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

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 1.Surgical therapy is the only means of cure and is the treatment of choice for early stage disease. 2.Endoscopic mucosal resection (EMR) is reserved for T1a disease. 3.Goal is complete resection with negative margins (R0). 4.Emerging role of laparoscopic resection for gastric and esophageal cancer. 5.Proximal cancer: total gastrectomy vs. esophagogastrectomy.

5. D1 vs D2 Lymphadenectomy

6. Minimally Invasive Gastrectomy 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 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)

7. Rationale for Preoperative Therapy in Proximal Gastric Cancer Studies demonstrating benefit of preoperative chemotherapy over surgery alone 1 Evidence of role of induction chemoradiation therapy in distal esophageal CA 2 1 MAGIC Trial. Cunningham et al. Radiother Oncol 104 (2012) 2 CROSS 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. MacDonald et al. NEJM 2001 Chemoradiation After Surgery Versus Surgery Alone for Gastric and GEJ Adenocarcinoma 20% GE Junction Criticized for inadequate surgical radicality

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

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

14. Recurrence-Free Survival P=0.029 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 Zhu et al. Radiother Oncol 104 (2012)

15. PreoperativeChemotherapy 3x ECC q 3 wks PreoperativeChemotherapy D1+ Surgery 3x ECC q 3 wks Chemoradiotherapy 45 Gy/25 fx + capecitabine + cisplatin R Within 4-12 weeks3-6 weeks2 weeks CRITICS Study

16. Summary Adjuvant Therapy for Proximal Gastric Cancer 1.While preoperative therapy may be preferred in most cases, initial gastrectomy is being commonly performed. 2.While R0 gastrectomy with D2 lymphadenectomy is recommended, less radical surgery is common. 3.Chemoradiation appears to have a role in reducing local recurrence. 4.Postoperative chemoradiation should be considered when managing a post-op patient, particularly when <D2 gastrectomy was performed.