1. Advanced gastric cancer has a poor prognosis, with most patients presenting with advanced or metastatic disease and a median survival of less than 1 year. 2. A multimodal approach including chemotherapy, surgery, and radiation therapy provides the best outcomes. Combination chemotherapy is preferred over single agents, with fluoropyrimidine/platinum regimens as the standard. 3. Select patients with positive lymph nodes or intestinal histology benefit from postoperative radiation therapy, which can decrease locoregional failures and improve survival outcomes. Molecular classification of gastric cancers may help identify targeted therapies for specific subtypes.

1. Advanced Gastric Cancer:
Can We Go Better?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Assiut 23/02/2016

2. 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

3. 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.

4. 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.

5. Recurrence After Surgery:
Wong et al. J Gastrointest Oncol 2015;6(1):89-107
Surgery Alone is Not Enough.

6. 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

7. Principles of Management:
2. Combination versus Single Agent Chemotherapy:
Wagner et al. J Clin Oncol 24:2903-2909. 2006
Wagner et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010; CD004064.
• Fluoropyremidines & Platinum.
• Fluoropyremidines
Monotherapy  Combination
is not Feasible.

8. Principles of Management:
3. Combination Chemotherapy:
5-Fu Cisplatin
Capecitabin
e
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

9. 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 =
.80
P = 0.02
Cunningham et al, N Engl J Med 2008; 358:36-46.

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

11. 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

12. Principles of Management:
3. Combination Chemotherapy: MAGIC Trial:
Cunningham et al, N Engl J Med. 2006;355:11-20

13. Principles of Management:
3. Combination Chemotherapy: INT 0116 Adjuvant:
556 Patients
(T1-4 N0-1)
Surgery
(D1 or Less)
Observation
CRT
S = 27 ms
S + CRT = 36 ms
P = 0.005
S = 19 ms
S + CRT = 30 ms
P < 0.001
Macdonald et al. N Engl J Med, Vol. 345, No. 10 · September 6, 2001

14. Updated Analysis of SOWG – Directed
Intergroup 01116 Trial
Smalley et al. J Clin Oncol. 2012 30:2327-2333.

15. 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:

16. 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.

17. Who Benefits of Adjuvant Radiation
Therapy?

18. Who Benefits of Adjuvant Radiation
Therapy?
OAS DFS
Ohri et al. Int J Radiation Oncol Biol Phys, Vol. 86, No. 2, pp. 330e335, 2013

19. 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

20. 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

21. 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).

22. Pathogenesis of Gastric Cancer:
Tan & Yeoh. Gastroenterology 2015;149:1153–1162

23. Molecular Subtypes of GC and Key Features

24. 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.

25. 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.

26. Role of Targeted Agents:
F. Lordick et al. / Cancer Treatment Reviews 40 (2014) 692–700

27. 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.