Gastric Cancer:From Molecular Classification
to Clinical Impact
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
PACC 16TH 30/04/2016
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+
AnthracyclinesDocetaxel/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 Resection
XP 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 TherapyIncomplete 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:
Sunakawa and HeinzCurr. Treat. Options in Oncol. (2015) 16: 17
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.
Thank You