Two field vs Three field Lymphadenectomy in Esophageal Cancer

Understanding controversies and current literature on management esophageal cancer lymph node metastasis

1. Presenter: Vinayaka S B Extent of Lymphadenectomy for Esophageal Cancer THORACIC DMG, TMH MUMBAI

2. Presentation Includes Anatomical Background: Lymphatic Drainage of Esophagus Pathological Background: Patterns of Spread, Adenocarcinoma vs SCC Lymph Node Dissection: Abdominal , Thoracic, Cervical 2F vs 3F Lymphadenectomy: Morbidity of Lymphadenectomy Conclusions

3. Lymphatic Drainage of Esophagus 1. Anatomical Background Esophagus has two embryological origin: Tracheal bifurcation Esophagus traverses three body compartments So “ LOCATION of TUMOR ” is key in deciding which Lymph nodes involved

4. Lymphatic Drainage of Esophagus 1. Anatomical Background Esophagus has extensive submucosal lymphatic network Longitudinal communication most patients —> has T3 + disease at time of presentation and with an up to 85% chance of lymph node involvement. Primary pathways blockage — involvement of eccentric lymph node So “ STAGE of TUMOR ” is key in deciding which Lymph nodes involved

5. SCC vs Adenocarcinoma 2. Pathological Background In early stage cancer—LN involvement: SCC >> adenocarcinoma If tumor has invaded into the muscularis mucosae (T1a-M3), —-> SCC = 12%, adenocarcinoma = only 1.3% Implication in Endoscopic Resection In lower esophageal cancers —involvement of upper abdominal nodes: adenocarcinoma >> SCC Intramural spread distally —-> adenocarcinoma (54%) compared with SCCs (10%), So Adenocarcinoma needs wider cover in surgery

6. SCC vs Adenocarcinoma 2. Pathological Background Pattern of Lymphatic Spread in SCC and Adenocarcinoma

7. So for what are options we have? Lymph Node Dissection Definition : International Society for Diseases of the Esophagus (ISDE) (i) standard 2 F: lymphadenectomy up to the subcarinal lymph nodes; (ii) extended 2 F : also includes paratracheal lymphadenectomy on the right side; (iii) total mediastinal 2 F: including both paratracheal and both recurrent nerves lymph nodes; and (iv) three‐field lymphadenectomy : Standard 2F + AP window + Left & right RLN nodes + B/L Neck 101, 104

8. ISDE definition

9. AJCC 8 th edition : LN stations

10. JEC 11th edition : LN stations

11. Abdominal LN Dissection Lymph Node Dissection Field includes the superior gastric group + celiac trunk nodes + common hepatic nodes Superior gastric lymph nodes Paracardial nodes Lesser curve nodes Left gastric artery nodes Celiac trunk nodes Common hepatic nodes

12. Then which is Optimal LN Dissection? Lymph Node Dissection Is it high yield of nodes of surgery? Or/And Is it covering concerned locations of lymphatic drainage?

13. What is Optimal LN Dissection? Lymph Node Dissection location of nodal involvement is an independent predictor of survival Anderegg et al. Ann Surg. 2016;264(5):847-853. In adenocarcinoma of the distal esophagus and esophagogastric junction 479 patients who underwent transthoracic esophagectomy and two-field lymphadenectomy, 253 patients had nodal metastases. Survival in those who had only locoregional lymph node involvement was 35 months compared with 16 months for those with nodes at the celiac trunk and 15 months for those with involvement in the proximal field Implication: wider cover is better, THE -poor outcomes

14. What is Optimal LN Dissection? Lymph Node Dissection High lymph node yields do not necessarily equate to an extensive lymphadenectomy, and it is the location from which the nodes come that is of higher importance Chen J-W, Xie J-D, Ling Y-H, et al. The prognostic effect of perineural invasion in esophageal squamous cell carcinoma. BMC Cancer. 2014;14:313. 24. Bhamidipati CM, Stukenborg GJ, Thomas CJ, Lau CL, Kozower BD, Jones DR. Pathologic lymph node ratio is a predictor of survival in esophageal cancer. Ann Thorac Surg. 2012;94(5):1643-1651. 25. Phillips AW, Lagarde SM, Navidi M, Disep B, Griffin SM. Impact of extent of lymphadenectomy on survival, post neoadjuvant chemotherapy and transthoracic esophagectomy. Ann Surg. 2017;265(4):750-756.

15. What is Optimal LN Dissection? Lymph Node Dissection Rizk et al. determined that the optimum lymph node yield was dependent on the “T” category of disease, recommending 31 to 42 nodes in those with T3 disease or worse. Patients who are considered for neoadjuvant treatment are likely to have more locally advanced disease, and this would suggest they will benefit from a more extensive lymphadenectomy. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg. 2010;251(1):46-50.

16. What is Optimal LN Dissection? Lymph Node Dissection Peyre et al. looked at whether systemic disease could be predicted by the number of lymph nodes involved. Their review of 1053 patients with both adenocarcinoma and SCC, without neoadjuvant treatment, indicated that the probability of systemic disease exceeds 50% when more than three nodes are involved approaches 100% when greater than eight nodes are involved Peyre CG, Hagen JA, DeMeester SR, et al. Predicting systemic disease in patients with esophageal cancer after esophagectomy. Ann Surg. 2008;248(6):979-985.

17. What is Optimal LN Dissection? Lymph Node Dissection JH Lee et al. EJSO Feb 2017 43(2): 432-39 LN status impacts survival

18. So can we tailor according to tumor stage/location? Lymph Node Dissection Sentinel node techniques have been attempted, but the occurrence of skip metastases and unpredictability of nodal involvement makes this currently unreliable van der Schaaf M, Johar A, Wijnhoven B, Lagergren P, Lagergren J. Extent of lymph node removal during esophageal cancer surgery and survival. JNCI J Natl Cancer Inst. 2015;107(5):djv043.

19. What is Optimal LN Dissection? Lymph Node Dissection Omloo et al. found that an extended resection is beneficial in patients with fewer than eight lymph node metastases. Thus, given the difficulty in identifying such patients, a complete two-field lymphadenectomy should be carried out in all patients where nodal involvement is a concern Omloo JMT, Lagarde SM, Hulscher JBF, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus. Ann Surg. 2007;246(6):992-1001.

20. Then, Do we need more than 2F? Lymph Node Dissection 3 FIELD LYMPHADENECTOMY in SCC: Japanese studies Chiba University, Japan: 1980’s : > 20% unforeseen cervical node involvement . ( almost a third of patient in some studies) Means 1st echelon for thoracic SCC

21. Then, Do we need more than 2F? Lymph Node Dissection 3 FIELD LYMPHADENECTOMY in SCC: Japanese studies Chiba University, Japan: 1980’s : > 20% unforeseen cervical node involvement . ( almost a third of patient in some studies) Means 1st echelon for thoracic SCC Akiyama et all 1994: 5 y OS 55% in 3F vs 38% in 2F

22. Chen et al. reviewed 1715 patients with SCC and cervical node involvement 44% of proximal-third tumors having cervical node involvement, 23% of lower-third tumors also had cervical node involvement. These had 5yOS 25-30%!

23. Then, Do we need more than 2F? Lymph Node Dissection 3 FIELD LYMPHADENECTOMY FOR Adenocarcinoma : Lerut et al. 2004 if cervical nodes involved then 0% 5 yr OS For GEJ 12% 5 yr OS For distal-third adenocarcinomas So doesn’t merit in era of Neoadjuvant What study suggested — if extensive mediastinal nodal disease should be considered for a three-field dissection. The decision will be dictated by extent of disease, likelihood of recurrence, and overall fitness.

24. Recent data Lymph Node Dissection Short term outcomes Significant: Longer operative time Longer hospital stay Greater blood loss High risk of hoarseness No difference: Post op mortality No significant difference in pneumonia and leak Long Term Outcomes Survival advantage conflictating

25. Recent data Lymph Node Dissection Short term outcomes 2017 Significant: More accurate staging / 3.5 % cervical nodes involvement Comparable: Post op mortality/morbidity Long Term Outcomes 2021 No Survival advantage N = 400, M/L 3rd SCC

26. In era of neoadjuvant treatment — extent of clearance? Lymph Node Dissection 3,859 patients with adenocarcinoma Survival is maximized when an optimum range of nodes are resected. Means nonlinear fashion relation NCCN -15 nodes This study —25-30 nodes

27. In era of neoadjuvant treatment — extent of clearance? Lymph Node Dissection 112 patients with SCC February 2021 5 y OS better

28. What is of price to pay ? Morbidity of Lymphadenectomy Lymph Node Dissection Respiratory problems are the main cause of major problems after esophagectomy, due to pneumonia and acute respiratory distress syndrome (ARDS) recurrent laryngeal nerve Injury chyle leak

29. TMH DATA 2005 to 2019 700 patients 3 FLND in comparison to 2FLND Significant difference : Prolonged ventilation, Pulmonary complications, Anastomotic leak No difference in cardiac complications, chyle leak, major morbidity and mortality.

30. ‘Elective’ 3F TMH Data N = 115 ( 2007 - 2016): excluded from 2F/3F trial 95% received neo-adjuvant therapy 89% SCC, 66% middle third, 31% MIS resections Major morbidity 30% Pulmonary complications 49.56% RLN palsy 48.69% Tracheostomy 21.73% Mortality 6% 5 year OS: 39% Median survival: 33 months

31. What can a surgeon do? No superior mediastinal or neck nodes on imaging Suspicious superior mediastinal or neck nodes on imaging: Attempt sampling Standard 2 F lymphadenectomy Total mediastinal or 3F lymphadenectomy The extent of lymphadenectomy is decided on the index scan

32. Where to draw the line? Siewerts 3 with neck node Bulky T-O groove nodes causing RLN palsy Bulky nodes in all compartments

33. Thank you