Combination Therapy With Temozolomide And Whole-Brain Radiation For Recurrent Or Refractory Primary Central Nervous System Lymphoma

BackgroundPrimary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin’s lymphoma limited to the central nervous system (CNS). Untreated, patients survive only a few months; however, in the last 2 decades, it has become apparent that high dose (HD) methotrexate-based regimens can lead to median survivals of 21 to 51 months. Despite aggressive therapy, however, nearly 50% of patients will relapse within 24 months of diagnosis. Furthermore, the expectant survival after relapse of PCNSL is between 8 months and 14 months, depending on whether further treatment is instituted. There is no standard salvage treatment for relapsed or refractory patients, although numerous approaches have been tried using radiation therapy (RT) or chemotherapy with variable degrees of activity. Unfortunately, the majority of patients with relapsed PCNSL still die from their disease. Methotrexate, WBRT, TMZ, rituximab ASCT, pemetrexed, topotecan and other therapeutic agents have used to treat it with salvage therapies, however, there is no standard regimen.ObjectiveThis study evaluates the efficacy and toxicity of whole-brain radiation therapy (WBRT) as salvage therapy for immunocompetent patients who failed initial high-dose methotrexate forprimary CNS lymphoma (PCNSL). PCNSL is a radiosensitive tumor, and radiotherapy has been the standard treatment for decades. Temozolomide is a well-tolerated alkylating agent that is capable of permeating the blood-brain barrier (BBB) and has additive cytotoxicity when administered with radiotherapy. Alkylating agents are generally effective against non-Hodgkin’s lymphoma and temozolomide has good CNS penetration and a favorable toxicity profile. Many different treatments have been applied as salvage therapies for recurrent or refractory PCNSL. We studied the efficacy and safety of combination with temozolomide and whole-brain radiation in the treatment of recurrent or refractory PCNSL.MethodsThe restrospective study included 16 consecutive patients with biopsy-proven PCNSL who experienced treatment failure with initial treatment with highdose MTX-based regimens and subsequently received combating therapy with TMZ and WBRT between July 2007 and 2013. All patients had a diffuse large B-cell type of PCNSL. WBRT was delivered using opposed lateral beams. The dose prescribed was 40 Gy to the whole brain. A boost of dose 6Gy delivered to the gross tumor volume. All patients were administered temozolomide (75mg/m2) on every day at the course of radiotherapy. When the radiotherapy completed, TMZ was used (TMZ 150 mg/m2 on day 1 to 5, orally) of each 4-week from four cycles to six-week cycles. The treatment response was assessed based on the International PCNSL Collaborative Group’(IPCG) criteria. Estimates of post-treatment progression free survival, and overall survival from first time of treatment were made using the method of Kaplan and Meier. Analysis was performed using SPSS 19.0. Results1. Failure was due to tumor relapse for 11 patients and progression of a refractory tumor for 5 patients.2. Sixteen patients completed the radiotherapy and thirteen patients completed the courseof adjuvant chemotherapy. Three patients failed the course of adjuvant chemotherapy for hematologic toxicity (2 patients) and heavy financial burden (1 patient).3. During the follow-up period from 4 to 27 months, brain MRI scans demonstrated complete response in 6 of 16 (37.5%),5 patients (5/16,31.3%) experienced partial response, 3 patients(3/16,18.8%) had stable disease, and 2 patients(2/16,12.5%) had progressive disease in response to treatment. The response rate was 70.8%(11/16) and the objective remission rate was 87.5%(14/16).4. The PFS-6 and PFS-6 were 50%(95% confidence interval [CI],7%～76%) and 31.3%(95%CI:21%～70%), respectively, with a median PFS of 5.7 months (95%CI,3.2～ 8.2 months). The median OS was 8.9 months (95%CI,6.3～11.4 months), with an OS-12 of 43.8%(95%CI,16%-74%) and OS-12 of 43.8%(95%CI,9.8～18.2 months).ConclusionsCombination with temozolomide and whole-brain radiation has activity in relapsed/refractory PCNSL. Further investigation of this treatment in relapsed/refractory PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population.