Advanced Gastric Cancer:Can We Go Better?

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

Assiut 23/02/2016

Speaker Disclosures:

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

Merck Serono, Novartis, Pfizer• 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.

• The value of adding 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.

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 01116 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:

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

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).

Pathogenesis of Gastric Cancer:

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

Molecular Subtypes of GC and Key Features

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

Lei et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology 2013;145:554–65.

Role of Targeted Agents:

• HER 2 Overexpression:– 15 – 20% of cases.– More in proximal lesions.– Never in diffuse type.– Different scoring system than in breast cancer.

• Angiogenesis:– Formation of abnormal new vasculature (Key process

in tumorogenesis.– Responsible for Oxygen and Nutrients delivery to a

growing tumor.

Role of Targeted Agents:

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

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.• Clinical trials are awaited.