Adjuvant Radiation is Required for Gastric Cancer Christopher H. Crane, M.D. Professor, Program Director GI Radiation Oncology

With no Adjuvant: Local Recurrence: Dominant POF Minnesota Second-look Laparotomy Series Tumor Bed Nodal LRF only 24/82 (29%) LRF + DM 72/86 (84%) Gunderson, IJROBP (8), 1-11, 1981

Adjuvant Chemotherapy Ineffective Meta-analysis 20 studies (3658 pts, 2180 deaths) Chemotherapy reduced the risk of death by 18% (HR=0.82; p<0.001) Absolute advantage in survival: stage I: 80% 82% stage II: 50% 54% stage III: 20% 24% Results similar to earlier meta-analysis by hermans (1993) in which HR was 0.88 (.78-1.08) Mari et al.Annals of Oncology,2000

MAGIC trial : Post-op Chemo Poor Compliance In the chemo arm 86% completed pre-operative chemotherapy 91% of pts who started pre-operative chemo completed all 3 cycles 57% commenced post-operative chemotherapy and 43% completed all 6 cycles The main reasons for failing to start post-operative chemo were death, progression, pt request and post-op complications

Randomized Data Adjuvant Gastric Ca / GEJ CXRT vs CTX alone Artist Trial Stahl Trial

ARTIST Phase III multi-institutional RCT comparing adjuvant chemoradiation vs. chemotherapy in patients with a D2 dissection All Patients Patients with stage Ib-IVa Gastric cancer resected with D2 dissection Randomized to Chemotherapy (XP) N= 228 Xeloda 1000mg/m2 bid, CDDP 60mg/m2 on day 1 6 cycles CRT N = 230 XP x 2 45 Gy in 25 fractions + xeloda 825 mg/m2 bid  XP x 2 P = 0.0862 N + P = 0.0365 Lee J et al. JCO 2012

ARTIST Trial Trend towards significant improvement in DFS (p = 0.086) Larger numbers could have shown benefit Significant improvement in DFS with CRT in N+ patients Different patient population (primarily from Asia)

Overall survival (intent to treat). Preoperative Chemotherapy vs Chemoradiation GEJ ACa Overall survival (intent to treat). Overall survival (intent to treat). Arm A, n = 59 (chemotherapy and surgery): median survival time 21.1 months, 3-year survival rate 27.7%. Arm B, n = 60 (chemoradiotherapy and surgery): median survival time 33.1 months, 3-year survival rate 47.7%. Stahl M et al. JCO 2009;27:851-856 ©2009 by American Society of Clinical Oncology

Intergroup Study INT-0116 Study design A N D O M I S E 5FU/LV 5FU/LV Eligibility: Resected Stage IB- VI M0 5FU/LV RADIATION 5FU/LV x 2 4,500 cGy Gastric or gastroesophageal adenocarcinoma OBSERVATION Macdonald et al. NEJM, 345 (10): 725,2001

Patient Characteristics Groups appear well matched ~ 70% were T3-T4 85% Node Positive 80% were distal stomach lesions

Results Initial Results (4 year f/u) Median OS 39 vs. 27 m.o. 3-yr OS 50% vs 41% 3-yr RFS 48% vs 31% Updated Results (> 10 year f/u) HR for OS 1.32 HR for RFS 1.51 P = 0.0046 P < 0 .001 Macdonald et.al NEJM 2001 Smalley S R et al. JCO 2012

INT-0116 SURGICAL PROCEDURES < D1 = 54% D1 = 36% *D2 = 10% (Based on 551 cases) < D1 = 54% D1 = 36% *D2 = 10% •No difference in overall survival by extent of dissection *D2 lymph node dissection was recommended

Toxicity Grade 3 events 3 deaths from toxicity reported 33% GI 54% hematologic 3 deaths from toxicity reported Only 65% of patients completed CRT 50% of these secondary to treatment toxicity

Conclusions: INT 0116 Less than a D1 most common Adjuvant ChemoRT improves OS and DFS Less than a D1 most common Pt toxicity “acceptable” Pivotal trial establishing chemoradiation as standard of care in United States

Conclusions Stahl Trial: Pre-op CXRT standard for GEJ Ca Artist Trial: OS benefit with CXRT vs CTX Artist Trial: Post-op CXRT necessary for N+ XRT debatable for N0/D2 dissection Minority of patients Best results with pre-op CTX, post-op CXRT? Critics Trial, stay tuned