What is the optimal sequence of therapies for stage II-III

adenocarcinoma of the proximal stomach? -

Chemoradiation followed by surgery

Bruce Minsky

INT 0116 Adjuvant Gastric Trial

• T3 and/or N1-2 (85%)• 20% GEJ• 54% D0

5-FU/LV x 4 + 45 Gy

Surgery alone

CMT SURGERY3-Year Survival (%) 40 30**Local Failure (%) 19 29

INT 0116 – 10.3 Yr Median F/U

Smalley et al JCO 2012

Postop RT Fields

Acute Toxicity – INT 0116

% Toxicity33 Gr 3-4 Diarrhea54 Gr 3-4 Neutropenia1 Death

• 65% Completed all therapy• 17% Stopped for toxicity

Postop S1 (ACTS-GC)

Sasaco et al JCO 2011

· 1059 pts, Stage II/III· D2 resection S1 Wks 1-4, q 6 weeks x 1 yr· Gr 3+ toxicity < 5%

% 5-Yr % LRSurvival Failure HR

Surgery only 61 8 0.669

Postop S1 72 13 0.572

Upper GI Adenocarcinomas

• Overlap of GE Junction and Gastric (Siewert II and III)

• 20% GE junction in INT 0116

• Preop CMT for GE junction

Adjuvant Preop RTZhang IJROBP 1998

370 pts, clinically resectable disease

% 5-Yr % Failure%R0 Survival Local LN

Surgery 62 20 47 55

40 Gy 80* 30* 33 31

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

Surgery

Phase III Preop CT +/- CMT for GE Junction Adeno

Induction Induction Chemotherapy ChemoRT P

# Entered 49 45% R0 Resection 70 72 -% Mortality 4 10 -% pCR 2 16 0.033-Yr Survival 28 47 0.07% 3-Yr Local Fail 41 24 0.06

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

CROSS Study Group

Van Hagen NEJM 2012

∙ 368 pts∙ 75% Adeno∙ T1N1 or∙ T2-3N0-1

Surgery

Preop paclitaxel/carboplatConcurrent 41.4 Gy (1.8 Gy/d)

∙ pCR: 29% (adeno: 23% vs. 49% SCC), 4% mortality

R0 % 5-Yr SPreop` 92 59Surg 69 48

p<0.003p=0.001

CROSS I + II Trials

422 Pts, 374 underwent surgery75% adenoF/U: 45 M median, 24 M min

# %LR %PS %DFPreop 34 14 35

p<0.001 p<0.001 p=0.025

Surg 14 4 29

5% LR (1% isolated) in the RT field

Oppedijk et al, JCO 2014

SCOPE1: CMT+ Cetuximab

∙ 258 Pts, Stage I-III ∙ (97% stage II,III)∙ 25% Adeno

50Gy/CDDP/Cape

50 Gy/CDDP/Cape + Cetuximab

∙ Stopped early – met futility

% 2-Yr Median % Gr 3+Cetuximab Survival Survival Non-heme ToxicityYes 41 22 m 79

No 56 25 m 63

RTOG 1010

Conclusions

• Postop CMT increases survival

• Overlap between GE junction and gastric

• Preop CMT improves survival (CROSS)

• Preop RT fields are smaller (no postop bed)