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High-Dose Methotrexate (HD-MTX) Used as an Adjunct with Other Chemotherapeutics for the Treatment of Osteosarcoma

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Abstract

The objective of this study is to evaluate retrospectively the effectiveness of multiple-drug chemotherapeutics regimen that included high-dose methotrexate (HD-MTX) for treating primary osteosarcoma. 148 newly diagnosed patients with Stage I and II osteosarcoma who received HD-MTX/HD-MTX/DDP(cisplatin)/ADM(doxorubicin) and/or HD-MTX/IFO(Ifosfamide)/DDP/ADM before and after the surgery were retrospectively analyzed to measure the efficacy of this regimen. The significance of various variables as predictive prognostic factors of the patient survival rate was also evaluated. The overall 3-year survival rate of the patients was 79.73 %. The survival rate was improved to 85.71 % in the patients who received surgery and a complete 4-cycle chemotherapy. In addition, the rates of disease-free survival (DFS), local recurrence, and distant metastasis were 68.13, 3.30, and 10.81 %, respectively. Our analysis showed that completing 4-cycle chemotherapy produced a significant impact on the overall 3-year survival and DFS rates (P < 0.05). The overall 3-year survival was correlated with pathological fracture, chemotherapy completion, histological response, local recurrence, and distance metastasis (single-factor P < 0.05). Multivariate analysis further evidenced that these predictive factors were independently correlated to the survival rate (multi-factor P < 0.05). The complete 4-cycle multiple-drug chemotherapy consisting of HD-MTX, doxorubicin, cisplatin, and ifosfamide combined with surgical resection was found to be effective in improving the survival rate of osteosarcoma patients. Furthermore, the presence of pathological fracture, poor histological response, local recurrence, and distant metastasis was negatively correlated with the survival rate. Patient age, gender, location of primary tumor, and serum alkaline phosphatase level were not found to show the prognostic significance.

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References

  1. Hu, Y., Wan, Y., et al. (2008). Minutes of The second national conference on neoadjuvant chemotherapy of Osteosarcoma Expert Meeting. Chin J Orthop, 28(10), 870–874.

    Google Scholar 

  2. Rosen, G., Marcove, R. C., & Huvos, A. G. (1983). Primary osteogenic sarcoma: Eight-year experience with adjuvant chemotherapy. Journal of Cancer Research and Clinical Oncology, 106(supplement), 55–67.

    Article  PubMed  Google Scholar 

  3. Bernthal, N. M., Federman, N., Eilber, F. R., et al. (2012). Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer, 118(23), 5888–5893.

    Article  CAS  PubMed  Google Scholar 

  4. Meyers, P. A., Gorlick, R., Heller, G., et al. (1998). Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. Journal of Clinical Oncology, 16(7), 2452–2458.

    CAS  PubMed  Google Scholar 

  5. Link, M. P., Goorin, A. M., & Miser, A. W. (1986). The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. New England Journal of Medicine, 314(25), 1600–1606.

    Article  CAS  PubMed  Google Scholar 

  6. Eilber, F., Giuliano, A., & Eckhardt, J. (1987). Adjuvant chemotherapy for osteosarcoma: A randomized prospective trial. Journal of Clinical Oncology, 5(1), 21–26.

    CAS  PubMed  Google Scholar 

  7. Jaffe, N. (2014). Historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma in current advances in osteosarcoma. In: Kleinerman, E. S. (Ed.), Advances in experimental medicine and biology (Vol 804, pp. 1–30). University Springer Cham Heidelberg New York Dordrecht London Springer International Publishing Switzerland.

  8. Le Deley, M.-C., Guinebretiere, J.-M., Gentet, J.-C., Pacquement, H., et al. (2007). SFOP OS94: A randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. European Journal of Cancer, 43, 752–761.

    Article  PubMed  Google Scholar 

  9. Haddox, C. L., Han, G., Anijar, L., Binitie, O., Letson, G. D., Bui, M. M., Damon, R., & Reed, D. R. (2014). Osteosarcoma in pediatric patients and young adults: A single institution retrospective review of presentation, therapy, and outcome. Sarcoma, Volume 2014, Article ID 402509.

  10. Kushnir, I., Kolander, Y., Bickels, J., Gortzak, Y., Flusser, G., Issakov, J., et al. (2014). Is it important to maintain high-dose intensity chemotherapy in the treatment of adults with osteosarcoma? Medical Oncology, 31, 936.

    Article  CAS  PubMed  Google Scholar 

  11. Rosen, G., Marcove, R. C., Caparros, B., Nirenberg, A., Kosloff, C., & Huvos, A. G. (1979). Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer, 43(6), 2163–2177.

    Article  CAS  PubMed  Google Scholar 

  12. Rosen, G., Caparros, B., Huvos, A. G., et al. (1982). Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer, 49(6), 1221–1230.

    Article  CAS  PubMed  Google Scholar 

  13. Bacci, G., Ferrari, S., Lari, S., et al. (2002). Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. Journal of Bone & Joint Surgery, 84(1):88–92.

  14. Eselgrim, M., Grunert, H., Kühne, T., et al. (2006). Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials. Pediatric Blood & Cancer, 47(1):42–50.

  15. Lewis, I. J., Weeden, S., Machin, D., Stark, D., & Craft, A. W. (2000). Received dose and dose-intensity of chemotherapy and outcome in nonmetastatic extremity osteosarcoma. European Osteosarcoma Intergroup. J Clin Oncol., 18(24), 4028–4037.

    CAS  Google Scholar 

  16. Fuchs, N., Bielack, S. S., Epler, D., et al. (1998). Long-term results of the cooperative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Annals of Oncology, 9(8), 893–899.

    Article  CAS  PubMed  Google Scholar 

  17. Gentet, J.-C., Brunat-Mentigny, M., Demaille, M. C., Pein, F, Avet-Loiseau, H., et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. European Journal of Cancer, 33(2):232–237.

  18. Bacci, G., Longhi, A., Versari, M., Mercuri, M., Briccoli, A., & Picci, P. (2006). Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy 15-year experience in 789 patients treated at a single Institution. Cancer, 106, 1154–1161.

    Article  PubMed  Google Scholar 

  19. Miwa, S., Takeuchi, A., Ikeda, H., Shirai, T., Yamamoto, N., et al. (2013). Prognostic value of histological response to chemotherapy in osteosarcoma patients receiving tumor-bearing frozen autograft. PLoS ONE, 8(8), e71362.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Davis, A. M., Bell, R. S., & Goodwin, P. J. (1994). Prognostic factors in osteoarcoma:a critical review. Journal of Clinical Oncology, 12(2), 423–431.

    CAS  PubMed  Google Scholar 

  21. Liu, S., Yi, Z., Ling, M., Shi, J., Qiu, Y., & Yang, S. Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy. Tumor Biology. doi:10.1007/s13277-014-1917-x.

  22. Sun, Xin, Guo, Wei, & Yang, Rongli. (2010). Follow-up analysis of 99 cases of non-metastatic Osteosarcoma. Chinese Journal of Orthopaedics, 30(7), 666–671.

    Google Scholar 

  23. Meyers, P. A., Heller, G., & Healey, J. H. et al. (1993). Osteogenic sarcoma with clinically detectable metastasis at initial presentation. Journal of Clinical Oncology, 11, 449–453.

  24. Bacci, G., Mercuri, M., Bnccoli, A., et al. (1997). Osteogenic sarcoma of the extremity with detectable lung metastases at presentation. Results of treatment of 23 patients with chemotherapy followed by simultaneous resection of primary and metastatic lesions. Cancer, 79, 245–254.

    Article  CAS  PubMed  Google Scholar 

  25. Harris, M. B., Gieser, P., Goorin, A. M., et al. (1998). Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group Study. Journal of Clinical Oncology, 16, 3641–3648.

    CAS  PubMed  Google Scholar 

  26. Niu, X., & Ding, Y. (2008). Treatment for Osteosarcoma with pathological fractures. Chin J Surg, 46(22), 1730–1733.

    PubMed  Google Scholar 

  27. Ferrari, S., Bertoni, F., Mercuri, M., et al. (2001). Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: An analysis of 300 patients treated at the Rizzoli Institute. Annals of Oncology, 12(8), 1145–1150.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, The Third People’s Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, People’s Republic of China

    Yunxia Liu, Yefeng Xu, Shenjun Jiang & Yiqing Wang

  2. Department of Orthopedics, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310009, People’s Republic of China

    Nong Lin & Zhaoming Ye

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  1. Yunxia Liu
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  2. Yefeng Xu
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  3. Nong Lin
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  4. Shenjun Jiang
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  5. Yiqing Wang
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  6. Zhaoming Ye
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Correspondence to Yunxia Liu or Zhaoming Ye.

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Yunxia Liu and Zhaoming Ye contributed equally to this study.

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Liu, Y., Xu, Y., Lin, N. et al. High-Dose Methotrexate (HD-MTX) Used as an Adjunct with Other Chemotherapeutics for the Treatment of Osteosarcoma. Cell Biochem Biophys 71, 1097–1104 (2015). https://doi.org/10.1007/s12013-014-0314-9

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