J Korean Med Sci.  2011 Apr;26(4):551-560. 10.3346/jkms.2011.26.4.551.

Factors Influencing the Response to High Dose Methotrexate-based Vincristine and Procarbazine Combination Chemotherapy for Primary Central Nervous System Lymphoma

• Sung KH
• Lee EH
• Kim YZ

• KMID: 1777887
• DOI: http://doi.org/10.3346/jkms.2011.26.4.551

Abstract

The authors investigated objective response rate to high dose methotrexate (HDMTX)-based combination chemotherapy in primary central nervous system lymphoma (PCNSL), and sought to identify factors that influence response to HDMTX-based combination therapy. Prospective observational analysis was performed on 52 PCNSL patients. All patients received HDMTX (3.5 g/m2) and vincristine (1.4 mg/m2/day) for one day during weeks 1, 3, 5, 7, and 9, and procarbazine (100 mg/m2/day) for one week during weeks 1, 5, and 9. Forty-one patients (78.8%) achieved complete or partial remission. Higher objective response rates were observed for patients with: 1) age < 60 yr; 2) Eastern Cooperative Oncology Group (ECOG) performance score of < 2; 3) low risk status as defined by the International Extranodal Lymphoma Study Group; 4) p53 positivity; 5) XBP-1 negativity; 6) MUM-1 negativity; and 7) homogenous gadolinium enhancement in MR images. Multivariate analysis showed that ECOG performance score of < 2, low risk, negativity for XBP-1, homogenous gadolinium enhancement by MRI, and response to chemotherapy were associated with longer overall survival. In particular, it is interesting to note that patients with a PCNSL that is homogenously enhanced by gadolinium have a higher objective response rate, and a longer progression-free survival and overall survival.

Keyword

Central Nervous System; Lymphoma; Response; Prognosis; Survival; Methotrexate; Chemotherapy

MeSH Terms

Adult
Age Factors
Aged
Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
Central Nervous System Neoplasms/*drug therapy/mortality
Contrast Media/chemistry/diagnostic use
DNA-Binding Proteins/metabolism
Disease-Free Survival
Drug Administration Schedule
Female
Follow-Up Studies
Gadolinium/chemistry/diagnostic use
Humans
Interferon Regulatory Factors/metabolism
Lymphoma/*drug therapy/mortality
Magnetic Resonance Imaging
Male
Methotrexate/*administration & dosage
Middle Aged
Odds Ratio
Procarbazine/*administration & dosage
Prospective Studies
Recurrence
Severity of Illness Index
Transcription Factors/metabolism
Tumor Suppressor Protein p53/metabolism
Vincristine/*administration & dosage

Figure

• 

  Fig. 1 Progression-free survival curves for the patients with homogeneously versus heterogeneously enhanced primary central nervous system lymphoma.

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  Fig. 2 Kaplan-Meier survival curves for the patients with homogeneously versus heterogeneously enhanced primary central nervous system lymphoma.

Reference

1. Lee CH, Jung KW, Yoo H, Park S, Lee SH. Epidemiology of primary brain and central nervous system tumors in Korea. J Korean Neurosurg Soc. 2010. 48:145–152.

2. Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol. 1999. 26:346–356.

3. Mead GM, Bleehen NM, Gregor A, Bullimore J, Shirley D, Rampling RP, Trevor J, Glaser MG, Lantos P, Ironside JW, Moss TH, Brada M, Whaley JB, Stenning SP. A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Cancer. 2000. 89:1359–1370.

4. Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, Fisher B, Abrams R, Meis-Kindblom J. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of Radiation Therapy Oncology Group protocol 88-06. J Clin Oncol. 1996. 14:556–564.

5. Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol. 1999. 43:241–247.

6. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000. 18:3144–3150.

7. Ferreri AJ, Reni M, Dell'Oro S, Ciceri F, Bernardi M, Camba L, Ponzoni M, Terreni MR, Tomirotti M, Spina M, Villa E. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology. 2001. 60:134–140.

8. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002. 20:4643–4648.

9. Ferreri AJ, Reni M, Villa E. Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials. Ann Oncol. 2000. 11:927–937.

10. Ferreri AJ, Abrey LE, Blay JY, Borisch B, Hochman J, Neuwelt EA, Yahalom J, Zucca E, Cavalli F, Armitage J, Batchelor T. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol. 2003. 21:2407–2414.

11. Ferreri AJ, Reni M, Pasini F, Calderoni A, Tirelli U, Pivnik A, Aondio GM, Ferrarese F, Gomez H, Ponzoni M, Borisch B, Berger F, Chassagne C, Iuzzolino P, Carbone A, Weis J, Pedrinis E, Motta T, Jouvet A, Barbui T, Cavalli F, Blay JY. A multicenter study of treatment of primary CNS lymphoma. Neurology. 2002. 58:1513–1520.

12. Herrlinger U, Küker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M. Neuro-Oncology Working Group of the German Society. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005. 57:843–847.

13. O'Brien PC, Roos DE, Pratt G, Liew KH, Barton MB, Poulsen MG, Olver IN, Trotter GE. Trans-Tasman Radiation Oncology Group. Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group). Int J Radiat Oncol Biol Phys. 2006. 64:408–413.

14. Ferreri AJ, Dell'Oro S, Foppoli M, Bernardi M, Brandes AA, Tosoni A, Montanari M, Balzarotti M, Spina M, Ilariucci F, Zaja F, Stelitano C, Bobbio F, Corazzelli G, Baldini L, Ponzoni M, Picozzi P, Caligaris Cappio F, Reni M. MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas. Neurology. 2006. 66:1435–1438.

15. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007. 25:4730–4735.

16. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982. 5:649–655.

17. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999. 17:1244.

18. Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell'Oro S, Zucca E, Cavalli F. Prognostic scoring system for primary CNS lymphomas: the International Exranodal Lymphoma Study Group Experience. J Clin Oncol. 2003. 21:266–272.

19. Chen BE, Kramer JL, Greene MH, Rosenberg PS. Competing risks analysis of correlated failure time data. Biometrics. 2008. 64:172–179.

20. Algazi AP, Kadoch C, Rubenstein JL. Biology and treatment of primary central nervous system lymphoma. Neurotherapeutics. 2009. 6:587–597.

21. Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F. International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomized phase 2 trial. Lancet. 2009. 374:1512–1520.

22. Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T, Treseler P, Berger M, McDermott M, Prados M, Karch J, Okada C, Hyun W, Parikh S, Haqq C, Shuman M. Gene expression and angiotropism in primary CNS lymphoma. Blood. 2006. 107:3716–3723.

23. Chang CC, McClintock S, Cleveland RP, Trzpuc T, Vesole DH, Logan B, Kajdacsy-Balla A, Perkins SL. Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma. Am J Surg Pathol. 2004. 28:464–470.

24. Lin CH, Kuo KT, Chuang SS, Kuo SH, Chang JH, Chang KC, Hsu HC, Tien HF, Cheng AL. Comparison of the expression and prognostic significance of differentiation markers between diffuse large B-cell lymphoma of central nervous system origin and peripheral nodal origin. Clin Cancer Res. 2006. 12:1152–1156.

25. Sugita Y, Tokunaga O, Nakashima A, Shigemori M. SHP-1 expression in primary central nervous system B-cell lymphomas in immunocompetent patients reflects maturation stage of normal B cell counterparts. Pathol Int. 2004. 54:659–666.

26. Momota H, Narita Y, Maeshima AM, Miyakita Y, Shinomiya A, Maruyama T, Muragaki Y, Shibui S. Prognostic value of immunohistochemical profile and response to high-dose methotrexate therapy in primary CNS lymphoma. J Neurooncol. 2010. 98:341–348.

27. Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K. Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neurooncol. 2007. 85:207–211.

28. Silvani A, Salmaggi A, Eoli M, Lamperti E, Broggi G, Marras CE, Fariselli L, Milanesi I, Fiumani A, Gaviani P, Erbetta A, Giovagnoli AR, Pollo B, Botturi A, Boiardi A. Methotrexate based chemotherapy and deferred radiotherapy for primary central nervous system lymphoma (PCNSL): single institution experience. J Neurooncol. 2007. 82:273–279.

29. Ferreri AJ, Crocchiolo R, Assaanelli A, Govi S, Reni M. High-dose chemotherapy supported by autologous stem cell transplantation in patients with primary central nervous system lymphoma: facts and opinions. Leuk Lymphoma. 2008. 49:2042–2047.