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Multidisciplinary Approach to GE junction tumors

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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 – PowerPoint PPT presentation

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Title: Multidisciplinary Approach to GE junction tumors


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
Histology Location
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
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
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
CTS 2 cycles 5FU 1g/m2 D1-4 Cisplatin 80mg/m2
CT
12
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13
Preop CT
  • IPD Thirion et al
  • 9 RCT
  • 11 GE jc
  • 54 pts SCC
  • HR OAS 0.87 (95CI 0.79-0.95 p0.003)
  • Survival diff. at 5yrs 4 (from 16 to 20)

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14
ASCO 2007 http//www.asco.org/ASCOv2/MultiMedia/Vi
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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
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
  • OAS 5yr
  • 24 vs 38 HR 0.69
  • DFS 5yr
  • HR 0.65 (95 CI 0.48-0.89 p0.003)
  • Multi-variant analysis shows gastric tumor and
    preop CT significant
  • No variation of treatment effect with tumor
    location

18
Preop RTCTS 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
Nomenclature precludes accurate identification of
proportion of GE junction tumors.
Inclusion criteria Location Adenos
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 lt2cm distal spread into gastric cardia SCC or adenos (?Siewert I/II) Not stated 75
  • 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
GE junction subgroup adeno subgroup
Gebski et al Survival benefits from neoadjuvant
chemoradiotherapy or chemotherapy in esophageal
carcinoma a meta-analysis Lancet Oncol 2007,
8226-34
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 95CI 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
Gastric trials
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 (1.23-1.86plt0.001)
  • No subgroup analysis
  • MacDonald et al CRT after S for adenocarcinoma of
    the stomach and GE jc NEJM 2001

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 (0.6-0.93p0.0009)
  • PFS HR 0.66 (0.53-0.81 plt0.0001)
  • Cummingham et al (MRC UK) Perioperative CT vs S
    alone for resectable GE cancer NEJM 2006

25
Subgroup analysis no sig interaction
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
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 27851-856, 2009
28
  • N 126 (119 evaluable)

CT CRT
3y OAS 27.7 47.4 HR 0.67 CI 0.41-1.07 p 0.07
Postop death 3.8 10.2 p 0.26
pCR 2 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 27851-856, 2009
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
Other considerations pattern of spread nodal
spread local spread larger non randomized
evidence
31
Radiotherapeutic considerations
  • 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 35Gy15 50Gy25
  • Nodal volume
  • periesophageal lymphatics 5cm cranial caudad
  • Celiac nodes

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

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

34
N 5 Preop Postop
Composite lung mean (Gy) 345 1119
Lung V20 3 16
Heart V20 31 66
Heart V30 16 35
Bowel mean (Gy) 1619 1517
Liver mean (Gy) 1762 1627
Kidney L mean (Gy) 1629 1547
Kidney R mean (Gy) 1225 1362
Cord Max (Gy) 3238 3525
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
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
Pattern of spread Lymphatic drainage
  • 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
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)

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

41
Summary
  • T1 surgery alone
  • cT2-4N, combined modalityPreop 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
Case 1
  • Siewert II GE junction tumor 3cm
  • Ideal cases for preop CRT

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

44
heart
lung
  • Case 1
  • Case 2

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

48
Gastric trials
Postop CRT Perioperative CT
Study Intergroup CRT MAGIC Periop CT
N 556 603
Location Cardia 7 Lower esophagus 15 GE Jc 12
T1-2 31 50
N0-1 (lt 6 nodes) 56 (? 3) 80
Acute toxicity (3) 25-40 ? 10
Treatment as planned 64 42
Death due to treatment 1 (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
  • Extent of esophageal involvement
  • lt15mm predicts for a low risk of lower esophageal
    perioesophageal nodes
  • Can limit paraesophageal mediastinal node
  • (can spare lung/heart)

lt15mm eso
gt15mm eso
50
  • Splenic artery/hilar
  • AEG I low risk
  • Include in AEG II/III T3/4
  • Celiac
  • No strong low risk group
  • gt20 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?

51
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52
Resectability
53
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