CancerCancer of Esophago-Gastric of Esophago-Gastric JunctionJunction

-AEG (adenocarcinomas of -AEG (adenocarcinomas of esophagogastric junction)-esophagogastric junction)-

Jong Ho Park

Korea Cancer Center HospitalDepartment of Thoracic Surgery

□ Adenocarcinomas which have their center within 5cm proximal or distal of the anatomic cardia.

□ Endoscopic point of view: the upper end of the typical longitudinal fold of the gastric mucosa is defined as the so called ‘endoscopic cardia’ rather than the Z-line

approved at the 2nd IGCA, 1997 ISDE & IGCA, 1998

J.R. Siewert & H.J.Stein

DEFINITION of AGE

Gastroesophageal (GE) junction

Z-line(squamo-columnar junction):moving with age & as a result of reflux esophagitis

Typical longitudinal gastric mucosa folds as endoscopic cardia classification

Siewert’s Classification

approved at the consensus conference during the 2nd International Gastric Cancer Congress, 1997

endoscopic cardia

5cm

5cm

Backgrounds• Incidence change in white men ; 10%/yr increase during last decade, in contrast to the

decreasing prevalence of gastric cancer.

• A preponderence of the male sex in Type I than Type II or III.

• Hx. Of a hiatal hernia, obesity and GE reflux in Type I than Type II or III.

• Reflux related intestinal epithelial metaplasia in Type I and H. pylori and intestinal metaplasia in Type II & III.

• The prevalence of undifferentiated tumors and tumors with a non-intestinal growth pattern in rather low in AGE Type I and increase significantly from Type II & III – cytokeratins, cell adhesion molecules, p53 & genomic pattern.

• Different lymphographic studies and micrometastasis pattern to L/N.

• pT3 (visceral peritoneum) in UICC classification – partial extraperitoneal location and lymphatic spread into retroperitoneum.

□ If more than 50% of the cancer involves the esophagus, the cancer is classified as esophageal.

□ If more than 50% of the tumor is below the GE junction, as gastric .

□ If the tumor is located equally above and below the GE junction, squamous cell, small cell, and undifferentiated carcinoma are classified as esophageal and adenocarcinoma and signet ring cell carcinomas as gastric.

□ When Barrett’s esophagus is present, adenocarcinoma in both the gastric cardia and lower esophagus is most likely to be esophageal in origin.

STAGING AJCC 6th edition

Cancer 1998;83:2049-53

0.7

3.22.1

3.3

TREND in USA

2.3 %

10.0 %

I

II

III

TREND in JAPAN

Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.

Gastroenterology 1997 May;112(5):1448-56

□2200 Olimsted County, Minnesota : 19.8% GE reflux

□730 Sydney residents (random sample): 17.5% GE reflux

□2243: 8.5% GE reflux

□6035: 6.6% GE reflux

GASTROESOPHAGEAL REFLUX

AUS

JPN

USA

KOR

Am J Gastroenterol 2000;95:914-920

□The decrease in H. pylori infection has paralleled the increasing rate of ADC of the esophagus Gut 1997;41:279-80

□Need prospective, randomized, placebo-controlled trials.

HELICOBACTER PYLORI

TREATMENTS

The management of ADC of EGJ continue to be a debate.; Definition, surgical approach, outcome…

Surgical resection is the mainstay of treatment of EGJ tumor of all resectable tumor stage

□1982-2005, 1602 AEG resected (290 women,1312 men)

Surgical strategies (based on tumor location); Complete removal of the primary tumor with its lymphatic drainage

□ Adenocarcinoma of esophagogastric junction (AEG) I tumors;distal esophageal adenocarcinoma

□ AEG II / III tumors; cardia carcinomas and subcardiac gastric cancers

Transthoracic en bloc esophagectomy with resection of the proximal stomach with 2-field lymphadenectomy

Total gastrectomy with transhiatal resection of the distal esophagus(transhiatally extended gastrectomy)

; Wide splitting of the diaphragmatic hiatus, Transhiatal resction of the distal esophagus, En bloc lymphadenctomy of the lower posterior mediastinum, D2 lymphadenectomy

Ann Surg. 2000 September; 232(3): 353–361

Extent of Lymphadenectomy; for AEG II and III

□ Distribution of LN metastases after surgery

Radioisotope Lymphography-Gastric Cancer 1998-

• Lymphatic pathways are mainly directed toward the abdomen.

Siewert Type I

Siewert Type II

Siewert Type III

Abdominal tier

53.8% 70.5% 90.7%

Chest L/N 46.2% 29.5% 9.3%

Extent of Lymphadenectomy; for AEG II and III

Lymph node station of Japanese Gastric Cancer Association(JGCA)

Gastric cancer. 1998;1:1-15

□ D2-lymphadenectomy(1-11)□ Pancreas-preserving splenectomy ; only in infiltration in splenic hilum

D1 Vs. D2 Lymphadenectomy-Guidelines of the Japanese Research Society of the

Study of Gastric Cancer-

• D1 dissection; removal of the involved part of the stomach (distal or total), including greater and lesser omentum. The spleen and pancreas tail are only resected when necessitated by tumor invasion. (1~4s)

• D2 dissection; the omental bursa is removed with the frontal leave of the transverse mesocolon, and the (Lt. gastric, common hepatic, celiac, splenic A.) vascular pedicles of the stomach are cleared completely. Standard resection of the spleen and pancreatic tail was only done in proximal tumors to achieve adequate removal of D2 lymph node stations 10 and 11. (1~11)

• D3 dissection; resection extended to the nodes in position 12~16.

Prognostic Factors after Surgery

• En bloc resection

• R0 resection

• Total involved L/N number - 4 or less (AJCC; 6)

• Node ratio (Involved L/N / Total resected L/N)

- 0.1 ~ 0.3

Treatment Algorithm for EGJ Cancer

Stage Good performance Poor performance

Stage 0 Surgery alone PDT, mucosal ablation

Stage I Surgery alone RT +/- chemo

Stage IIA, IIB, III, IVA

Surgery +/- chemo/RT

Or Chemo/RT alone

RT +/- chemo

Stage IVB Chemo +/- RT/stents

RT/stent

Specific Drug Regimens

• Locoregionally advanced stage (T3,4, N1, or M1a)-alternative to surgery

; 5-FU + cisplatin + RTx. (50.4 Gy)

• Investigational for locoregionally advanced stage (T3,4, N1, or M1a)-alternative to surgery alone or chemoradiation Tx. Alone

; 5-FU + cisplatin + RTx. (50.4 Gy) followed by surgery

• Advanced stage (M1b, systemic micrometastases) ; 5-FU + cisplatin (standard regimen)

• Advanced stage (M1b, systemic micrometastases) ; 5-FU + cisplatin + Taxol (alternative regimen #1)

• Advanced stage (M1b, systemic micrometastases) ; cisplatin + CPT-11 (alternative regimen #2)

Radiation Therapy

• T1-2, No; cannot tolerate surgery - RTx.(50.4 Gy over 5.5 weeks) +/- chemo (cisplatin + 5-FU)

• Locoregional advanced stage (T3,4, N1 or M1a) - can be treated with RTx. with chemoTx. alone (or surgery

alone) but poor result - recommend neoadjuvant RTx. with chemoTx. or postop.

Adjuvant RTx. with chemoTx.

• Metastatic (M1b) with obstructive symptom - can be treated with RTx. alone (30Gy over 2 weeks) or in combination with chemoTx.

5YSR(R0) 43.2 %, 10 YSR(R0) 32.7 %

Outcomes in Germany

Overall 5YSR 52.83 %Type I 134, Type II 1129

Outcomes in Japan

5YSR (R0) 37.5 % in type I (29) , 34.5% in type II (80), 33.3% in type III (94)

Outcomes in China

MULTIMODAL TREATMNET

Neoadjuvant chemotherapy 3 preop+3 postop ECF (epirubicin,cisplatin, fluorouracil)

MAGIC(Medical Research Coucil Adjuvant Gastric Infusional Chemotherapy) trial

UK Perioperative chemotherapy vs surgery alone for resectable gastroesophageal cancer

Neoadjuvant radiotherapy 40 Gy / 4 weeks by 2 Gy qd x 20

Neoadjuvant CCRT 2 /week Chemo (fluorouracil + cisplatin) + 40 Gy ,15/3week

Germany Phase III preop CT vs CRT in locally advanced ADC of EGJ

Neoadjuvant CT vs. CCRT 2.5 PLF (cisplatin+fluorouracil+leucovorin) vs. 2 PLF + cisplatin+etoposide+30 Gy, 2 Gy fr. /week

Early closed due to low accrual

•A general application of multimodal treatment protocols in patients with potentially resectable adenocarcinoma of the esophagogastric junction was not recommanded.

•Restrict neoadjuvant therapy to locally advanced tumors at the esophagogastric junction to patients in whom an R0-resection appears questionable.

Neoadjuvant therapy

Recommendations of the ISDE/ IGCA consensus conference

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

December 1987-August 2008 , 265 complete resection

M / F 193 / 72

3 distal esophageal adenocarcinoma

1 Barrett’s esophagus

257 Total gastrectomy (91 thoracoabdominal incision)

8 Ivor Lewis operation

Stage IA 13, IB 19, II 35, IIIA 104, IIIB 45, IV 49

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Recurrence 80/265, 30.1%

Abdominal LN 26 (9.8%)

Liver 18 (6.8%)

Lung 12 (4.5%)

Mesentery seeding 11 (4.2%)

Anastomosis site 7 (2.7%)

Mediastinal LN 5

Ovary 5

Brain 4

Neck node 4

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Survival (R0) Median 44.8

5YSR 40.1 %

10YSR 28.3 %

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Stage

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Invasion depth

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Node metastasis

61

204

AdenocarcinomaAdenocarcinoma of Esophago-Gastric Junction of Esophago-Gastric Junction

in KCCHin KCCH

Grade

28

117

92

Extended total gastrectomy with transhiatal resection of the distal esophagus