| Background and PurposePrimary central nervous system lymphoma(PCNSL)is a rare and aggressive extranodal non-hodgkin lymphoma(NHL),which is confined to the central nervous system without infringing other lymph nodes and lymphatic tissue.Due to the unique occurrence site and aggressive biological behavior,its clinical manifestations are complex,and the diagnosis and treatment are difficult.PCNSL tends to occur in the elderly,and its incidence increases with age,with a median age of onset of 65 years.The pathological type is mainly diffuse large B cell lymphoma(DLBCL),and the rest can also be manifested as lymphoblastic lymphoma,T cell lymphoma,Burkitt lymphoma and marginal zone lymphoma.Immunodeficiency is a clear high risk factor for the onset of PCNSL.Immunodeficiency patients include patients receiving immunosuppressive therapy,organ transplant patients,and human immunodeficiency virus(HIV)infection patients.In the past 30 years,the incidence of PCNSL in immunocompetent people has increased by nearly three times.Compared with other brain tumors,PCNSL is more sensitive to chemotherapy,but compared with other systemic DLBCL,the prognosis is poor,and the 5-year survival rate is only 20%-30%.The treatment of PCNSL includes two stages of induction chemotherapy and consolidation therapy.There is currently no standard treatment.High-dose methotrexate(HD-MTX)based chemotherapy combined with whole brain radiotherapy(WBRT)is the most commonly used treatment strategy.Chemotherapy combined with radiotherapy can significantly improve the efficacy,but the side effects associated with HD-MTX chemotherapy are severe,and some patients cannot tolerate it.Fotemustine is an anti-tumor drug that inhibits tumor growth and has better effect on brain malignant tumors in clinical studies.It is highly fat-soluble and easy to pass through the blood-brain barrier.The concentration in cerebrospinal fluid can reach 30%-50%of plasma concentration.Clinical studies have shown that fotemustine intravenous chemotherapy is effective and safe for central nervous system lymphoma.Therefore,it is listed as the first choice for brain tumor chemotherapy.Our center has carried out a prospective randomized controlled clinical trial of a fotemustine-based chemotherapy regimen comparing high-dose methotrexate combined with cytarabine in the first-line treatment of PCNSL.The results showed that the two regimens had equivalent efficacy,and the adverse reactions in the fotemustine group were mild.Based on the above results,this study intends to compare the clinical efficacy and adverse reaction occurrence of rituximab combined with fotemustine,pemetrexed,dexamethasone regimen compared with rituximab combined with high-dose methotrexate-based regimen(R-M)in PCNSL patients,in order to explore safe and effective treatment methods for patients in china and further analyze the relevant prognostic factors in PCNSL patients.Materials and Methods1.Inclusion criteria and exclusion criteria:A retrospective analysis of 64 newly-treated PCNSL patients who were treated at the First Affiliated Hospital of Zhengzhou University from January 1,2017 to September 1,2020,and all patients were diagnosed based on WHO blood and lymphoid tissue tumor classification scheme.The inclusion criteria:①.Age 14-80 years;②.Human Immunodeficiency Virus(HIV)negative;④.Naive patients who have not received radiotherapy,chemotherapy,or targeted therapy;④.PCNSL of tissue specimens confirmed by 2 pathologists;⑤.The lesion was confined to the central nervous system,and there was no systemic lymphoid hematopoietic tissue and other tissue involvement;⑥.At least one measurable lesion;⑦.No major organ dysfunction,no obvious contraindication of chemotherapy.The exclusion criteria are:①.Age<14 or>80 years;②.HIV positive;③.Previous anti-tumor treatments such as chemotherapy,immunotherapy,radiotherapy,targeted therapy,etc.;④.Pregnant or lactating women;⑤.Any uncontrollable medical disease(including severe organ dysfunction,uncontrollable active infection,interstitial pneumonia,etc.);⑥.Those with a history of uncontrollable mental illness;⑦.Previous experience with other malignancies;⑧Patients with chemotherapy contraindications such as dyscrasias.2.Treatment regimen:64 patients were divided into two groups according to the chemotherapy regimen.There were 36 patients in the R-FPD chemotherapygroup,of which 15 patients underwent WBRT after chemotherapy;28 patients in the methotrexate-based chemotherapy group,of which 14 patients underwent WBRT after chemotherapy,and 1 patient underwent autologous stem-cell transplantation.All patients received intrathecal injection of methotrexate MTX 12 mg+cytarabine Ara-C 50 mg+dexamethasone Dex 5 mg during chemotherapy.21 days as a cycle,the efficacy is evaluated every 2 cycles,and adverse reactions are recorded.3.Efficacy evaluation criteria:The efficacy evaluation refers to the evaluation consensus standards of the International PCNSL collaborative group(IPGG):it is divided into complete remission(CR),partial remission(PR),stable disease(SD)and progressive disease(PD).Adverse reactions during treatment were evaluated according to the National Cancer Institute CTCAE3.0.The overall survival time is recorded from diagnosis to death or the last follow-up time,and the progression-free survival time is recorded from diagnosis to disease recurrence,progression,death,start of new treatment or last follow-up time.4.Statistical methods:Statistical analysis were performed with SPSS21.0 software,based on follow-up data,calculates the remission rate and survival rate of the two groups.We analyzed the relevant factors of the classification data between the groups with chi-square test.The log-rank test was used to compare the survival rate,the Cox proportional hazard regression model was used for multivariate survival analysis;and the kaplan-Meier curve was used for survival analysis.Two-sided test P<0.05 indicates that the difference is statistically signifi cant.Results1.Clinical characteristics:A total of 64 patients were included in the retrospective analysis,including 29 males and 35 females.The male to female ratio was 1:1.2,and the median age of onset was 56 years(18-80 years).There were 43 patients(67.2%)aged ≤60 years,29 patients(45.3%)with an ECOG score of<2.All patients received serum lactate dehyrogenase(LDH)and β-2 microglobulin tests,31 patients(48.4%)had elevated serum LDH levels,and 3 patients(4.7%)had elevated β-2 microglobulin levels.The biochemical examination of cerebrospinal fluid protein(CSF protein)found that 33 patients(51.6%)had elevated protein levels.Thirty-eight patients(59.4%)had involvement of deep brain regions(including the basal ganglia,corpus callosum,paraventricle,brainstem and cerebellum).The main clinical manifestations are symptoms of increased intracranial pressure(such as headache,nausea,vomiting,etc.)and focal nervous system damage(including language expression disorders,limb weakness,incontinence,etc.).There were 36 patients in the R-FPD chemotherapy group,15 of them underwent WBRT after chemotherapy;28 patients in the RM combined chemotherapy group,of which 14 patients underwent WBRT after chemotherapy,and 1 patient underwent ASCT;29 patients in the chemotherapy combined radiotherapy group,34 cases in the chemotherapy alone group.There was no significant difference in age,gender,ECOG score,LDH level,cerebrospinal fluid protein level,and deep intracranial lesions between the two groups of patients(P>0.05).The pathological types of all patients were diffuse large B-cell lymphoma.2.Response and Outcomes:The deadline for follow-up is November 1,2020.The median follow-up time was 10(1-46)months.There were 2 patients who were lost due to the change of contact information,including 1 in R-FPD group and 1 in R-M combined chemotherapy group.The median PFS and median OS of the two groups were not reached.There were 36 patients in the R-FPD group.After 2 cycles of treatment,the ORR was 94.4%(34/36),including 1 CR,33 PR,1 SD,and 1 PD.The ORR evaluated after 4 cycles was 76.7%(23/30),including 13 cases of CR,10 cases of PR,4 cases of SD,and 3 cases of PD.Note:6 patients failed to perform the 4th cycle of efficacy evaluation(4 patients died of disease progression after 2 cycles,1 patient was lost to follow-up due to changes in contact information,and 1 patient had not completed 4 cycles of chemotherapy).There were 28 patients in the R-M combined chemotherapy group,and the ORR was 89.2%(25/28)after 2 cycles,including 2 CR,23 PR,1 SD,and 2 PD.The ORR evaluated after 4 cycles was 68%(17/25),including 6 cases of CR,11 cases of PR,2 cases of SD,and 7 cases of PD.Note:3 patients failed to evaluate the efficacy of the 4th cycle(2 patients died of disease progression after 2 cycles,and 1 patient was lost to follow-up due to a change in contact information).The difference in the 4-cycle remission rate between the two groups was not statistically significant(P=0.472).The ORR of the chemotherapy group and chemotherapy combined with radiotherapy group was 55%and 76%,respectively,and the difference was not statistically significant(P=0.073).The CR rates of the chemotherapy group and chemotherapy combined with radiotherapy group were 55%and 21%,respectively,and the difference was statistically significant(P=0.016)..There was no significant difference in PFS rate and OS rate between the two groups(P>0.05).3.Toxic and side effects:all patients were evaluated for adverse reactions.The incidence of hematological toxicity,liver damage and mucosal damage in the R-M combined chemotherapy group was significantly higher than that in the R-FPD chemotherapy group,and the difference was statistically significant(P<0.05).A total of 29 patients received radiotherapy.According to the follow-up results of the patients,delayed neurotoxicity occurred in 3 patients,1 in the R-FPD chemotherapy group,and 2 in the R-M combined chemotherapy group.The difference was not statistically significant(P=0.406).4.Prognostic analysis:The results of single factor analysis showed that age>60 years,increased LDH level,deep brain structure involvement,cerebrospinal fluid protein elevation,ECOG score≥2,β 2 microglobulin elevation,Bcl-2≥60%,Bcl-6 positive,C-myc<40%were poor prognostic factors(P<0.05).Multivariate analysis showed that deep brain structure involvement,Bcl-2≥60%,Bcl-6 positive,and 40%were prognostic risk factors.Conclusions1.The first-line treatment of R-FPD chemotherapy for PCNSL has the same effect as R-M combined chemotherapy,and the incidence of toxicity is low.2.Combination of chemotherapy and radiotherapy can improve the complete remission rate of PCNSL patients.3.Deep brain structure involvement,Bcl-2≥ 60%,Bcl-6 positive,and C-myc<40%are poor prognostic factors for PCNSL. |
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