Gastric Cancer:From Molecular Classification

to Clinical Impact

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

Lilli Advisory Board01/09/2016Sofitel Hotel & Tower

Speaker Disclosures:

Member of Advisory Board, Consultant, and Speaker for:• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,

Sanofi, MSD, Merck Serono, Novartis, Pfizer, Eli Lilly.• The content of this presentation does not relate to any product of a

commercial interest

Objectives:

• Emphasizing the multi-modal approach in gastric cancer management.

• Lessons from landmark trials• Role of Radiation Therapy.• Molecular classification of gastric cancer.• Biologics can expand the landscape of

advanced stages of disease.

Basic Facts:• Decreasing incidence over past decades.• 3rd Leading Cause of Cancer Related Death (2012). • 80% at presentation: advanced, metastatic or recurrent

median survival < 1 year. 10 – Year OAS (all stages) 20%.• Shift from distal to proximal lesions (GEJ) & among whites.• Surgical resection is the cornerstone in curative

management loco-regional failures (40 – 65%).• East versus West.

Landry et al. Patterns of failure following curative resection of gastric cancer. Int J Ra- diat Oncol Biol Phys 1990;191:1357-62. Jemal etal. Cancer Statistics, 2010. CA Cancer J Clin 2010. Ferlay et al, GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide. IARC CancerBase, accessed 16/12/14. International Agency for Research on Cancer.

Recurrence After Surgery:

Wong et al. J Gastrointest Oncol 2015;6(1):89-107

Surgery Alone is Not Enough.

Surgical treatment of gastric cancer: 15-year follow-up results of the randomized nationwide Dutch D1D2 trial

Sonogun et al. Lancet Oncol 2010; 11: 439–49

Principles of Management:1. Chemotherapy versus BSC:

• HR (OAS) = 0.49.• Survival Advantage = 4.3 to 11 months.• Total Survival with maintained High Quality of Life (69% - 47% P < .05)

Wagner et al. J Clin Oncol 24:2903-2909. 2006

Principles of Management:2. Combination versus Single Agent Chemotherapy:

Wagner et al. J Clin Oncol 24:2903-2909. 2006Wagner et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010; CD004064.

• Fluoropyremidines & Platinum.• Fluoropyremidines

Monotherapy Combination is not Feasible.

Principles of Management:3. Combination Chemotherapy:

5-Fu Cisplatin

Capecitabine Oxaliplatin+

Anthracyclines Docetaxel/Irinotecan

• Basic Benchmark Duplet.• Substitutions = Variations on Same Melody.• Triplets REAL 2 Study.

5-Fu – Cisplatin =Capecitabine – Cisplatin =5-Fu – Oxaliplatin =Capecitabine – Oxaliplatin

Wagner et al. Cochrane Database Syst Rev 2010; CD004064. Kang et al, Ann Oncol 2009; 20:666-73. Cunningham et al, N Engl J Med 2008; 358:36-46. Okines et al, Ann Oncol 2009; 20:1529-34

1002 AGC Patients

263 = ECF

250 = ECX

245 = EOF

244 = EOX

Principles of Management:3. Combination Chemotherapy: REAL 2 Study:

Non - Inferiority

HR = .86

HR = .92 HR = .80P = 0.02

Cunningham et al, N Engl J Med 2008; 358:36-46.

Principles of Management:3. Combination Chemotherapy: First Line Trials:

Principles of Management:3. Combination Chemotherapy: MAGIC Trial:

503 Resectable

Gastric Cancer

Surgery =253

ECF X 3 =250 Surgery

ECF X 3 =250

1ry Endpoint: OAS

Principles of Management:3. Combination Chemotherapy: MAGIC Trial:

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

Principles of Management:3. Combination Chemotherapy: INT 0116 Adjuvant:

556 Patients(T1-4 N0-1)

Surgery (D1 or Less)

Observation

CRT

S = 27 msS + CRT = 36 msP = 0.005

S = 19 msS + CRT = 30 msP < 0.001

Macdonald et al. N Engl J Med, Vol. 345, No. 10 · September 6, 2001

Updated Analysis of SOWG – Directed Intergroup 0116 Trial

Smalley et al. J Clin Oncol. 2012 30:2327-2333.

458 Patients Non-Metastatic Gastric Cancer

D2 ResectionXP X 6

XP/XRT/XP

Lee at al. J Clin Oncol. 2012 30:268-273

Principles of Management:3. Combination Chemotherapy: ARTIST Trial:

Rth improves DFS by Stage of Disease & for

Entire Group.

ARTIST Trial: 7 – Year Updated Analysis:

Park et al. J Clin Oncol. 2015.33:3130-3136

XP XRT P

LR 13% 7% 0.0033

DFS (LNs +) 72% 76% 0.004

Postoperative Radiation Therapy:• Positive LNs.• Intestinal (Non Diffuse) histopathology.

Who Benefits of Adjuvant Radiation Therapy?

Who Benefits of Adjuvant Radiation Therapy?

OAS DFS

Ohri et al. Int J Radiation Oncol Biol Phys, Vol. 86, No. 2, pp. 330e335, 2013

Who Benefits of Adjuvant Radiation Therapy?

Ohri et al. Int J Radiation Oncol Biol Phys, Vol. 86, No. 2, pp. 330e335, 2013

OAS By Nodal Dissection

20% in OAS & DFS

Who Benefits of Adjuvant Radiation Therapy?

Ohri et al. Int J Radiation Oncol Biol Phys, Vol. 86, No. 2, pp. 330e335, 2013

Radiation Therapy Incomplete Nodal Dissection

Intestinal Type

Positive Nodal Disease

Trial design

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Results: Study Profile

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Results: Overall Survival

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Results: Progression-Free Survival

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Conclusions

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Fujitani et al. Lancet Oncol 2016; 17: 309–18

Non-Curable Gastric Cancer:• Liver Deposits.• Peritoneal Metastases.• Para-Aortic LNs.

D1 Resection + Chemotherapy

D1 Resection + Chemotherapy

REGATTA Phase 3Trial:

Fujitani et al. Lancet Oncol 2016; 17: 309–18

Multi-Modal Treatment of GC:

Schirren et al. Ther Adv Med Oncol.2015, Vol. 7(1) 39–48

Multimodal Treatment is Superior to Single Modality (Surgery).

Neoplasia:

1. Enhanced Cell Survival

2. Angiogenesis

++ A

ggre

ssiv

enes

s C

ompr

omis

ed S

urvi

val O

utco

me

Pathogenesis of Gastric Cancer:

Tan & Yeoh. Gastroenterology 2015;149:1153–1162

Slide 2

Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

Dysplasia Cancer

Lancet 376:687, 2010

Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

Trastuzumab: The FDA Update

Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

Disease Overview:Angiogenesis:

Hallmark of Malignancy:

Proliferation Invasion Metastases

Treatment Failure Apoptosis Resistance

VEGF ++

TK+

m-TOR

Angiogenic Factors:

Tyrosine Kinase Receptors

VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2

VEGFs

VEGF - A VEGF - B VEGF - C VEGF - D PlGF

Angiogenesis in Gastric Cancer:

Yasuhiko Kitadai. Journal of Oncology Volume 2010, Article ID 468725, 8 pages

Anti-Angiogenic Therapy in GC:

Targeted Therapy in Gastric Cancer. Thiel & Ristimaki. APMIS. 2015.123:365-372.

Role of Targeted Agents:

F. Lordick et al. / Cancer Treatment Reviews 40 (2014) 692–700

Gastric Cancer: Molecular Subtypes, Genetic Alterations & Treatment Sensitivity:

Sunakawa and HeinzCurr. Treat. Options in Oncol. (2015) 16: 17

Take Home Message:

• Heterogenous disease entity.• Multimodal approach is highly appreciated.• Radiation therapy in selected patients decreasing

locoregional failures.• Duplets and triples are the backbone of any agent.• Targeted agents are contributing in expanding the

disease landscape.• Clinical trials are awaited.

Thank You