Jimmy B.Y. So Professor of Surgery

National University of Singapore

Head, Division of Surgical Oncology

National University Cancer Institute

National University Hospital

Singapore Gastric Cancer Consortium (SGCC)

Singapore

Surgery for Gastric and GE Junction Cancer,Primary, Palliative: When & Where

4th Master Workshop on Gastric Surgery & Endoscopy, Hong Kong 2012

Outline for today

• Current standards of surgery for gastric cancer

• Approach to Gastroesophageal junction cancer

• Recent advances on Gastric Cancer treatment

Gastric Cancer in the world

GLOBOCAN 2015

Globocan 2015• 3rd leading cause of cancer death worldwide

• 700,000 deaths annually, majority of cases in Asia

27

7667

57

14 12

85 81 85

020406080

100

Sto

mac

h

Bre

ast

Cer

vica

l

Co

lon

&…

Live

r

Lun

g &

…

Pro

stat

e

Thyr

oid

Ute

rin

e

Survival for Gastric Cancer remains Poor

5 year Survival,

International

5 year Survival,

Singapore

24

69

50 49

513

7287 76

-10

10

30

50

70

90

Sto

mac

h

Bre

ast

Cer

vica

l

Co

lon

&…

Live

r

Lun

g &

…

Pro

stat

e

Thyr

oid

Ute

rin

e

Cancer of Gastric Cardia: Rising Trend

Deans C, So J et al. World J Surg 2011

Increasing

trend

Principles of Treatment for Gastric Cancer

Cancer at Stomach Lymph nodesPeritoneum

Blood circulation

Local disease Systemic disease

Treatment

Endoscopic resection

Laparoscopic surgeryAdjuvant chemotherapy

Surgical treatment

Gastrectomy+LN dissection

Gotoda T, Gastric Cancer 2007

Treatment

Multidisciplinary tumor (MDT) meeting

Surgeons, Medical & Radiation Oncologists, GI, pathologists, radiologists

and research nurses

NUH UGI Cancer weekly meeting

Our weekly MDT patient list- example

Name Age Diagnosis Comorbid OGD Biopsy CT Surgery Histology Board Decision

SBA 64 Gastric CA DM Antralulcer

Poorly diff adenoCA

AntrallesionNo node

LADG 10/7/15

T1bN1M0 Adjuvant therapy

LW 60 Gastric GIST

Nil Fundal ulcer

GIST Nodistant mets

Surgery first

WBH 51 EsophagealCA

HT Tumorat 38cm-42 cm

adenoCA Peri-esophagealnodes

Neoadjuanttherapy

Surgical Strategies- “Tailor Approach”

Endoscopic (EMT/ESD)

Laparoscopic Open

Endoscopic mucosal resection(EMR)

Gastrointestinal Endoscopy 2003

• T1a (mucosal), <1cm cancer

• >1cm cancer : piecemeal resection

Endoscopic Submucosal Dissection

【 Concept 】

Simple.

‘Inject, Cut & Dissect,’ ‘Remove tumor in one piece.’

En bloc resection, less risk of local recurrenceOno et al.,Gut 2001

Indications for Endoscopic resection

Gotoda et al., Gastric Cancer 2007

Cancer with minimal risk of lymph node metastasis

Based on tumor depth and histology

• D1: removal of tier 1 nodes (#1-6)

• D2: removal of tiers 1 and 2 nodes (#7-12)

Principle of Surgery: D2 gastrectomy

Distal gastrectomy

D1 blue

D1+ blue + orange

D2 blue + orange + red

Japanese Gastric Cancer Guidelines. Gastric Cancer 2011

#7 now classified as D1

Total Gastrectomy

Japanese Gastric Cancer Guidelines. Gastric Cancer 2011

D1 blue

D1+ blue + orange

D2 blue + orange + red

Br J Surg 2004

Lancet Onco 2006

(Taiwan D2 Study)

D2 and D1 had no difference in mortality rate (zero)D2 has better survival than D1 (60% vs 54%)

D2

D2

Dutch D2 Trial- 15 year follow-up results

NEJM 1999

Lancet 2010

Lymph nodes specimen

Adjuvant Therapy for gastric cancer

Surgery + ChemoradiotherapyMcDonald et al.2001

Perioperative chemotherapy + SurgeryCunningham et al. 2006

Al-Batran et al., 2017 (FLOT4)*

Surgery + postop chemotherapySakuramoto et al. 2007

Bang et al. 2012

Indication: Stage 2 or above GC

GE Junction Cancer: Siewart Classification

Tumor epicenter

within 5cm above

or below GEJ

Differences in pathological features

Siewart et al., Ann Surg 2000

Treatment approach for GEJ cancer

• Type 1: Treat as esophageal cancer

- Esophagectomy

• Type 2: controversial

- Total gastrectomy + distal esophagectomy

- Esophagectomy + proximal gastrectomy

• Type 3: Treat as gastric cancer

- Gastrectomy

Current recommendation for Type 2

• For tumor with esophageal invasion <2cm

• Extended gastrectomy

• For tumor with esophageal invasion >2cm

• Esophagectomy

Surgical Outcomes NUH (2000-2013, n=379)

Type of gastrectomy Total 116 (30%)

Distal 255 (68%)

Lymph node dissection D1 87 (23%)

D2 292 (77%)

R0 resection

Mortality (30 day)

353 (93%)

1.8%

Morbidity 28%, No difference between D1 and D2

Lui S, So JB et al., manuscript submitted

Disease Free Survival (n=379)0.0

00.2

50.5

00.7

51.0

0

Re

curr

ence

-fre

e s

urv

iva

l pro

ba

bili

ty

0 2 4 6 8 10Time to recurrence (years)

I

II

III

IV

5YSR

96%

72%

41%

14%

Recent advances on Gastric Cancer treatment

Intraperitoneal chemotherapy

• Peritoneum is a common site of metastasis from gastric and colon cancers1

• It is resistant to systemic chemotherapy

• Prognosis is very poor with median survival about 3 - 6 months 2

1Yoo et al., British J Surgery 2000; Sasako et al. JCO 20122 Thomassen et al., Int J Cancer 2014

Current treatment for peritoneal disease

• Palliative systemic chemotherapy

• Hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS)

• Intraperitoneal normothermicchemotherapy with Paclitaxel

HIPEC and CRS

• Increasingly accepted as treatment options for PC (eg. Colorectal origin, low PCI)

• For gastric cancer, results of HIPEC are inferior compared to other cancers

Coccolini et al. Eur J Surg Oncol 2014

Gill et al. J Surg Oncol 2011

Katayama et al., J Surg Onco 2014

Intraperitoneal Chemotherapy for Ovarian Cancer with Paclitaxel

429 patients with stage 3 ovarian cancer

New Eng J Med 2006

OS: 50 vs 66 months

Paclitaxel as Intraperitoneal chemotherapy

1. Large size molecule

– less absorption into

circulation

2. Antiproliferative

– Less adhesion

– Allows repeated use

Advantages:

• Safe

• Simple administration

• Outpatient treatment

Ishigami H et al., Cancer 2013

NUH Phase 2 Study protocol

Week 1 Week 2 Week 3 Rest

Day 1 only

Day 1 Day 8

• This was repeated for 8 cycles

• After 8 cycles, oxaliplatin is discontinued, IP paclitaxel may continue with or without capecitabine

Kono K, WP, Yong, So J et al Gastric Cancer 2017

ClinicalTrials.gov identifier: NCT01739894

Set-up of outpatient IP Chemotherapy

Surgical Technique: Laparoscopy

Survival outcomes (n=34, P≥1*)

1-year survival rate 64.9% (95% CI: 45.5%–78.9%)

Median OS 16.4 months (IQR: 10.1–27.2)

Chan, So, Yong et al., J Gastrointesinal Surgery 2017

* JCGA 1st edit.

Results From Conversion Gastrectomy (n=8)

With conversion surgery (n=8)

1 year OS 87.5%

Without conversion surgery (n=26)

1 year OS 57.2 %

Chan, So, Yong et al., J Gastrointesinal Surgery 2017

Strait Times 26 May 2016

PHOENIX-GC trial Japan intraperitoneal chemotherapy study group (JIPG)

PHOENIX-GC trial(Courtesy of H Ishigami)

Gastric cancer with peritoneal metastasis R

IP PTX + S-1/PTX

S-1/CDDP

Primary Endpoint

• Overall survival

Secondary

Endpoints

• Response rate

• 3-yr OS rate

• Safety

Key Eligibility Criteria

• No or <2mo prior chemo.

• No other distant metastasis

• No prior gastrectomy

• No frequent ascites

drainage

Stratification

• Institution

• Prior chemo. +/-

• Peritoneal

meta.

P1 / P2-3

2

1

PHOENIX-GC trial Japan intraperitoneal chemotherapy study group (JIPG)

Follow-up analysis for OS

Stratified log-rank test

p=0.034

Cox regression analysis

HR 0.68 (95% CI 0.48-

0.97)

p=0.035

in the FAS population (n=164)

Number at riskTime (Months)

IP 114 82 44 25 4

SP 50 35 15 3 0

0

0.5

1

0 12 24 36 48 60

Surv

ival

Rat

e

IPSP

3-year OS rate

IP 21.9% (95% CI 14.9 - 29.9)

SP 6.0% (95% CI 1.6- 14.9)

Courtesy of Prof H Ishigami JGCA annual meeting 2017

Outpatient IP Chemotherapy (paclitaxel)

Advantages

– Day surgery

– Outpatient treatment

– Allows conversion

surgery if good

response

Disadvantages

– Port related

complications

– Limited drug

distribution in patients

with adhesions

– Limited drug

penetration*

*Flessner et al., Am J Physiol Renal Physiol 2005

PIPAC(Pressurized intraperitoneal aerosol chemotherapy)

Solass et al., Ann Surg Onco 2014. Tempfer et al., Gynael Oncol 2015

Reymond et al., J GI Surgery 2016.Demtroder et al., Colorectal Dis 2016

• 16 preclinical studies and

• 13 clinical studies: 841 PIPAC procedures in 346 patients (gastric, colon, ovarian primaries)

• Technical success rate 83-100%

• Low postoperative morbidity

• minimal impact on QoL

• Histological response: 62-100%

British Journal of Surgery 2017 May

PIPAC for gastric cancer

J GI Surg 2016

N=24 GC with PM

Mean PCI 18

Cisplatin and

Doxorubicin

Overall Median

survival = 15 months

PM alone

with other mets

POTENTIAL Advantages of PIPAC

1. Minimally invasive

2. Better distribution (gas >liquids)

3. Better drug penetration with pressure

4. Allow direct assessment of response with biopsy at laparoscopy

Br J Surgery 2017

Drug distribution (ex-vivo)

Conventional lavage PIPAC

Solass W, Reymond M et al., Surg Endosc July 2012

Tissue penetration

up to 7 cell layers

Solass Surg Endoscopy 2012

“conventionalLavage”

“PIPAC” Control

PIPAC treatment in Europe

PIPAC in Singapore

PIPAC course, Italy, 2016

We performed the first PIPAC in Asia:

with Prof Marc Reymond

12 Dec 2016

PIPAC: set-up

High pressure injector Micropump- Capnopen®

PIPAC: set-up

Gas disposable system Operative room safety

PIPAC: safety

Remote control

PIPAC procedure (video)

Our first patient: The day after PIPAC with our Team and Prof Marc Reymond (13 Dec 2016)

PIPAC clinical Trial

• Phase 1 Dose finding study with Oxaliplatin

• Patients with peritoneal carcinomatosis from advanced Gastric and Colon cancers, where further systemic chemotherapy is not indicated or tolerated

• Study pharmacokinetics and safety

Clinicaltrials.gov no: NCT03172416

Plasma level of Oxaliplatin after PIPAC

Preclinical study: PIPAC Paclitaxel

Aims to determine:

• Safety

• Pharmacokinetic profile

• Depth of tissue penetration of Paclitaxel with PIPAC

Design:

Day 1. PIPAC

Paclitaxel

administration

Day 6. IV

Paclitaxel

administration

Day 7.

Pig sacrificed

PK and short-term safety PK

Summary (2)

• Epidemiology of GC is changing

• Surgical treatment is tailored according to stage and expertise

• Siewart classification is widely accepted for management of cancer of gastric cardia

• Multi-disciplinary treatment is essential for best outcomes

Summary 1: JGCA guideline 2011

(+ adjuvant therapy)

National University Health System

Thank You

jimmyso@nus.edu.sg

Preoperative imaging- CT reconstruction of Celiac Axis

National University Hospital Singapore

Celiac nodes dissection

CHA

SPA

LGA