Carcinoma of the Gastric Cardia: Transhiatal Approach

Transcription

1 XXVII CONGRESSO NAZIONALE SPIGC SOCIETÀ POLISPECIALISTICA ITALIANA DEI GIOVANI CHIRURGHI Brescia, giugno 2015 Carcinoma of the Gastric Cardia: Transhiatal Approach Marco Lotti MD Division of Advanced Surgical Oncology Department of General Surgery 1 Papa Giovanni XXIII Hospital Bergamo - Italy

2 Recurrence with surgery alone Percentage of SiewertI SiewertII SiewertIII Perioperative Deaths Recurrence at 2 and 5 years haematogenous local/anastomotic peritoneal lymph node coeliac axis / - porta / - retrocrural/aortocaval cervical/mediastinal

3 The Randomized Trials

4 TRANSHIATAL ESOPHAGECTOMY: the tumor and its adjacent lymph nodes were dissected en bloc. A 3-cm-wide gastric tube was constructed. The left gastric artery was transected at its origin, with resection of local lymph nodes. Celiac lymph nodes were dissected only when there was clinical suspicion of involvement. Anastomosis in the neck. A The New England Journal of Medicine EXTENDED TRANSTHORACIC RESECTION COMPARED WITH LIMITED TRANSHIATAL RESECTION FOR ADENOCARCINOMA OF ESOPHAGUS JAN B.F. HULSCHER, M.D., JOHANNA W. VAN SANDICK, M.D., ANGELA G.E.M. DE BOER, PH.D., BAS P.L. WIJNHOVEN, M.D., JAN G.P. TIJSSEN, PH.D., PAUL FOCKENS, M.D., PEEP F.M. STALMEIER, PH.D., FIEBO J.W. TEN KATE, M.D., HERMAN VAN DEKKEN, M.D., HUUG OBERTOP, M.D., HUGO W. TILANUS, M.D., AND J. JAN B. VAN LANSCHOT, M.D. L type I ONG-TERM survival after surgery with cu TRANSTHORACIC ESOPHAGECTOMY: the thoracic duct, azygos vein, ipsilateral pleura, and all periesophageal tissue in the mediastinum were dissected en bloc. The paracardial, lesser-curvature, left-gastricartery (along with lesser-curvature), celiac trunc, common-hepatic-artery, and splenicartery nodes were dissected, and a gastric tube was constructed. A mean (±SD) of 16±9 nodes were identified in the resection specimen after transhiatal resection, and 31± 14 after transthoracic resection (p<0.001). Different lymphadenectomy in the mediastinum and even in the abdomen

5 . Local regional recurrence occurred in 14 perand 12 percent of patients, respectively; distant rence in 25 percent and 18 percent; and both in 18 ent and 19 percent (P=0.60). For the transhiatal transthoracic procedures, the median disease-free val was 1.4 years (95 percent confidence inter- terval, 1.1 to 2.8) after transthoracic resection with extended en bloc lymphadenectomy (P=0.38) (Fig. 2). 0.8 to 2.0) and 1.7 years (95 percent confidence val, 0.7 to 2.7), respectively (P=0.15) (Fig. 1). The estimated rate of overall survival at five years was estimated rate of disease-free survival The at New five years England Journal 29 percent of Medicine (95 percent confidence interval, 20 to percent (95 percent confidence interval, 19 to percent) after transhiatal resection, as compared with ercent) after transhiatal resection, as compared 39 percent (95 percent confidence interval, 30 to percent EXTENDED (95 percent confidence TRANSTHORACIC interval, 30 toresection percent) after COMPARED transthoracic WITH resection. LIMITED The 95 percent ercent) after TRANSHIATAL transthoracic resection. RESECTION The 95 FOR per-adenocarcinomconfidence interval for the difference in the rates to 23 percent. The median number of quality-adjust- confidence interval for OF the difference ESOPHAGUS was 3 percent 1 percent to 24 JAN percent B.F. HULSCHER, (the negative M.D., JOHANNA value indithat survival W. VAN SANDICK, ed life-years M.D., ANGELA after transhiatal G.E.M. DE BOER, resection PH.D., was 1.5 (95 percent BAS was P.L. better WIJNHOVEN, with transhiatal M.D., JAN G.P. resection). TIJSSEN, PH.D., PAUL confidence FOCKENS, M.D., interval, PEEP F.M. 0.8 to STALMEIER, 2.1), as PH.D., compared with FIEBO J.W. TEN KATE, M.D., HERMAN VAN DEKKEN, M.D., HUUG OBERTOP, M.D., HUGO W. TILANUS, M.D., the end of follow-up, 142 patients had died 1.8 (95 percent confidence interval, 1.1 to 2.4) after AND J. JAN B. VAN LANSCHOT, M.D. ABSTRACT Background Controversy 100 exists about the best surgical treatment for esophageal carcinoma. Methods We randomly assigned 220 patients with adenocarcinoma of the mid-to-distal esophagus or adenocarcinoma of the gastric cardia involving the distal esophagus either to transhiatal esophagectomy or to transthoracic esophagectomy with extended en bloc lymphadenectomy. 80 Principal end points were overall survival and disease-free survival. Early morbidity and mortality, the number of quality-adjusted life-years gained, and cost effectiveness were also determined. Results A total of 106 patients were assigned to undergo transhiatal esophagectomy, and 114 to undergo transthoracic esophagectomy. 60 Demographic characteristics and characteristics of the tumor were similar in the two groups. Perioperative morbidity was higher after transthoracic esophagectomy, but there was no significant difference in in-hospital mortality (P=0.45). After a median follow-up of 4.7 years, 142 patients had died 74 (70 percent) 40 after transhiatal resection and 68 (60 percent) after transthoracic resection (P= 0.12). Although the difference in survival was not statistically significant, there was a trend toward a survival benefit with the extended approach at five years: disease-free survival was 27 percent in the transhiatalesophagectomy group, as compared with 39 percent in the transthoracic-esophagectomy 20 group (95 percent confidence interval for the difference, 1 to 24 percent [the negative value indicates better survival with transhiatal resection]), whereas overall survival was 29 percent as compared with 39 percent (95 percent confidence interval for the difference, 3 to 23 percent). 0 Conclusions Transhiatal 0 esophagectomy 1 2 was associated with lower morbidity than transthoracic esoph- 3 agectomy with extended en bloc lymphadenectomy. Although median overall, disease-free, and qualityadjusted survival did not differ statistically between NO. AT RISK the Transhiatal groups, there was 106 a trend toward 68 improved 47 longterm mesophagectomy survival at five years with the extended transtho- 32 racic Transthoracic approach. (N Engl 114 J Med ;347: ) Copyright mesophagectomy 2002 Massachusetts Medical Society. Cumulative Disease-free Survival (%) Five years later the survival benefit is less than expected cent) and 68 in the transthoracic group (60 percent; P=0.12). Thirteen patients died of causes unrelated to cancer. The median overall survival was 1.8 years (95 percent confidence interval, 1.2 to 2.4) after transhiatal resection and 2.0 years (95 percent confidence in- Omloo et al Johannes Annals B. Reitsma, of MD, Surgery PhD, Paul Volume Fockens, MD, 246, PhD, Herman Number van Dekken, 6, December MD, PhD, 2007 L ONG-TERM survival after surgery with curative intent for adenocarcinoma of the distal esophagus and gastric cardia is only 20 percent. 1,2 Surgery is generally considered to offer the best chance for cure, but opinions differ on how to improve survival by surgery. One strategy aims at decreasing early postoperative risk by the use of limited cervicoabdominal (transhiatal) esophagectomy without formal lymphadenectomy. Another is intended to improve long-term survival by performing a combined cervicothoracoabdominal resection, with wide excision of the tumor and peritumoral tissues and extended lymph-node dissection in the posterior mediastinum and the upper abdomen (transthoracic esophagectomy with extended en bloc lymphadenectomy). 1-5 We studied whether transthoracic esophagectomy with extended en bloc lymphadenectomy sufficiently improves overall, disease-free, and quality-adjusted survival over the rates Transthoracic with transhiatal esophagectomy esophagectomy to compensate for the possibly higher perioperative morbidity and mortality and the increased costs of the treatment. Study Design METHODS The study was performed in two academic medical centers, each performing more than Transhiatal 50 esophagectomy esophagectomy procedures per year. The eligible patients had histologically confirmed adenocarcinoma of the mid-to-distal esophagus or adenocarcinoma of the gastric cardia involving the distal esophagus, had no evidence of distant metastases (including the absence of histologically confirmed tumor-positive cervical lymph nodes and unresectable celiac lymph nodes), and did not have unresectable local disease. These patients were randomly assigned 4 to undergo 5 transhiatal 6 esophagectomy 7 or 8transthoracic esophagectomy with extended en bloc lymphadenectomy between April Years 1994 and February Patients had to be older than 18 years of age and in adequate physical condition to undergo surgery (as indicated by their assignment 20 to American 15 Society of 11 Anesthesiologists 4 class I or II 6 ). Exclusion criteria were previous or coexisting cancer, previous gastric or esophageal 31 surgery, 20 receipt 13 of neoadjuvant 7 chemotherapy or ra- From the Departments of Surgery (J.B.F.H., J.W.S., H.O., J.J.B.L.), Medical Figure 1. Kaplan Meier Curves Showing Disease-free Survival among Patients Randomly Assigned to Transhiatal Psychology (A.G.E.M.B., P.F.M.S.), Cardiology (J.G.P.T.), Gastroenterology Esophagectomy or Transthoracic Esophagectomy with Extended (P.F.), en Bloc and Pathology Lymphadenectomy. (F.J.W.K.), Academic Medical Center, University of Amsterdam, Amsterdam; the Departments of Surgery (B.P.L.W., H.W.T.) and Pathology (H.D.), Erasmus University Hospital Rotterdam, Rotterdam; and RADIAN and Medical Technology Assessment (P.F.M.S.), Nijmegen all N Engl J Med, Vol. 347, No. 21 November 21, in the Netherlands. Address reprint requests to Dr. van Lanschot at the Academic Medical Center at the University of Amsterdam, Department of Surgery, Suite G4-112, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, or at j.j.vanlanschot@amc.uva.nl. Although survival did not differ statistically The New England Journal of Medicine 1662 N Engl J Med, Vol. 347, No. 21 November 21, between Downloaded from nejm.org on May 25, the For personal use groups, only. No other uses without permission. there was Copyright 2002 Massachusetts Medical Society. All rights reserved. a trend toward improved 5y survival The New England Journal of Medicine Downloaded from nejm.org on May 25, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved. with the extended transthoracic approach. survival Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus Objective: To determine whether extended transthoracic esophagectomy for adenocarcinoma of the mid/distal esophagus improves 1,0 long-term survival. Background: A randomized trial was performed to compare surgical techniques. Complete 5-year survival data are now available. Methods: A total of 220 patients with adenocarcinoma of the distal esophagus (type I) or gastric cardia involving the distal esophagus (type II) were randomly assigned to limited transhiatal esophagec- 0,8 tomy or to extended transthoracic esophagectomy with en bloc lymphadenectomy. Patients with peroperatively irresectable/incurable cancer were excluded from this analysis (n 15). A total of 95 patients underwent transhiatal esophagectomy and 110 patients underwent transthoracic esophagectomy. Results: After transhiatal and transthoracic resection, 5-year survival was 34% and 36%, respectively (P 0.71, per protocol 0,6 analysis). In a subgroup analysis, based on the location of the primary tumor according to the resection specimen, no overall survival benefit for either surgical approach was seen in 115 patients with a type II tumor (P 0.81). In 90 patients with a type I tumor, a survival benefit of 14% was seen with the transthoracic approach (51% vs. 37%, P 0.33). There was evidence that the treatment 0,4 0,2 umbers 992 at risk >8 (n=46) Five-Year Survival of a Randomized Clinical Trial Jikke M. T. Omloo, MD,* Sjoerd M. Lagarde, MD,* Jan B. F. Hulscher, MD,* Fiebo J. W. ten Kate, MD, Huug Obertop, MD, Hugo W. Tilanus, MD, PhD, and J. Jan B. van Lanschot, MD effect differed depending on the number of positive lymph nodes in the resection specimen (test for interaction P 0.06). In patients (n 55) without positive nodes locoregional disease-free survival after transhiatal esophagectomy was comparable to that after transthoracic esophagectomy (86% and 89%, respectively). The same was true for patients (n 46) with more than 8 positive nodes (0% in both groups). Patients (n 104) with 1 to 8 positive lymph nodes in the resection specimen showed a 5-year locoregional disease-free survival advantage if operated via the transthoracic route (23% vs. 64%, P 0.02). Conclusion: There is no significant overall survival benefit for either approach. However, compared with limited transhiatal resection extended transthoracic esophagectomy for type I esophageal adenocarcinoma shows an ongoing trend towards better 5-year survival. Moreover, patients with a limited number of positive lymph nodes in the resection specimen seem to benefit from an extended transthoracic esophagectomy. (Ann Surg 2007;246: ) T follow-up (years) he incidence of adenocarcinoma of the esophagus and gastroesophageal junction is rapidly rising. It is an aggressive disease with early lymphatic and hematogenous dissemination. Long-term survival rates barely exceed 25%, even after surgery with curative intent. 1,2 Surgery is still considered the best curative treatment option. However, much controversy concerning the optimal surgical approach exists. From the *Departments of Surgery, Clinical Epidemiology, Biostatistics, and Bioinformatics, and Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands. Supported by ZonMw Health Care Efficiency Research ( ; to Two main operation techniques are currently advocated. Limited transhiatal esophagectomy () (without J. M. T. O.). Supported by the Maag Lever Darm Stichting (Dutch Digestive Foundation, formal lymphadenectomy) aims at decreasing early postoperative morbidity and mortality. Whereas extended transtho ; to S. M. L.). Supported by the Dutch Health Care Insurance Funds Council ( ; to J. B. F. H.). racic esophagectomy () with en bloc lymphadenectomy 0,0 Reprints: Jikke M. T. Omloo, Department of Surgery, Academic Medical is intended to improve long-term survival by performing a Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, combined (cervico) thoracoabdominal resection, with wide The Netherlands. j.m.omloo@amc.uva.nl. excision of the tumor and peritumoral tissues and extended Copyright 2007 by Lippincott Williams & Wilkins ISSN: /07/ lymph node 6 dissection 7 in the 8posterior 9mediastinum 10 and 11 DOI: /SLA.0b013e31815c4037 upper abdomen. Annals of Surgery Volume 246, Number 6, December 2007 Location There is no significant survival benefit for either approach. However, transthoracic esoph. for type I esophageal adk shows an ongoing trend towards better 5y survival.

6 A No difference is not no results is difficult to accept The New England Journal of Medicine EXTENDED TRANSTHORACIC RESECTION COMPARED WITH LIMITED TRANSHIATAL RESECTION FOR ADENOCARCINOMA OF ESOPHAGUS JAN B.F. HULSCHER, M.D., JOHANNA W. VAN SANDICK, M.D., ANGELA G.E.M. DE BOER, PH.D., BAS P.L. WIJNHOVEN, M.D., JAN G.P. TIJSSEN, PH.D., PAUL FOCKENS, M.D., PEEP F.M. STALMEIER, PH.D., FIEBO J.W. TEN KATE, M.D., HERMAN VAN DEKKEN, M.D., HUUG OBERTOP, M.D., HUGO W. TILANUS, M.D., AND J. JAN B. VAN LANSCHOT, M.D. L ONG-TERM survival after surgery with cu Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus A Five-Year Survival of a Randomized Clinical Trial Jikke M. T. Omloo, MD,* Sjoerd M. Lagarde, MD,* Jan B. F. Hulscher, MD,* Johannes B. Reitsma, MD, PhD, Paul Fockens, MD, PhD, Herman van Dekken, MD, PhD, Fiebo J. W. ten Kate, MD, Huug Obertop, MD, Hugo W. Tilanus, MD, PhD, and J. Jan B. van Lanschot, MD 1,0 0,8 survival 0,6 0,4 0,2 Patients were stratified to a type 1 and type 2, according to the endoscopy report. The gastroenterologists and surgeons were perhaps a bit too prone to call a tumor type I esophageal. For that reason several tumors were called esophageal when they were actually in the gastrocardial region. We thought it was better to look at the actual localization site in the pathology report and that is the reason for the difference in numbers. 0, B umbers follow-up (years) 1,0 at risk ,8 survival 0,6 0,4 0,2 0, Numbers at risk follow-up (years)

7 Omloo et al Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus Five-Year Survival of a Randomized Clinical Trial Annals of Surgery Volume 246, Number 6, December 2007 A locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0, follow-up (years) Numbers at risk C locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0,0 Numbers at risk B locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0, follow-up (years) Numbers at risk follow-up (years) FIGURE 5. A, Locoregional disease-free survival of all patients without positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.64). B, Locoregional disease-free survival of all patients with 1 to 8 positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.02). C, Locoregional disease-free survival of all patients with more than 8 positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.24). Based on this best available evidence, we favor an extended transthoracic procedure for type I esophageal carcinoma, especially if there is a limited number of suspicious nodes, and a (limited) transhiatal procedure for type II carcinoma of the gastric cardia.

8 Omloo et al Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus Five-Year Survival of a Randomized Clinical Trial Annals of Surgery Volume 246, Number 6, December 2007 A locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0,0 Look: this is locoregional disease free survival (!!!) follow-up (years) Numbers at risk C locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0,0 Numbers at risk B locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0, follow-up (years) Numbers at risk follow-up (years) FIGURE 5. A, Locoregional disease-free survival of all patients without positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.64). B, Locoregional disease-free survival of all patients with 1 to 8 positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.02). C, Locoregional disease-free survival of all patients with more than 8 positive lymph nodes in the resection specimen after transhiatal (drawn line) or transthoracic (dotted line) esophagectomy (P 0.24). 5yr OS: 39% 19% Meaning: is useful to 9% of pts who undergo Based on this best available evidence, we favor an extended transthoracic procedure for type I esophageal carcinoma, especially if there is a limited number of suspicious nodes, and a (limited) transhiatal procedure for type II carcinoma of the gastric cardia.

9 Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus Five-Year Survival of a Randomized Clinical Trial Jikke M. T. Omloo, MD,* Sjoerd M. Lagarde, MD,* Jan B. F. Hulscher, MD,* Johannes B. Reitsma, MD, PhD, Paul Fockens, MD, PhD, Herman van Dekken, MD, PhD, Fiebo J. W. ten Kate, MD, Huug Obertop, MD, Hugo W. Tilanus, MD, PhD, and J. Jan B. van Lanschot, MD Annals of Surgery Volume 246, Number 6, December 2007 B locoregional disease free survival 1,0 0,8 0,6 0,4 0,2 0, follow-up (years) Numbers at risk Based on this best available evidence, we favor an extended transthoracic procedure for type I esophageal carcinoma, especially if there is a limited number of suspicious nodes, and a (limited) transhiatal procedure for type II carcinoma of the gastric cardia.

10 TRANSHIATAL APPROACH: total gastrectomy with D2 lymphadenectomy (including splenectomy). Additional dissection of the lymph nodes along the left inferior phrenic vessels and the para-aortic nodes lateral to the aorta and above the left renal vein was done in curable patients. Mediastinal resection included the lower oesophagus and only the perioesophageal lymph nodes. Left thoracoabdominal approach versus abdominaltranshiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial Mitsuru Sasako, Takeshi Sano, Seiichiro Yamamoto, Motonori Sairenji, Kuniyoshi Arai, Taira Kinoshita, Atsushi Nashimoto, Masahiro Hiratsuka, for the Japan Clinical Oncology Group (JCOG9502) Summary III TRANSTHORACIC APPROACH: the same procedure as that for TH was done in the abdominal cavity, including lymphadenectomy. Through an oblique incision over the left thorax a thorough mediastinal nodal dissection below the left inferior pulmonary vein was undertaken with oesophagectomy of sufficient length. A median of 68 nodes were identified in the resection specimen after transhiatal resection, and 60 after transthoracic resection. Different lymphadenectomy in the lower mediastinum

11 TH (n=82) LTA (n=85)* Type of gastrectomy Total Proximal 3 3 Not resected 0 2 Reconstruction method Roux-en-Y Interposition 5 3 Other 2 4 Length of resected oesophagus (cm) Median (range) 4 2 ( ) 4 5 ( ) Splenectomy Yes No 4 4 Pancreatic-tail resection Yes No Thoracotomy Intercostal 3 79 Transabdominal 10 3 None 69 3 Dissected lymph nodes (median [range]) Total 68 (14 147) 60 (16 160) Mediastinal 2 (0 13) 8 (0 24) Para-aortic 7 (0 63) 6 (0 60) Operation time (min) Median (range) 305 ( ) 338 (73 635) Blood loss (ml) Median (range) 673 ( ) 655 ( ) Allogeneic blood transfusion Yes No Data are number of patients unless stated otherwise. *Two patients undergoing Left thoracoabdominal approach versus abdominaltranshiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial Mitsuru Sasako, Takeshi Sano, Seiichiro Yamamoto, Motonori Sairenji, Kuniyoshi Arai, Taira Kinoshita, Atsushi Nashimoto, Masahiro Hiratsuka, for the Japan Clinical Oncology Group (JCOG9502) (Continued from previous page) Oesophageal invasion (cm) TH Summary Median (range) 1 6 (0 4 5) 1 2 (0 7 0) Washing cytology Negative Positive 11 9 Not done 2 3 Residual tumour R R1/ Para-aortic nodal metastasis Positive 13 9 Negative Not dissected Mediastinal nodal metastasis LTA Positive 3 9 Negative Not dissected 0 2 Data are number of patients unless stated otherwise. *Data not available for two patients in LTA group who did not undergo resection because of peritoneal seeding. Includes five patients with Siewert type 2 tumours and four with other types.

12 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 Y. Kurokawa 1,M.Sasako 2,T.Sano 3,T.Yoshikawa 6,Y.Iwasaki 4,A.Nashimoto 7, S. Ito 8, A. Kurita 9, J. Mizusawa 5 and K. Nakamura 5 for the Japan Clinical Oncology Group (JCOG9502) TH group LTA group 167 pt4patients 7 4 (n = 82) (n = 85) Pathological node category Age Siewert pn0 (years)* classification 60 (36 75) (38 75) 15 Sex pn1 Type ratio II (M : F) : : 22 Borrmann pn2 Type pt4 III type Pathological pn3/4 Non-OGJ tumour node category Pathological pn0 node category pn1 pn pn2 pn pn3/4 pn Pathological pn3 node category No. of positive nodes* 5(0 53) 5(0 52) Histological oesophageal invasion (cm)* 1 6 (0 4 5) 1 2 (0 7 0) Residual tumour Table 2 Sites of first recurrence TH group (n = 82) LTA group (n = 85) P* Lymph nodes 12 (15) 19 (22) Peritoneum 9 (11) 10 (12) Liver 8 (10) 9 (11) Lung 5 (6) 5 (6) Pleura 3 (4) 1 (1) Other 5 (6) 2 (2) Values in parentheses are percentages. TH, transhiatal; LTA, left Overall survival No. at risk TH LTA a Siewert type II Overall survival No. at risk TH LTA b Siewert type III TH LTA 35% vs 29% p= % vs 22% p= Left thoraco-abdominal resections should be avoided in the treatment of adenocarcinoma of the esophago-gastric junction or gastric cardia a t P I 4 a a t t t ( 1 5 p c T c p D T c o t T r b n a c p

13 The Meta-Analyses

14 There were no significant differences of survival rate and postoperative morbidity and mortality between transthoracic resection group and nontransthoracic resection group. Transthoracic Resection versus Non-Transthoracic Resection for Gastroesophageal Junction Cancer: A Meta-Analysis Transthoracic Resection for GEJ Cancers Kun Yang 1., Hai-Ning Chen 2., Xin-Zu Chen 1, Qing-Chun Lu 2, Lin Pan 2, Jie Liu 1, Bin Dai 1, Bo Zhang 1 *, Zhi- Xin Chen 1, Jia-Ping Chen 1, Jian-Kun Hu 1 Both surgical approaches are acceptable, and no one offers clear advantage over the other. However, the results should be interpreted cautiously since the qualities of included studies were suboptimal. Figure 2. Forest plot of 5-year overall survival rates for RCTs and non-rcts. a: RCTs; b: non-rcts. The 95% confidence interval (CI) for the hazard ratio for each study is represented by a horizontal line and the point estimate is represented by a square. The size of the square corresponds to the weight of the study in the meta-analysis. The 95% CI for pooled estimates is represented by a diamond. Data for a fixed-effects model are shown as there was no statistical heterogeneity. df = degrees of freedom; I 2 = percentage of the total variation across studies due to heterogeneity; IV = Inverse Variance; SE = standard error; Z = test of overall treatment effect. doi: /journal.pone g002

15 For overall survival, no significance was found in either all Siewert s types or single Siewert s type. A potential survival benefit was achieved for type III tumors using the transhiatal approach compared with the transthoracic approach. We conclude that, for cancers of the esophagogastric junction (especially for Siewert s type III tumors) the transhiatal approach should be recommended as the optimal choice. A B C D Transthoracic vs transhiatal surgery for cancer of the esophagogastric junction: A meta-analysis Ming-Tian Wei, Yuan-Chuan Zhang, Xiang-Bing Deng, Ting-Han Wei Yang, MT et Ya-Zhou al. TT vs He, TH Zi-Qiang for esophagogastric Wang cancer Study or subgroup log(hazard ratio) SE Weight Hazard ratio Hazard ratio IV, random, 95%CI Nakamura % 1.63 (1.02, 2.61) Omloo % 0.97 (0.67, 1.41) Sasako % 1.35 (0.84, 2.16) Zheng % 0.76 (0.48, 1.19) Total (95%CI) 100.0% 1.11 (0.81, 1.54) Heterogeneity: Tau 2 = 0.06; χ 2 = 6.53, df = 3 (P = 0.09); I 2 = 54% Test for overall effect: Z = 0.65 (P = 0.51) IV, random, 95%CI Favours transthoracic Favours transhiatal Study or subgroup log(hazard ratio) SE Weight Hazard ratio Hazard ratio IV, fixed, 95%CI Omloo % 0.95 (0.51, 1.78) Total (95%CI) 100.0% 0.95 (0.51, 1.78) Heterogeneity: Not applicable Test for overall effect: Z = 0.16 (P = 0.88) IV, fixed, 95%CI Favours transthoracic Favours transhiatal Study or subgroup log(hazard ratio) SE Weight Hazard ratio Hazard ratio IV, fixed, 95%CI Nakamura % 1.86 (0.78, 4.40) Omloo % 0.94 (0.59, 1.51) Sasako % 1.19 (0.63, 2.22) Total (95%CI) 100.0% 1.13 (0.80, 1.59) Heterogeneity: χ 2 = 1.88, df = 2 (P = 0.39); I 2 = 0% Test for overall effect: Z = 0.67 (P = 0.50) IV, fixed, 95%CI Favours transthoracic Favours transhiatal Study or subgroup log(hazard ratio) SE Weight Hazard ratio Hazard ratio IV, fixed, 95%CI Nakamura % 1.72 (0.54, 5.45) Sasako % 1.65 (0.80, 3.40) Total (95%CI) 100.0% 1.67 (0.90, 3.08) Heterogeneity: χ 2 = 0.00, df = 1 (P = 0.95); I 2 = 0% Test for overall effect: Z = 1.63 (P = 0.10) Submit a Manuscript: World J Gastroenterol 2014 August 7; 20(29): IV, fixed, 95%CI Favours transthoracic Favours transhiatal Figure 5 Forest plot of overall survival in the transthoracic group vs transhiatal group of cancers of the esophagogastric junction. A: All Siewert types; B: Siewert ; C: Siewert ; D: Siewert. IV: Inverse variance.

16 Lymphatic pathways

17 scopically (volume, 1.0 ml) into the submucosa of the gastric Before surgery, paraesophageal lymph node drainage was predicted scintigraphically by consensus reading (nuclear medicine cardia. After the first 5 patients, nanocolloid was exchanged for C. Okholm et al. / Surgical Oncology 23 (2014) 140e146 sulfur colloid to investigate whether the use of a smaller particle physician and surgeon). The specific lymph node stations were size would show more intense adjacent lymph nodes and more retrospectively evaluated using the visualization on the various distant lymph nodes on the lymphoscintigraphy. The endoscopic scintigraphic acquisitions in combination with the knowledge of procedures were performed with a standard upper gastrointestinal the peri- and postoperative probe measurements (reference standard; vide infra). endoscope (GIF-100 or GIF-140; Olympus Optical Co.). During this preoperative procedure, the endoscope was introduced with the patient in the left lateral position and was advanced into the esophagus. The injection site was chosen at the posterior wall of the lesser curvature, about 3 cm distal from the tubular esophagus. The radioactive tracer was injected into the submucosa using a standard 21-gauge needle (Boston Scientific Microvasive). This needle had a dead volume of 1.0 ml, for which the total volume and activity to be injected was corrected. After injection, the injection site was marked with an endoscopically placed hemoclip (Olympus Optical Co.) for future reference. Lymphoscintigraphy Lymphoscintigraphy of the lower chest and upper abdomen was performed early (15 30 min) and late (4 and 20 h) after injection of the radioactive tracers with a dual-head -camera (Millennium; GE Medical Systems). Planar anterior and posterior acquisitions (600 s; matrix) were obtained at all time points. SPECT ( matrix) was performed at 4 and 20 h after injection. In the last 5 patients, tracer accumulation was localized by CT (Hawkeye; GE Medical Systems) (Fig. 1). Patent Blue Administration, Surgical Resection, and Probe Measurement Surgery was started shortly after the last scintigraphic acquisition. Immediately after induction of anesthesia, a second endoscopic procedure was performed. The endoscopically placed hemoclip was identified in the cardia, and at the same site, patent blue (sterile patent V 2.5% in aquadest and mannitol 5%; raw material from Brunschwig Chemie) was injected into the submucosa using a similar standard 21-gauge needle (Fig. 2). Subsequently, all patients underwent subtotal esophagectomy plus gastric cardia resection with limited lymph node dissection under direct vision by a transhiatal approach via a widened hiatus. After completion of the resection, nondissected regional lymph node stations were systematically measured in vivo for radioactivity using a -probe (Europrobe; PI Medical). Background measurements were performed on the jejunum and liver. Thereafter, the resection specimen itself was measured ex vivo for radioactivity, by -probe, in the Nuclear Medicine Department. For verification, a scintigram of the resection specimen was obtained (Fig. 3). Status and prognosis of lymph node metastasis in patients with cardia cancer: a systematic review of English publications dealing with adenocarcinoma of the cardia was conducted to elucidate patterns of nodal spreadandprognostic implications. C. Okholm et al. / Figure 2. Lymph node metastasis according to JGCA stations in % with median and range. Figure 3. 5-Y-S according to JGCA lymph node stations in % with median and range. TABLE 1 Number of Active Lymph Node Stations Identified In Vivo During Surgery and in Resection Specimen After Surgery, in Relation to Preoperative Lymphoscintigraphy FIGURE 1. Radioactivity in paraesophageal lymph nodes (PE) as identified preoperatively by lymphoscintigraphy in combination with CT. Shown are CT scan (left), scintigram (middle), and a combination of CT scan and scintigram (right). This sagittal projection also shows the injection site (IS) at the gastric cardia and celiac trunk nodes (CTN). See also patient 9 in Table 1. Lymph node station Patient 1 Patient 2 Nanocolloid Sulfur colloid Total Patient 3 Patient 4 Patient 5 Total Total RA B Patient Patient Patient Patient Patient RA B RA B 248 JOURNAL OF NUCLEAR MEDICINE Vol. 45 No. 2 February 2004 Intraoperative probe measurement Greater curvature, left and right Supra- and infrapyloric Celiac trunk Splenic hilum Splenic artery Hepatoduodenal ligament Mesenteric root Paraaortal Probe measurement of specimen Paracardial, right * Paracardial, left * Lesser curvature * * * 4 3 * * Paraesophageal 0 0 * Total

18 INDEX OF BENEFIT OF LYMPH NODE DISSECTION of each station multiplication of the frequency of metastasis at the station and the 5-year survival rate of patients with metastasis at that station Yamashita et al Annals of Surgery Volume 254, Number 2, August 2011 TABLE 3. Incidence, 5-year Survival Rate, and Calculated Index of Estimated Benefit from Lymph Node Dissection single-center large cohort of 225 patients with Siewert type II tumors Nodal station Number of patients with metastatic nodes Number of patients in whom the station was dissected Incidence of lymph node metastasis (%) 5-year overall survival rate of patients with metastatic nodes (%) No No No No. 4sa No. 4sb No. 4d NA NA No No No No. 8a No No No. 11p No. 11d No. 12a NA NA No No No No. 16a No. 16b Lymph node stations are defined as: 1 = right cardial; 2 = left cardial; 3 = lesser curvature; 4sa = along the short gastric artery; 4sb = along the left gastroepiploic Optimal artery; Extent 4d = along the ofright Lymph gastroepiploicnode artery; 5 = Dissection suprapyloric; 6 = infrapyloric; for Siewert 7 = along the left Type gastric artery; II 8a = along the common hepatic artery (anterosuperior side); 9 = along the celiac artery; 10 = splenic hilum; 11p = along the proximal splenic artery; 11d = along the distal splenic artery; Esophagogastric 12a = along the proper hepatic artery; Junction 110 = paraesophageal Carcinoma the lower thorax; 111 = supradiaphragmatic; 112 = posterior mediastinal; 16a2 = around the abdominal aorta (from the upper margin of the celiac trunk to the lower margin of the left renal vein); Hiroharu 16b1 = around Yamashita, the abdominal MD, aorta Hitoshi (fromkatai, the lower MD, margin Shinji of Morita, the left renal MD, vein Makoto the upper Saka, margin MD, ofhirokazu the inferior Taniguchi, mesentericmd, artery) NA indicates not analyzed. and Takeo Fukagawa, MD Index Dissection of perigastric nodes 4sb, 4d, 5, and 6, offered only marginal therapeutic benefit. Involvement of the lymph nodes in these stations appeared to represent distant rather than locoregional metastasis. The index of estimated benefit from mediastinal lymph node dissection was marginal, except for the periesophageal nodes (110). This result might explain why the oncologic outcomes between extended esophagectomy and total gastrectomy are comparable.

19 Gastric Cancer (2015) 18: DOI /s ORIGINAL ARTICLE The optimal extent of lymph node dissection for adenocarcinoma of the esophagogastric junction differs between Siewert type II and Siewert type III patients Hironobu Goto Masanori Tokunaga Yuichiro Miki Rie Makuuchi Norihiko Sugisawa Yutaka Tanizawa Etsuro Bando Taiichi Kawamura Masahiro Niihara Yasuhiro Tsubosa Masanori Terashima single-center large cohort of 132 patients with Siewert type II tumors According to the results of the present study, total gastrectomy should be selected as a standard treatment for Siewert type III AEG. In contrast, preservation of the distal part of the stomach may be an acceptable procedure in patients with Siewert type II AEG, because the present study did not show survival benefit for lower perigastric lymph node dissection. The IEBLD of the splenic hilar lymph nodes was zero in patients with Siewert type II and III AEG. t t Lymph node station Number of patients with metastatic nodes Number of patients in whom the station was dissected Incidence of lymph node metastasis (%) 5-year survival rate of patients with metastatic nodes (%) sa sb d a p d a Lymph node station Number of patients with metastatic nodes Number of patients in whom the station was dissected Incidence of lymph node metastasis (%) 5-year survival rate of patients with metastatic nodes (%) sa sb d a p d a IEBLD IEBLD

20 Lymphadenectomy around the left renal vein in Siewert type II adenocarcinoma of the oesophagogastric junction S. Mine, T. Sano, N. Hiki, K. Yamada, S. Nunobe and T. Yamaguchi Department of Gastroenterological Surgery, Cancer Institute Hospital, , Ariake, Koto-ku, Tokyo, , Japan Correspondence to: Dr S. Mine ( Lymph node station Incidence of involvement* 5-year survival rate of patients with positive nodes (%) First tier Lesser curvature (no. 3) 69 of 150 (46 0) 45 Right cardia (no. 1) 67 of 150 (44 7) 42 Left cardia (no. 2) 52 of 150 (34 7) 44 Left gastric artery (no. 7) 42 of 150 (28 0) 53 Second tier Lower mediastinum 18 of 99 (18) 35 Left renal vein area (no. 16A2lat) 16 of 94 (17) 19 Splenic artery (no. 11) 23 of 139 (16 5) 23 Coeliac axis (no. 9) 19 of 150 (12 7) 11 Third tier Proper hepatic artery (no. 12) 3 of 39 (8) 0 Splenic hilum (no. 10) 5 of 107 (4 7) 40 Upper or middle mediastinum 2 of 46 (4) 50 Greater curvature (no. 4) 5 of 146 (3 4) 0 Common hepatic artery (no. 8) 3 of 130 (2 3) 0 Suprapyloric (no. 5) 1 of 102 (1 0) 0 Infrapyloric (no. 6) 0 of 102 (0) Node stations were divided into three tiers: first tier, more than 20 per cent involvement; second tier, per cent involvement; third tier, less than 10 per cent involvement.

21 Should we look better at the hole we are about to go through?

22 The mammalian diaphragm is primarily a respiratory muscle. However, it should be considered as two separate muscles consisting of the crural and the costal diaphragms. During human development myoblasts originating in the body wall and derived from the cervical segments invade two pleuroperitoneal membranes and form the costal diaphragm. On the other hand, the two crura develop in the mesentery of the esophagus.

23 The crural diaphragm has two functions: respiratory and gastrointestinal The upper part is fully muscular and measures 2.5 cm in length. The lower part forms a gutter that is open anteriorly. The central fibers have a relatively circular arrangement. The peripheral fibers are oriented in a craniocaudal direction. The unique arrangement of its muscle fibers results in two different types of actions on the esophagus when it contracts: a vertical or craniocaudal motion, and a circumferential squeeze.

24 All of the maneuvers that increase gastroesophageal pressure gradients are accompanied by contraction of diaphragmatic sphincter. Thus the rapid changes in pressure gradients between esophagus and stomach, caused by skeletal muscle contraction of the chest and abdomen, are antagonized by rapidly contracting skeletal sphincter muscles of the diaphragmatic sphincter.

25 What does the hiatus do when it doesn t know it is observed

26 Lymphatic flow from the esophagus

27 Lymphatic flow within the esophagus

28 Adenocarcinoma of the Gastroesophageal Junction Influence of Esophageal Resection Margin and Operative Approach on Outcome Andrew P. Barbour, MD, PhD,* Nabil P. Rizk, MD,* Mithat Gonen, PhD, Laura Tang, MD, PhD, Manjit S. Bains, MD,* Valerie W. Rusch, MD,* Daniel G. Coit, MD,* and Murray F. Brennan, MD* Annals of Surgery Volume 246, Number 1, July 2007 URE 2015 Marco 1. Esophageal Lotti transection greater than 3.8 cm With formalin fixation the fresh esophagus has been shown to contract by up to 27%. Hence, the true in situ margin length treated by surgery alone would be at least 5 cm TABLE 3. Clinicopathologic Variables for Patients Treated by Gastrectomy Compared With Those Treated by Esophagectomy Clinicopathologic Factor Gastrectomy Esophagectomy P Male 119 (78) 292 (83) Female 34 (22) 60 (17) Age (yr) (median) Postop. death 7 (4.6) 16 (4.5) Siewert type I 12 (8) 100 (28) Siewert type II 77 (50) 199 (57) Siewert type III 64 (42) 53 (15) pt stage 1 23 (15) 87 (24) pt stage 2 29 (19) 80 (23) pt stage 3 96 (63) 183 (52) pt stage 4 5 (3) 2 (1) pn stage 0 49 (32) 147 (42) pn stage 1 58 (38) 144 (41) pn stage 2 34 (22) 49 (14) pn stage 3 12 (8) 12 (3) AJCC stage I 33 (22) 123 (35) AJCC stage II 43 (21) 66 (19) AJCC stage III 70 (46) 150 (43) AJCC stage IV 17 (11) 13 (4) R1 14 (9) 35 (10) Positive proximal margin 7 (5) 7 (2)* Positive distal margin 1 (1) 4 (1)* Positive deep margin 6 (4) 26 (7) Proximal margin 3.8 cm 15 (10) 201 (57) nodes removed 96 (63) 240 (68) Total

29 Conclusion

30 The EGJ is a borderline region, located between the thorax and the abdomen, in which physical forces are continuously in action to regulate flow by varying pressure and resistance. It is a physiologic concept more than an anatomic structure: in fact, it is an apparatus. You can t figure the EGJ without a thorough assessment of the hiatus => it s work for YOU, not for the pathologist. The hiatus is one (if not the most important) engine of the lymphatic flow at the EGJ: the direction of the flow follows the action of the hiatus.

31 The therapeutic value of extended mediastinal lymphadenectomy seems marginal for Siewert II and III EGJC. Mediastinal nodes positivity means advanced disease. The great deal of lymphadenectomy is in the abdomen, and the most important phase is in the area under the action of the hiatus. The need to go into the thorax will be for the adequate margin, not for lymphadenectomy. If it is below the hiatus you can safely go through it so far. If it looks through the hiatus watch out and mind the need for an adequate margin and the option for a gastric tube reconstruction. If the hiatus is embraced, it is esophagus: you won t get the adequate margin transhiatally.

32 Thank You