Review on Management of Gastro-esophageal Junction Cancer 14/4/2018 Review on Management of Gastro-esophageal Junction Cancer  joint hospital surgical grand round    Dr. Vincent Chan  Pamela Youde Nethersole Eastern Hospital

content Definition Latest Trend Surgical Approach Resection extent Adjuvant/ neoadjuvant therapy

definition GEJ SCJ (Z-line) Upper limit of the gastric folds/ Lower limit of the palisade longitudinal vessels (Japan)   SCJ (Z-line) Where squamous mucosa of the esophagus and columnar mucosa of the stomach meet  Distance between GEJ and SCJ: 3 to 11mm large veins exceeding 100 mm in diameter are observed much more frequently in the lamina propria of the lower oesophageal sphincter (LOS)

GEJ tumor Siewert classification (Siewert 1996) Type I 1 to 5 cm proximal to GEJ Type II Between 1 cm proximal and 2 cm distal to GEJ Type III 2 to 5 cm distal to GEJ center

GEJ tumor Siewert classification (Siewert 1996) Type I Male predominance Predominant intestinal-type pathology (similar to Esophageal adenocarcinoma) Arisen from Barrett's intestinal metaplasia Type II Mixed etiology Type III Similar proportion of diffuse and intestinal histologic types as Gastric Cancer Might be associated with Helicobacter pylori and atrophic gastritis

GEJ tumor Siewert classification- Lymph node metastases Type Mullen JT, et al. What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer. Ann Surg Oncol 2016; 23:3780. GEJ tumor Siewert classification- Lymph node metastases Type Percent of tumors with lymph node metastases Location of nodal metastases I 65 Upper abdominal nodes (54%) Mediastinum (46%) II 70 Abdominal nodes (paracardial, lesser curvature, left gastric) (71%) Mediastinum (30%) III 90 Abdominal nodes (91%) Mediastinum (9%) Type 1: upper mediastinum

8th edition AJCC/UICC staging 2017 cancers of the esophagus and esophagogastric junction Upper edge of cancer in distal thoracic esophagus/EGJ/ within the proximal 5 cm of stomach that extend into EGJ Esophageal cancer Epicenter <2 cm into the proximal stomach Epicenter >2 cm involvement into the proximal stomach Stomach cancer 7th edition epicenter is determined from upper and lower border measurements, which also provide cancer length  epicenter is more than 2 cm distal from the EGJ = Stomach Cancer even if the EGJ is involved. 8th edition

8th edition AJCC/UICC staging 2017 cancers of the esophagus and esophagogastric junction Staging grouping by histopathology Adenocarcinoma Squamous cell carcinoma Staging grouping by clinical status before treatment decision (clinical) after esophagectomy alone (pathologic) after preresection therapy followed by esophagectomy (postneoadjuvant pathologic) ideally, cancer stage grouping and survival should be connected.

8th edition AJCC/UICC staging 2017 cancers of the esophagus and esophagogastric junction SCC Adenocarcinoma Survival of patients with early-stage and intermediate-stage disease was worse for those who had squamous cell carcinomas than for those who had similarly staged adenocarcinomas

Liu et al. Changes of Esophagogastric Junctional Adenocarcinoma and Gastroesophageal Reflux Disease Among Surgical Patients During 1988–2012. Ann Surg 2016;263:88–95 latest trend Worldwide: Increasing number of adenocarcinoma of esophagus and GEJ China: Increasing proportion of GEJ tumor     Retrospective cohort in China for 25 years (>5000 cases)  proportion of EGJA was increased from 22.3% in period 1

latest trend China: Increasing proportion of Type I and III GEJ tumor   Positive correlation with increase in GERD for Type I tumor The proportion of Siewert type III (35.9% vs 47.0%) (P<0.001) and type I (8.7% vs 15.8%) (P?0.002) tumors of EGJA increased

workup OGD CT thorax + abdomen EUS +/- FNA PET/ PET-CT Exploratory laparoscopy EUS allows assessment of both perigastric and mediastinal lymph node PET detect 15 to 20% of cases metastasis non visible on the Ct-

surgical approach (Type I) Ann Surg 2017;266:232–236 surgical approach (Type I) Transthoracic esophagectomy with partial gastrectomy & two- field lymphadenectomy  Minimally invasive? Two field = mediastinal, upper abdomen

surgical approach (Type I) Ann Surg 2017;266:232–236 surgical approach (Type I) Randomized Controlled Trial 115 patients with resectable intrathoracic esophageal carcinoma 54.7% (distal esophagaus/ Siewert Type I) Randomized between open and minimally invasive esophagectomy Overall 3-year survival 40.4% (open) VS 50.5% (minimally invasive)  (P=0.207) Disease-free 3-year survival 35.9% (open) VS 40.2% (minimally invasive) [HR 0.691 (0.389 to 1.239)] Right thoracoscopy in the prone position with single-lumen tracheal intubation, upper abdominal laparoscopy, and cervical incision  bronchus blocker was placed in the right bronchus to help with 1-lung ventilation during anastomosis

surgical approach (Type II and III) Total gastrectomy + D2 lymphadenectomy +/- distal esophagectomy At least 15 lymph node R0 Resection At least 5 cm proximal (esophageal) margin > 4cm distal margin D1: station 1-7 D2: station 1-12

surgical approach (Type II and III) British Journal of Surgery 2013; 100: 1050–1054 surgical approach (Type II and III) Proximal margin

surgical approach (Type II and III) Retrospective cohort 140 patients with Siewert type II and III tumor (pT2–4 N0–3 M0) Transhiatal gastrectomy + R0 resection Multivariable analysis : Gross proximal margin of 20mm or less is an independent prognostic factor (hazard ratio (HR) 3.56)

surgical approach (Type II and III) World J Gastroenterol 2017 April 21; 23(15): 2723-2730 surgical approach (Type II and III) Lymph node dissection single-center, retrospective, cohort

surgical approach (Type II and III)  Index of estimated benefit from LN dissection (IEBLD):  frequency of metastasis to the station x 5year survival rate of patients with metastases to that station

lymph node dissection (Siewert Type II/III) LN along the lesser curvature (3), the left gastric artery (7) ; right and left paracardial LN (2,1) should be dissected Tumors affecting ≤ 3 cm of esophagus achieved no benefit from lower mediastinal LN dissection

surgical approach (Type II and III) Y. Kurokawa. Ten-year follow-up results of a randomized clinical trial comparing left thoracoabdominal and abdominal transhiatal approaches to total gastrectomy for adenocarcinoma of the oesophagogastric junction or gastric cardia. BJS 2015; 102: 341–348 surgical approach (Type II and III) Trans-hiatal VS Thoracoabdominal Randomized clinical trial (JCOG9502) 167 patients 10-year overall survival rate of TH VS LTA (left thoracoabdominal approach) Hazard ratio for death 1.42 for the LTA technique No significant survival benefit for LTA

surgical approach (Summary) Type I Transthoracic esophagectomy with partial gastrectomy & two-field lymphadenectomy  (Open/ minimal invasive) Type II and III Transhiatal total gastrectomy + D2 lymphadenectomy +/- distal esophagectomy (2cm proximal margin)

Adjuvant therapy Indication: Previous trials focus on two subgroups: margin-positive disease node-positive disease pT3 or above Previous trials focus on two subgroups: distal esophagus/EGJ EGJ/ gastric More favorable towards neo-adjuvant lack of trials that focus on the EGJ

perioperative treatment MAGIC trial (N Engl J Med 2006) Patient with distal esophageal, EGJ, and gastric adenocarcinoma Perioperative chemotherapy (ECF) decrease tumor size and stage and significantly improved progression-free and overall survival

neoadjuvant therapy CROSS trial (N Engl J Med 2012) 366 patients with potentially resectable esophageal or EGJ cancers (T1N1/ T2-3N0-1) 75% EGJ tumor 5 week Carboplatin + Paclitaxel + concurrent radiotherapy Neoadjuvant chemoradiotherapy improved survival compared with surgery alone (Hazard ratio 0.65; 95% C.I. 0.49 to 0.87) Significant benefit for SCC, marginal benefit for adenocarcinoma Majority adenocarcinoma

neoadjuvant therapy Systemic review (Eur J Cancer 2013) Eight RCTs (1049 patients with gastro/esophageal adenocarcinoma) Preoperative chemotherapy associated with longer overall survival (hazard ratio [HR] 0.81; p<0.0001) Appeared larger survival advantages in GEJ tumours, but subgroup differences not statistically significant

conclusion Increasing prevalence of GEJ tumor New staging system Role of minimally invasive approach Shorter proximal resection margin might be appropriate

Q&A

Thank you

Integrated genomic characterization of oesophageal carcinoma Nature. 2017 January 12; pathogenesis Barrett’s esophagus and Esophageal adenocarcinoma might originate from proximal gastric cells or embryonic remnant cell populations at the GEJ molecular similarity between EACs and CIN gastric cancers

surgical approach (Summary) Type I 8cm proximal margin Type II Proximal gastrectomy might be acceptable (IEBLD for distal perigastric LN = 0) Type III Total gastectomy

neoadjuvant therapy POET trial (Journal of Clinical Oncology 2009) First randomized study limited exclusively to EGJ tumor Locally advanced tumor (T3-4 NXM0) Arm A: Induction chemotherapy > Surgery Arm B: Chemotherapy > Chemoradiotherapy > Surgery Significant higher probability of showing pathologic complete response and tumor-free lymph nodes Closed prematurely because of poor accrual