Ki-67 Can Predict the Response to the Gemcitabine, Oxaliplatin And L-asparaginase Regimen (GELOX) and Prognosis in Patients with Nasal Natural Killer/T-cell Lymphoma

  • Zhang, Jing (Department of Medical Oncology, Hubei Cancer Hospital) ;
  • Jiang, Wei (Department of Radiation Oncology, the Affiliated Hospital of Guilin Medical University) ;
  • Wang, Wei-Da (Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center) ;
  • Liu, Cheng-Cheng (Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center) ;
  • Hu, Yan-Ping (Department of Medical Oncology, Hubei Cancer Hospital) ;
  • Xia, Zhong-Jun (Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center)
  • Published : 2015.06.26


GELOX (gemcitabine, oxaliplatin and L-asparaginase) regimen showed an impressive result in our previous study, but the effect of this new regimen is still dissatisfying for some patients, so it is necessary to identify which patients will benefit from this regimen. A total of fifty-one cases with nasal natural killer/T-cell lymphoma receiving initial GELOX chemotherapy were enrolled in this study. The ki-67 expression detected by immunohistochemistry (IHC) in the specimens ranged from 10% to 90%, with a median value of 70%, so cases higher than the median value (${\geq}70%$) were defined as high ki-67 expression, and the others were designated as low ki-67 expression. The response rate had no statistical difference between low ki-67 expression group and high ki-67 expression group (P=0.291) though the value in the former group was relatively high. After a median follow-up of 18.03 months, the 3-year progression-free survival (PFS) for patients with low ki-67 expression was significantly higher than those with high ki-67 expression (83.8% vs. 47.9%, P=0.038). In the stage I/II subgroup, 3-year PFS and overall survival (OS) were statistically higher in the patients with low ki-67 expression than those with high ki-67 expression. Multivariate analysis revealed high ki-67 expression was an independent prognostic factor for PFS. These results suggest that low ki-67 expression can predict a good response of GELOX in these patients, and the combination of ki-67 expression and early stage is helpful to identify an excellent prognosis subgroup from patients receiving GELOX in this disease.


Ki-67;gemcitabine;oxaliplatin;l-asparaginase;natural killer/T-cell lymphoma


  1. Argatoff LH, Connors JM, Klasa RJ, et al (1997). Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood, 89, 2067-78.
  2. Ayoub JP, Palmer JL, Huh Y, et al (1999). Therapeutic and prognostic implications of peripheral blood lymphopenia in patients with Hodgkin's disease. Leuk Lymphoma, 34, 519-27.
  3. Bahnassy AA, Zekri AR, Asaad N, et al (2006). Epstein-Barr viral infection in extranodal lymphoma of the head and neck: correlation with prognosis and response to treatment. Histopathology, 48, 516-28.
  4. Bari A, Marcheselli L, Sacchi S, et al (2010). Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story. Ann Oncol, 21, 1486-91.
  5. Broyde A, Boycov O, Strenov Y, et al (2009). Role and prognostic significance of the Ki-67 index in non-Hodgkin's lymphoma. Am J Hematol, 84, 338-43.
  6. Cheson BD, Horning SJ, Coiffier B, et al (1999). Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI sponsored international working group. J Clin Oncol, 17, 1244.
  7. El Gnaoui T, Dupuis J, Belhadj K, et al (2007). Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol, 18, 1363-8.
  8. Gerdes J, Lemke H, Baisch H, et al (1984). Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol, 133, 1710-5.
  9. Grogan TM, Lippman SM, Spier CM, et al (1988). Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67. Blood, 71, 1157-60.
  10. He X, Chen Z, Fu T, et al (2014). Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis. BMC Cancer, 14, 153.
  11. Huang JJ, Jiang WQ, Lin TY, et al (2011). Absolute lymphocyte count is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type. Ann Oncol, 22, 149-55.
  12. Huang X, Sun Q, Fu H, et al (2014). Both c-Myc and Ki-67 expression are predictive markers in patients with extranodal NK/T-cell lymphoma, nasal type: a retrospective study in China. Pathol Res Pract, 210, 351-6.
  13. Jaccard A, Gachard N, Marin B, et al (2011). Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood, 117, 1834-9.
  14. Jaccard A, Petit B, Girault S, et al (2009). L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol, 20, 110-6.
  15. Jiang L, Li P, Wang H, et al (2014). Prognostic significance of Ki-67 antigen expression in extranodal natural killer/T-cell lymphoma, nasal type. Med Oncol, 31, 218.
  16. Katzenberger T, Petzoldt C, Holler S, et al (2006). The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood, 107, 3407.
  17. Kim M, Kim TM, Kim KH, et al (2015). Ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) plus L-asparaginase as a first-line therapy improves outcomes in stage III/IV NK/T cell-lymphoma, nasal type (NTCL). Ann Hematol, 94, 437-44
  18. Kim SJ, Kim BS, Choi CW, et al (2007). Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type. Ann Oncol, 18, 1382-7.
  19. Li ZM, Huang JJ, Xia Y, et al (2012). High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy. Eur J Haematol, 88, 510-7.
  20. Lin N, Song Y, Zheng W, et al (2013). A prospective phase II study of L-asparaginase- CHOP plus radiation in newly diagnosed extranodal NK/T-cell lymphoma, nasal type. J Hematol Oncol, 6, 44.
  21. Liu J, Song B, Fan T, et al (2011). Pathological and clinical characteristics of 1,248 non-Hodgkin's lymphomas from a regional cancer hospital in Shandong, China. Asian Pac J Cancer Prev, 12, 3055-61.
  22. Nagafuji K, Fujisaki T, Arima F, et al (2001). L-asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol, 74, 447-50.
  23. Oki Y, McLaughlin P, Pro B, et al (2005). Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma. Cancer, 104, 781-7.
  24. Ott G, Ziepert M, Klapper W, et al (2010). Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood, 116, 4916-25.
  25. Raty R, Franssila K, Joensuu H, et al (2002). Ki-67 expression level, histological subtype, and the International Prognostic Index as outcome predictors in mantle cell lymphoma. Eur J Haematol, 69, 11-20.
  26. Rosenwald A, Ott G (2008). Burkitt lymphoma versus diffuse large B-cell lymphoma. Ann Oncol, 19, 67-9.
  27. Schluter C, Duchrow M, Wohlenberg C, et al (1993). The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol, 123, 513-22.
  28. Wang L, Wang ZH, Chen XQ, et al (2013). First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer, 119, 348-55.
  29. Wen JY, Li M, Li X, et al (2014). Efficacy and tolerance of pegaspargase-based chemotherapy in patients with nasaltype extranodal NK/T-cell lymphoma: a pilot study. Asian Pac J Cancer Prev, 15, 6275-81.
  30. Went P, Agostinelli C, Gallamini A, et al (2006). Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol, 24, 2472-9.
  31. Yamaguchi M, Kwong YL, Kim WS, et al (2011). Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/Tcell lymphoma, nasal type: the NK-Cell tumor study group study. J Clin Oncol, 29, 4410-6.
  32. Yasuda H, Sugimoto K, Imai H, et al (2009). Expression levels of apoptosis-related proteins and Ki-67 in nasal NK / T-cell lymphoma. Eur J Haematol, 82, 39-45.
  33. Yong W, Zhang Y, Zheng W (2000). The efficacy of L-asparaginase in the treatment of refractory midline peripheral T-cell lymphoma. Zhonghua Xue Ye Xue Za Zhi, 21, 577-9.
  34. Zinzani PL, Venturini F, Stefoni V, et al (2010). Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol, 21, 860-3.