Current curative standards and controversies
Modalities of perioperative treatment
Study | Inclusion | Treatment and number of patients | AC/SCC (%) | ITT R0 | pCR (%) | DR (%) | LR (%) | Location (%) | 3-year OS (%) | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|
AJCC 6thEd. | EGJ Seiwert | GC | ||||||||||
T/N | I | II | III | |||||||||
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 1/3rd; 51 lower 1/3rd; 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
| ||||||||||||
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 |
Comparisons to surgery alone
i. Neoadjuvant chemoradiotherapy (CRT→S) vs. surgery alone
ii. Adjuvant chemoradiotherapy (S→C-CRT-C) vs. surgery alone
iii. Neoadjuvant chemotherapy (C→S) vs. surgery alone
Trial | Setting | N (To be enrolled) | Location | Primary endpoint | Intervention | Expected completion date |
---|---|---|---|---|---|---|
Alderson et al.[30], 2013 | Neoadjuvant | 842 | Esophageal | Survival and QOL | A: C (ECX x 4) → S | NR |
MRC OEO5 | EGJ I-II | B: C (CFx2) → S | ||||
Kang et al.[35], 2013 | Adjuvant CRT | 1000 | Gastric and EGJ | DFS (3 years) | A: S → C (S1) | January 2016 |
NCT01761461 | B: S → C (S1x1) → CRT (S1) → C (S1x6) | |||||
‘ARTIST II’ | C: S → C (SOX) | |||||
D: S → C (SOX) → CRT (S1) → C (SOXx4) | ||||||
Lorenzen et al.[53], 2010 | Neoadjuvant CRT | NR | Resectable EGJ (I-II) | Non-randomized, single institution | Not initiated | |
NCT01271322 | A: C (Cisplatin/Taxotere) → PET | |||||
‘HICON’ Trial (Phase II) | If Response: Continue C | |||||
If No response: Cross to Arm B | ||||||
B: Taxane based CRT (45 Gy) → PET | ||||||
If Response: CRT (TP x 3) | ||||||
If No response: Cross to Arm A | ||||||
Goodman et al.[54], 2013 | Neoadjuvant CRT | 204 | Esophageal and EGJ I and II | pCR | A: C (FOLFOX x 3) → PET | September 2011 |
NCT01333033 | If Response: CRT (FOLFOX x 3) | |||||
CALGB 80803 (Phase II) | If No response: Cross to Arm B | |||||
B: C (TP x 3) → PET | ||||||
If Response: CRT (TP x 3) | ||||||
If No response: Cross to Arm A | ||||||
Nordwest et al.[74], 2012 | Perioperative | 590 | Gastric EGJ I-III | DFS (2 years) | A: C (FLOTx4) → S (D2) → C (FLOTx4) | July 2015 |
NCT01216644 | B: C (ECFx3) → S (D2) → C (ECFx3) | |||||
‘FLOT4’ | ||||||
Chen et al.[72], 2012 | Perioperative | 722 | Gastric EGJ II or III | DFS (3 years) | A: C (SOX) → S (D2) → C (SOX) | September 2014 |
NCT01583361 | B: S (D2) → C (SOX) | |||||
‘RESONANCE’ | ||||||
Shen et al.[73], 2012 | Perioperative | 1059 | Gastric EGJ I-III | DFS (3 years) | A: S (D2) → C (SOXx8) | September 2014 |
NCT01534546 | B: S (D2) → C (XELOXx8) | |||||
C: C (SOXx3) → S (D2) → C (SOXx5) → C (S-1x3) | ||||||
Reynolds et al.[60], 2013 | Perioperative | 366 | Esophageal EGJ (I-III) | OS (3 years) | A: C (ECF) → S → C (ECF) | September 2021 |
NCT01726452 | B: CRT (TP) → S | |||||
‘MAGIC vs. CROSS EGJ’ | ||||||
Verheji et al.[61], 2011 | Perioperative CRT | 788 | Gastric | OS | A: C (ECCx3) → S (D1+) → CRT (CC, 45Gy) | June 2013 |
NCT00407186 CRITICS Trial | B: C (ECCx3) → S (D1+) → C (ECCx3) | |||||
Leong et al.[62], 2013 | Peri-operative CRT | 752 | Gastric EGJ | OS | A: C (ECF/Xx2) → CRT (5-FU/RT) → S → C (ECF/Xx3) | NR |
‘TOP GEAR’ (Australia) | B: C (ECF/Xx3) → S → C (ECF/Xx3) | |||||
Molecularly targeted trials
| ||||||
Safran et al.[67], 2013 | Neoadjuvant CRT | 480 | Mid and Distal Esophagus including EGJ | DFS | A: CRT (TP) → S → T (13) | August 2018 |
NCT01196390 | B: CRT (TP) → S | |||||
RTOG 1010 | ||||||
Reed et al.[68], 2012 | Neoadjuvant CRT | 69 | Distal Esophagus and EGJ | pCR | CRT (CDP) → S | Study Completed |
NCT00757172 | ||||||
ACASOG Z4051 | ||||||
Phase II | ||||||
Ilson et al.[69], 2012 | Neoadjuvant CRT | 420 | Esophageal (Squamous allowed) GEJ I-II | OS | A: CRT (CCT, 50.4 Gy) | August 2018 |
NCT00655876 | B: CRT (CT, 50.4 Gy) | -Closed at interim analysis for AC arm due to low clinical complete response | ||||
RTOG 0436 | -Closed SCC arm due to SCOPE-1 results (see text) | |||||
Cunningham et al.[75], 2012 | Perioperative | 1100 | Gastric EGJ I-III | OS, Safety, Efficacy | A: C (ECXB) → S → C (ECXB) | December 2014 |
NCT00450203 | ||||||
‘MAGIC-B’ (ST03) | B: C (ECX) → S → C (ECX) |
iv. Adjuvant chemotherapy (S→C) vs. surgery alone
v. Perioperative ‘sandwich’ chemotherapy (C→S→C) vs. surgery alone
vi. Comparison of post-operative chemotherapy regimens
S→FOLFIRI then DC vs S→5FU
(S→UFT vs S→S1 vs S→paclitaxel then UFT vs. S→ paclitaxel then S1)
vii. Adjuvant CRT comparing peri-RT chemotherapy regimens
(S→5FU-CRT-5FU vs S→ ECF-CRT-ECF)
viii. PET directed therapy
ix. Induction chemotherapy followed by chemoradiation
(C→CRT→S vs. C→S; C→CRT→S vs. CRT→S)
x. Adjuvant chemotherapy versus CRT (S→C vs. S→C-CRT-C)
The devil is in the details: which perioperative approach?
Addition of molecularly targeted agents to perioperative therapy
Patient | Oncogene | Tumor suppressor |
---|---|---|
1
| HER2 Amp+, SRC Amp+, TOP1 Amp+ | |
2
| FGFR2 Amp+ | TP53 mt, CDH1 mt |
3
| SRC Amp+, AURKA Amp+, CCND1 Amp+, CDK4 Amp+, RICTOR Amp+, MDM2 Amp+ | CDKN2A/B Loss, ATM mt |
4
| HER2 Amp+, PIK3CA mt, CDK6 Amp+ | TP53 mt, PTEN mt |
5
| MDM2 Amp+ | |
6
| MYCN Amp+ | TP53 mt, FANCA Loss |
7
| PIK3CA mt | |
8
| ARID1A mt, ARID2 mt, Smad2 mt, MLL2 mt | |
9
| HER2 Amp+, PIK3CA mt | TP53 mt |
10
| CDH1 mt, CDH1 Splice Site mt | |
11
| CCND1 Amp+, EZH2 mt, FGF19 Amp+, FGF3 Amp+, FGF4 Amp+ | |
12
| CDH1 Splice Site mt, CDKN2A mt, ARID1A mt, ARID2 mt | |
13
| PIK3CA mt, ERBB3 mt, AXL mt, KDR mt | NF1 mt, ARID1A mt, CREBBP mt, CTCF mt, MLH1 mt |
14
| ARID1A mt | |
15
| KRAS Amp+, CCNE1 Amp+, MDM4 Amp+ | TP53 mt, FBXW7 mt, PTEN mt |
16
| HER2 Amp+ | |
17
| KRAS mt | TP53 mt, CDKN2A mt |
18
| CDH1 Splice Site mt, LRP1B mt, MLL2 mt | |
19
| Rictor Amp+ | TP53 mt, KDM6A splice mt |
20
| CTNNB1 | TP53 mt |
21
| HER2 mt, ERBB3 mt | TP53 mt (x2), DNMT3A mt, MSH2 mt |