大剂量甲氨蝶呤(HD-MTX)联合利妥昔单抗治疗初发原发性中枢神经系统淋巴瘤(PCNSL)的疗效
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摘要
目的大剂量甲氨蝶呤(high-dose methotrexate,HD-MTX)联合利妥昔单抗(rituximab,R)与单用HDMTX治疗初发的原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)效果的评价。方法收集2012年1月1日至2015年12月31日在复旦大学附属华山医院就诊的初发PCNSL患者的临床资料,采用回顾性的队列研究,对于接受HD-MTX联合R及单用HD-MTX治疗的患者进行疗效和预后的生存分析。结果共有73例患者纳入研究,HD-MTX+R组38例,HD-MTX组35例。HD-MTX+R组患者的完全缓解(complete response,CR)率为84%,HD-MTX组患者的CR率为83%(P=0.878)。HD-MTX+R组患者的中位生存时间(overall survival,OS)为53个月,HD-MTX组患者的中位生存时间为27个月(P=0.047)。HD-MTX+R组患者的中位无进展生存期(progression-free survival,PFS)为44个月,HD-MTX组患者的中位无进展生存期为17个月(P=0.02)。两组患者两组的不良反应发生率差异无统计学意义。结论 HD-MTX+R组与HD-MTX组相比CR率相似,但是加用R有利于延长PCNSL患者的OS和PFS,且加用R不会增加不良反应。
Objective To evaluate therapeutic effect of high-dose methotrexate(HD-MTX)combined with rituximab(R)compared with HD-MTX in patients with newly diagnosed primary central nervous system lymphomas(PCNSLs). Methods With a retrospective cohort,we collected the clinical data of patients with newly diagnosed PCNSL at Huashan Hospital of Fudan University since 2012 January 1to 2015 December 31.We analyzed the therapeutic effect and prognosis of the patients received HDMTX combined with R and HD-MTX. Results A total of 73 patients were identified,38 received HD-MTX+R,35 received HD-MTX.Complete response(CR)rates was 84%in the HD-MTX+R group and 83%in the HD-MTX group(P=0.878).Median overall survival(OS)was 53 months in the HD-MTX+R group and 27 months in the HD-MTX group(P=0.047).Median progression-free survival(PFS)was 44 months in the HD-MTX+R group and17 months in the HD-MTX group(P=0.020).The differences of incidence of adverse between the two groups had no statistical significance.Conclusions CR rate of HD-MTX+ R and HD-MTX cohorts is similar,meanwhile addition of rituximab to HD-MTX appears to improve OS and PFS without increasing adverse reactions in patients with newly diagnosed PCNSL.
Objective To evaluate therapeutic effect of high-dose methotrexate(HD-MTX)combined with rituximab(R)compared with HD-MTX in patients with newly diagnosed primary central nervous system lymphomas(PCNSLs). Methods With a retrospective cohort,we collected the clinical data of patients with newly diagnosed PCNSL at Huashan Hospital of Fudan University since 2012 January 1to 2015 December 31.We analyzed the therapeutic effect and prognosis of the patients received HDMTX combined with R and HD-MTX. Results A total of 73 patients were identified,38 received HD-MTX+R,35 received HD-MTX.Complete response(CR)rates was 84%in the HD-MTX+R group and 83%in the HD-MTX group(P=0.878).Median overall survival(OS)was 53 months in the HD-MTX+R group and 27 months in the HD-MTX group(P=0.047).Median progression-free survival(PFS)was 44 months in the HD-MTX+R group and17 months in the HD-MTX group(P=0.020).The differences of incidence of adverse between the two groups had no statistical significance.Conclusions CR rate of HD-MTX+ R and HD-MTX cohorts is similar,meanwhile addition of rituximab to HD-MTX appears to improve OS and PFS without increasing adverse reactions in patients with newly diagnosed PCNSL.
引文
[1] SWERDLOW SH.WHO classification of tumors of hematopoietic and lymphoid tissues[C].2008.
[2] RUBENSTEIN J,FERRERI AJM,PITTALUGA S.Primary lymphoma of the central nervous system:epidemiology,pathology and current approaches to diagnosis,prognosis and treatment[J].Leukemia Lymphoma,2015,49(suppl 1):43-51.
[3] SCHFER N,GLAS M,HERRLINGER U.Primary CNS lymphoma:a clinician’s guide[J].Expert Review Neurotherapeutics,2012,12(10):1197-1206.
[4] HOANG-XUAN K,BESSELL E,BROMBERG J,et al.Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients:guidelines from the European Association for Neuro-Oncology[J].Lancet Oncol,2015,16(7):e322-e332.
[5] MURAKAMI M,FUJIMAKI T,ASANO S,et al.Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma[J].Yonsei Med J,2011,52(6):1031.
[6] FRITSCH K, KASENDAB, HADERC,et al.Immunochemotherapy with rituximab, methotrexate,procarbazine,and lomustine for primary CNS lymphoma(PCNSL)in the elderly[J].Annals Oncol,2011,22(9):2080-2085.
[7] BIRNBAUM T,STADLER EA,VON BAUMGARTEN L,et al.Rituximab significantly improves complete response rate in patients with primary CNS lymphoma[J].J Neuro-Oncol,2012,109(2):285-291.
[8] ZHANG J,CHEN B,XU X.Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma:a systematic review and meta-analysis[J].Leukemia Lymphoma,2015,55(3):509-514.
[9]孙步彤,赵亚男,卢振霞.淋巴瘤合并HBV感染的临床研究[C].第十四届全国临床肿瘤学大会暨2011年CSCO学术年会,厦门,2011.
[10] SANCHEZ MJ,BUTI M,HOMS M,et al.Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab[J].J Hepatol,2009,51(6):1091-1096.
[11] MARTYAK LA, TAQAVIE, SAABS. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients:a meta-analysis[J].Liver Int,2008,28(1):28-38.
[12] ABREY LE,BATCHELOR TT,FERRERI AJ,et al.Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma[J].J Clin Oncol,2005,23(22):5034-5043.
[13] GHESQUIERES H,DROUET Y,SUNYACH MP,et al.Evidence of time-dependent prognostic factors predicting early death but not long-term outcome in primary CNS lymphoma:a study of 91patients[J].Hematol Oncol,2013,31(2):57-64.
[14] FERRERI AJM, VERONAC, POLITILS,et al.Consolidation radiotherapy in primary central nervous system lymphomas:impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy[J].Int J Rad Oncol Biol Phy,2011,80(1):169-175.
[15] THIEL E,KORFEL A,MARTUS P,et al.High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma(G-PCNSL-SG-1):a phase 3,randomised,non-inferiority trial[J].Lancet Oncol,2010,11(11):1036-1047.
[16] KUMAR R,LAACK N,POLLOCK BE,et al.Stereotactic Radiosurgery in the treatment of recurrent CNS lymphoma[J].World Neurosurg,2015,84(2):390-397.
[17] DOLECEK TA,PROPP JM,STROUP NE,et al.CBTRUS statistical report:primary brain and central nervous system tumors diagnosed in the United States in 2005-2009[J].Neuro-Oncol,2012,14(suppl 5):v1-v49.
[18] KADAN-LOTTICK NS,SKLUZACEK MC,GURNEY JG.Decreasing incidence rates of primary central nervous system lymphoma[J].Cancer,2002,95(1):193-202.
[19] VILLANO JL,KOSHY M,SHAIKH H,et al.Age,gender,and racial differences in incidence and survival in primary CNS lymphoma[J].Br J Cancer,2011,105(9):1414-1418.
[20] BESSELL EM,DICKINSON P,DICKINSON S,et al.Increasing age at diagnosis and worsening renal function in patients with primary central nervous system lymphoma[J].J Neuro-Oncol,2011,104(1):191-193.
[21] O′NEILL BP,DECKER PA,TIEU C,et al.The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin's lymphoma[J].Amer J Hematol,2013,88(12):997-1000.
[22] MORRIS PG, CORREADD, YAHALOMJ,et al.Rituximab, methotrexate,procarbazine,andvincristine followedbyconsolidationreduced-dosewhole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma:final results and long-term outcome[J].J Clin Oncol,2013,31(31):3971-3979.
[23] ABREY LE,BEN-PORAT L,PANAGEAS KS,et al.Primary central nervous system lymphoma:The Memorial Sloan-Kettering Cancer Center prognostic model[J].J Clin Oncol,2006,24(36):5711-5715.
[24] SCHULTZ C,SCOTT C,SHERMAN W,et al.Preirradiation chemotherapywithcyclophosphamide, doxorubicin,vincristine,and dexamethasone for primary CNS lymphomas:Initial report of Radiation Therapy Oncology Group protocol88-06[J].J Clin Oncol,1996,14(2):556-564.
[25] MEAD GM,BLEEHEN NM,GREGOR A,et al.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[J].Cancer,2000,89(6):1359-1370.
[26] HIRAGA S,ARITA N,OHNISHI T,et al.Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas[J].J Neurosurg,1999,91(2):221-230.
[27] GERSTNER ER,CARSON KA,GROSSMAN SA,et al.Long-term outcome in PCNSL patients treated with highdose methotrexate and deferred radiation[J].Neurology,2008,70(5):401-402.
[28] HERRLINGER U,KUKER W,UHL M,et al.NOA-03trial of high-dose methotrexate in primary central nervous system lymphoma:final report[J].Ann Neurol,2005,57(6):843-847.
[29] TAOKA K,OKOSHI Y,SAKAMOTO N,et al. A nonradiation-containing, intermediate-dosemethotrexate regimen for elderly patients with primary central nervous system lymphoma[J].Int J Hematol,2010,92(4):617-623.
[30] HOANG-XUAN K. Chemotherapyaloneasinitial treatment for primary cns lymphoma in patients older than60 years:a multicenter phase ii study(26952)of the european organization for research and treatment of cancer brain tumor group[J].J Clin Oncol,2003,21(14):2726-2731.
[31] RUBENSTEIN JL,COMBS D,ROSENBERG J,et al.Rituximab therapy for CNS lymphomas:targeting the leptomeningeal compartment[J].Blood,2003,101(2):466-468.
[32] HOLDHOFF M,AMBADY P,ABDELAZIZ A,et al.High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma[J].Neurology,2014,83(3):235-239.
[33] MADLE M,KRMER I,LEHNERS N,et al.The influence of rituximab,high-dose therapy followed by autologous stem cell transplantation,and age in patients with primary CNS lymphoma[J].Ann Hematol,2015,94(11):1853-1857.
[34] KANSARA R,SHENKIER TN,CONNORS JM,et al.Rituximab with high-dose methotrexate in primary central nervous system lymphoma[J].Amer J Hematol,2015,90(12):1149-1154.
[35] RUBENSTEIN JL,FRIDLYAND J,ABREY L,et al.Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma[J].J Clin Oncol,2007,25(11):1350-1356.
[36] CHAMBERLAIN MC, JOHNSTONSK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma[J].Neuro-Oncol,2010,12(7):736-744.
[37] CHAMBERLAIN MC.High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma[J].Neurology,2015,84(7):758-759.
[38] LIU J,SUN XF,QIAN J,et al.Immunochemotherapy for primarycentralnervoussystemlymphomawith rituximab,methotrexate,cytarabine and dexamethasone:Retrospective analysis of 18 cases[J].Mol Clin Oncol,2015,3(4):949-953.
[39] KASI PM,TAWBI HA,ODDIS CV,et al.Clinical review:Serious adverse events associated with the use of rituximab-a critical care perspective[J].Crit Care,2012,16(4):231.
[2] RUBENSTEIN J,FERRERI AJM,PITTALUGA S.Primary lymphoma of the central nervous system:epidemiology,pathology and current approaches to diagnosis,prognosis and treatment[J].Leukemia Lymphoma,2015,49(suppl 1):43-51.
[3] SCHFER N,GLAS M,HERRLINGER U.Primary CNS lymphoma:a clinician’s guide[J].Expert Review Neurotherapeutics,2012,12(10):1197-1206.
[4] HOANG-XUAN K,BESSELL E,BROMBERG J,et al.Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients:guidelines from the European Association for Neuro-Oncology[J].Lancet Oncol,2015,16(7):e322-e332.
[5] MURAKAMI M,FUJIMAKI T,ASANO S,et al.Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma[J].Yonsei Med J,2011,52(6):1031.
[6] FRITSCH K, KASENDAB, HADERC,et al.Immunochemotherapy with rituximab, methotrexate,procarbazine,and lomustine for primary CNS lymphoma(PCNSL)in the elderly[J].Annals Oncol,2011,22(9):2080-2085.
[7] BIRNBAUM T,STADLER EA,VON BAUMGARTEN L,et al.Rituximab significantly improves complete response rate in patients with primary CNS lymphoma[J].J Neuro-Oncol,2012,109(2):285-291.
[8] ZHANG J,CHEN B,XU X.Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma:a systematic review and meta-analysis[J].Leukemia Lymphoma,2015,55(3):509-514.
[9]孙步彤,赵亚男,卢振霞.淋巴瘤合并HBV感染的临床研究[C].第十四届全国临床肿瘤学大会暨2011年CSCO学术年会,厦门,2011.
[10] SANCHEZ MJ,BUTI M,HOMS M,et al.Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab[J].J Hepatol,2009,51(6):1091-1096.
[11] MARTYAK LA, TAQAVIE, SAABS. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients:a meta-analysis[J].Liver Int,2008,28(1):28-38.
[12] ABREY LE,BATCHELOR TT,FERRERI AJ,et al.Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma[J].J Clin Oncol,2005,23(22):5034-5043.
[13] GHESQUIERES H,DROUET Y,SUNYACH MP,et al.Evidence of time-dependent prognostic factors predicting early death but not long-term outcome in primary CNS lymphoma:a study of 91patients[J].Hematol Oncol,2013,31(2):57-64.
[14] FERRERI AJM, VERONAC, POLITILS,et al.Consolidation radiotherapy in primary central nervous system lymphomas:impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy[J].Int J Rad Oncol Biol Phy,2011,80(1):169-175.
[15] THIEL E,KORFEL A,MARTUS P,et al.High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma(G-PCNSL-SG-1):a phase 3,randomised,non-inferiority trial[J].Lancet Oncol,2010,11(11):1036-1047.
[16] KUMAR R,LAACK N,POLLOCK BE,et al.Stereotactic Radiosurgery in the treatment of recurrent CNS lymphoma[J].World Neurosurg,2015,84(2):390-397.
[17] DOLECEK TA,PROPP JM,STROUP NE,et al.CBTRUS statistical report:primary brain and central nervous system tumors diagnosed in the United States in 2005-2009[J].Neuro-Oncol,2012,14(suppl 5):v1-v49.
[18] KADAN-LOTTICK NS,SKLUZACEK MC,GURNEY JG.Decreasing incidence rates of primary central nervous system lymphoma[J].Cancer,2002,95(1):193-202.
[19] VILLANO JL,KOSHY M,SHAIKH H,et al.Age,gender,and racial differences in incidence and survival in primary CNS lymphoma[J].Br J Cancer,2011,105(9):1414-1418.
[20] BESSELL EM,DICKINSON P,DICKINSON S,et al.Increasing age at diagnosis and worsening renal function in patients with primary central nervous system lymphoma[J].J Neuro-Oncol,2011,104(1):191-193.
[21] O′NEILL BP,DECKER PA,TIEU C,et al.The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin's lymphoma[J].Amer J Hematol,2013,88(12):997-1000.
[22] MORRIS PG, CORREADD, YAHALOMJ,et al.Rituximab, methotrexate,procarbazine,andvincristine followedbyconsolidationreduced-dosewhole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma:final results and long-term outcome[J].J Clin Oncol,2013,31(31):3971-3979.
[23] ABREY LE,BEN-PORAT L,PANAGEAS KS,et al.Primary central nervous system lymphoma:The Memorial Sloan-Kettering Cancer Center prognostic model[J].J Clin Oncol,2006,24(36):5711-5715.
[24] SCHULTZ C,SCOTT C,SHERMAN W,et al.Preirradiation chemotherapywithcyclophosphamide, doxorubicin,vincristine,and dexamethasone for primary CNS lymphomas:Initial report of Radiation Therapy Oncology Group protocol88-06[J].J Clin Oncol,1996,14(2):556-564.
[25] MEAD GM,BLEEHEN NM,GREGOR A,et al.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[J].Cancer,2000,89(6):1359-1370.
[26] HIRAGA S,ARITA N,OHNISHI T,et al.Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas[J].J Neurosurg,1999,91(2):221-230.
[27] GERSTNER ER,CARSON KA,GROSSMAN SA,et al.Long-term outcome in PCNSL patients treated with highdose methotrexate and deferred radiation[J].Neurology,2008,70(5):401-402.
[28] HERRLINGER U,KUKER W,UHL M,et al.NOA-03trial of high-dose methotrexate in primary central nervous system lymphoma:final report[J].Ann Neurol,2005,57(6):843-847.
[29] TAOKA K,OKOSHI Y,SAKAMOTO N,et al. A nonradiation-containing, intermediate-dosemethotrexate regimen for elderly patients with primary central nervous system lymphoma[J].Int J Hematol,2010,92(4):617-623.
[30] HOANG-XUAN K. Chemotherapyaloneasinitial treatment for primary cns lymphoma in patients older than60 years:a multicenter phase ii study(26952)of the european organization for research and treatment of cancer brain tumor group[J].J Clin Oncol,2003,21(14):2726-2731.
[31] RUBENSTEIN JL,COMBS D,ROSENBERG J,et al.Rituximab therapy for CNS lymphomas:targeting the leptomeningeal compartment[J].Blood,2003,101(2):466-468.
[32] HOLDHOFF M,AMBADY P,ABDELAZIZ A,et al.High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma[J].Neurology,2014,83(3):235-239.
[33] MADLE M,KRMER I,LEHNERS N,et al.The influence of rituximab,high-dose therapy followed by autologous stem cell transplantation,and age in patients with primary CNS lymphoma[J].Ann Hematol,2015,94(11):1853-1857.
[34] KANSARA R,SHENKIER TN,CONNORS JM,et al.Rituximab with high-dose methotrexate in primary central nervous system lymphoma[J].Amer J Hematol,2015,90(12):1149-1154.
[35] RUBENSTEIN JL,FRIDLYAND J,ABREY L,et al.Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma[J].J Clin Oncol,2007,25(11):1350-1356.
[36] CHAMBERLAIN MC, JOHNSTONSK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma[J].Neuro-Oncol,2010,12(7):736-744.
[37] CHAMBERLAIN MC.High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma[J].Neurology,2015,84(7):758-759.
[38] LIU J,SUN XF,QIAN J,et al.Immunochemotherapy for primarycentralnervoussystemlymphomawith rituximab,methotrexate,cytarabine and dexamethasone:Retrospective analysis of 18 cases[J].Mol Clin Oncol,2015,3(4):949-953.
[39] KASI PM,TAWBI HA,ODDIS CV,et al.Clinical review:Serious adverse events associated with the use of rituximab-a critical care perspective[J].Crit Care,2012,16(4):231.