Highlighting the algorithm of 1st line therapeutics in advanced gastric cancer

1. Time to Make A Decision: Critical
Considerations for 1st Line Therapy
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Ritz Carlton Hotel, Cairo
28/09/2017

2. Speaker Disclosures:
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen Cilag,
Sanofi, MSD, Merck Serono, Novartis, Pfizer, Eli Lilly, Mundipharma.

3. 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.

4. Stomach Cancer (C16): 2010-2011
One-, Five- and Ten-Year Net Survival (%), Adults Aged 15-99, England & Wales
1-Year
Survival (%)
5-Year
Survival (%)
10-Year
Survival (%)
Men
Net Survival 43.9 19.5 15.3
95% LCL 43.6 18.3 13.3
95% UCL 44.2 20.7 17.3
Women
Net Survival 38.0 17.9 14.6
95% LCL 37.5 16.2 12.0
95% UCL 38.6 19.6 17.4
Adults
Net Survival 41.8 18.9 15.0
95% LCL 41.6 18.0 13.5
95% UCL 42.1 19.9 16.7
Five- and Ten-year survival has been predicted for patients diagnosed in 2010-2011 (using an excess hazard statistical model)
95% LCL and 95% UCL are the 95% lower and upper confidence limits
Please include the citation provided in our Frequently Asked Questions when reproducing this chart:
http://info.cancerresearchuk.org/cancerstats/faqs/#How
Prepared by Cancer Research UK
Original data sources:
Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of
Hygiene and Tropical Medicine. http://www.lshtm.ac.uk/eph/ncde/cancersurvival/
Goals of Systemic Treatment Enhancing Quality of Life
Prolong Survival Parameters
Symptom Palliation

5. Problems with Gastric Cancer:
Early:
• Indigestion
• Nausea & vomiting
• Dysphagia
• Postprandial fullness
• Loss of appetite
• Hematemesis
• Loss of Weight
Late:
• Peritoneal affection
• Obstruction
• Bleeding
• Evident nutritional
deficiency
Poor Performance & Comorbidities
Uptodate.com Accessed 17/08/2017

7. Changes in Practice Trends:
• 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
Cochrane Data Base Syst Reviews. 2010

8. Single Agent Activity
Older Agents
Newer Agents
Uptodate.com Accessed 17/08/2017

9. Single versus Combined Agents:
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.

10. Combination Chemotherapy:
1st Line AGC
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

11. 1002 AGC
Patients
263 = ECF
250 = ECX
245 = EOF
244 = EOXNon - Inferiority
HR =
.86
HR =
.92
HR =
.80
P = 0.02
Cunningham et al, N Engl J Med 2008; 358:36-46.
Combination Chemotherapy:
1st Line AGC: REAL2 STUDY

13. Network Meta-analysis:
ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

14. ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:
Treatment versus BSC

15. ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:
Treatment versus FU

16. ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:
Different Regimens: OAS

17. ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:
Different Regimens: PFS

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

19. Trastuzumab Mode of Action:
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

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

21. TOGA Trial: Updated Results
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

22. TOGA Trial: Updated Results
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

23. Refining The Role of Trastuzumab

24. Updated TOGA OS
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

25. Trastuzumab beyond progression
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

26. GASTHER 1
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

27. Phase IIIB trastuzumab post marketing in AGC trial design (HELOISE)
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

28. Uptodate.com Accessed 17/08/2017

29. Do we need a 2nd Line Therapy in
Gastric Cancer?

30. Two pivotal RCTs establishing second- or subsequent-line therapy for gastric cancer
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

31. 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

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

33. 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

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

35. Take Home Message:
• No international consensus for the optimal regimen.
• Triplets versus Duplets: Higher response rate & modest
survival improvement but with higher toxicity.
• IV and Oral FP are equivalent.
• Platinum Analogues: No superiority over each other.
• Anti-Her 2neu therapy had expanded the therapeutic
platform of gastric cancer
• Anti-angiogenic therapy is an emerging keyplayer
• Still we have an unmet need.