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The metronomic therapy with prednisone, etoposide, and cyclophosphamide reduces the serum levels of VEGF and circulating endothelial cells and improves response rates and progression-free survival in patients with relapsed or refractory non-Hodgkin’s lymphoma

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Abstract

Purpose

There is an urgent need for a better strategy in the management of relapsed or refractory non-Hodgkin’s lymphoma (NHL). The present study was designed to evaluate the efficacy and safety of the regimen using metronomic prednisone, etoposide, and cyclophosphamide in the treatment of patients with relapsed or refractory NHL, in comparison with conventional salvage chemotherapy.

Methods

Eligible patients were randomized to the test group (n = 23) receiving metronomic prednisone, etoposide, and cyclophosphamide or the control group (n = 21) receiving conventional salvage chemotherapy. The serum levels of circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured before and after two cycles of treatment; overall response rate (ORR) and disease control rate (DCR) were evaluated at cycles 2, 4, 6, and 12 months after treatment.

Results

After two cycles of treatment, the ORRs of the test and control groups were statistically similar, while the DCR of the test group (87.0 %) was significantly higher than that of the control group (57.1 %). At 12 months after treatment, the ORR and DCR of the test group (47.8 and 69.6 %, respectively) were significantly higher than that of the control group (19.0 and 33.3 %, respectively). The serum CECs and VEGF levels in the test group after treatment were significantly lower than that before treatment or that of the control group. In the patients with ORR and DCR in the test group, the serum CECs and VEGF levels remained relatively low at cycles 2, 4, and 6 and at 12 months after treatment. There was a progression-free survival (PFS) benefit of 6.5 months in the test group, compared with the control group.

Conclusion

Metronomic chemotherapy with prednisone, etoposide, and cyclophosphamide resulted in higher ORR and DCR, fewer adverse effects, and longer PFS in patients with relapsed or refractory NHL, with significant reduction in serum CECs and VEGF levels.

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References

  1. Fisher RI, Gaynor ER, Dahlberg S et al (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328(14):1002–1006

    Article  CAS  PubMed  Google Scholar 

  2. Abali H, Urun Y, Oksuzoglu B et al (2008) Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest 26(4):401–406

    Article  CAS  PubMed  Google Scholar 

  3. Park SH, Kim S, Ko OB et al (2006) ESHAP salvage therapy for refractory and relapsed non-Hodgkin’s lymphoma: a single center experience. Korean J Intern Med 21(3):159–164

    Article  PubMed  PubMed Central  Google Scholar 

  4. Huang HQ, Jiang WQ, Wang W et al (2003) Preliminary outcome for patients with relapsed or resistant advanced non-Hodgkin’s lymphoma treated by EPOCH regimen. Ai Zheng 22(4):389–392

    PubMed  Google Scholar 

  5. Schutt P, Passon J, Ebeling P et al (2007) Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas. Eur J Haematol 78(2):93–101

    Article  CAS  PubMed  Google Scholar 

  6. Visani G, Malerba L, Stefani PM et al (2011) BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood 118(12):3419–3425

    Article  CAS  PubMed  Google Scholar 

  7. Andre N, Carre M, Pasquier E (2014) Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 11(7):413–431

    Article  CAS  PubMed  Google Scholar 

  8. El Bary NA, Hashem T, Metwally H et al (2010) A phase II study of high-dose celecoxib and metronomic ‘low-dose’ cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma. Hematol Oncol Stem Cell Ther 3(1):13–18

    Article  PubMed  Google Scholar 

  9. Coleman M, Martin P, Ruan J et al (2008) Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy. Cancer 112(10):2228–2232

    Article  CAS  PubMed  Google Scholar 

  10. Ruan J, Martin P, Coleman M et al (2010) Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer 116(11):2655–2664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Buckstein R, Kerbel R, Cheung M et al (2014) Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 clinical study with biomarkers of angiogenesis. Leuk Res 38(7):756–763

    Article  CAS  PubMed  Google Scholar 

  12. Mehran R, Nilsson M, Khajavi M et al (2014) Tumor endothelial markers define novel subsets of cancer-specific circulating endothelial cells associated with antitumor efficacy. Cancer Res 74(10):2731–2741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. WangYuan Z, JiangZheng Z, Lu YD et al (2016) Clinical efficacy of metronomic chemotherapy after cool-tip radiofrequency ablation in the treatment of hepatocellular carcinoma. Int J Hyperth 32(2):193–198

    Article  Google Scholar 

  14. Mancuso P, Colleoni M, Calleri A et al (2006) Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108(2):452–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Elsamany S, Farooq MU, Elsirafy M et al (2014) Phase II study of low-dose fixed-rate infusion of gemcitabine combined with cisplatin and dexamethasone in resistant non-Hodgkin lymphoma and correlation with Bcl-2 and MDR expression. Med Oncol 31(3):872

    Article  PubMed  Google Scholar 

  16. Masuda N, Higaki K, Takano T et al (2014) A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer. Cancer Chemother Pharmacol 74(2):229–238

    Article  CAS  PubMed  Google Scholar 

  17. Gisselbrecht C, Glass B, Mounier N et al (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28(27):4184–4190

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ruan J, Hajjar K, Rafii S et al (2009) Angiogenesis and antiangiogenic therapy in non-Hodgkin’s lymphoma. Ann Oncol 20(3):413–424

    Article  CAS  PubMed  Google Scholar 

  19. Ribatti D, Nico B, Ranieri G et al (2013) The role of angiogenesis in human non-Hodgkin lymphomas. Neoplasia 15(3):231–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Salven P, Orpana A, Teerenhovi L et al (2000) Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood 96(12):3712–3718

    CAS  PubMed  Google Scholar 

  21. Niitsu N, Okamato M, Nakamine H et al (2002) Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin’s lymphoma. Eur J Haematol 68(2):91–100

    Article  CAS  PubMed  Google Scholar 

  22. UskudarTeke H, Gunduz E, Akay OM et al (2015) Are the high serum interleukin-6 and vascular endothelial growth factor levels useful prognostic markers in aggressive non-hodgkin lymphoma patients? Turk J Haematol 32(1):21–28

    Article  Google Scholar 

  23. Pedersen LM, Klausen TW, Davidsen UH et al (2005) Early changes in serum IL-6 and VEGF levels predict clinical outcome following first-line therapy in aggressive non-Hodgkin’s lymphoma. Ann Hematol 84(8):510–516

    Article  CAS  PubMed  Google Scholar 

  24. Lyden D, Hattori K, Dias S et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7(11):1194–1201

    Article  CAS  PubMed  Google Scholar 

  25. Igreja C, Courinha M, Cachaco AS et al (2007) Characterization and clinical relevance of circulating and biopsy-derived endothelial progenitor cells in lymphoma patients. Haematologica 92(4):469–477

    Article  PubMed  Google Scholar 

  26. Ruan J (2011) Antiangiogenic therapies in non-Hodgkin’s lymphoma. Curr Cancer Drug Targets 11(9):1030–1043

    Article  CAS  PubMed  Google Scholar 

  27. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4(6):423–436

    Article  CAS  PubMed  Google Scholar 

  28. Norrby K (2014) Metronomic chemotherapy and anti-angiogenesis: can upgraded pre-clinical assays improve clinical trials aimed at controlling tumor growth? APMIS 122(7):565–579

    Article  CAS  PubMed  Google Scholar 

  29. Pasquier E, Tuset MP, Street J et al (2013) Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells. Angiogenesis 16(2):373–386

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This Project was supported by the key medical research projects of Hainan Health Department (Grant No. 2010-19).

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    Authors and Affiliations

    1. Department of Medical Oncology, Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou, 570102, People’s Republic of China

      Jiangzheng Zeng, Fen Huang, Tao Hong, Zhihui He, Junhua Lei, Huamao Sun, Yanda Lu & Xinbao Hao

    2. Department of Hepatobiliary Surgery, Affiliated Hospital of Hainan Medical College, Haikou, 570102, People’s Republic of China

      Liangxia Yang

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    1. Jiangzheng Zeng
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    Correspondence to Yanda Lu or Xinbao Hao.

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    Jiangzheng Zeng and Liangxia Yang contributed equally to this article.

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    Zeng, J., Yang, L., Huang, F. et al. The metronomic therapy with prednisone, etoposide, and cyclophosphamide reduces the serum levels of VEGF and circulating endothelial cells and improves response rates and progression-free survival in patients with relapsed or refractory non-Hodgkin’s lymphoma. Cancer Chemother Pharmacol 78, 801–808 (2016). https://doi.org/10.1007/s00280-016-3136-1

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