Skip to main content
SpringerLink
Log in

Lymph Node Ratio as a Risk Factor for Recurrence After Adjuvant Chemotherapy in Stage III Colorectal Cancer

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Although several markers, including the lymph node ratio (LNR), have been proposed as a clinically prognostic tool for colorectal cancer (CRC), it remains unclear which markers have the most relevance in determining recurrence following adjuvant chemotherapy for stage III CRC.

Methods

Independent risk factors for recurrence-free survival (RFS) were retrospectively determined using the Cox proportional hazard model in 360 stage III CRC patients and validated using an independent cohort comprising 172 stage III CRC patients.

Results

The LNR was independently associated with RFS (HR, 1.96; 95% CI, 1.11 to 3.28; P = 0.020). A higher LNR value was significantly associated with recurrence, microsatellite stable, and shorter time to recurrence. A combination of the LNR with pre-chemotherapy CEA and CA19-9, other independent risk factors, provided accurate risk stratification of RFS and conferred additional information on recurrence within each stage III CRC subgroup, which was then validated in an independent cohort. A beneficial effect in patients at risk of recurrence, and a reduced effect in patients at low risk, was exhibited by the addition of oxaliplatin to 5-fluorouracil-based adjuvant chemotherapy.

Conclusion

A higher LNR is one of the most aggressive phenotypes with recurrence risk following adjuvant chemotherapy for stage III CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA: a cancer journal for clinicians 2014; 64: 104–17.

    Google Scholar 

  2. Bertelsen CA, Neuenschwander AU, Jansen JE et al. Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study. The Lancet Oncology 2015; 16: 161–8.

    Article  PubMed  Google Scholar 

  3. Obrand DI, Gordon PH. Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Diseases of the colon and rectum 1997; 40: 15–24.

    Article  CAS  PubMed  Google Scholar 

  4. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA: a cancer journal for clinicians 2006; 56: 106–30.

    Google Scholar 

  5. The National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology, colon cancer. http://www.nccnorg/professionals/physician_gls/f_guidelinesasp 2016; version 2.

  6. Gao P, Song YX, Wang ZN et al. Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the Surveillance, Epidemiology, and End Results (SEER) database. BMC Cancer 2013; 13: 123.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ooki A, Yamashita K, Kobayashi N et al. Lymph node metastasis density and growth pattern as independent prognostic factors in advanced esophageal squamous cell carcinoma. World journal of surgery 2007; 31: 2184–91.

    Article  PubMed  Google Scholar 

  8. Yamashita K, Ooki A, Sakuramoto S et al. Lymph node metastasis density (ND)-factor association with malignant degree and ND40 as “non-curative factor” in gastric cancer. Anticancer research 2008; 28: 435–41.

    PubMed  Google Scholar 

  9. Qiu HB, Zhang LY, Li YF et al. Ratio of metastatic to resected lymph nodes enhances to predict survival in patients with stage III colorectal cancer. Annals of surgical oncology 2011; 18: 1568–74.

    Article  PubMed  Google Scholar 

  10. Chen SL, Steele SR, Eberhardt J et al. Lymph node ratio as a quality and prognostic indicator in stage III colon cancer. Annals of surgery 2011; 253: 82–7.

    Article  PubMed  Google Scholar 

  11. Berger AC, Sigurdson ER, LeVoyer T et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2005; 23: 8706–12.

    Article  Google Scholar 

  12. Weisenberger DJ, Siegmund KD, Campan M et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nature genetics 2006; 38: 787–93.

    Article  CAS  PubMed  Google Scholar 

  13. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science (New York, NY) 1993; 260: 816–9.

    Article  CAS  Google Scholar 

  14. Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. The New England journal of medicine 1988; 319: 525–32.

    Article  CAS  PubMed  Google Scholar 

  15. Chau I, Allen MJ, Cunningham D et al. The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2004; 22: 1420–9.

    Article  CAS  Google Scholar 

  16. Filella X, Molina R, Grau JJ et al. Prognostic value of CA 19.9 levels in colorectal cancer. Annals of surgery 1992; 216: 55–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McMillan DC, Crozier JE, Canna K et al. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. International journal of colorectal disease 2007; 22: 881–6.

    Article  PubMed  Google Scholar 

  18. Kishi Y, Kopetz S, Chun YS et al. Blood neutrophil-to-lymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy. Annals of surgical oncology 2009; 16: 614–22.

    Article  PubMed  Google Scholar 

  19. Sargent DJ, Marsoni S, Monges G et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2010; 28: 3219–26.

    Article  CAS  Google Scholar 

  20. Hutchins G, Southward K, Handley K et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011; 29: 1261–70.

    Article  Google Scholar 

  21. Ogino S, Shima K, Meyerhardt JA et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clinical cancer research : an official journal of the American Association for Cancer Research 2012; 18: 890–900.

    Article  CAS  Google Scholar 

  22. Ooki A, Akagi K, Yatsuoka T et al. Combined microsatellite instability and BRAF gene status as biomarkers for adjuvant chemotherapy in stage III colorectal cancer. Journal of surgical oncology 2014; 110: 982–8.

    Article  CAS  PubMed  Google Scholar 

  23. Katoh H, Yamashita K, Wang G et al. Prognostic significance of preoperative bowel obstruction in stage III colorectal cancer. Annals of surgical oncology 2011; 18: 2432–41.

    Article  PubMed  Google Scholar 

  24. Haller DG, Catalano PJ, Macdonald JS et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2005; 23: 8671–8.

    Article  Google Scholar 

  25. Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. The New England journal of medicine 2005; 352: 2696–704.

    Article  CAS  PubMed  Google Scholar 

  26. Lembersky B, Wieand H, Petrelli N et al. Oral Uracil and Tegafur Plus Leucovorin Compared With Intravenous Fluorouracil and Leucovorin in Stage II and III Carcinoma of the Colon: Results From National Surgical Adjuvant Breast and Bowel Project Protocol C-06. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2006; 24: 2059–64.

    Article  CAS  Google Scholar 

  27. Yoshida M, Ishiguro M, Ikejiri K et al. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 2014; 25: 1743–9.

    Article  CAS  Google Scholar 

  28. Haller DG, Tabernero J, Maroun J et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011; 29: 1465–71.

    Article  CAS  Google Scholar 

  29. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. The New England journal of medicine 2004; 350: 2343–51.

    Article  CAS  PubMed  Google Scholar 

  30. Locker GY, Hamilton S, Harris J et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2006; 24: 5313–27.

    Article  CAS  Google Scholar 

  31. Guthrie GJ, Charles KA, Roxburgh CS et al. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Critical reviews in oncology/hematology 2013; 88: 218–30.

    Article  PubMed  Google Scholar 

  32. Bockelman C, Engelmann BE, Kaprio T et al. Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature. Acta oncologica (Stockholm, Sweden) 2015; 54: 5–16.

    Article  Google Scholar 

  33. Yothers G, O’Connell MJ, Lee M et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013; 31: 4512–9.

    Article  CAS  Google Scholar 

  34. Yothers G, O’Connell MJ, Allegra CJ et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011; 29: 3768–74.

    Article  CAS  Google Scholar 

  35. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2015; 33: 1787–96.

    Article  CAS  Google Scholar 

  36. Shah MA, Renfro LA, Allegra CJ et al. Impact of Patient Factors on Recurrence Risk and Time Dependency of Oxaliplatin Benefit in Patients With Colon Cancer: Analysis From Modern-Era Adjuvant Studies in the Adjuvant Colon Cancer End Points (ACCENT) Database. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2016; 34: 843–53.

    Article  CAS  Google Scholar 

  37. de Miranda NF, Goudkade D, Jordanova ES et al. Infiltration of Lynch colorectal cancers by activated immune cells associates with early staging of the primary tumor and absence of lymph node metastases. Clinical cancer research: an official journal of the American Association for Cancer Research 2012; 18: 1237–45.

    Article  Google Scholar 

  38. Michael-Robinson JM, Biemer-Huttmann A, Purdie DM et al. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 2001; 48: 360–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mlecnik B, Tosolini M, Kirilovsky A et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011; 29: 610–8.

    Article  Google Scholar 

  40. Pages F, Berger A, Camus M et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. The New England journal of medicine 2005; 353: 2654–66.

    Article  CAS  PubMed  Google Scholar 

  41. Oberg A, Samii S, Stenling R, Lindmark G. Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. International journal of colorectal disease 2002; 17: 25–9.

    Article  CAS  PubMed  Google Scholar 

  42. Zuckerman NS, Yu H, Simons DL et al. Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients. International journal of cancer 2013; 132: 2537–47.

    Article  CAS  PubMed  Google Scholar 

  43. de Vries NL, Swets M, Vahrmeijer AL et al. The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment. International journal of molecular sciences 2016; 17.

  44. Ceelen W, Van Nieuwenhove Y, Pattyn P. Prognostic value of the lymph node ratio in stage III colorectal cancer: a systematic review. Annals of surgical oncology 2010; 17: 2847–55.

    Article  CAS  PubMed  Google Scholar 

  45. Mandelker DL, Yamashita K, Tokumaru Y et al. PGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. Cancer research 2005; 65: 4963–8.

    Article  CAS  PubMed  Google Scholar 

  46. Ooki A, Yamashita K, Kikuchi S et al. Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer. Oncogene 2010; 29: 3263–75.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors declare no conflicts of interest. This study received no grant support.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Saitama Cancer Center, 780 Komuro, Ina, Kita-adachi-gun, Saitama, 362-0806, Japan

    Akira Ooki, Masako Asayama, Hiroki Hara & Kensei Yamaguchi

  2. Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan

    Kiwamu Akagi

  3. Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan

    Toshimasa Yatsuoka & Yoji Nishimura

  4. Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan

    Hiroshi Katoh, Keishi Yamashita & Masahiko Watanabe

Authors
  1. Akira Ooki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiwamu Akagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshimasa Yatsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masako Asayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroki Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoji Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Katoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keishi Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masahiko Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kensei Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Ooki.

Ethics declarations

Grant Support

This study received no grant support.

Conflict of Interest

No potential conflicts of interest.

Synopsis

Lymph node ratio has a great potential as a risk factor for recurrence in stage III colorectal cancer.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(GIF 9 kb)

High resolution image (TIF 80 kb)

ESM 2

(RTF 545 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ooki, A., Akagi, K., Yatsuoka, T. et al. Lymph Node Ratio as a Risk Factor for Recurrence After Adjuvant Chemotherapy in Stage III Colorectal Cancer. J Gastrointest Surg 21, 867–878 (2017). https://doi.org/10.1007/s11605-017-3382-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-017-3382-5

Keywords

Search

Navigation