managementof metastatic or advanced gastric cancer : first line options
TRANSCRIPT
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Time to Make A Decision: Critical Considerations for 1st Line Therapy
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Ritz Carlton Hotel, Cairo28/09/2017
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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.
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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.
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Stomach Cancer (C16): 2010-2011One-, 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/#HowPrepared by Cancer Research UKOriginal 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
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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
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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. 2006Cochrane Data Base Syst Reviews. 2010
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Single Agent ActivityOlder Agents
Newer Agents
Uptodate.com Accessed 17/08/2017
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Single versus Combined Agents:
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.
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Combination Chemotherapy:1st Line AGC
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
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1002 AGC Patients
263 = ECF
250 = ECX
245 = EOF
244 = EOXNon - Inferiority
HR = .86
HR = .92
HR = .80P = 0.02
Cunningham et al, N Engl J Med 2008; 358:36-46.
Combination Chemotherapy:1st Line AGC: REAL2 STUDY
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Network Meta-analysis:
ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
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ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:Treatment versus BSC
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ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:Treatment versus FU
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ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:Different Regimens: OAS
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ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)
Network Meta-analysis:Different Regimens: PFS
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Pathogenesis of Gastric Cancer:
Tan & Yeoh. Gastroenterology 2015;149:1153–1162
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Trastuzumab Mode of Action:
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362
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Lancet 376:687, 2010
Presented By Jaffer Ajani at 2016 ASCO Annual Meeting
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TOGA Trial: Updated Results
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362
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TOGA Trial: Updated Results
R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362
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Refining The Role of Trastuzumab
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Updated TOGA OS
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
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Trastuzumab beyond progression
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
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GASTHER 1
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
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Phase IIIB trastuzumab post marketing in AGC trial design (HELOISE)
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
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Uptodate.com Accessed 17/08/2017
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Do we need a 2nd Line Therapy in Gastric Cancer?
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Two pivotal RCTs establishing second- or subsequent-line therapy for gastric cancer
Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium
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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
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Disease Overview:Angiogenesis:
Hallmark of Malignancy:
Proliferation Invasion Metastases
Treatment FailureApoptosis Resistance
VEGF +
+
TK+
m-TOR
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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
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Angiogenesis in Gastric Cancer:
Yasuhiko Kitadai. Journal of Oncology Volume 2010, Article ID 468725, 8 pages
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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.