Cancer of Esophago-Gastric Junction -AEG (adenocarcinomas of esophagogastric junction)- Jong Ho Park Department of Thoracic Surgery Korea Cancer Center Hospital

Endoscopic point of view: DEFINITION of AGE 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 J.R. Siewert & H.J.Stein approved at the 2nd IGCA, 1997 ISDE & IGCA, 1998

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 5cm endoscopic cardia 5cm approved at the consensus conference during the 2nd International Gastric Cancer Congress, 1997

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. These observations indicate a possible heterogeneity in the pathogenesis and biologic behavior of adenocarcinoma arising in the EGJ.

STAGING AJCC 6th edition 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.

TREND in USA 2.1 3.3 0.7 3.2 Cancer 1998;83:2049-53

TREND in JAPAN III II 10.0 % 2.3 % I

GASTROESOPHAGEAL REFLUX USA Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. 2200 Olimsted County, Minnesota : 19.8% GE reflux Gastroenterology 1997 May;112(5):1448-56 AUS 730 Sydney residents (random sample): 17.5% GE reflux KOR 2243: 8.5% GE reflux JPN 6035: 6.6% GE reflux

HELICOBACTER PYLORI 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. Am J Gastroenterol 2000;95:914-920

TREATMENTS

The management of ADC of EGJ continue to be a debate. ; Definition, surgical approach, outcome… 1982-2005, 1602 AEG resected (290 women,1312 men) Surgical resection is the mainstay of treatment of EGJ tumor of all resectable tumor stage

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 Transthoracic en bloc esophagectomy with resection of the proximal stomach with 2-field lymphadenectomy AEG II / III tumors ; cardia carcinomas and subcardiac gastric cancers 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) D2-lymphadenectomy(1-11) Pancreas-preserving splenectomy ; only in infiltration in splenic hilum Gastric cancer. 1998;1:1-15

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 RT +/- chemo Stage IIA, IIB, III, IVA Surgery +/- chemo/RT Or Chemo/RT alone 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) ; 5-FU + cisplatin + Taxol (alternative regimen #1) ; 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.

Outcomes in Germany 5YSR(R0) 43.2 %, 10 YSR(R0) 32.7 %

Outcomes in Japan Overall 5YSR 52.83 % Type I 134, Type II 1129

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

MULTIMODAL TREATMNET

Neoadjuvant chemotherapy 3 preop+3 postop ECF (epirubicin,cisplatin, fluorouracil) UK Perioperative chemotherapy vs surgery alone for resectable gastroesophageal cancer 250 vs 253 patients Postop. Complication; 46% vs 45% DFS; p < 0.001 Overall survival; p=0.009 MAGIC(Medical Research Coucil Adjuvant Gastric Infusional Chemotherapy) trial

Neoadjuvant radiotherapy 40 Gy / 4 weeks by 2 Gy qd x 20 China Ramdomized clinical trial on preop RT + S vs S of adenocarcinoma of gastric cardia 5YSR 30.1% vs 19.7% N Engl J Med 1996;335:462-7 5YSR 30.1% vs 19.7%

Neoadjuvant CCRT 2 /week Chemo (fluorouracil + cisplatin) + 40 Gy ,15/3week Ireland Comparison of multimodal therapy and surgery for esophageal adenocarcinoma 5YSR 30.1% vs 19.7% N Engl J Med 1996;335:462-7 3YSR 32% vs 6%

Neoadjuvant CT vs. CCRT 2.5 PLF (cisplatin+fluorouracil+leucovorin) vs. 2 PLF + cisplatin+etoposide+30 Gy, 2 Gy fr. /week Germany Phase III preop CT vs CRT in locally advanced ADC of EGJ Early closed due to low accrual 2009년 report 119 patients Complete tumor resection (69.5% vs 71.5%) Pathologic complete response (15.6% vs 2.0%) Tumor free L/N (64.4% vs 37.7%) 3-year SR (27.&% vs 47.4%, p=0.07) Postop mortality (10.2% vs 3.8%)

Recommendations of the ISDE/ IGCA consensus conference Neoadjuvant therapy Recommendations of the ISDE/ IGCA consensus conference 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. Meta-analysis including 20 randomized trials have demonstrated decent survival benefits. But these are esophageal cancers. Response rate of preoperative antineoplastic regimen; 30-60% Early response group with FDG-PET.

Adenocarcinoma of Esophago-Gastric Junction in 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

Adenocarcinoma of Esophago-Gastric Junction in 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 Brain 4 Neck node

Adenocarcinoma of Esophago-Gastric Junction in KCCH Survival (R0) Median 44.8 5YSR 40.1 % 10YSR 28.3 %

Adenocarcinoma of Esophago-Gastric Junction in KCCH Stage

Adenocarcinoma of Esophago-Gastric Junction in KCCH Invasion depth

Adenocarcinoma of Esophago-Gastric Junction in KCCH Node metastasis 61 204

Adenocarcinoma of Esophago-Gastric Junction in KCCH Grade 28 117 92

Extended total gastrectomy with transhiatal resection of the distal esophagus