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Multidisciplinary Approach to GE junction tumors

Multidisciplinary Approach to GE junction tumors. MOTP Academic Half Day Sep 8 2009 11-1 PMH Boardroom Dr. Darling Dr. Wong Thoracic Oncology Radiation Oncology. Overview. Part I Staging Anatomic considerations Surgical approach Part II Strategy to interpret the evidence

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Multidisciplinary Approach to GE junction tumors

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

  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. 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. Esophagus vs GE junction Stomach GE ESO ADENO HistologyLocation

  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. 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. Esophagus trials

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

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

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

  11. 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 MRC Esophagus Gastric cardia N = 802 CT+S 2 cycles 5FU 1g/m2 D1-4 Cisplatin 80mg/m2 CT

  12. 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%) Preop CT ASCO 2007 http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=47&sessionID=356

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

  14. 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

  15. ACCORD 07 1995-2003 N = 224 75% esophagus/GE Peri-operative CT 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

  16. 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

  17. 10 trials HR 0.81 [0.7-0.93] 2 y survival 35% S 47% CRT Preop RTCT+S vs S Gebski et al Lancet Oncol 2007, 8; 226-34

  18. Nomenclature precludes accurate identification of proportion of GE junction tumors…. • 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%

  19. 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

  20. 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

  21. Gastric trials

  22. 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 Gastric adjuvant trial:INT 0113 MacDonald et al

  23. 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 MAGIC

  24. Subgroup analysis – no sig interaction

  25. 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

  26. 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 Preop CT vs Preop CRT 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

  27. N = 126 (119 evaluable) 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. 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….

  29. Other considerationspattern of spreadnodal spreadlocal spreadlarger non randomized evidence

  30. 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

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

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

  33. 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

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

  35. N = 1002 GE jc tumors Nodal spread Siewert type II more similar to type III Pattern of spread: Lymphatic drainage 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

  36. 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) Type I Type II Splenic 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

  37. 32 GE jn tumors Microscopic spread… Gao et al Pathological analysis of CTV margin for RT in patients with esopahgeal and GE junction carcinoma IJROBP 67, 2, 389-396, 2007

  38. 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

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

  40. 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

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

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

  43. lung heart • Case 1 • Case 2 Cord Cord

  44. 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

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

  46. Gastric trials

  47. 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

  48. 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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