Overview of the management of gastric cancer with emphasis upon landmark trials and newly arrived strategies in management.

1. Gastric Cancer:
From Molecular Classification
to Clinical Impact
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Lilli Advisory Board
01/09/2016
Sofitel Hotel & Tower

2. 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

3. 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.

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. 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

7. 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

8. 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.

9. 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

10. 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.

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

12. 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

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

14. 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

15. Updated Analysis of SOWG – Directed
Intergroup 0116 Trial
Smalley et al. J Clin Oncol. 2012 30:2327-2333.

16. 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:
Rth improves DFS by
Stage of Disease & for
Entire Group.

17. 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.

18. Who Benefits of Adjuvant Radiation
Therapy?

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

20. 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

21. 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

22. Trial design
Presented By Marcel Verheij at 2016 ASCO Annual Meeting

23. Results: Study Profile
Presented By Marcel Verheij at 2016 ASCO Annual Meeting

24. Results: Overall Survival
Presented By Marcel Verheij at 2016 ASCO Annual Meeting

25. Results: Progression-Free Survival
Presented By Marcel Verheij at 2016 ASCO Annual Meeting

26. Conclusions
Presented By Marcel Verheij at 2016 ASCO Annual Meeting

27. 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

28. REGATTA Phase 3Trial:
Fujitani et al. Lancet Oncol 2016; 17: 309–18

29. 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).

30. Neoplasia:
Enhanced Cell
Survival
Angiogenesis
++AggressivenessCompromisedSurvivalOutcome

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

32. Slide 2
Presented By Jaffer Ajani at 2016 ASCO Annual Meeting
Dysplasia  Cancer

33. Lancet 376:687, 2010
Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

34. Trastuzumab: The FDA Update
Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

35. Disease Overview:
Angiogenesis:
Hallmark of Malignancy:
Proliferation Invasion Metastases
Treatment Failure
Apoptosis
Resistance
VEGF +
+
TK
+
m-TOR

36. 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

37. Angiogenesis in Gastric Cancer:
Yasuhiko Kitadai. Journal of Oncology Volume 2010, Article ID 468725, 8 pages

38. Anti-Angiogenic Therapy in GC:
Targeted Therapy in Gastric Cancer. Thiel & Ristimaki. APMIS. 2015.123:365-372.

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

41. Gastric Cancer: Molecular Subtypes, Genetic
Alterations & Treatment Sensitivity:
Sunakawa and HeinzCurr. Treat. Options in Oncol. (2015) 16: 17

42. 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.

43. Thank You