1. Multidisciplinary Approach to GE junction tumors MOTP Academic Half Day Sep 8 2009 11-1 PMH Boardroom Dr. Darling Dr. Wong Thoracic OncologyRadiation Oncology

2. 2 Overview Part I –Staging –Anatomic considerations – Surgical approach Part II –Strategy to interpret the evidence –Adjuvant and neo-adjuvant therapies –Radiotherapy issues –Summary

3. 3 GE junction tumors Type II: arising from cardiac epithelium –True ca of the cardia arsing from the cardiac epithelium or short segments with intestinal metaplasia at the GE junction: this entity is also often referred to as “junctional ca” ( Siewert et al Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998: 1457-9)

4. 4 Esophagus vs GE junction Histology Location Stomach ESO ADENO GE

5. 5 Interpreting the evidence What you would like –High level evidence –GE junction tumors What is available –RCTs and meta-analysis in esophagus (and GE), Gastric (and GE) –1 underpowered RCT

6. 6 Interpreting the evidence Strategy –Esophagus and Gastric literature –Subgroup analysis Supportive evidence –Lower levels of evidence focused on GE junctions only –Anatomical consideration –Recurrence patterns –Radiotherapeutic considerations

7. 7 Esophagus trials

8. 8 Surgery Preop CRT Treatment options for localized esophageal cancer Preop CT Pre or post op RT post op CT

9. 9 Preop CT (published meta-analysis) Gebski et al Lancet Oncol 2007, 8; 226-34

10. 10 GE junction subgroup? … Adeno subgroup No. of pts with adenos (533/1702) 31% Only 1 trial with subgroup outcomes for adenos (MRC) HR = 0.78 (0.64-0.95) Gebski et al Lancet Oncol 2007, 8; 226-34

11. 11 MRC GE junction tumors? –10% Cardia –64% lower third N+ –58% (Control gp) Outcomes –OAS 0.79 95% CI 0.67-0.93; p =0.004 –2yS 43% vs 34% Subgroup analysis –No difference between histology, site, age, sex, dysphagia, PS Toxicity reporting no in great detail Esophagus Gastric cardia N = 802 CT+S 2 cycles 5FU 1g/m2 D1-4 Cisplatin 80mg/m2 CT

12. 12

13. 13 Preop CT IPD Thirion et al 9 RCT 11% GE jc 54% pts SCC HR OAS 0.87 (95%CI 0.79-0.95; p=0.003) Survival diff. at 5yrs: 4% (from 16 to 20%) ASCO 2007 http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=47&sessionID=356

14. 14 ASCO 2007 http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=47&sessionID=356

15. 15 For the whole group –OAS 0.79 95% CI 0.67-0.93; p =0.004 –2yS 43% vs 34% Effect more significant in adenos Proportion that would qualify as GE junction tumors not clear ? 11% Generalisability to GE junction tumors acceptable

16. 16 Peri-operative CT ACCORD 07 1995-2003 N = 224 75% esophagus/GE Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. ASCO 2007

17. 17 OAS 5yr –24% vs 38%; HR 0.69 DFS 5yr –HR 0.65 (95% CI 0.48- 0.89; p=0.003) Multi-variant analysis shows gastric tumor and preop CT significant No variation of treatment effect with tumor location

18. 18 Preop RTCT+S vs S  10 trials  HR 0.81 [0.7-0.93]  2 y survival 35% S 47% CRT Gebski et al Lancet Oncol 2007, 8; 226-34

19. 19 Nomenclature precludes accurate identification of proportion of GE junction tumors…. Inclusion criteriaLocationAdenos Walsh 1996 Esophageal adenocarcinoma Lower 1/3 50% Cardia 35% 100% Urba 2001 Thoracic esophagus and GE junction SCC or adenos mid/distal 82%75% Burmeister 2005 Thoracic esophagus Involving gastric cardia eligible provided tumor mainly in esophagus (? Siewert I/II) Lower 1/3 79%62% Tepper 2006 Thoracic esophagus and GE junction with <2cm distal spread into gastric cardia SCC or adenos (?Siewert I/II) Not stated75%  5 trials include adenos, 1 dedicated to adeno  Proportion adenos (in 3 trials) approx 75%  Proportion lower/GE (in 2 trials) approx 80%  Cardia (1 trial) 35%

20. 20 GE junction subgroup … adeno subgroup Gebski et al Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in esophageal carcinoma: a meta-analysis Lancet Oncol 2007, 8:226-34

21. 21 From the esophagus literature…. Preop CRT  OAS HR 0.81 [0.7-0.93] (Gapski)  No diff. in effect between adeno and SCC Preop CT  OAS HR 0.87 [95%CI 0.79-0.95] (Thirion)  Effect for adeno, but not SCC Perioperative CT  5 yr OAS 24 to 38% No GE junction subgroup analysis available Subgroup analysis on adeno ? Generalizability to GE junction tumors acceptable

22. 22 Gastric trials

23. 23 Gastric adjuvant trial: INT 0113 MacDonald et al N = 556 Location –Cardia 7% –Lesion present in GE jc approx 20% Intervention –5FU 425mg/m2/d, FA 20mg/m2/d, 4 cycles –45Gy in 25 fr Outcomes –HR death 1.35 (1.09-1.66; p = 0.005) –HR relapse 1.52 (1.23-1.86;p<0.001) No subgroup analysis MacDonald et al CRT after S for adenocarcinoma of the stomach and GE jc NEJM 2001

24. 24 MAGIC N = 503 ECF –(E 50mg/m2, C 60mg /m2, F 200mg/m2 CI 21d) 3 cycles pre and post op Lower eso 15%, GE jc 12% Treatment compliance –55% (137/250) began postop CT –42% (104/250) of pt assigned to CT completed 6 cycles Outcomes –OAS 5 yr 23 vs 36% –OAS HR 0.75 (0.6-0.93;p=0.0009) –PFS HR 0.66 (0.53-0.81; p<0.0001) Cummingham et al (MRC UK) Perioperative CT vs S alone for resectable GE cancer NEJM 2006

25. 25 Subgroup analysis – no sig interaction

26. 26 From gastric trials… GE junction tumors represent 10% of patients in stomach trials –7% postop CRT (INT 0113) –Approx 12% peri-operative CT (MAGIC) Generalizable to GE junction tumors? –Yes Toxicity with postop CRT more sensitive to location of tumor

27. 27 Preop CT vs Preop CRT XRT 5cm sup, 3cm inf, 2cm radial L and R cardiac, L gastric, lesser curve, celiac axis, splenic a, hepatic a Sample size Planned 200 Superiority trial, 3 y S 25 to 35% Slow accrual, stopped at interim with 125 pts (projected final sample size 288) FU 21m nT3-4NxM0 Adeno Lower esophagus or gastric cardia Preop CT PLF x 2.5cycles Cisplatin 50mg/m2 biwkly 5FU 2g/m2 24 hr inf Leucovorin 500mg/m2 Preop CRT PLF x 2 cycles CRT Cisplatin 50mg/m2 D1,8 Etoposide 80mg/m2 D3-5 30Gy in 15 fr Stahl Phase III comparison of preop CT compared with CRT in patients with locally advanced adenocarcinoma of the esophagogastric junction JCO 27:851-856, 2009

28. 28 N = 126 (119 evaluable) CTCRT 3y OAS27.7%47.4% HR 0.67 CI 0.41-1.07 p = 0.07 Postop death 3.8%10.2% p = 0.26 pCR2%15.6% P = 0.03 3y Local control 59%76.5% p = 0.06 Stahl Phase III comparison of preop CT compared with CRT in patients with locally advanced adenocarcinoma of the esophagogastric junction JCO 27:851-856, 2009

29. 29 Summary? There is evidence to support the use of –Preoperative CRT –Preop CT –Perioperative CT (5FU Cisplatin) –Perioperative CT (ECF) –Postoperative CRT (5FU FA, 45 in 25) Underpowered RCT (D/C due to slow accrual) negative.. But favors preop CRT Other considerations….

30. 30 Other considerations pattern of spread nodal spread local spread larger non randomized evidence

31. 31 Postop stomach –Dose: 45Gy in 25 –Nodal volume : –Celiac nodes –Portal hepatis –Splenic hilar –Pancreaticoduodenal –Preop stomach –Post op residual stomach –Anastomosis –L medial hemidiaphragm Preop esophagus CRT –Dose 35Gy:15 – 50Gy:25 –Nodal volume: –periesophageal lymphatics 5cm cranial caudad –Celiac nodes Radiotherapeutic considerations

32. 32 Preop GE junction Primary tumor + 3cm sup and inf for microsopic extension Periesophageal nodes Celiac nodes

33. 33 Stomach involving GE junction Celiac nodes Portal hepatis Splenic hilar Pancreaticoduodenal Preop stomach Post op residual stomach Anastomosis L medial hemidiaphragm

34. 34 Tillman et al Preoperative vs postoperative RT for locally advanced GE junction and proximal gastric cancers: a comparison of normal tissue radiation doses Diseases of the esophagus 21, 437-444, 2008 N = 5PreopPostop Composite lung mean (Gy)3451119 Lung V203%16% Heart V2031%66% Heart V3016%35% Bowel mean (Gy)16191517 Liver mean (Gy)17621627 Kidney L mean (Gy)16291547 Kidney R mean (Gy)12251362 Cord Max (Gy)32383525

35. 35 GE junction tumors: patterns of spread N = 169 patients with GE junction tumors Curative surgery Wayman Brit J Cancer (2002) 86, 1223-1229

36. 36 N = 1002 GE jc tumors Nodal spread Siewert type II more similar to type III Siewert et al Adenocarcinoma of the esophagogastric junction Annals of surgery 232, 3, 353-361, 2000 Update: Feith Surgical oncology clinics of north america 15,4,751-64, 2006 Pattern of spread: Lymphatic drainage

37. 37 University Hospital of Erlangen, Germany Prospective tumor registry AEG post primary resection  15 nodes examined AEGI 42%, II 54%, III 4% N = 326 Lower esophageal nodes –at risk for all locations (T3/4 tumors) Meier et al Adenoca of the esophagogastric junction: the pattern of metastastic lymph node dissemination as a rationale for elective lymphatic target volume definition IJROBP 70, 5, 1408-1417, 2008 Type I Type II Splenic

38. 38 Microscopic spread… 32 GE jn tumors Gao et al Pathological analysis of CTV margin for RT in patients with esopahgeal and GE junction carcinoma IJROBP 67, 2, 389-396, 2007

39. 39 Clinical outcomes: Large non RCT 1002 consecutive pts University of Munich Surgery: –Type I: radical transmediastinal or transthoracic en bloc esophagectomy with resection of the proximal stomach –Type II: generally with extended gastrectomy with transhiatal resection of the distal esophagus –Type III: extended gastrectomy with transhiatal resection of the distal esophagus Siewert et al Adenocarcinoma of the esophagogastric junction Annals of surgery 232, 3, 353-361, 2000 Update: Feith Surgical oncology clinics of north america 15,4,751-64, 2006

40. 40 Other factors Tolerability of combined modality vs benefit –Pulmonary and cardiac status –Other co-morbid conditions –Age –Nutritional status –Dysphagia status

41. 41 Summary T1 surgery alone cT2-4N+, combined modality:Preop CRT recommended In pts with bulky tumor, where RT volumes calls for incremental toxicities, need to tailor strategy –Anatomic considerations Esophageal extension – paraesophageal Gastric extension – splenic artery Celiac axis –Reasonable alternatives Preop/perioperative CT (based on esophagus literature) ? Reduce RT dose ? Plan RT with surgical approach/nodal clearance Post op pT2-4N+ R0, Postop CRT where feasible

42. 42 Siewert II GE junction tumor 3cm Ideal cases for preop CRT Case 1

43. 43 Siewert I paraesophageal nodes to upper mediastinum extension of volume superiorly to upper mediastinum large volume Case 2

44. 44 Case 1 Case 2 heartlung Cord

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46. 46 Severe dysphagia GE junction tumor 4cm Significant dilatation of esophagus Extension into cardia require gastric mucosa to be involved Target volume has not included splenic, gastric celiac

47. 47 RT considerations: At risk organs Stomach volumes –Residual stomach –Liver –Kidney –Small bowel Esophagus volumes –Heart –Lung –Liver –Spinal cord

48. 48 Gastric trials Gastric trials Postop CRT Perioperative CT StudyIntergroupCRTMAGIC Periop CT N556603 LocationCardia 7%Lower esophagus 15% GE Jc 12% T1-231%50% N0-1 (< 6 nodes+) 56% (  3) 80% Acute toxicity (3+)25-40%? 10% Treatment as planned64%42% Death due to treatment1%(periop deaths) 14 vs 15(S)% 3 yr OS (Study vs S only)50%/41%50%/41% (2 yr) 5 yr OS (study vs S only)40%/30%36%/23%

49. 49 Extent of esophageal involvement <15mm predicts for a low risk of lower esophageal perioesophageal nodes Can limit paraesophageal mediastinal node (can spare lung/heart) <15mm eso >15mm eso

50. 50 Splenic artery/hilar –AEG I low risk –Include in AEG II/III T3/4 Celiac –No strong low risk group –>20% for AEG I-III Recommendations for CTV selection based on –T stage –AEG designation –Length of tumor –Depth of invasion –Grade, Lymphatic involvement Adaptive strategy for nodal control between S and RT?

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52. 52 Resectability

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