Does it matter that lymphadenectomy through right or left side thoracotomy during esophagectomy?

Lymph node metastasis is one of the critical determinants in the prognosis of esophageal cancer. Many lymph node-associated parameters, such as regional or nonregional location (1,2), number of positive nodes (3-6), number of total harvested nodes (7), ratio of positive to total nodes (5,6,8), and even number of negative nodes (9), have been reported to have prognostic relevance. There are also abundant studies assessing the diagnostic and therapeutic value of lymphadenectomy (10,11). The diagnostic purpose of lymphadenectomy is to identify the presence of lymphatic spread, which can be a surrogate of systemic disease. Although lymph node dissection itself may not have a survival benefit, the adjuvant treatments for lymph node metastasis are expected to. However, if viable malignant cells initially nest in lymph nodes and gradually spread to systemic metastases, lymphadenectomy would be an opportunity to cure patients, especially those with early phase of lymphatic dissemination.

Even though lymph node metastasis is such a crucial factor, the procedure of lymphadenectomy is not standardized. Various types of lymphadenectomy have been proposed. The Consensus Conference of the International Society for Diseases of the Esophagus (ISDE), held in Munich in 1994, has defined four types of lymphadenectomies: standard lymphadenectomy, extended lymphadenectomy, total lymphadenectomy, and 3-field lymphadenectomy (12). Whereas standard lymphadenectomy refers to dissection of the infracarinal nodes, extended lymphadenectomy includes the right upper mediastinal nodes in addition to the standard procedure; total lymphadenectomy involves bilateral upper mediastinal nodes in addition to standard procedure; and 3-field lymphadenectomy adds resection of the bilateral cervical nodes to total lymphadenectomy. In 2009, Jamieson classified lymphadenectomy into nonradical lymphadenectomy, which includes only peritumoral nodes; and radical lymphadenectomy, which could be subclassified into 3-field, 2-field, and infracarinal 2-field lymphadenectomy (11). In the Japan Classification of Esophageal Cancer, regional lymph nodes are classified as ‘‘compartment 1 to 3’’ according to tumor location, while distant lymph nodes are categorized as ‘‘compartment 4’’ (13). Based on this lymph node grading classification, the N category is defined as N0–N4 and the extent of lymphadenectomy is defined as D0–D3. Whereas D0 is incomplete dissection of Group 1 lymph nodes, D1, 2 and 3 refer to complete dissection of Group 1, 2, and 3 lymph nodes.

To investigate the impact of types of surgical procedure, Li et al. randomized 300 patients with middle and lower thoracic esophageal carcinoma into esophagectomy through the right (Ivor Lewis, right thoracic plus upper midline incisions) or left (Sweet, left thoracic incision) thoracic approach (14). The 3-year disease-free survival rates were 62% and 52% and the 3-year overall survival rates were 74% and 60%, favoring right side approach. Although Li et al. stated that the differences were owing to the extent, i.e., radical or limited, of lymphadenectomy, rather than simply right or left side incisions, their results should be carefully interpreted especially when many factors were not well controlled. First, the incision itself may affect patient outcome. For example, in the recent open vs. laparoscopically-assisted esophagectomy for cancer: a multicentric phase III prospective randomized controlled trial (the MIRO trial), which compared hybrid minimally invasive esophagectomy (laparoscopic plus thoracotomy) to open esophagectomy (laparotomy plus thoracotomy), not only 69% reduction in major intra- and post-operative morbidity, but improved outcomes in the laparoscopic group were noted (15). Laparoscopic group was also associated with slightly better overall survival and disease-free survival (67% vs. 55%, P=0.05 and 57% vs. 48%, P=0.15). Thus, surgical incisions (right thoracic and upper midline abdominal vs. left thoracic) itself may be with prognostic impact. In addition, the lymph node dissection fields were not well controlled. Whereas Ivor Lewis procedure included upper mediastinal and intraabdominal lymph node dissection, the Sweet procedure was difficult in upper mediastinal, common hepatic and celiac lymphadenectomies. Although higher upper mediastinal recurrence was noted in Sweet procedure, it is difficult to attribute survival difference to lymphadenectomy in this area since there were many unequal factors between two groups. With regard to the significance of upper (right side) mediastinal lymph node dissection, retrospective analysis by Hsu et al. has shown that 30% of right upper mediastinal lymphadenectomy for esophageal squamous cell carcinoma would have positive results (2). However, the survival difference was not significant between patients with or without right upper mediastinal lymphadenectomy, implicating the diagnostic, rather than therapeutic value of right upper mediastinal lymph node dissection. Moreover, despite the fact that this is a prospective randomized trial, the application of postoperative adjuvant treatments is not protocolized. Substantial percentage of patients were with poor prognostic factor, such as pT3/4 (52%), pN(+) (45%), and non-R0 resection (36%); however, less than half received postoperative adjuvant treatments. Postoperative chemoradiation, which has been reported to associate with better outcome by nation wide database studies, was used in only 12% of patients (16,17). Lack of protocolized indications for postoperative adjuvant treatments is one of the major concerns.

Last but not least, their results, which are based on patients after upfront esophagectomy, may not be applicable to those after neoadjuvant treatments. The Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) group has studied the impact of surgical approach on survival in esophageal cancer patients with or without neoadjuvant chemoradiotherapy (18). The transthoracic esophagectomy with extended 2-field lymphadenectomy had differential effects on overall survival in patients who received surgery alone compared with patients who had neoadjuvant chemoradiotherapy and surgery. In patients treated with surgery alone, the transthoracic approach was associated with would have a better prognosis; however, its favorable prognostic effect over transhiatal esophagectomy with limited lymphadenectomy was absent in the neoadjuvant group. They concluded that the downstaging effect of neoadjuvant therapy may reduce the potential positive impact of extended lymphadenectomy on survival. Using the total number of resected lymph nodes as a surrogate for the radicalness of lymphadenectomy, the same group also studied the lymph node dissection during esophagectomy with and without neoadjuvant chemoradiotherapy (19). Similarly, the number of resected nodes had a prognostic effect only in patients who received surgery alone, but not in those after neoadjuvant treatments. Their data question the indication for maximization of lymphadenectomy in patients already have been treated with neoadjuvant treatments. Considering the effect of chemotherapy and radiotherapy, the tumor biology may change after neoadjuvant treatments. Accordingly, the optimal extent of lymphadenectomy and surgical approach may be different in patients with or without neoadjuvant treatments. Thus, the differences between Ivor Lewis and Sweet procedures shown in the study from Li et al. may not present in patients after neoadjuvant treatment followed by surgery, which is the current standard.

In sum, Li et al. tried to highlight the impact of “right side”, “radical” lymphadenectomy; however, the results were biased many hidden factors, which are not balanced and standardized between two groups. However, Li et al. made a conclusion that right side approach is associated with better outcome compared to left side approach. As nearly 70% of esophagectomies in China were done via left side thoracic approaches, the finding of the study from Li et al. will potentially change many China thoracic surgeon’s practice.

Acknowledgements

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Qingyuan Huang, PhD (Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2017.09.13). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tanaka K, Yano M, Motoori M, et al. The significance of abdominal para-aortic lymph node metastasis in patients with lower thoracic esophageal cancer. Dis Esophagus 2012;25:146-52. [Crossref] [PubMed]
2. Hsu PK, Huang CS, Hsieh C, et al. Role of right upper mediastinal lymph node metastasis in patients with esophageal squamous cell carcinoma after tri-incisional esophagectomies. Surgery 2014;156:1269-77. [Crossref] [PubMed]
3. Mariette C, Piessen G, Briez N, et al. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008;247:365-71. [Crossref] [PubMed]
4. Robb WB, Dahan L, Mornex F, et al. Impact of neoadjuvant chemoradiation on lymph node status in esophageal cancer: post hoc analysis of a randomized controlled trial. Ann Surg 2015;261:902-8. [Crossref] [PubMed]
5. Hsu WH, Hsu PK, Hsieh CC, et al. The metastatic lymph node number and ratio are independent prognostic factors in esophageal cancer. J Gastrointest Surg 2009;13:1913-20. [Crossref] [PubMed]
6. Chien HC, Chen HS, Wu SC, et al. The prognostic value of metastatic lymph node number and ratio in oesophageal squamous cell carcinoma patients with or without neoadjuvant chemoradiation. Eur J Cardiothorac Surg 2016;50:337-43. [Crossref] [PubMed]
7. Altorki NK, Zhou XK, Stiles B, et al. Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg 2008;248:221-6. [Crossref] [PubMed]
8. Greenstein AJ, Litle VR, Swanson SJ, et al. Prognostic significance of the number of lymph node metastases in esophageal cancer. J Am Coll Surg 2008;206:239-46. [Crossref] [PubMed]
9. Hsu PK, Huang CS, Wang BY, et al. The prognostic value of the number of negative lymph nodes in esophageal cancer patients after transthoracic resection. Ann Thorac Surg 2013;96:995-1001. [Crossref] [PubMed]
10. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 2010;251:46-50. [Crossref] [PubMed]
11. Jamieson GG, Lamb PJ, Thompson SK. The role of lymphadenectomy in esophageal cancer. Ann Surg 2009;250:206-9. [Crossref] [PubMed]
12. Fujita H, Sueyoshi S, Tanaka T, et al. Optimal lymphadenectomy for squamous cell carcinoma in the thoracic esophagus: comparing the short- and long-term outcome among the four types of lymphadenectomy. World J Surg 2003;27:571-9. [Crossref] [PubMed]
13. Japan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus 2017;14:1-36.
14. Li B, Hu H, Zhang Y, et al. Extended Right Thoracic Approach Compared With Limited Left Thoracic Approach for Patients With Middle and Lower Esophageal Squamous Cell Carcinoma: Three-year Survival of a Prospective, Randomized, Open-label Trial. Ann Surg 2017; [Epub ahead of print]. [Crossref] [PubMed]
15. Mariette C, Markar S, Dabakuyo-Yonli TS, et al. Hybrid Minimally Invasive vs. Open Esophagectomy for patients with Esophageal Cancer: Long-term outcomes of a multicenter, open-label, randomized phase III controlled trial, the MIRO trial. Available online: http://www.esmo.org/Press-Office/Press-Releases/MIRO-Trial-3-year-Outcomes-Favour-Laparoscopic-Surgery-for-Oesophageal-Cancer
16. Hwang JY, Chen HS, Hsu PK, et al. A Propensity-matched Analysis Comparing Survival After Esophagectomy Followed by Adjuvant Chemoradiation to Surgery Alone for Esophageal Squamous Cell Carcinoma. Ann Surg 2016;264:100-6. [Crossref] [PubMed]
17. Hsu PK, Chen HS, Huang CS, et al. Patterns of recurrence after oesophagectomy and postoperative chemoradiotherapy versus surgery alone for oesophageal squamous cell carcinoma. Br J Surg 2017;104:90-7. [Crossref] [PubMed]
18. Noordman BJ, van Klaveren D, van Berge Henegouwen MI, et al. Impact of Surgical Approach on Long-term Survival in Esophageal Adenocarcinoma Patients With or Without Neoadjuvant Chemoradiotherapy. Ann Surg 2017; [Epub ahead of print]. [Crossref] [PubMed]
19. Koen Talsma A, Shapiro J, Looman CW, et al. Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival. Ann Surg 2014;260:786-92; discussion 792-3. [Crossref] [PubMed]