Current Standard of Care of Gastro-

Esophageal Cancer

Andrés CervantesProfessor of Medicine

Classical approach to localised gastric cancer

Surgical resection

Pathology assessment and estimation of risk

Treatment based upon classical TNM stage

Postoperative chemotherapy of limited value

Postoperative chemoradiation in US

Meta-analysis of trials involving adjuvant

chemotherapy versus surgery alone for

gastric cancer

Meta-analysis YearNo.

trials

No.

pts

Odds

Ratio95% CI Conclusions

Hermanns (1)

J Clin Oncol1993 11 2096 0.88 0.78-1.08 No benefit

Earle (2)

Eur J Cancer1999 13 1990 0.80 0.66–0.97

Small survival benefit

In N+ patients

Mari (3)

Ann Oncol2000 20 3658 0.82 0.75–0.89 Small survival benefit

Janunger (4)

Eur J Surg2002 21 3962 0.84 0.74–0.96

Very heterogeneous

group of trials

Western 0.96 0.83–1.12

Asian 0.58 0.44–076

Gastric Group (5)

JAMA2010 17 3871 0.82 0.76-090 P

The Gastric Group. JAMA 2010;303:1729–37

Meta-analysis of individual data of trials

involving adjuvant chemotherapy versus

surgery alone for gastric cancer

Noh SH, et al. Lancet Oncol 2014;15:1389–1396, © (2014), with permission from Elsevier

Adjuvant capecitabine plus oxaliplatin for

gastric cancer after D2 gastrectomy

versus surgery alone: 5-year follow-up of

a randomised phase III trial

SURGERY

NO TREATMENT

STRATIFICATION

T 1–4

NODES CT+ CT-RT + CT

0, 1–3, >3

MacDonald JS, et al. N Engl J Med 2001;345:725–730

The role of radiation in the postoperative setting:

Adjuvant chemoradiotherapy for gastric cancer

after surgery versus surgery alone: A randomised

Phase III Trial

Study design

Smalley S, et al. J Clin Oncol 2012;30:2327–2333

Adjuvant chemoradiotherapy for gastric

cancer after surgery versus surgery

alone: Long term data of a randomised

Phase III Trial

ARTIST: The role of Radiation in the Postoperative SettingAdjuvant Cisplatin and Capecitabine versus Chemoradiation forGastric Cancer after Surgery: A Randomized phase III Trial

Park SH, et al. J Clin Oncol 2015; 33: 3130-3136

CRITICS TRIALDesign: 788 pts: 393 CT and 395 CRT

Tissue

banking

QoL

Chemoradiation

3x EC/OC q 3 wks

D1 + surgery

D1 + surgery

Preoperative

chemotherapy

3x EC/OC q 3 wks

Preoperative

chemotherapy

3x EC/OC q 3 wks

R

45 Gy/25 fx +

/ capecitabine

cisplatin

-

Stratified for:

- Center

- Histological type

- Localisation of tumorVerheij M, et al. ASCO 2016; Abstract 4000

Final Results from the CRITICS study

Verheij M, et al. ASCO 2016; Abstract 4000

Eligible patients:

Adenocarcinoma of the stomach

or lower third of the oesophagus

(from 1999), suitable for curative

resection

Non-metastatic disease

Stage II or greater

Chemotherapy (ECF):

Epirubicin 50 mg/m2, IV day 1

Cisplatin 60 mg/m2, IV day 1

5-FU 200 mg/m2/day, continuous

infusion, days 1-21

(cycles repeated every 3 weeks)

Primary

Overall survival

Secondary

Progression-free survival

Surgical resectability

Quality of Life

Recruitment: July 1994-April 2002

Study entry and randomisation

S arm

N=253

CSC arm

N=250

3-6 weeks

6-12 weeks

Cunningham D, et al. N Engl J Med 2006;355:11–20

MAGIC: Study design

Pre-operative chemotherapy:

ECFx3

Post-operative chemotherapy:

ECFx3

Surgery

Surgery

MAGIC Trial results

Logrank p-value = 0.0001

Hazard Ratio = 0.66(95% CI 0.53 - 0.81)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomisation

0 12 24 36 48 60 72

163 250

190 253

EventsTotal

CSC

S

Logrank p-value = 0.009

Hazard Ratio = 0.75 (95% CI 0.60 - 0.93)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomisation

0 12 24 36 48 60 72

149 250

170 253

EventsTotal

CSC

S

2 year

survival

5 year

survival

Median

survival

CSC 50% 36% 24 mo

S 41% 23% 20 mo

Benefit to

CSC arm9% 13% 4 mo

PFS* Overall

On multivariate analysis, treatment

effect unchanged after adjustment

for age, performance status, site of

primary and gender

Hazard ratio for death

Adjusted: 0.74 (95%CI: 0.59-0.93)

Unadjusted: 0.75

Cunningham D, et al, N Engl J Med 2006;355:11–20. Copyright © (2006) Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society

Regression grade after neoadjuvant ECF and Overall

Survival in Oesophagogastric Cancer in MAGIC

Smyth EC, et al, J Clin Oncol 2016; 34:2721.2727.

Trial CTNo. pts

control

No. pts

CT

5-year

survival

control

5-year

survival CT

HR

(CI at 95%)

Cunningham

N Eng J Med 2006 ECF

253

No CT250 23% 36 %

0.75

0.60-0.93

p=0.009

Ychou

J Clin Oncol 2011

CDDP

5-FU

111

No CT113 24% 38%

0.69

0.50-0.95

p=0.021

Allum

J Clin Oncol 2009

CDDP

FU

402

No CT

40017,6% 25.5%

0.84

0.72-0.98

P=0.03

Summary of trials of perioperative

chemotherapy for localized Oesophago-

gastric cancer

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.

2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.

3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer

FLOT-4 Study

FLOT x4 - RESECTION - FLOT x4

ECF/ECX x3 - RESECTION - ECF/ECX x3

• Gastric or EGJ

cancer typ I-III

• Medically and

anatomically

operable

• cT2-4/cN-any/cM0 or

cT-any/cN+/cM0

R

n=716

S

T

R

A

T

I

F

I

K

A

T

I

O

N

FLOT: Docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1;

Leucovorin 200 mg/m², d1; Oxaliplatin 85 mg/m², d1, q2w

ECF/ECX: Epirubicin 50 mg/m2, d1; Cisplatin 60 mg/m²,

d1; 5-FU 200 mg/m² (or Capecitabin 1250 mg/m² p.o.

geteilt in 2 doses d1-d21), q2w

Stratification: ECOG (0 or 1 vs. 2), localization

(GEJ Type I vs. Type II/III vs. Gastric), age (< 60

vs. 60-69 vs. ≥70 years) and nodal status (cN+

vs. cN-).

Randomized, multicenter, Phase II/III Study

23% had Siewert type I

33% had Siewert type II/III

Survival ECF/ECX versus FLOT

Al-Batran et al. J Clin Oncol 2017; 35(suppl): #4004

ECF/ECX FLOT

mOS 35 months 50 months

[27-46] [38-na]

HR 0.77 [0,63 – 0,94]

p=0.012 (log rank)

2y. 59% 68%

3y. 48% 57%

5y. 36% 45%

OS rate* ECF/ECX FLOT

*projected OS-rates

Median follow-up time: 43 months

Trial CTNo. pts

control

No. pts

CT

5-year

survival

control

5-year

survival CT

HR

(CI at

95%)

Cunningham

N Eng J Med 2006 ECF

253

No CT250 23% 36 %

0.75

0.60-0.93

p=0.009

Ychou

J Clin Oncol 2011

CDDP

5-FU

111

No CT113 24% 38%

0.69

0.50-0.95

p=0.021

Allum

J Clin Oncol 2009

CDDP

FU

402

No CT

40017,6% 25.5%

0.84

0.72-0.98

P=0.03

Al-Batran

ASCO 2017FLOT

360

ECF

356

FLOT36% 45%

0.77

0.63-0.94

P=0.012

Summary of trials of perioperative

chemotherapy for localized Oesophago-

gastric cancer

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.

2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.

3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer

4. Al-Batran SA, et al 2017; 35(suppl): #4004

TrialCT

ExperimentalNo. pts

pCR

Control vs

Experimental

5-year

survival

Control vs

Exp

HR

(CI at

95%)

Cunningham

N Eng J Med 2006 ECF 503 0% vs 8% 23% vs 36 %

0.75

0.60-0.93

p=0.009

Al-Batran

ASCO 2017FLOT 716 5,8% vs 15,6% 36% vs 45%

0.77

0.63-0.94

P=0.012

Alderson +

Lancet Oncol 2017ECX 897 3% vs 11% 39% vs 42%*

0.90

0.77-1.05

0.19

Cunningham

Lancet Oncol 2017BEV-ECX 1063 8% vs 11% 50% vs 48%*

1.09

0.91-1.29

0.36

Perioperative chemotherapy for localized

Oesophago-gastric cancer: a new standard

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.

2. Al-Batran SA, et al 2017; 35(suppl): #4004

3. Alderson D. et al Lancet Oncol 2017 on line +Only Esophageal, *3 year OS

4. Cunningham D, et. Lancet Oncology 2017; 18:357-370

Neoadjuvant chemotherapy

in gastric cancer: Conclusions

Perioperative chemotherapy:

Induces downstaging

May increase the R0 resection rate

Prolongs disease free survival

Improves overall survival

Evidence level I based upon 2 well designed and properly

conducted randomised trials.

FLOT is current standard of care

Preoperative therapy is better tolerated than postoperative

Localised gastric cancer requires a multidisciplinary team approach

Further research on biological predictive factors is needed

Currently recommended approach to

localised gastric cancer

Clinical assessment and staging

Multidisciplinary team discussion

FLOT preoperative treatment in clinical stage II and III patients

Surgical resection after FLOT chemotherapy

Pathology assessment and estimation of risk

Postoperative chemotherapy if tolerated

Radiotherapy still experimental

No biological agents (Bevacizumab) to be used in this setting

Treatment for localised gastric cancer:

What is standard of care?

ESMO guidelines

Gastric Cancer

(Adenocarcinoma)

Operable

Stage > T1N0

Preoperative

chemotherapy

Consider

endoscopic /

limited resection

Operable

Stage T1N0

SurgeryAdjuvant

chemotherapy

Adjuvant

chemoradiation

Surgery

Post-operative

chemotherapy

Preferred pathway

Treatment for advanced gastric cancer:

What is standard of care?

ESMO guidelines

Smyth EC, et al. Ann Oncol 2016;27(Suppl 5):38–49. By permission of the European Society of Medical Oncology

Surgery

Re-assess

HER-2 negative

Platinum+

fluorpyrimidine-

based doublet or

triplet regimen

HER-2 positive

Trastuzumab

+ CF/CX

Consider clinical

trials of

novel agents

2nd line chemo

Clinical trials if

adequate PS

Palliative

chemotherapy

Best supportive

care if unfit for

treatment

Inoperable or

metastatic

Treatment for metastatic/unresectable

gastric cancer: Active agents in first line

Based upon superiority trials:

5-FU

Cisplatin

Docetaxel

Trastuzumab

Based upon non-inferiority trials

Oxaliplatin

Capecitabine

S1

Irinotecan

Cervantes A, et al. Cancer Treat Rev 2012; 39:60-67

Best

supportive

care1

5-FU monotherapy1

Transtuzumab + CDDP+ FU or Cape6

EOX5

5-FU + LV + Oxaliplatin (FLO)4

Capecitabine + Cisplatin (XP)3

Docetaxel +Cisplatin + 5-FU2

4 months

7 months

9.2 months

10.5 months

10.7 months

11.2 months

13.8 months

MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER

1. Wagner A, et al. JCO 2006. 2. van Cutsem E, et al. J Clin Oncol 2006;24:4991–4997. 3.Kang YK et al, Ann Oncol 2009;

20:666–73. 4. Al Batran SE, et al. J Clin Oncol 2008;26:1435–1442. 5. Cunningham D, et al. N Engl J Med 2008;358:36-46.

6. Bang YJ, et al. Lancet 2010;376:687–697

EOX: Epirubicin/Oxaliplatin/Capecitabine.

Have we made any progress in

the treatment of advanced gastric cancer?

FFCD-GERCOR-FNCLCC 03-07 Phase III

Study. FOLFIRI vs ECF in advanced

gastric cancer

Objective II: Response Rate (RR), PFS and OS

ECF

N=209

FOLFIRI

n=207p value

TTF (months) 4.2 5,1 0.008

RR 1st

RR 2nd39.2%

10.1%

37.8%

13.7%n.s.

PFS (months)

Median range

5.29

4.53-6.31

5.75

5.19-6.740.96

OS (months)

Median range

9.49

8.77-11.14

9.72

8.54-11.270.95

Guimbaud R, et al. J Clin Oncol 2014;32:3520–3526

Phase II Study of modified DCF vs DCF

plus G-CSF in advanced gastric cancer

Stratification:

Measurable or not

Gastric vs GEJ

Center

A: modified DCF

B: standard DCF plus G-CSF

Objective : 6 months-PFS

Objectives II:

RR, OS, Toxicity

Shah MA, et al. J Clin Oncol 2015;33:3874–3879

R

Phase II Study of modified DCF vs DCF

plus G-CSF in advanced gastric cancer

Shah MA, et al. J Clin Oncol 2015;33:3874–3879

Phase II Study of modified DCF vs DCF

plus G-CSF in advanced gastric cancer

Shah MA, et al. J Clin Oncol 2015;33:3874–3879

Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine

TE vs TEF vs TEX

Van Cutsem E, et al. Ann Oncol 2015;26:149–156.

Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine

TE vs TEF vs TEX

Van Cutsem E, et al. Ann Oncol 2015;26:149–156.

Treatment Patients

nr

RR

%

95% CI PFS

months

95% CI OS

months

95% CI

TE 79 23,1 14,3-34,0 4,50 3,68-5,32 8,97 7,79-10,9

TEX 86 25,6 16,6-36,6 5,55 4,30-6,37 11,30 8,08-14,0

TEF 89 46.6 35,9-57,5 7,66 6,97-9,40 14,59 11,7-21,8

1. Bang YJ, et al. Lancet 2010;376:687–697. 2. Van Cutsem E, J Clin Oncol 2012;30 (17):2119–2127. 3. Lordick F, Lancet Oncol

2013;14:490–499. 4. Waddell T, Lancet Oncol 2013;14:481–489. 5. Cunigham ASCO 2015.. 6. Shah M. J Clin Oncol 2015;33(15)

Trial Chemotherapy BiologicalHR

OS

P

value

Increase in

median survival

ToGA1Cisplatin+5-FU/

capecitabineTrastuzumab 0.74 0.04 +2.8 months

AVAGAST2Cisplatin+

capecitabineBevacizumab 0.87 0.10 +2.0 months

EXPAND3 Cisplatin+

capecitabineCetuximab 1.00 0.95 -1.3 months

REAL-34Oxaliplatin+

epirubicin +

capecitabine

Panitumumab 1.37 0.013 -2.5 months

RILOMET-15Cisplatin+

epirubiicin+

capecitabine

Rilotumumab -- --Stopped in futility

analysis

METGASTRIC6 FOLFOX6 Onartuzumab 1.06 0.83 -0.6 months

Targeted therapies in first-line treatment

for advanced gastric cancer: Summary of

Phase III Trials

321. Bang YJ, et al. Lancet 2010;376:687–697.2. Hecht JR, et al. ASCO abstract 2013 LBA4001.

3. Satoh N, et al. J Clin Oncol 2014; 32:2039–2049. 4. Kang YK et al. ASCO GI 2016 5. Tabernero j, et al. ESMO 2017

Targeted therapies against HER2 in advanced

gastric cancer: Summary of Phase III Trials on

tratuzumab, lapatinib, TDM-1 and pertuzumab

TRIALChemotherapy

backbone

Line of

therapy

number

HR

OS

P

value

Response

rate

Increase in

median survival

ToGA1Cisplatin+5-FU/

capecitabine

First

5840.74 0.04

51% vs 37%

p=0.0017+2.8 months

LOGiC2Oxaliplatin/

capecitabine +/-

Lapatinib

First

5450.91 0.35

53% vs 39%

p=0.031+1.7 months

TyTAN3Paclitaxel+/-

Lapatinib

Second

2610.84 0.20

27% vs 9%

p=0.001+2.1 months

GATSBY4TDM-1

vs Taxane

Second

3451.15 0.85 NP - 0,7 months

JACOB5Cisplatin+5-FU/

cap/Trastu

+/- Pertuzumab

First

7800.84 0.056 56% vs 48% 3.3 months

1. Thuss-Patience PC, et al. Eur J Cancer 2011;47:2306–2314.

2. Kang JH, et al. J Clin Oncol 2012;30:1513–1518.

3. Ford HE, et al. Lancet Oncol 2014;15:78–86.

Trial

authorYear

Patients

random

(n)

TreatmentResponse

rate (%)

HR

OS

P

value

Gain in

median

survival

Thuss-Patience,

et al.12011

40

1:1Irinotecan

NR

SD 58%0.48 0.0023

2.4

months

Kang, et al.2 2012193

2:1

Irinotecan

DocetaxelNR 0.65 0.004

1.3

months

Ford, et al.3 2014168

1:1Docetaxel NR 0.67 0.01

1.6

months

Gastric cancer: Second line

chemotherapy. Trials comparing BSC

versus active treatment

Ford HE, et al. Lancet Oncol 2014;15:78-86.

Gastric cancer second line chemotherapy:

Docetaxel vs BSC (COUGAR-02 Trial) is

improving survival

1. Thuss-Patience PC, et al. Eur J Cancer 2011;47:2306–2314. 2. Kang JH, et al. J Clin Oncol 2012;30:1513–1518.

3. Ford HE, et al. Lancet Oncol 2014;15:78–86. 4. Otshu A. et al. J Clin Oncol 2013;31:3935–3943. 5. Fuchs CS, et al. Lancet

2014;383:31–39.

Trial author YearPatients

random (n)Treatment

HR

OS

P

value

Gain in median

survival

Thuss-Patience,

et al.12011

40

1:1Irinotecan 0.48 0.0023 2.4 months

Kang, et al.2 2012193

2:1

Irinotecan

Docetaxel0.65 0.004 1.3 months

Ford, et al.3 2014168

1:1Docetaxel 0.67 0.01 1.6 months

Otshu, et al4 2013656

2:1Everolimus 0.90 0.124 0.9 months

Fuchs, et al5 2014355

2:1Ramucirumab 0.77 0.047 1.4 months

Gastric cancer: Second line

chemotherapy trials comparing BSC

versus active treatment

Reprinted from Fuchs CS, et al. Lancet Oncol 2014;383:31–39 © (2005) with permission from Elsevier

Gastric cancer second line treatment:

Ramucirumab vs BSC (REGARD Trial) is

improving survival

1. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444.

2. Wilke H, et al. Lancet Oncol 2014;15:1224–1235.

Trial author YearPatients

(n)Treatment

HR

OS

P

value

Gain in median

survival

Hironaka, et al.1 2013 223Irinotecan

vs paclitaxel1.13 0.38

0.9 months

for irinotecam

Wilke et al.2 2014 665Paclitaxel+/-

ramucirumab0.80 0.017 2.2 months

Gastric cancer: Second line

chemotherapy trials comparing two active

treatments

Gastric cancer second line treatment:

Addition of ramucirumab to paclitaxel

improves overall survival (Rainbow Trial)

Wilke HJ, et al. Lancet Oncol 2014;15:1224–1235© (2005) with permission from Elsevier

Pembrolizumab induces responses in

chemorefractory gastric cancer

Central reviewN = 36a

Investigator review

N = 39

ORR, % (95% CI) 22.2 (10.1, 39.2) 33.3 (19.1, 50.2)

Best overall response, n (%)

Complete responseb 0 0

Partial responseb 8 (22.2) 13 (33.3)

Stable disease 5 (13.9) 5 (12.8)

Progressive disease 19 (52.8) 21 (53.8)

No assessmentc 1 (2.8) —

Not determinedd 3 (8.3) —

.

Muro K, et al. Lancet Oncol 2016; 17:717-726.

Nivolumab (ONO-4538/BMS-936558) as Salvage Treatment After Second- or Later-Line

Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer (AGC):

A Double-Blinded, Randomized, Phase 3 Trial

Yoon-Koo Kang,1 Taroh Satoh,2 Min-Hee Ryu,1 Yee Chao,3 Ken Kato,4 Hyun Cheol Chung,5

Jen-Shi Chen,6 Kei Muro,7 Won Ki Kang,8 Takaki Yoshikawa,9 Sang Cheul Oh,10 Takao Tamura,11

Keun-Wook Lee,12 Narikazu Boku,4 Li-Tzong Chen13

1Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 2Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan; 3Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Gastrointestinal Medical Oncology, National Cancer

Center Hospital, Tokyo, Japan; 5Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Song Dang Institute for Cancer Research, YonseiUniversity College of Medicine, Yonsei University Health System, Seoul, Korea; 6Division of Hematology/Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; 7Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 8Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 9Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan; 10Division of Hematology/Oncology, Internal Medicine Department, College of Medicine, Korea University, Seoul, Korea; 11Medical Oncology, Kindai

University, Faculty of Medicine, Osakasayama, Japan; 12Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; 13National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

Study Design and Endpoints

BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV; intravenous; ORR, objective response

rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response.

R

2:1

Nivolumab

3 mg/kg IV Q2W

Placebo

Key eligibility criteria:

• Age ≥ 20 years

• Unresectable advanced or

recurrent gastric or

gastroesophageal junction

cancer

• Histologically confirmed

adenocarcinoma

• Prior treatment with ≥ 2

regimens and refractory

to/intolerant of standard

therapy

• ECOG PS of 0 or 1

Primary endpoint:

• OS

Secondary endpoints:

• Efficacy (PFS,

BOR, ORR, TTR,

DOR, DCR)

• Safety

Exploratory endpoint:

• Biomarkers

Stratification based on:

• Country (Japan vs Korea vs Taiwan)

• ECOG PS (0 vs 1)

• Number of organs with metastases (< 2 vs ≥ 2)

Patients were permitted to continue treatment beyond initial RECIST v1.1–defined disease progression,

as assessed by the investigator, if receiving clinical benefit and tolerating study drug

Overall Survival

Time (months)

Pro

ba

bil

ity o

f S

urv

iva

l (%

)

22181614121086420

0

10

20

30

40

50

60

70

80

90

100

Hazard ratio, 0.63 (95% CI, 0.50–0.78)

P < 0.0001

0351019395795142275330

0133410163253121163

Nivolumab

Placebo

At risk:

20

193

82

Patien

ts, n

Event

s, n

Median OS

[95% CI],

months

12-Month OS

Rate [95% CI],

%

Nivolumab 330 225 5.32 [4.63–

6.41]

26.6 [21.1–

32.4]

Placebo 163 141 4.14 [3.42–

4.86]

10.9 [6.2–

17.0]

Classification of gastric adenocarcinoma:

Pathology

Intestinal versus diffuse subtypes

Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31–49

Cancer Genome Atlas Research Network. Nature 2014;513:202–209

9%

22%20%

50%

Advanced Gastric cancer: Conclusions I

Her2 status to be determined in all patients with advanced disease

Trastuzumab to be added if HER2 positive (+++)

Platinum-based chemotherapy as first option, with FOLFIRI as an

alternative

Second line chemotherapy also prolongs survival in good PS

patients

Ramucirumab as single agent prolongs survival versus BSC

Ramucirumab in combination with paclitaxel improves outcomes

over paclitaxel

These statements could also be valid for junctional and lower third

esophageal adenocarcinoma

Advanced Gastric cancer: Conclusions II

Most targeted therapies failed in molecularly unselected trials

Immunotherapy (Pembrolizumab/Nivolumab) under development

with interesting data to be confirmed

Better selection of patients needed in clinical trials

Validation of molecular classification in trials

International cooperation

Oesophageal cancer: Specific features

Squamous histology in upper and middle third location

Adenocarcinoma histology in lower third location

Lower third located tumours treated frequently as gastric cancer

Different diseases according to histology, biology and

epidemiological factors

PET scanning of value in apparently localized tumours, detecting

metastatic disease in up to 15-20% of cases

Staging based in TNM (endoscopy, EUS, CT-scan, Pet-CT)

Localized Oesophageal cancer: Principles

of Therapy

Single modality (Surgery or Radiation) not adequate for locally

advanced disease (T3 or N+)

Low prevalence of early stages

Assessment of comorbidities related to etiological factors such as

tobacco and alcohol: respiratory failure due to COPD and chronic

liver disease

Multimodality treatment provides better results in randomised trials

Preoperative treatment strategy preferred to postoperative

Localized Oesophageal cancer: Principles

of Therapy

Current validated options are:

Preoperative Chemotherapy

Preoperative Chemoradiation

Definitive Chemoradiation

Preoperative Chemotherapy in Localized

Oesophageal cancer

1. Sjoquist KM, et al. Lancet Oncol 2011;12:681–692.

Preoperative Chemo-Radiotherapy in

Localized Oesophageal cancer

Sjoquist KM, et al. Lancet Oncol 2011;12:681–692.

Preoperative Chemo-Radiotherapy in

Localized Oesophageal cancer: Long term

data of the CROSS trial

Shapiro KM, et al. Lancet Oncol 2015;16:1090-1098.

Median OS: 24.0 vs 48.6 months

HR: 0.68 (CI at 95%:0.53-0.88)

p: 0.003

Preoperative Chemotherapy versus Chemo-

Radiotherapy in Localized Oesophageal

cancer

Keblebro F, et al. Ann Oncol 2016; 27:660-667:8.

Definitive Chemo-Radiotherapy in

Localized Oesophageal cancer

Al Sarraf M, et al. J Clin Oncol 1997;15:277–2842.

Localized Oesophageal cancer:

Conclusions

Most patients do present with locally advanced tumors

Multimodality approach is mandatory

Multimodality approach does benefit both squamous and

adenocarcinoma histologies

Preoperative chemotherapy and preoperative chemoradiation are

better that surgery alone

Comparisons between both strategies are underway

Definitive chemoradiation is better than radiation as single arm in

squamous tumours located at cervical and middle third who are not

operable