Michael A. Choti, MD Department of Surgery UT Southwestern Medical Center

1. Great Debates & Updates in GI Malignancies March 28-29, 2014 DEBATE: What is the Optimal Sequence of Therapies for Stage II-III Adenocarcinoma of the Proximal Stomach? Surgery Followed By Adjuvant Chemoradiation Therapy Michael A. Choti, MD Department of Surgery UT Southwestern Medical Center

2. Disclosures none

3. GE junction / Gastric Cardia Tumors • Making the distinction between lower esophageal CA can be problematic • Rising in incidence • Poorer prognosis • Resection: esophagogastrectomy vs. total gastrectomy

4. Treatment of Localized Gastric Cancer • Surgical therapy is the only means of cure and is the treatment of choice for early stage disease. • Endoscopic mucosal resection (EMR) is reserved for T1a disease. • Goal is complete resection with negative margins (R0). • Emerging role of laparoscopic resection for gastric and esophageal cancer. • Proximal cancer: total gastrectomy vs. esophagogastrectomy.

5. D1 vs D2 Lymphadenectomy

6. Minimally Invasive Gastrectomy • Emerging as treatment of choice in many centers • Outcomes appear comparable • Important to ensure the same (or better) oncologic outcome that is possible with open surgery (including D2) Kim et al. Ann Surg 2010 KLASS Trial. RCT comparing open vs lap gastrectomy No difference in short term outcomes Chen et al. World J Surg 2013 Meta-analysis comparing lap vs open gastrectomy Enhanced recovery with no difference in long-term outcome

7. Rationale for Preoperative Therapy in Proximal Gastric Cancer • Studies demonstrating benefit of preoperative chemotherapy over surgery alone1 • Evidence of role of induction chemoradiation therapy in distal esophageal CA2 1MAGIC Trial. Cunningham et al. RadiotherOncol 104 (2012) 2CROSS Trial. van Hagen et al. NEJM (2012)

8. Importance of Preoperative Staging When Considering Neoadjuvant Therapy • Accuracy of predicting nodal involvement is 60-80% • Surgery alone may be sufficient for Stage II disease • Neoadjuvant therapy may be overtreating some patients

9. Rationale for Up Front Surgery in Patients With Gastric Cancer • Pathologic staging may result in more appropriate choice of adjuvant therapy (accurate stage II vs III, D1 vs D2, margins). • Symptomatic patients may require initial surgery. • In reality, gastrectomy is often performed before MDT consultation.

10. Algorithm for Management of Gastric Cancer* *ESMO-ESSO-ESTRO 2013

11. Chemoradiation After Surgery Versus Surgery Alone for Gastric and GEJ Adenocarcinoma • 20% GE Junction • Criticized for inadequate surgical radicality MacDonald et al. NEJM 2001

12. Impact of Extent of Surgery and Postop Chemoradiation: Dutch Gastric Cancer Group Trial D1 D2 Dikken et al. JCO May 2010

13. Post-Operative Chemo vs Chemoradiation: ARTIST Trial • Samsung University • 458 patient RCT • D2 gastrectomy • ~5% proximal CA • Postoperative adjuvant Cap-Cis ± RT • No difference in DFS • No difference in locoregional rec Lee et al. JCO Jan 2012

14. Post-Operative Chemo vs Chemoradiation: Nanjing University • 380 patients • Randomized trial • All D2 gastrectomy • ~10% GE junction • Postoperative adjuvant 5FU-LV ± IMRT • Improved RFS with IMRT (50 vs 32 mo) • No difference in OS Recurrence-Free Survival P=0.029 Zhu et al. RadiotherOncol 104 (2012)

15. CRITICS Study Preoperative Chemotherapy 3x ECC q 3 wks 3x ECC q 3 wks D1+ Surgery R Chemoradiotherapy 45 Gy/25 fx + capecitabine + cisplatin Preoperative Chemotherapy 3x ECC q 3 wks D1+ Surgery 2 weeks 3-6 weeks Within 4-12 weeks

16. Adjuvant Therapy for Proximal Gastric Cancer Summary • While preoperative therapy may be preferred in most cases, initial gastrectomy is being commonly performed. • While R0 gastrectomy with D2 lymphadenectomy is recommended, less radical surgery is common. • Chemoradiation appears to have a role in reducing local recurrence. • Postoperative chemoradiation should be considered when managing a post-op patient, particularly when <D2 gastrectomy was performed.