N + or II-IV

A: C (CF) → S → C (CF): 113

100/0

A: 84

3

A: 30

A: 24

11

64

25

A: 38 (5-year)

FFCD9703 Trial

B: 38

B: 26

B: 24

ACCORD 07

B: S: 111

B: 74

5-yr HR 0.69 (0.5-0.95); p = 0.02

vi. Comparison of post-operative chemotherapy regimens

Bajetta et al.[43], 2012

N + or N0 with T2b-4

A: S → C (CPT-11 + 5-FU/LV – TXT + CDDP): 562

100/0

NA

NA

NR

NR

0

0

15

85

No significant difference

Abstract NCT01640782 ITACA-S Trial

B: S → C (5-FU/LV): 538

HR: 1.00 (0.83-1.20); p = 0.98

Kobayashi Yoshida et al.[44], 2012

T3-4, N0-2

A: S → C (UFT): 359

100/0

NA

NR

NR

NR

None

100

No significant difference in DFS between C + D and A + B

‘SAMIT’ Trial

B: S → C (S1): 364

HR: 0.92 (0.80-1.07); p = 0.273

C: S → C (T – > UFT): 355

D: S → C (T – > S1): 355

vii. Adjuvant CRT comparing peri-RT chemotherapy regimens

Fuchs et al.[46], 2011

Locally Advanced

A: S → C (5FU/LV) → CRT (5FU) → C (5FU/LV): 280

100/0

NR

NR

NR

NR

None

100

A: 50

CALGB 80101

B: S → C (ECF) → CRT (5FU) → C (ECF): 266

B: 52

NCT00052910

HR 1.03 (0.80-1.34) p = 0.80

viii. PET directed therapy

Lordick et al.[50], 2007

cT3/4 Locally advanced

C (CF) → Assess for metabolic response

100/0

NA

A: 58

NR

NR

68

32

0

0

A: Not reached

Phase II Municon trial

A: Response → C → S: 54

B: 0

B: 25.8 (2.3 years median follow up)

B: No-Response → S: 56

(Major Histologic Response)

HR = 2.13 (1.14-3.99)

P = 0.015

zum Buschenfelde et al.[52], 2011

cT3/4 Locally advanced

C (CF) → Assess for metabolic response

100/0

NA

A: 36

A: 30

A: 9

69

31

0

0

A: 71

Phase II Municon II

A: Response → C → S: 33

B: 26

B: 48

B: 17

B 42

B: No-Response → CRT → S: 23

(Major Histologic Response)

HR = 1.9 (0.87-4.24)

P = 0.10

ix. Induction chemotherapy followed by CRT versus chemotherapy or CRT alone

Stahl et al.[57], 2009,

T3/4, Nx

A: C (PLF) → CRT (PE) → S: 60

100/0

A: 72

A: 16

A: 23

NR

54

46

0

A: 47.4

‘POET’ Trial

B: C (PLF) → S: 59

B: 70

B: 2

B: 41

B: 27.7

HR 0.67 (0.41-1.07)

p = 0.07

Alberts et al.[58], 2013

T3-4, N0 or Tany, N(+)

A: C (DOX) → CRT (5Fu + Ox): 21

100/0

NA

A: 33

NR

NR

40

0

NR

N0849 Trial

B: CRT alone: 21

B: 48

(SCC 55)

P = 0.53

x. Adjuvant chemotherapy versus CRT

Lee et al.[26], 2012

II-IV

A: S → C (XP): 228

100/0

NA

NA

A: 25

A: 8.3

0

0

5

95

A: 74.2 (3-year DFS)

‘ARTIST’ Trial

Any N+

B: S → C (XP) → CRT (X) → C (XP): 230

B: 20

B: 4.8

B: 78.2

p = 0.35

p = 0.086