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Better Regimens & Predictive Markers For Advanced Esophagogastric Cancer?

Better Regimens & Predictive Markers For Advanced Esophagogastric Cancer?. Peter C. Enzinger , M.D. Dana-Farber Cancer Institute/Harvard Medical School. Disclosures. Speaker / Consultant / Honoraria (prior to 6.09): Sanofi – Aventis Roche. Posters Discussed. Kishimoto et al.

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Better Regimens & Predictive Markers For Advanced Esophagogastric Cancer?

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  1. Better Regimens & Predictive Markers For Advanced Esophagogastric Cancer? Peter C. Enzinger , M.D. Dana-Farber Cancer Institute/Harvard Medical School

  2. Disclosures Speaker / Consultant / Honoraria (prior to 6.09): Sanofi – Aventis Roche

  3. Posters Discussed Kishimoto et al. Does Paclitaxel or Irinotecan improve a Japanese Standard – S1? ----------------------------------------------------------------- Shah et al. Is “Docetaxel, Cisplatin + mod de Gramont” better than DCF? Al-Batran et al. Is “Docetaxel + mFOLFOX” better than DCF? ----------------------------------------------------------------- Atmaca et al. What do we do with a new prognostic molecular factor?

  4. Japan Can we improve S1?

  5. Evolution of S1 Therapy in Gastric CA RR: OS: Less toxic S1 31% 11 mos Japan SPIRITS* P = 0.04 54% 13 mos Cisplatin + S1 Cisplatin + S1 29% 8.6 mos “West” FLAGS** P = NS Cisplatin + 5-FU 32% 7.9 mos *Koizumi. Lancet Oncol 2008 **Ajani. J Clin Oncol 2010

  6. Random Phase II: S1+ CPT or S1 + Pacli H0: 30% RR vs. HA: 50% RR power 80%; 2-sided α 5% • Unresectable, measurable advanced or recurrent gastric cancer • No prior chemotherapy except adjuvant CTX

  7. Progression-Free Survival Overall Survival HR=1.18; p=0.42 HR=0.99; p=0.96 Phase III: START *Koizumi. Lancet Oncol 2008 #Boku. Lancet Oncol 2009 **Ikeda. Proc ASCO 2009 ***Imamura. Proc ASCO 2008

  8. Conclusions The authors conclude that neither S1+ paclitaxel or S1 + irinotecan should be developed further – I agree! S1 seems to be happiest by itself … or perhaps with cisplatin. Where are the biologics – there seem to be no combinations with S1?

  9. “West” Can we improve DCF?

  10. DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?Dose and Schedule

  11. DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?Substitutions

  12. Conclusions DCF is too toxic – worst way of giving either cisplatin or fluorouracil Smaller, more frequent doses or substitutions are better but which one? or both? Randomized trials are needed to move this forward:

  13. DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity?Dose and ScheduleSubstitutions (Shah) (Al-Batran) DCF (original) Docetaxel 75mg/m2 Cisplatin 75mg/m2 5-FU 750mg/m2/d CI x 5d Every three weeks R A N D O M I Z A T I O N FLO (mFOLFOX) 5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m² Every two weeks R A N D O M I Z A T I O N mDCF Docetaxel 40mg/m2 Cisplatin 40 mg/m², day 3 Leucovorin 400 mg/m² 5-FU 400 IVP 5-FU 1000 mg/m²/d CI x 2d Every two weeks FLOT Docetaxel 50mg/m2 5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m² Every two weeks

  14. DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity? Dose and Schedule Substitutions (mDCF) (FLOT)

  15. Conclusions Hard to choose between the two; mDCF perhaps less toxic but more complicated mDCF arm is still in progress and must wait for 6 mo PFS primary endpoint FLOT– higher RR and toxicity more suited for adjuvant comparison Randomization against ECF would require large pt numbers for significant difference

  16. Matrix Metalloproteinase-9 mRNA expression What do we do with a new prognostic molecular factor in esophagogastric ca?

  17. Other Molecular Prognostic Markers “Hundreds” of prognostic molecular markers for gastric cancer in the literature … HER2/neu – prognostic and antibody is effective VEGF – prognostic – AVAGAST on Monday EGFR – prognostic  REAL 3 and EXPAND

  18. Impressive Results! Pooled OS by Quartile Validation Cohort Median OS: 5,5 mo vs. 11,9 mo 1 yr Survival: 25% vs. 50% 2 yr Survival: 0% vs. 26% MMP-9 effect only in highest quartile Independant by multivariate analysis

  19. Questions? Training & Validation Cohorts in “cisplatin-based” therapy – same results in non-platinum regimens or Asian patients? Are there agents that target MMP-9? - ATRA*?Epigallocatechine-3-gallate**? If interacts with angiogenesis or EGFR pathway, what would be the effect in bevacizumab or anti-EFGR studies? Should one change treatment based on MMP9 status? More aggressive for high? What about adjuvant? *Dutta. Cell Adh Migr. 2010 **Farabegoli. Biosci Rep. 2010

  20. Next steps … 1st step is for another group to run a validation cohort (West and East Asia) Ideal cohorts to test interaction with MMP-9 would be the AVAGAST, REAL 3, and EXPAND studies Too early for treatment changes – everybody gets max tolerated chemo for metastatic dz and in the adjuvant setting anyway.

  21. Thank You!

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