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Journal of Gastrointestinal Surgery

, Volume 23, Issue 5, pp 1006–1014 | Cite as

Prognostic Implication of Negative Lymph Node Count in ypN+ Rectal Cancer after Neoadjuvant Chemoradiotherapy and Construction of a Prediction Nomogram

  • Yanwu Sun
  • Yiyi Zhang
  • Zhekun Huang
  • Pan ChiEmail author
Original Article

Abstract

Purpose

This study aimed to investigate the prognostic significance of negative lymph nodes (NLNs) for ypN+ rectal cancer after neoadjuvant chemoradiotherapy (nCRT) and radical surgery and to construct a nomogram predicting disease-free survival (DFS).

Method

One hundred fifty-eight eligible patients were included. X-tile analysis was performed to determine cutoff values of NLNs. Clinicopathological and survival outcomes were compared. A Cox regression analysis was performed to identify prognostic factors of DFS. A nomogram was constructed and validated internally.

Results

X-tile analysis identified cutoff values of 4 and 16 in terms of DFS (χ2 = 8.129, p = 0.017). The 3-year DFS rates for low (≤ 4), middle (5–16), and high (≥ 17) NLNs group was 15.2, 55.5, and 73.1%, respectively (P = 0.017). NLN count (NLNs ≥ 17, HR = 0.400, P = 0.022), IMA nodal metastasis (HR = 1.944, P = 0.025), tumor differentiation (poor/anaplastic, HR = 1.805, P = 0.021), and ypT4 stage (HR = 7.787, P = 0.047) were independent prognostic factors of DFS. A predicting nomogram incorporating the four significant predictors was developed with a C-index of 0.64.

Conclusion

NLN count was an independent prognostic factor of DFS in patients with ypN+ rectal cancer following nCRT. A nomogram incorporating NLN count, IMA nodal metastasis, tumor differentiation, and ypT stage could stratify rectal cancer patients with different DFS and might be helpful during clinical decision-making.

Keywords

Rectal cancer Chemoradiotherapy Negative lymph nodes Prognosis Nomogram 

Notes

Acknowledgements

This study was supported by National Clinical Key Specialty Construction Project (General Surgery) of China (Grant number 2012-649), Startup Fund for scientific research, Fujian Medical University (Grant number 2017XQ1028), and guiding key project of social development by the Fujian Provincial Science and Technology Department (Grant number 2015Y0058).

Author Contribution

Yanwu Sun and Pan Chi designed the study. Yanwu Sun, Yiyi Zhang, and Zhekun Huang collected the data and were major contributors in writing the manuscript. All the authors read and approved the final manuscript.

Compliance with Ethical Standards

This study was performed according to the ethical principles described in the Declaration of Helsinki. The institutional review board (IRB) of our hospital approved this study.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009; 27: 5124–30.CrossRefGoogle Scholar
  2. 2.
    van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011; 12: 575–82.CrossRefGoogle Scholar
  3. 3.
    Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012; 39: 1926–33.CrossRefGoogle Scholar
  4. 4.
    Glynne-Jones R. Neoadjuvant treatment in rectal cancer: do we always need radiotherapy-or can we risk assess locally advanced rectal cancer better? Recent Results Cancer Res. 2012; 196: 21–36.CrossRefGoogle Scholar
  5. 5.
    Schmoll H, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde C, Balmana J, Regula J, Nagtegaal I, Beets-Tan R, Arnold D, Ciardiello F, Hoff P, Kerr D, Köhne C, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard J, El Ghazaly H, Gallardo J, Garin A, Glynne-Jones R, Jordan K, Meshcheryakov A, Papamichail D, Pfeiffer P, Souglakos I, Turhal S, Cervantes A. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol. 2012; 23: 2479–516.CrossRefGoogle Scholar
  6. 6.
    Leibold T, Shia J, Ruo L, Minsky B, Akhurst T, Gollub M, Ginsberg M, Larson S, Riedel E, Wong W, Guillem J. Prognostic implications of the distribution of lymph node metastases in rectal cancer after neoadjuvant chemoradiotherapy. J Clin Oncol. 2008; 26: 2106–11.CrossRefGoogle Scholar
  7. 7.
    Okada K, Sadahiro S, Suzuki T, Tanaka A, Saito G, Kamijo A, Akiba T, Kawada S. Effects of chemoradiotherapy on lymph nodes in patients with rectal adenocarcinoma: evaluation of numbers and sizes of retrieved lymph nodes inside and outside the radiation field. Anticancer Res. 2014; 34: 4195–200.Google Scholar
  8. 8.
    Amin M, Edge S, Greene F, Byrd D, Brookland R, Washington M, Gershenwald J, Compton C, Hess K, Sullivan D, Jessup J, Brierley J, Gaspar L, Schilsky R, Balch C, Winchester D, Asare E, Madera M, Gress D, Meyer L, AJCC Cancer Staging Manual. 8th ed ed. 2017, New York: Springer. 252–74.CrossRefGoogle Scholar
  9. 9.
    Willaert W, Mareel M, Van De Putte D, Van Nieuwenhove Y, Pattyn P, Ceelen W. Lymphatic spread, nodal count and the extent of lymphadenectomy in cancer of the colon. Cancer Treat Rev. 2014; 40: 405–13.CrossRefGoogle Scholar
  10. 10.
    Damin D, Rosito M, Contu P, Tarta C, Ferreira P, Kliemann L, Schwartsmann G. Lymph node retrieval after preoperative chemoradiotherapy for rectal cancer. J Gastrointest Surg. 2012; 16: 1573–80.CrossRefGoogle Scholar
  11. 11.
    Ogino S, Nosho K, Irahara N, Shima K, Baba Y, Kirkner G, Mino-Kenudson M, Giovannucci E, Meyerhardt J, Fuchs C. Negative lymph node count is associated with survival of colorectal cancer patients, independent of tumoral molecular alterations and lymphocytic reaction. Am J Gastroenterol. 2010; 105: 420–33.CrossRefGoogle Scholar
  12. 12.
    Wong J, Bowles B, Bueno R, Shimizu D. Impact of the number of negative nodes on disease-free survival in colorectal cancer patients. Dis Colon rectum. 2002; 45: 1341–8.Google Scholar
  13. 13.
    Deng J, Liang H, Wang D, Sun D, Ding X, Pan Y, Liu X. Enhancement the prediction of postoperative survival in gastric cancer by combining the negative lymph node count with ratio between positive and examined lymph nodes. Ann Surg Oncol. 2010; 17: 1043–51.CrossRefGoogle Scholar
  14. 14.
    Zhu Z, Chen H, Yu W, Fu X, Xiang J, Li H, Zhang Y, Sun M, Wei Q, Zhao W, Zhao K. Number of negative lymph nodes is associated with survival in thoracic esophageal squamous cell carcinoma patients undergoing three-field lymphadenectomy. Ann Surg Oncol. 2014; 21: 2857–63.CrossRefGoogle Scholar
  15. 15.
    Chen Y, Zhang L, Tian J, Ren X, Hao Q. Combining the negative lymph nodes count with the ratio of positive and removed lymph nodes can better predict the postoperative survival in cervical cancer patients. Cancer Cell Int. 2013; 13: 6.CrossRefGoogle Scholar
  16. 16.
    Ryan R, Gibbons D, Hyland J, Treanor D, White A, Mulcahy H, O'Donoghue D, Moriarty M, Fennelly D, Sheahan K. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005; 47: 141–6.CrossRefGoogle Scholar
  17. 17.
    Camp R, Dolled-Filhart M, Rimm D. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004; 10: 7252–9.CrossRefGoogle Scholar
  18. 18.
    Steyerberg E, Clinical prediction models: a practical approach to development, validation, and updating. 2009, New York, NY: Springer.CrossRefGoogle Scholar
  19. 19.
    Habr-Gama A, Perez R, Proscurshim I, Rawet V, Pereira D, Sousa A, Kiss D, Cecconello I. Absence of lymph nodes in the resected specimen after radical surgery for distal rectal cancer and neoadjuvant chemoradiation therapy: what does it mean? Dis Colon rectum. 2008; 51: 277–83.Google Scholar
  20. 20.
    Persiani R, Biondi A, Gambacorta M, Bertucci Zoccali M, Vecchio F, Tufo A, Coco C, Valentini V, Doglietto G, D'Ugo D. Prognostic implications of the lymph node count after neoadjuvant treatment for rectal cancer. Br J Surg. 2014; 101: 133–42.CrossRefGoogle Scholar
  21. 21.
    Kim H, Jo J, Lee S, Kim C, Kim Y, Kim H. Low lymph node retrieval after preoperative chemoradiation for rectal cancer is associated with improved prognosis in patients with a good tumor response. Ann Surg Oncol. 2015; 22: 2075–81.CrossRefGoogle Scholar
  22. 22.
    Beresford M, Glynne-Jones R, Richman P, Makris A, Mawdsley S, Stott D, Harrison M, Osborne M, Ashford R, Grainger J, Al-Jabbour J, Talbot I, Mitchell I, Meyrick Thomas J, Livingstone J, McCue J, MacDonald P, Northover J, Windsor A, Novell R, Wallace M, Harrison R. The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy. Clin Oncol (R Coll Radiol). 2005; 17: 448–55.CrossRefGoogle Scholar
  23. 23.
    Kim N, Kim Y, Min B, Le EK, Sohn S, Cho C. Factors associated with local recurrence after neoadjuvant chemoradiation with total mesorectal excision for rectal cancer. World J Surg. 2009; 33: 1741–9.CrossRefGoogle Scholar
  24. 24.
    Lee W, Lee S, Baek J, Lee W, Lee J, Kim N, Park Y. What does absence of lymph node in resected specimen mean after neoadjuvant chemoradiation for rectal cancer. Radiat Oncol. 2013; 8: 202.CrossRefGoogle Scholar
  25. 25.
    Rullier A, Laurent C, Capdepont M, Vendrely V, Belleannée G, Bioulac-Sage P, Rullier E. Lymph nodes after preoperative chemoradiotherapy for rectal carcinoma: number, status, and impact on survival. Am J Surg Pathol. 2008; 32: 45–50.CrossRefGoogle Scholar
  26. 26.
    McDonald J, Renehan A, O'Dwyer S, Haboubi N. Lymph node harvest in colon and rectal cancer: Current considerations. World J Gastrointest Surg. 2012; 4: 9–19.CrossRefGoogle Scholar
  27. 27.
    Bhangu A, Kiran R, Brown G, Goldin R, Tekkis P. Establishing the optimum lymph node yield for diagnosis of stage III rectal cancer. Tech Coloproctol. 2014; 18: 709–17.CrossRefGoogle Scholar
  28. 28.
    Mogoantă S, Calotă F, Vasile I, Crafciuc A, Gherghinescu M, Sapalidis K, Ilie D, Ion D. Histological and immunohistochemical study on sentinel lymph node in colorectal cancer - values and limitations. Rom J Morphol Embryol. 2016; 57: 65–74.Google Scholar
  29. 29.
    Rahbari N, Bork U, Motschall E, Thorlund K, Büchler M, Koch M, Weitz J. Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2012; 30: 60–70.CrossRefGoogle Scholar
  30. 30.
    George S, Primrose J, Talbot R, Smith J, Mullee M, Bailey D, du Boulay C, Jordan H, Wessex Colorectal Cancer Audit Working G. Will Rogers revisited: prospective observational study of survival of 3592 patients with colorectal cancer according to number of nodes examined by pathologists. Br J Cancer. 2006; 95: 841–7.CrossRefGoogle Scholar
  31. 31.
    Johnson P, Porter G, Ricciardi R, Baxter N. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol. 2006; 24: 3570–675.CrossRefGoogle Scholar
  32. 32.
    Popat S, Hubner R, Houlston R. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005; 23: 609–18.CrossRefGoogle Scholar
  33. 33.
    Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. Clin Cancer Res. 2008; 14: 1413–7.CrossRefGoogle Scholar
  34. 34.
    Ogino S, Nosho K, Irahara N, Shima K, Baba Y, Kirkner G, Mino-Kenudson M, Giovannucci E, Meyerhardt J, Fuchs C. Negative lymph node count is associated with survival of colorectal cancer patients, independent of tumoral molecular alterations and lymphocytic reaction. Am J Gastroenterol. 2010; 105: 420–33.CrossRefGoogle Scholar
  35. 35.
    Kim J, Lee K, Yu C, Kim H, Kim J, Chang H, Kim J, Kim J, Kim T. The clinicopathological significance of inferior mesenteric lymph node metastasis in colorectal cancer. Eur J Surg Oncol. 2004; 30: 271–9.CrossRefGoogle Scholar
  36. 36.
    Chin C, Yeh C, Tang R, Changchien C, Huang W, Wang J. The oncologic benefit of high ligation of the inferior mesenteric artery in the surgical treatment of rectal or sigmoid colon cancer. Int J Colorectal Dis. 2008; 23: 783–8.CrossRefGoogle Scholar
  37. 37.
    Sun Y, Chi P, Lin H, Lu X, Huang Y, Xu Z, Huang S, Wang X. Inferior mesenteric artery lymph node metastasis in rectal cancer treated with neoadjuvant chemoradiotherapy: Incidence, prediction and prognostic impact. Eur J Surg Oncol. 2017; 43: 85–91.CrossRefGoogle Scholar
  38. 38.
    Qiu H, Wu B, Xiao Y, Lin G. Combination of differentiation and T stage can predict unresponsiveness to neoadjuvant therapy for rectal cancer. Colorectal Dis. 2011; 13: 1353–60.CrossRefGoogle Scholar
  39. 39.
    Reggiani Bonetti L, Lionti S, Domati F, Barresi V. Do pathological variables have prognostic significance in rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and surgery? World J Gastroenterol. 2017; 28: 1412–23.CrossRefGoogle Scholar
  40. 40.
    Cui J, Yang L, Guo L, Shao Y, Tan D. The combination of early treatment response and ypT stage is a novel metric to stage rectal cancer patients treated with neoadjuvant chemoradiotherapy. Oncotarget. 2017; 8: 37845–54.Google Scholar
  41. 41.
    Gill A, Brunson A, Lara P J, Khatri V, Semrad T. Implications of lymph node retrieval in locoregional rectal cancer treated with chemoradiotherapy: a California Cancer Registry Study. Eur J Surg Oncol. 2015; 41: 647–52.CrossRefGoogle Scholar
  42. 42.
    De Stefano A, Moretto R, Bucci L, Pepe S, Romano F, Cella A, Attademo L, Rosanova M, De Falco S, Fiore G, Raimondo L, De Placido S, Carlomagno C. Adjuvant treatment for locally advanced rectal cancer patients after preoperative chemoradiotherapy: when, and for whom? Clin Colorectal Cancer. 2014; 13: 185–91.CrossRefGoogle Scholar
  43. 43.
    Pita-Fernández S, Alhayek-Aí M, González-Martín C, López-Calviño B, Seoane-Pillado T, Pértega-Díaz S. Intensive follow-up strategies improve outcomes in nonmetastatic colorectal cancer patients after curative surgery: a systematic review and meta-analysis. Ann Oncol. 2015; 26: 644–56.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2018

Authors and Affiliations

  1. 1.Department of Colorectal SurgeryFujian Medical University Union HospitalFuzhouPeople’s Republic of China

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