1. Gastric Cancer:
From Molecular Classification
to Clinical Impact
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Eli Lilly Symposium
30/03/2017
Ritz Carlton Hotel
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. Outline:
• How to deal with problems at presentation?
• Focus on PREHABILITATION.
• Emphasizing the multi-modal approach in gastric
cancer management.
• Lessons from landmark trials
• Role of Radiation Therapy.
• Biologics can expand the landscape of advanced
stages of disease.
• Exploring the need for 2nd line therapy
• Molecular classification of gastric cancer.
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. Enhancing Preoperative Management:
80% advanced disease at presentation:
• Weight loss.
• Treatment interruptions.
• Poor outcome.
Lebwohl et al. Cancer Invest. Mar;28(3)289-94
PREHABILITATION
1. Smoking Cessation
2. Glycemic Control
3. Nutritional Aids
4. Medications
11. 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
12. 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
13. 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.
14. 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
15. 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.
17. 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
18. Principles of Management:
3. Combination Chemotherapy: MAGIC Trial:
Cunningham et al, N Engl J Med. 2006;355:11-20
19. 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
20. Updated Analysis of SOWG – Directed
Intergroup 0116 Trial
Smalley et al. J Clin Oncol. 2012 30:2327-2333.
21. 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.
22. 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.
24. Who Benefits of Adjuvant Radiation
Therapy?
OAS DFS
Ohri et al. Int J Radiation Oncol Biol Phys, Vol. 86, No. 2, pp. 330e335, 2013
25. 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
26. 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
34. 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).
45. Do we need a 2nd Line Therapy in
Gastric Cancer?
46. Two pivotal RCTs establishing second- or subsequent-line therapy for gastric cancer
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
47. Overall survival with second-line chemotherapy in advanced oesophago-gastric cancer: <br />meta-analysis of patient-level data
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
50. Angiogenesis in Gastric Cancer:
Yasuhiko Kitadai. Journal of Oncology Volume 2010, Article ID 468725, 8 pages
51. Anti-Angiogenic Therapy in GC:
Targeted Therapy in Gastric Cancer. Thiel & Ristimaki. APMIS. 2015.123:365-372.
52. Biomarker analyses in REGARD trial (n=152)
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
53. Role of Targeted Agents:
F. Lordick et al. / Cancer Treatment Reviews 40 (2014) 692–700
54. Overall survival with second-line chemotherapy in advanced oesophago-gastric cancer
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
55.
56. Gastric Cancer: Molecular Subtypes, Genetic
Alterations & Treatment Sensitivity:
Sunakawa and HeinzCurr. Treat. Options in Oncol. (2015) 16: 17
57. Take Home Message:
• Heterogeneous disease entity.
• Special focus on Prehabilitation.
• Multimodal approach is highly appreciated.
• Radiation therapy in selected patients
decreasing locoregional failures.
• Duplets and triples are the backbone for any
treatment protocol.
• Targeted agents are contributing in expanding the
disease landscape.
• Clinical trials are awaited.