Multidisciplinary Multidisciplinary Approach to GE Approach to GE junction tumorsjunction tumors

MOTP Academic Half DaySep 8 2009

11-1PMH Boardroom

Dr. Darling Dr. Darling Dr. WongDr. WongThoracic OncologyThoracic Oncology Radiation OncologyRadiation Oncology

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OverviewOverview

• Part I– Staging– Anatomic considerations– Surgical approach

• Part II– Strategy to interpret the evidence– Adjuvant and neo-adjuvant therapies– Radiotherapy issues– Summary

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GE junction tumorsGE 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)

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Esophagus vs GE junction Esophagus vs GE junction

HistologyHistologyLocation Location

StomachStomachESO

ADENO

GE

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Interpreting the evidence 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

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Interpreting the evidenceInterpreting 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

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Esophagus trialsEsophagus trials

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SurgerySurgery

Preop CRTPreop CRT

Treatment options for localized Treatment options for localized esophageal canceresophageal cancer

Preop CTPreop CT

Pre or post op Pre or post op RTRT

post op post op CTCT

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Preop CTPreop CT(published meta-analysis)(published meta-analysis)

Gebski et al Lancet Oncol 2007, 8; 226-34

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GE junction subgroup? … Adeno GE junction subgroup? … Adeno subgroupsubgroup

• 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

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MRC 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

EsophagusGastric cardia

N = 802

CT+S2 cycles

5FU 1g/m2 D1-4Cisplatin 80mg/m2

CT

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Preop CTPreop 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

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

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• 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

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Peri-operative CTPeri-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

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• 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

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Preop RTCT+S vs SPreop 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

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Nomenclature precludes accurate identification of Nomenclature precludes accurate identification of proportion of GE junction tumors….proportion of GE junction tumors….

Inclusion criteria Location AdenosWalsh

1996

Esophageal adenocarcinoma Lower 1/3 50%

Cardia 35%

100%

Urba

2001

Thoracic esophagus and GE junction

SCC or adenosmid/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 stated 75%

5 trials include adenos, 1 dedicated to adenoProportion adenos (in 3 trials) approx 75% Proportion lower/GE (in 2 trials) approx 80%Cardia (1 trial) 35%

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GE junction subgroup … adeno subgroupGE 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

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From the esophagus literature….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

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Gastric trialsGastric trials

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Gastric adjuvant trial:Gastric adjuvant trial:INT 0113 MacDonald et alINT 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

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MAGICMAGIC

• 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

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Subgroup analysis – no sig interactionSubgroup analysis – no sig interaction

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From gastric trials… 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

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Preop CT vs Preop CRTPreop 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 CTPLF x 2.5cyclesCisplatin 50mg/m2 biwkly

5FU 2g/m2 24 hr infLeucovorin 500mg/m2

Preop CRTPLF x 2 cycles

CRTCisplatin 50mg/m2 D1,8Etoposide 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

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• 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 27:851-856, 2009

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Summary?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….

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Other considerationsOther considerations

pattern of spreadpattern of spreadnodal spreadnodal spreadlocal spreadlocal spread

larger non randomized evidencelarger non randomized evidence

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• 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

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• Preop esophagus CRT– Dose 35Gy:15 – 50Gy:25

– Nodal volume: – periesophageal lymphatics 5cm

cranial caudad

– Celiac nodes

Radiotherapeutic considerationsRadiotherapeutic considerations

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Preop GE junction Preop GE junction

• Primary tumor + 3cm sup and inf for microsopic extension

• Periesophageal nodes• Celiac nodes

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Stomach involving GE Stomach involving GE junctionjunction

• Celiac nodes• Portal hepatis• Splenic hilar• Pancreaticoduodenal• Preop stomach• Post op residual stomach• Anastomosis• L medial hemidiaphragm

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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 = 5 PreopPreop PostopPostop

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

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GE junction tumors: patterns of spreadGE junction tumors: patterns of spread

• N = 169 patients with GE junction tumors

• Curative surgery

Types of recurrences Type I(%)

N = 55/94

Type II(%)

N = 48/75Haematogenous 30 26 56%Local 18 14 32%Lymph Node

Celiac axisPortaRetrocrural/aortocavalSupraclavicular

104313

123430

22%

Peritoneal 4 7 11%

Wayman Brit J Cancer (2002) 86, 1223-1229

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• 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 Pattern of spread: Lymphatic drainage

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University Hospital of Erlangen, GermanyUniversity 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

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Microscopic spread… 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

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Clinical outcomes: Large non RCT 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

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Other factorsOther factors

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

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SummarySummary• 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

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• Siewert II GE junction tumor 3cm

• Ideal cases for preop CRT

Case 1Case 1

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• Siewert I

• paraesophageal nodes to upper mediastinum

• extension of volume superiorly to upper mediastinum

• large volume

Case 2Case 2

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• Case 1

• Case 2

heartlung

Cord

Cord

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• 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

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RT considerations: At risk organsRT considerations: At risk organs

• Stomach volumes– Residual stomach

– Liver

– Kidney

– Small bowel

• Esophagus volumes– Heart

– Lung

– Liver

– Spinal cord

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Gastric trialsGastric trials

Postop CRTPostop CRT Perioperative CTPerioperative CT

StudyStudyIntergroupIntergroup

CRTCRT

MAGICMAGIC

Periop CTPeriop CT

N 556 603

Location Cardia 7% Lower esophagus 15%

GE Jc 12%

T1-2 31% 50%

N0-1 (< 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%

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• 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

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• 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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Resectability Resectability

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