Abstract
Differences in lymph node yield and tumour-involved resection margins comparing neoadjuvant therapy plus surgery with surgery alone for oesophageal cancer are unclear. Patients who underwent oesophageal cancer surgery in Sweden in 1987–2010 were included. Patients treated with neoadjuvant therapy were compared with those who underwent surgery alone. Outcomes were the number of examined lymph nodes (main outcome), number metastatic lymph nodes, and resection margin status. Rate ratios (RRs) and 95% CIs of lymph node yield were calculated by Poisson regression, and odds ratios (ORs) and 95% CIs of resection margin status by multivariable logistic regression, both adjusted for confounders. Among 1818 patients, 587 (32%) had received neoadjuvant therapy and 1231 (68%) had not. Lymph node yield was lower in the neoadjuvant therapy group (median 6 versus 8; adjusted RR 0.75, 0.73–0.78). Fewer metastatic nodes were identified following neoadjuvant therapy (median 0 versus 1; adjusted RR 0.76, 0.69–0.84). Neoadjuvant therapy associated to decreased risk of tumour-involved resection margins when adjusted for confounders except T-stage (OR 0.52, 0.38–0.70), but the association did not remain after adjustment for T-stage (OR 0.91, 0.64–1.29). Neoadjuvant therapy seems to decrease the lymph node yield and decrease the risk of tumour-involved resection margins by shrinking primary tumour.
Similar content being viewed by others
Introduction
The curatively intended treatment of most patients with oesophageal cancer includes oesophageal resection with lympadenectomy1. In the recent decade, the routine addition of neoadjuvant chemotherapy or chemoradiotherapy to surgery and centralization of surgery to fewer centres have improved the 5-year survival in oesophageal cancer1,2. More extensive lymphadenectomy has been associated with better survival in some studies3,4, but the independent prognostic role of more extensive lymphadenectomy has been challenged by recent studies controlling for confounding by surgeon volume5,6. The debate whether the differences in opportunities of lymphadenectomy between the main surgical approaches, i.e. open transthoracic, transhiatal, or minimally invasive oesophagectomy, influence the survival is also ongoing, but no clear survival differences have been shown thus far7,8,9,10. The use of neoadjuvant therapy might complicate the assessment of lymphadenectomy and how it may influence survival. By shrinking lymph nodes, it is possible that neoadjuvant therapy makes the removal or detection of nodes more difficult. The few investigations examining the association between neoadjuvant therapy and the number of resected lymph nodes show contradictory findings, with some studies reporting a reduction in the number of nodes, while other studies do not11,12,13,14,15,16,17. A main aim of neoadjuvant therapy is to shrink the primary tumour. This in turn could facilitate radical (R0) resection, but this question requires more research18.
Taken together, there is a need to better understand how neoadjuvant therapy influences the lymph node yield and resection margins status in oesophageal cancer patients who undergo surgery. The aim of this study was to clarify these questions while taking confounding into account, including the potentially critical factors surgeon volume and tumour stage.
Methods
Study design
In this population-based and nationwide Swedish cohort study from 1987 to 2010, the study exposure was the administration of neoadjuvant therapy (yes or no) before surgery for oesophageal cancer. The primary outcome was the number of removed and examined lymph nodes, while secondary outcomes were the number of removed and examined metastatic lymph nodes and the rate of radical resection without microscopic or macroscopic residual tumour in the resection margin (R0-resection).
Cohort
Earlier versions of this cohort have been used for other clinical studies examining oesophageal cancer surgery6,19,20, and the updated current version has also been described elsewhere21. Briefly, the cohort included 98% of all oesophageal cancer patients who underwent curatively intended treatment in Sweden between 1987 and 2010. The patients were selected by combining data from the Swedish Cancer Registry for identifying all patients with oesophageal cancer, and the Swedish Patient Registry for selecting only patients who had undergone oesophagectomy. The information from these registers was linked for all individual patients using the Swedish personal identity number, a unique 10-digit identifier assigned to each Swedish resident upon birth or immigration, which is a well-validated tool for research purposes22. For collection of more detailed clinical data, including the number of nodes, resection margin status, surgeon volume and tumour stage, surgery charts and pathology records were retrieved from all hospitals conducting oesophageal cancer surgery in Sweden during the study period. The data retrieved from the medical records followed a detailed predefined protocol, an assessment that has been validated for high concordance20. Comorbidity data were retrieved from the Patient Registry and were defined and categorized using the most recently updated and well-validated Charlson Comorbidity Index23. The study was approved by The Regional Ethical Review Board in Stockholm, Sweden. All methods were carried out in accordance with relevant guidelines and regulations. Individual informed consent was not acquired as this is not necessary for this type of study (based on registry data and medical records) according to Swedish law.
Treatment
The treatments, including neoadjuvant treatment, of the individual patients were agreed upon by surgeons and oncologists (typically in multidisciplinary meetings) together with the patients. The most frequently used neoadjuvant therapy was chemoradiotherapy, consisting of cisplatin- and fluorouracil-based chemotherapy supplemented by radiotherapy in 2Gy fractions for a total dose of up to 40Gy, but also radiotherapy and chemotherapy alone were used. Of those 1767 (97%) patients with data on surgical approach available, transthoracic resection with intrathoracic anastomosis was the dominating (96%) surgical procedure and a gastric tube which was pulled up and anastomosed to the proximal oesophagus was the preferred reconstruction. Only 4% of the patients underwent transhiatal oesophagectomy. No consensus on the extent of lymphadenectomy existed during the study period.
Statistical analysis
All statistical analyses were carried out according to an a priori specified study protocol, defining and categorizing all exposures, outcomes and covariates. Because of the logarithmic distribution of the lymph node variables, Poisson regression was used to estimate ratios (RRs) with 95% confidence intervals (CIs) for associations between neoadjuvant therapy and number of removed and examined lymph nodes and metastatic lymph nodes. A stratified analysis was performed for T-stage groups. A subgroup analysis was conducted comparing patients receiving neoadjuvant chemoradiotherapy (excluding unknown neoadjuvant therapy and neoadjuvant chemotherapy or radiotherapy) to patients receiving surgery only. Multivariable logistic regression was used to calculate odds ratios (ORs) with 95% CIs for associations between neoadjuvant therapy and non-radical resection margins (R1/R2). In all models, the following covariates were selected as potential confounders: 1) age (continuous variable, per year), 2) calendar year (continuous variable), 3) tumour histology (adenocarcinoma or squamous cell carcinoma), 4) comorbidity (Charlson Comorbidity score 0, 1, or ≥2), 5) surgeon volume (0–6, 7–16, 17–46, or ≥47 cumulative number of oesophagectomies during the study period), and 6) pathological T-stage (T0-T1, T2, T3, T4, or Tx). Missing data covariate data were few (Table 1) and therefore handled by conducting a complete case analysis. The statistical software IBM SPSS v24.0 (IBM Corp., Armonk, NY) was used for all statistical analyses.
Results
Patient characteristics
Among 1821 patients included in the cohort, 1818 had information on neoadjuvant therapy and were selected for the present study. Of these, 587 (32%) had neoadjuvant therapy prior to surgery and 1231 (68%) had surgery alone. The regimen of neoadjuvant therapy was available for 516 patients, of which 354 (69%) received neoadjuvant chemoradiotherapy, 113 (22%) received neoadjuvant radiation therapy, and 49 (9%) received neaodjuvant chemotherapy. Characteristics of the study participants are presented in Table 1. The neoadjuvant therapy group contained younger patients and a larger proportion of patients with squamous cell carcinoma and tumours of favourable pathological tumour stage than patients in the surgery alone group, while comorbidity was equally distributed. The characteristics of the patients in the subgroup analysis of neoadjuvant chemoradiotherapy versus surgery were highly similar compared to the main analysis, and are shown in the Supplementary Table S1.
Lymph node yield
Among all study participants, 1347 (74%) had information on the number of removed and examined lymph nodes and were thus included in this analysis. The distribution of number of removed and examined lymph nodes was skewed (Fig. 1). The number of nodes was lower among patients having had neoadjuvant therapy (median 6, interquartile range 3–12), compared to those having undergone surgery alone (median 8, interquartile range 5–16). The difference was confirmed in the fully adjusted Poisson regression for all pathological T-stages combined showing a 25% decrease in the number of lymph nodes after neoadjuvant therapy compared to surgery only (RR 0.75, 95% CI 0.73–0.78, and for each pathological T-stage analysed separately (Table 2). In the subgroup analysis of patients undergoing neoadjuvant chemoradiotherapy compared to those undergoing surgery, the difference was even more pronounced (32% reduction) in the fully adjusted Poisson regression model (RR 0.68, 95% CI 0.65–0.72, Table 2).
The number of removed and examined metastatic lymph nodes was also lower among patients who had received neoadjuvant therapy (median 0, interquartile range 0–2), when compared to patients who had undergone surgery alone (median 1, interquartile range 0–4). This difference was confirmed in the fully adjusted model showing 24% decrease in number of metastatic lymph nodes after neoadjuvant therapy, compared to surgery only (RR 0.76, 95% CI 0.69–0.84, Table 3). The stratified analysis showed that the association was strongest in the pathological T-stage 3 category (Table 3). In the subgroup analysis of patients undergoing neoadjuvant chemoradiotherapy compared to those undergoing surgery, the difference was even more pronounced (32% reduction) in the fully adjusted Poisson regression model (RR 0.68, 95% CI 0.60–0.77, Table 3).
Resection margins
A total of 1553 (85%) patients had data on resection margins and were included in the analysis of this outcome. The proportion of patients with tumour-involved resection margins (R1/R2) was lower (14%) in the neoadjuvant therapy group compared to surgery alone group (20%). After adjustment for confounders, except for T-stage, neoadjuvant therapy was associated with a decreased risk of tumour-involved resection margins (OR 0.52, 95% CI 0.38–0.70. When tumour T-stage was included in the fully adjusted model, no association remained (OR 0.91, 95% CI 0.64–1.29) (Table 4). Additionally, no associations between neoadjuvant therapy and resection margin status were found in the analysis stratified by T-stage categories (Table 4). In the subgroup analysis of patients undergoing neoadjuvant chemoradiotherapy compared to those undergoing surgery, the results were highly similar to the main analysis (Table 3).
Discussion
The results of this study suggest that any neoadjuvant therapy, as well as neoadjuvant chemoradiotherapy, reduces the lymph node yield and reduces the proportion of tumour-involved resection margins in relation to tumour stage during surgery for oesophageal cancer. The latter association seems to be mediated by shrinkage of the primary tumour.
Among methodological strengths of the study are the population-based nationwide design, the complete and validated data collection, and the large sample size. To counteract confounding, which is an inherent source if bias in observation studies, adjustments were made for several key covariates. Lymph node yield increases with surgical experience21, and thus surgeon volume was adjusted for. Changes over time regarding surgical and oncological treatments and pathological examination of the surgical specimen were taken into account by adjusting for calendar year of the surgery. Because surgeons might prefer less radical surgery in frail patients, patient age and comorbidities were adjusted for. Surgeons operating on patients with more advanced tumours, including advanced tumours down-staged by neoadjuvant therapy, might conduct more radical surgery compared to less advanced tumours not receiving neoadjuvant therapy. Therefore, the results were adjusted for and stratified by T-stage. We did not have data on clinical T-stage, but could only assess pathological T-stage. In addition to the surgeon, the pathologist also has an important role in the final lymph node count24. Therefore, lymph node yield was labelled as removed and examined nodes. The smallest nodes in the specimen are harder to detect25, but yet up to 30–40% of the nodal metastases in gastroesophageal cancer are found in small (<5 mm) nodes24,26,27. This might affect the number of removed and examined lymph nodes in the present and previous studies evaluating the association between neoadjuvant therapy and lymph node yield. A weakness in the present study is the low median number of removed and examined lymph nodes, which might be considered a poor oncological resection. This might reflect the lack of centralization and consensus regarding the extent of lymphadenectomy in Sweden during most of the long study period. However, it is unlikely that the extent of lymphadenectomy would differ in those undergoing neoadjuvant therapy or surgery alone after adjustments for calendar year and surgeon volume.
The present study indicates that neoadjuvant therapy reduces the number of removed and examined lymph nodes. The available literature on this topic is limited. Randomized clinical trials have shown that neoadjuvant therapy increases the resectability of oesophageal cancer, but without reporting the lymph node yield28,29,30,31,32,33,34,35,36. Two post-hoc analyses of randomized clinical trials from the Netherlands (n = 320) and France (n = 195), and one French hospital-based cohort study of R0-resected patients (n = 536), suggested a reduced lymph node yield after neoadjuvant therapy compared to surgery alone for oesophageal cancer11,16,17. A register-based study from the United States on patients undergoing oesophagectomy for gastroesophageal cancers (n = 18,777) suggested that neoadjuvant therapy was associated with a decreased likelihood of obtaining 15 or more nodes, but did not assess specific numbers of nodes37. Another register-based study from the United States (n = 5,805), a Taiwanese register-based study (n = 2,151), and a hospital-based study (n = 111) from the United States found no association between neoadjuvant therapy and lymph node yield in oesophageal cancer14,15,38, but none of these studies adjusted the results for surgeon volume, or other potential confounders.
Neoadjuvant therapy was also associated with a decreased number of removed and examined metastatic lymph nodes in this study, which has also been observed earlier and is one of the goals of neoadjuvant therapy11. The stratified analysis showed that the association is the strongest in the high-T-stage category, suggesting that neoadjuvant therapy could reduce the number of lymph node metastases even when no significant down-staging occurs in the primary tumour.
The risk of tumour-involved resection margins was decreased in the neoadjuvant therapy group of the present study, which is in line with some previous studies28,29,30,31,32,33,34,35,36,39. The disappearance of the association after adjustment and stratification for T-stage suggests, in line with a previous study40, that the influence of neoadjuvant therapy on tumour-involved resection margins is mediated by shrinkage of the primary tumour.
This study has some potential clinical and research implications. The number of removed lymph nodes during surgery is considered an indicator of the quality of the esophagectomy41. This study suggests that the expected lymph node yield should be 25% lower after neoadjuvant therapy (and 32% lower after neoadjuvant chemoradiotherapy) than after surgery alone, even when adjusting for important confounders surgeon experience and time. This might not be a concern because recent large studies have not found any survival benefit of more extensive lymphadenectomy after neoadjuvant therapy11, or altogether in oesophageal cancer5,6. On the other hand, a recent large study from the Netherlands showed better survival (adjusted HR 0.77, 95% CI 0.68–0.86) after more extensive lymphadenectomy in oesophageal cancer after neoadjuvant chemoradiotherapy42. However, it is still unclear whether the previously suggested cut-offs for adequate lymph node yield are relevant in the neoadjuvant therapy era, or whether they are a proxy for skill and experience of the surgeon6. The association between neoadjuvant therapy and lymph node yield also indicates that future studies assessing lymphadenectomy should adjust for the use of neoadjuvant therapy.
In conclusion, this nationwide and population-based study with adjustment for several confounders indicates that neoadjuvant therapy reduces the number of removed and examined lymph nodes and the risk of tumour-involved resection margins in patients who undergo surgery for oesophageal cancer. These findings might contribute to changing the view regarding the need for a certain lymph node yield following neoadjuvant therapy and that neoadjuvant therapy should be taken into account in analyses of lymph node yield in future research.
References
Lagergren, J. & Lagergren, P. Recent developments in esophageal adenocarcinoma. CA Cancer J Clin 63, 232–248, https://doi.org/10.3322/caac.21185 (2013).
van Hagen, P. et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366, 2074–2084, https://doi.org/10.1056/NEJMoa1112088 (2012).
Rizk, N. P. et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 251, 46–50, https://doi.org/10.1097/SLA.0b013e3181b2f6ee (2010).
Peyre, C. G. et al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg 248, 549–556, https://doi.org/10.1097/SLA.0b013e318188c474 (2008).
Lagergren, J. et al. Extent of Lymphadenectomy and Prognosis After Esophageal Cancer Surgery. JAMA Surg 151, 32–39, https://doi.org/10.1001/jamasurg.2015.2611 (2016).
van der Schaaf, M., Johar, A., Wijnhoven, B., Lagergren, P. & Lagergren, J. Extent of lymph node removal during esophageal cancer surgery and survival. J Natl Cancer Inst 107, https://doi.org/10.1093/jnci/djv043 (2015).
Omloo, J. M. 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. Ann Surg 246, 992–1000; discussion 1000–1001, https://doi.org/10.1097/SLA.0b013e31815c4037 (2007).
Hulscher, J. B. et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347, 1662–1669, https://doi.org/10.1056/NEJMoa022343 (2002).
Yerokun, B. A. et al. Minimally Invasive Versus Open Esophagectomy for Esophageal Cancer: A Population-Based Analysis. Ann Thorac Surg 102, 416–423, https://doi.org/10.1016/j.athoracsur.2016.02.078 (2016).
Wang, H. et al. Outcomes, quality of life, and survival after esophagectomy for squamous cell carcinoma: A propensity score-matched comparison of operative approaches. J Thorac Cardiovasc Surg 149, 1006–1014; discussion 1014–1005 e1004, https://doi.org/10.1016/j.jtcvs.2014.12.063 (2015).
Koen Talsma, A. et al. Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival. Ann Surg 260, 786–792; discussion 792–783, https://doi.org/10.1097/SLA.0000000000000965 (2014).
Schuhmacher, C. et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol 28, 5210–5218, https://doi.org/10.1200/JCO.2009.26.6114 (2010).
Solomon, N., Zhuge, Y., Cheung, M., Franceschi, D. & Koniaris, L. G. The roles of neoadjuvant radiotherapy and lymphadenectomy in the treatment of esophageal adenocarcinoma. Ann Surg Oncol 17, 791–803, https://doi.org/10.1245/s10434-009-0819-4 (2010).
Chien, H. C. 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 50, 337–343, https://doi.org/10.1093/ejcts/ezw016 (2016).
Wu, S. G. et al. Impact of the number of resected lymph nodes on survival after preoperative radiotherapy for esophageal cancer. Oncotarget 7, 22497–22507, https://doi.org/10.18632/oncotarget.8113 (2016).
Robb, W. B. et al. Impact of neoadjuvant chemoradiation on lymph node status in esophageal cancer: post hoc analysis of a randomized controlled trial. Ann Surg 261, 902–908, https://doi.org/10.1097/SLA.0000000000000991 (2015).
Mariette, C., Piessen, G., Briez, N. & Triboulet, J. P. 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 247, 365–371, https://doi.org/10.1097/SLA.0b013e31815aaadf (2008).
Kidane, B., Coughlin, S., Vogt, K. & Malthaner, R. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev, CD001556, https://doi.org/10.1002/14651858.CD001556.pub3 (2015).
Derogar, M., Sadr-Azodi, O., Johar, A., Lagergren, P. & Lagergren, J. Hospital and surgeon volume in relation to survival after esophageal cancer surgery in a population-based study. J Clin Oncol 31, 551–557, https://doi.org/10.1200/JCO.2012.46.1517 (2013).
Rouvelas, I. et al. Survival after surgery for oesophageal cancer: a population-based study. Lancet Oncol 6, 864–870, https://doi.org/10.1016/S1470-2045(05)70347-8 (2005).
Markar, S. R., Mackenzie, H., Lagergren, P., Hanna, G. B. & Lagergren, J. Surgical Proficiency Gain and Survival After Esophagectomy for Cancer. J Clin Oncol 34, 1528–1536, https://doi.org/10.1200/JCO.2015.65.2875 (2016).
Ludvigsson, J. F., Otterblad-Olausson, P., Pettersson, B. U. & Ekbom, A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 24, 659–667, https://doi.org/10.1007/s10654-009-9350-y (2009).
Armitage, J. N. & van der Meulen, J. H., Royal College of Surgeons Co-morbidity Consensus, G. Identifying co-morbidity in surgical patients using administrative data with the Royal College of Surgeons Charlson Score. Br J Surg 97, 772–781, https://doi.org/10.1002/bjs.6930 (2010).
Hanna, G. B. et al. Improving the standard of lymph node retrieval after gastric cancer surgery. Histopathology 63, 316–324, https://doi.org/10.1111/his.12167 (2013).
Abbassi-Ghadi, N., Boshier, P. R., Goldin, R. & Hanna, G. B. Techniques to increase lymph node harvest from gastrointestinal cancer specimens: a systematic review and meta-analysis. Histopathology 61, 531–542, https://doi.org/10.1111/j.1365-2559.2012.04357.x (2012).
Noda, N., Sasako, M., Yamaguchi, N. & Nakanishi, Y. Ignoring small lymph nodes can be a major cause of staging error in gastric cancer. Br J Surg 85, 831–834, https://doi.org/10.1046/j.1365-2168.1998.00691.x (1998).
Funai, T., Osugi, H., Higashino, M. & Kinoshita, H. Estimation of lymph node metastasis by size in patients with intrathoracic oesophageal cancer. Br J Surg 87, 1234–1239, https://doi.org/10.1046/j.1365-2168.2000.01527.x (2000).
Bosset, J. F. et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337, 161–167, https://doi.org/10.1056/NEJM199707173370304 (1997).
Burmeister, B. H. et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 6, 659–668, https://doi.org/10.1016/S1470-2045(05)70288-6 (2005).
Burmeister, B. H. et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer 47, 354–360, https://doi.org/10.1016/j.ejca.2010.09.009 (2011).
Kelsen, D. P. et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 25, 3719–3725, https://doi.org/10.1200/JCO.2006.10.4760 (2007).
Lee, J. L. et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 15, 947–954 (2004).
Medical Research Council Oesophageal Cancer Working, G. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359, 1727–1733, https://doi.org/10.1016/S0140-6736(02)08651-8 (2002).
Walsh, T. N. et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335, 462–467, https://doi.org/10.1056/NEJM199608153350702 (1996).
Lv, J. et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol 16, 1649–1654 (2010).
Klevebro, F. et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol 27, 660–667, https://doi.org/10.1093/annonc/mdw010 (2016).
Samson, P. et al. Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy. Ann Thorac Surg 103, 406–415, https://doi.org/10.1016/j.athoracsur.2016.08.010 (2017).
Luna, R. A. et al. Lymph Node Harvest During Esophagectomy Is Not Influenced by Use of Neoadjuvant Therapy or Clinical Disease Stage. J Gastrointest Surg 19, 1201–1207, https://doi.org/10.1007/s11605-015-2821-4 (2015).
Stahl, M. et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 27, 851–856, https://doi.org/10.1200/JCO.2008.17.0506 (2009).
Markar, S. R. et al. Significance of Microscopically Incomplete Resection Margin After Esophagectomy for Esophageal Cancer. Ann Surg 263, 712–718, https://doi.org/10.1097/SLA.0000000000001325 (2016).
Markar, S. R. et al. Assessment of the quality of surgery within randomised controlled trials for the treatment of gastro-oesophageal cancer: a systematic review. Lancet Oncol 16, e23–31, https://doi.org/10.1016/S1470-2045(14)70419-X (2015).
Visser, E., van Rossum, P. S. N., Ruurda, J. P. & van Hillegersberg, R. Impact of Lymph Node Yield on Overall Survival in Patients Treated With Neoadjuvant Chemoradiotherapy Followed by Esophagectomy for Cancer: A Population-based Cohort Study in the Netherlands. Ann Surg 266, 863–869, https://doi.org/10.1097/SLA.0000000000002389 (2017).
Acknowledgements
This study was supported by grants from the Swedish Cancer Society (JL), Swedish Research Council (JL), Stockholm Cancer Society (PL), Sigrid Jusélius Foundation (JHK) and Orion Research Foundation (JHK). The data will not be made publicly available, but is available upon request from the authors. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Contributions
Conception and study design, J.H.K., K.W., P.L. and J.L.; Data acquisition, J.L. and P.L.; Data analysis, J.H.K. and K.W.; Interpretation of the data, J.H.K., P.L. and J.L.; Drafting and revising the work, J.H.K., K.W., P.L. and J.L.; Final approval, J.H.K., K.W., P.L. and J.L.
Corresponding author
Ethics declarations
Competing Interests
The authors declare that they have no competing interests.
Additional information
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Kauppila, J.H., Wahlin, K., Lagergren, P. et al. Neoadjuvant therapy in relation to lymphadenectomy and resection margins during surgery for oesophageal cancer. Sci Rep 8, 446 (2018). https://doi.org/10.1038/s41598-017-18879-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-017-18879-6
This article is cited by
-
Impacts of neoadjuvant therapy on the number of dissected lymph nodes in esophagogastric junction cancer patients
BMC Gastroenterology (2023)
-
Current standards of lymphadenectomy in gastric cancer
Updates in Surgery (2023)
-
The Value of Lymphadenectomy Post-Neoadjuvant Therapy in Carcinoma Esophagus: a Review
Indian Journal of Surgical Oncology (2020)
-
Perioperative chemotherapy versus neoadjuvant chemoradiation for patients with adenocarcinoma of the distal esophagus in Austria: a retrospective analysis
World Journal of Surgical Oncology (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.