Fotemustine,Teniposide And Dexamethasone Versus High-dose Methotrexate Plus Cytarabine In Newly Diagnosed Primary Cns Lymphoma

ObjectivePrimary central nervous system lymphoma(PCNSL)is a rare and aggressive extranodal non-Hodgkin lymphoma(NHL).It is confined to the brain,eyes,spinal cord,or leptomeninges without systemic involvement at the time of diagnosis.It accounts for up to 4%?6%of NHL cases and approximately 2%?4%of all primary central nervous system(CNS)tumors,with increasing incidence.PCNSL is a highly aggressive non-Hodgkin lymphoma,usually of diffuse large B-cell histology(DLBCL),which can occur in patients with normal and defective immune function.Treatment of PCNSL has evolved over the last decades,but no uniform consensus on the optimal treatment regimen exists currently.Experts in the field agree that high-dose methotrexate(HD-MTX)is the backbone of multimodal therapy.Survival rates in clinical studies have improved due to the addition of high-dose methotrexate-based chemotherapy regimens to whole-brain radiotherapy(WBRT).Long-term survival,however,is complicated by clinically devastating delayed neurotoxicity.Given these unsatisfactory outcomes,it is imperative to develop more effective and less toxic innovative therapeutic regimens for PCNSL.This prospective,randomized,controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen(fotemustine,teniposide and dexamethasone)compared to HD-MA therapy(high-dose methotrexate plus cytarabine)and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma in a clinical trial setting.Methods1.Immunocompetent patients with newly diagnosed PCNSL according to the World Health Organization criteria treated at the lymphoma center of the First Affiliated Hospital of the Zhengzhou University between November 2011 and November 2015 were eligible.The diagnosis was established by a neuro-pathological analysis of tumor samples using conventional histology and immuno-histochemistry with CD20,Bcl-6,MUM1,CD10 and MIB-1 staining.The inclusion criteria were as follows:(1)age range 14?69 years old;(2)Eastern Cooperative Oncology Group(ECOG)performance status 0-2;(3)estimated survival time>3 months;(4)histologically confirmed PCNSL;(5)no previous chemotherapy or radiotherapy;(6)no chemotherapy contraindications;(7)at least one measurable lesion;(8)no other serious diseases;(9)negative pregnancy test for women of reproductive age;(10)patients could be followed-up and submitted written informed consent;and(11)no other relative treatments including traditional Chinese medicine,immunotherapy,and biotherapy,except for symptomatic treatments.2.Randomisation and Treatment regimen:After staging,if the patients fulfilled the entry criteria,they were randomized in a 1:1 ratio based on a computer-generated randomisation schedule to receive either the FTD or HD-MA therapeutic regimen.The FTD regimen included fotemustine 100 mg/m~2,1h infusion,on day 1;teniposide 60mg/m~2,>0.5 h infusion,on days 2?4;and dexamethasone 40mg,1h infusion,on days1-5.The HD-MA therapy combined methotrexate 3.5 g/m2,0.5 g/m2in 15 min,followed by 3.0 g/m2in a 6h infusion on day 1;and cytarabine 1.0 g/m21h infusion,every 12h,on days 2?3.Both regimens were administered methotrexate 12mg,cytarabine 50mg plus dexamethasone 5mg intrathecally,days 2 and 7.Dosage adjustments should be made during treatments(decrease up to 80%of planned doses)in patients who develop grade 3 or 4 neutropenia or thrombocytopenia to maintain the timing of chemotherapy.Each cycle was repeated 4 times every 21 days,unless there was evidence of progressive disease(PD)or significant toxicity to contraindicate continuation of the treatment.Efficacy was evaluated every 2 cycles.The patients in CR and those with a PR after two chemotherapy cycles received two more cycles of the same regimen.After four chemotherapy cycles,patients aged 60 years or younger in CR were treated with30Gy consolidating WBRT;those older than 60 years in CR were treated with watchful waiting.Patients who had PD at any time and patients without CR after four chemotherapy cycles,regardless of age,were referred for rescue WBRT with 30Gy plus a 15Gy boost.This work was approved by the Local Ethics Committee of Zhengzhou University and the Scientific Council of the Faculty of Medicine.All patients were fully informed about the nature and possible toxicities of the treatment protocol and submitted written informed consent.3.Assessment of adverse effects and response criteria:Adverse reactions were monitored by biochemistry and hematological tests,electrocardiograms and routine physical examination.These reactions were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0 and assessed from the first cycle of the regimen until one month after the terminal treatment,and delayed neurotoxicity assessed by clinical examination,and by white matter changes or brain atrophy on MRI or CT.The response definition was based on changes in the tumor size of enhanced lesions on MRI,which was performed every two cycles and after WBRT,following the International PCNSL Collaborative Group(IPCG)Response Criteria.4.Statistical analysis:The primary objectives were to assess the overall response rate(ORR),PFS and overall survival(OS).Several secondary endpoints included assessing toxicity and investigating the immunophenotypic markers influencing outcomes.PFS was defined as the time from diagnosis to disease recurrence,disease progression,or death.OS was defined as the time from diagnosis to death or to the last follow-up.We analyzed the differences between therapeutic groups in response rates with the?test.Mann-Whitney tests were used to compare quantitative and ordinal variables.The Kaplan-Meier method was used for the univariate analysis of survival,with the assessment of differences by the log-rank test.A multivariate analysis was performed using the Cox proportional hazard model.All P values reported were two-sided,and P<0.05 was considered statistically significant.Follow-up was closed for analysis in November 2017.Statistical analyses were performed with SPSS version 21(SPSS,Inc.,Chicago,IL,USA)and GraphPad Prism 6(GraphPad Software Inc.,La Jolla,CA,USA).Results1.Baseline characteristics of the patients:Forty-nine patients with PCNSL were recruited between November 2011 and November 2015.24 patients were randomly allocated to FTD group,25 to HD-MA group.The median age at initial diagnosis of PCNSL was 55 years(range,16?69 years),and 30(61%)patients were male.Thirty-three(67%)patients were aged 60 years or younger,and 23(47%)patients had elevated LDH levels.Twenty-eight(57%)patients had elevated CSF protein levels.Major clinical characteristics observed in the patients were increased intracranial pressure and focal neurological deficits.Enhanced MRI scan showed that the signal intensity of T1phase was slightly low or that of equal signal signal T2 phase was equal signal or high signal intensity.Most of the patients showed homogeneous or nodular enhancement after enhanced imaging.A few patients have midline displacement or ventricle compression.Eventually,of the 49 eligible patients,diffuse large B-cell lymphoma was diagnosed in 47 cases(96%),Burkitt lymphoma in 1 cases(2%),B-cell lymphoma in1 cases(2%).Two(4%)patients had concurrent sites of CNS involvement:one intraocular,and one spinal cord.Patient characteristics were well balanced,and no significant differences were observed between the FTD(24 cases)and HD-MA(25cases)groups(P?0.05).The frequencies of expression for Bcl-2,Bcl-6,c-Myc,MUM-1,CD5,CD10,PTEN and p53 were 61%,65%,57%,73%,59%,33%,53%and 55%,respectively.Seventeen of the 49 patients(35%)showed high tumor cell proliferation(?90%).2.Response and Outcomes:All patients were evaluable for response.At the end of chemotherapy,8(33%)of 24 patients in FTD group,10(40%)of 25 in HD-MA group achieved a complete response.13 patients in FTD group,11 in HD-MA group achieved a partial response,with an overall response rate of 88%in FTD group and 84%in HD-MA group,whereas no significant difference was detected in terms of the ORR between the FTD group and the HD-MA group(P=0.628).At a median follow-up time of 28.8 months(range,4.2?74.0 months)for eligible patients,the 2-year PFS rate was37%in the FTD group and 39%in the HD-MA group(P=0.984)with a median PFS of17.4 months(95%CI 13.9?20.1)versus 16.7 months(95%CI 5.2?28.4),respectively.The 3-year OS rate was 51%and 46%in the FTD and HD-MA groups,respectively(P=0.509),with a median OS of 48.8 months(95%CI 24.2?73.4)versus44.9 months(95%CI 18.7?71.2),respectively.No significant differences were recorded for either PFS or OS in patients from the two treatment groups.3.Toxicity:Adverse reactions were assessed in all eligible patients,including hematological and non-hematological toxicities.The HD-MA group showed more serious neutropenia(P=0.009)and hepatic dysfunction(P=0.010)than the FTD group.In addition,one case underwent grade 4 infection,which led to patient death in the HD-MA arm.Delayed neurotoxicity on MRI or CT was assessed in 42 patients,FTD group followed by WBRT in 5 cases and HD-MA group followed by WBRT in 8 cases(P=0.317).4.Survival analysis:The univariate analysis suggested that age(60 years or younger),ECOG performance status of?1,and the expression of Bcl-6 were significantly associated with improved OS.Multivariate analysis showed that age was the independent risk factor.Conclusions1.FTD chemotherapy appeared to be safe and effective for PCNSL patients.2.Both age,ECOG performance status and Bcl-6 expression were significantly associated with overall survival and age was the independent risk factor.