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 or Palliative: When & Where

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

Disclosures

None

Outline for today

• Surgical standards for gastric cancer in 2018

• Approach to Gastroesophageal Junction Cancer

• Recent advances in treatment of peritoneal

carcinomatosis

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

Principles of Treatment for Gastric Cancer

Cancer at Stomach Lymph nodes PeritoneumBlood circulation

Local disease Systemic disease

Treatment

Endoscopic resection

Laparoscopic surgery

Surgical treatmentGastrectomy+LN dissection

Gotoda T, Gastric Cancer 2007

Adjuvant chemotherapy

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

cancer

DM Antral

ulcer

Poorly

diff

adenoCA

Antral

lesion

No node

LADG

10/7/15

T1bN1M0 Adjuvant

therapy

LW 60 Gastric

GIST

Nil Fundal

ulcer

GIST No

distant

mets

Surgery

first

WBH 51 Esophageal

cancer

HT Tumor

at

38cm-

42 cm

adenoCA Peri-

esophag

eal

nodes

Neoadjuant

therapy

Japanese Gastric Cancer Treatment

Guideline 2014

(if stage 2 or above, + adjuvant therapy)

Surgical Strategies- “Tailor Approach”

EndoscopicLaparoscopic/

RoboticOpen

EMR

Endoscopic mucosal resection

ESD

Endoscopic submucosal dissection

• D1: removal of tier 1

nodes (#1-6)

• D2: removal of tiers 1

and 2 nodes (#7-12)

Principle of Surgery: D2 gastrectomy

Surgical Treatment of Gastric Cancer

Distal Gastrectomy Total Gastrectomy

Japanese Gastric Cancer Guidelines 2018

D1 blue (perigastric)

D1+ blue + orange

D2 blue + orange + red (perigastric and coeliac LN)

Proximal Gastrectomy Pylorus preserving gastrectomy

For Early Gastric Cancer

EGC at upper 1/3 stomach EGC at middle 1/3 stomach

Celiac nodes dissection

CHA

SPA

LGA

Br J Surg 2004Lancet 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- better staging

Laparoscopic Gastrectomy

• Become much more

established

• Multiple RCTs showed

improvement in outcomes

for early GC

• For advanced GC, it

remains controversial due

to technical challenges

Robotic Gastrectomy

• A tool for laparoscopic

surgery

• No advantages compared

to lap surgery*

• More costly

• Easier to learn for open

surgeons

Kim HI et al, Ann Surg 2015

Need for splenectomy

• Splenectomy was considered to be standard for total

gastrectomy to remove #10 splenic hilar LN

• But , it is associated with immune suppression

Ann Surg 2017

Splenectomy vs No Splenectomy

Non-inferiority P=0.025

Spleen preservation group

Splenectomy group

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12

Years after randomization

Sano T. et al, Ann Surg 2017

Overall Survival

Splenectomy is unnecessary unless the tumor is at the greater curvature

Adjuvant Therapy for gastric cancer

Surgery + Chemoradiotherapy

McDonald et al.2001

Perioperative chemotherapy + Surgery

Cunningham et al. 2006

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

Surgery + postop chemotherapy

Sakuramoto et al. 2007

Bang et al. 2012

Indication: Stage 2 or above GC

SURGERY FOR GE JUNCTION

CANCER

GE Junction Cancer: Siewart Classification

Tumor epicenter

within 5cm above

or below GEJ

Differences in pathological features

Siewart et al., Ann Surg 2000

Overall the incidence is increasing

Surgical treatment for GEJ cancer

• Type 1: Treat as esophageal

cancer – Esophagectomy

• Mediastinal Lymph node

dissection

Surgical approach for GEJ cancer

Type 3: Treat as gastric cancer

- Total Gastrectomy

• Celiac lymph node dissection

Surgery for Type 2 GEJ Cancer

• Controversial

• Extended gastrectomy or Esophagectomy

Esophagectomy or Gastrectomy for T2 GEJ?

Determining Factors:

1. Extent of esophageal involvement

1. <2 cm: Gastrectomy (with distal Esophagus)

2. >2 cm: Esophagectomy

2. Mediastinal nodal involvement (on Imaging)

3. Patient fitness

Recent advances on

Treatment of Peritoneal Metastasis

from Gastric cancer

Peritoneal Metastasis

• Peritoneum is the most common site of metastasis from gastric cancer

• 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

Recent treatment options for PC

• Systemic chemotherapy

• Hyperthermic intraperitoneal chemotherapy (HIPEC)

with cytoreductive surgery (CRS)

• Intraperitoneal chemotherapy

• Pressurized intraperitoneal aerosol chemotherapy

(PIPAC)

Recent treatment options for PC

• Systemic chemotherapy

• Hyperthermic intraperitoneal chemotherapy (HIPEC)

with cytoreductive surgery (CRS)

• Intraperitoneal chemotherapy

• Pressurized intraperitoneal aerosol chemotherapy

(PIPAC)

Intraperitoneal chemotherapy with Paclitaxel

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

Why Paclitaxel

Intraperitoneal catheter and

subcutaneous access port

Medium survival= 19 months1 YSR= 72-2%

Markman M. Lancet Oncology 2003Kono, So JB. Gastric Cancer 2017

Laparoscopic insertion

Access port

Outpatient chemotherapy

NUH Phase 2 Study Design

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

Primary endpoint: Overall Survival

(n=41)

Best overall response – no./total no. of

evaluable pts (%)†

• Complete response 1/38 (2.6)

• Partial response 7/38 (18.4)

• Stable disease 22/38 (57.9)

• Progressive disease 8/38 (21.1)

Cytological response – no./total no. (%)

• Turned negative 19/35 (54.3)

• Remained positive 16/35 (45.7)

• Remained negative 4/6 (67.0)

• Turned positive 2/6 (33.0)

Result – Response (n=41)

†Clinical benefit rate (CBR) = CR + PR + SD = 78.9%

†Objective response rate (ORR) = CR + PR = 21.1%

NS1

Slide 37

NS1 CBR is sometimes also known as the "Disease control rate (DCR)" - these terms can be used interchangeablyNicholas Syn, 02/09/2018

Result for Salvage Gastrectomy

Median survival 18.8 vs 13.4 months

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

22

11

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

PHOENIX-GC trial

Stratified log-rank test

p=0.034

Cox regression analysis

HR 0.68 (95% CI 0.48 -0.97)

p=0.035

0

0.5

1

0 12 24 36 48 60

Su

rviv

al

Ra

te

IP

SP 3-year OS rate

IP 21.9% (95% CI 14.9 - 29.9)

SP 6.0% (95% CI 1.6- 14.9)

Ishigami et al., JCO 2018

Follow-up analysis for

Overall Survival

PIPAC (Pressurized intraperitoneal aerosol chemotherapy)

- (M Reymond Surg Endosc 2000, Ann Surg Onco 2014)

Reymond M et al., Surg Endosc 2000, Solass, Reymond et al., Ann Surg Onco 2014 Tempfer et al., Gynael Oncol 2015, Reymond M et al., J GI Surgery 2016, Demtroder et al., Colorectal Dis 2016

Chemotherapy

solution

Unique features of PIPAC

1. Minimally invasive (only 30-60 mins, day surgery possible)

2. Better drug distribution (gas >liquids)

3. Better drug penetration with pressure (12mmHg)

4. Allow direct assessment of response (with laparoscopy)

Br J Surgery 2017

Drug distribution (ex-vivo)

Conventional lavage PIPAC

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

PIPAC: Tissue penetration in-human (DOX) (in vivo)

Solaß et al, Ann Surg Oncol 2012, Sugarbaker PH et al. Eur J Surg Oncol. 2011 37:719-26.

Normal Peritoneum Tumor nodule

After PIPAC: presence of DOX throughout the peritoneum up into the retroperitoneal tissue

- Highest concentration ~100 - 200 µm (from the surface)

- concentration in tumor ~ up to 4,1 µmol/g

= higher dose and deeper penetration than reported after HIPEC - with 10% dose

44

• 16 preclinical studies and

• 13 clinical studies: 841 PIPAC procedures in 346 patients

• Technical success rate 83-100%

• Histological response: 62-100%

• Low postoperative morbidity

• minimal impact on QoL

� Safe and promising treatment for PC

British Journal of Surgery 2017

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

PIPAC: during treatment

Operative room Laparoscopic view

Prospective studies on PIPAC (selected)

Country Design Status Research questions Primary

Germany Phase 2

Single arm

Completed* Feasibility, safety and

efficacy of PIPAC

Gastric

Italy Phase 2

Single arm

Recruiting Feasibility, safety and

efficacy of PIPAC

Colorectal,

ovarian and

gastric

France Phase 3 Recruiting Feasibility, safety and

efficacy of PIPAC

Ovarian

France Phase 2

randomised

Recruiting Efficacy of PIPAC + IV

chemo vs IV chemo

alone

Gastric

United States

(Mayo clinic)

Phase 2 Active, recruiting

soon

Feasibility, safety and

efficacy of PIPAC

Colorectal,

Ovarian

Singapore Phase 1 dose

escalation

Recruiting Feasibility, safety and

optimal dosing of PIPAC

with Oxaliplatin

Gastric, colon

Singapore Porcine model On going PIPAC vs IV Paclitaxel:

safety, PK, dosing and

Tissue penetration

Normal

PIPAC clinical Trial @NUH

• 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

Inclusion criteria

• Gastrointestinal cancer patients with peritoneal metastasis on peritoneal cytology/histology

• Patients who have received at least 1st line chemotherapy

• ECOG performance status 0-3

• Expected survival >3 months

Clinicaltrials.gov no: NCT03172416

Design

Prospective, single arm, phase I dose finding

study

3 + 3 dose escalation

2 PIPAC per patient, 6 weeks apart

Kim et al., Pleura and Peritoneum (in press)

Current status since 2017 March

• 18 PIPAC procedures for 12 patients

• Gastric (7), Colorectal (4), Gallbladder (1)

• Median age 58 years (range 51 – 65)

• Mean PCI score: 15 (range 1 – 36)

• Mean operating time: 103.8 mins (68 – 146)

• No mortality, 2 cases of pancreatitis

Preliminary pharmacokinetics results

The mean plasma maximum concentration (Cmax) = 675.7 ng/mL, about 50%

the Cmax when the same dose is administered intravenously1

1based on FDA’s CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW

N=5

Dosage of oxaliplatin= 45mg/m2

HIPEC vs PIPAC

HIPEC (+CRS)

• Curative intent

• Maximally Invasive

• For selected patients

• Limited drug penetration

and distribution

• Allow only single

treatment

• Loss of QoL

PIPAC

• Palliative intent

• Minimally invasive

• For most patients with PM

• Better drug penetration

and distribution

• Allow repeated treatment

• Maintain QoL

Our first patient:

The day after PIPAC with our Team and Prof Marc Reymond

(13 Dec 2016)

Summary

• Surgery for GC is tailored to the stage of cancer

• Siewart classification is useful for management

of junctional cancer

• More treatment options are now available for

peritoneal carcinomatosis

• Multi-disciplinary management is essential

National University Hospital Singapore

Thank You

jimmyso@nus.edu.sg

Issues of IP Chemotherapy

• Port related complications

• Limited drug distribution in patients with adhesions

• Limited drug penetration*

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

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