1. What is the optimal sequence of therapies for stage II-III adenocarcinoma of the proximal stomach? - Chemoradiation followed by surgery Bruce Minsky

2. INT 0116 Adjuvant Gastric Trial T3 and/or N1-2 (85%) 20% GEJ 54% D 0 5-FU/LV x 4 + 45 Gy Surgery alone CMTSURGERY 3-Year Survival (%)4030** Local Failure (%)1929

3. INT 0116 – 10.3 Yr Median F/U Smalley et al JCO 2012

4. Postop RT Fields

5. Acute Toxicity – INT 0116 %Toxicity 33 Gr 3-4 Diarrhea 54 Gr 3-4 Neutropenia 1 Death 65% Completed all therapy 17% Stopped for toxicity

6. Postop S1 (ACTS-GC) Sasaco et al JCO 2011 · 1059 pts, Stage II/III · D2 resectionS1 Wks 1-4, q 6 weeks x 1 yr · Gr 3+ toxicity < 5% % 5-Yr % LR Survival FailureHR Surgery only 61 8 0.669 Postop S1 72 130.572

7. Upper GI Adenocarcinomas Overlap of GE Junction and Gastric (Siewert II and III) 20% GE junction in INT 0116 Preop CMT for GE junction

8. Adjuvant Preop RT Zhang IJROBP 1998 370 pts, clinically resectable disease % 5-Yr % Failure %R0 SurvivalLocalLN Surgery62 204755 40 Gy80* 30*3331

9. Phase III Preop CT +/- CMT for GE Junction Adeno Stahl et al JCO 2009 · 119/126 eligible pts T3-4Nx GE junction (Siewert I-III) FU/LV/CDDP X 2.5 FU/LV/CDDP VP-16/CDDP X 2.5 30 Gy (2 Gy/d) Surgery

10. Phase III Preop CT +/- CMT for GE Junction Adeno Induction ChemotherapyChemoRTP # Entered4945 % R0 Resection7072 - % Mortality410 - % pCR216 0.03 3-Yr Survival2847 0.07 % 3-Yr Local Fail4124 0.06

11. Preop CMT for Gastric 43 pts EUS T2-3 and/or N1-2, lap negative 5FU/LV/CDDP x 2 then 45 Gy/5FU/Paclitaxel 36 had surgery (7 POD), 50% D2 26% pCR 21% Gr 4 toxicity 23 M median survival RTOG 9904 JCO 2006

12. CROSS Study Group Van Hagen NEJM 2012 ∙ 368 pts ∙ 75% Adeno ∙ T1N1 or ∙ T2-3N0-1 Surgery Preop paclitaxel/carboplat Concurrent 41.4 Gy (1.8 Gy/d) ∙ pCR: 29% (adeno: 23% vs. 49% SCC), 4% mortality R0 % 5-Yr S Preop`9259 Surg6948 p<0.003 p=0.001

13. CROSS I + II Trials  422 Pts, 374 underwent surgery  75% adeno  F/U: 45 M median, 24 M min #%LR%PS%DF Preop341435 p<0.001 p<0.001 p=0.025 Surg14429  5% LR (1% isolated) in the RT field Oppedijk et al, JCO 2014

14. SCOPE1: CMT+ Cetuximab ∙ 258 Pts, Stage I-III ∙ (97% stage II,III) ∙ 25% Adeno 50Gy/CDDP/Cape + Cetuximab ∙ Stopped early – met futility % 2-YrMedian% Gr 3+ CetuximabSurvivalSurvivalNon-heme Toxicity Yes4122 m79 No5625 m63

15. RTOG 1010

16. Conclusions Postop CMT increases survival Overlap between GE junction and gastric Preop CMT improves survival (CROSS) Preop RT fields are smaller (no postop bed)