Purpose To improve survival and reduce toxicity in primary CNS lymphoma (PCNSL) treatment, we conducted a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiotherapy (WBRT) for newly diagnosed PCNSL patients younger than 65 years of age Patients and Methods Chemotherapy included three steps: three cycles of methotrexate (8 g/m 2 ); cytarabine (AraC; two doses of 3 g/m 2 ) and thiotepa (40 mg/m 2 ) followed by stem-cell harvest; HDT with carmustine (400 mg/m 2 ) and thiotepa (two doses of 5 mg/kg body weight) followed by ASCT WBRT (45 Gy, two doses of 1 Gy/d) was administered for consolidation Results Thirty patients with PCNSL younger than 65 years of age (median, 54 years; range, 27 years to 64 years) were enrolled (nine pilot-phase; 21 phase II) Twenty-eight patients responded to methotrexate: six patients with complete remission (CR), 15 patients with partial remission (PR), and seven patients with stable disease (SD) with clinical improvement Of 26 patients proceeding to AraC and thiotepa, 10 patients achieved CR, 14 patients achieved PR, one patient experienced SD with clinical improvement, and one patient suffered disease progression Twenty-three patients received HDT plus ASCT, resulting in 15 patients with CRs and eight patients with PRs After WBRT, 21 of 21 patients had CRs One patient died from liver failure after methotrexate HDT was well tolerated apart from WHO grade 3/4 cytopenia With a median follow-up of 63 months (range, 4 months to 84 months), 5-year overall survival probability is 69% for all patients and 87% for the 23 patients receiving HDT plus ASCT The 5-year probability of relapse-related death is 21% for all patients (n 30) and 87% for patients treated with HDT plus ASCT (n 23)

https://ascopubs.org/doi/pdf/10.1200/JCO.2006.06.2117

High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma

PurposeThis study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life.Patients and MethodsThe phase I study increased TMZ doses from 100 to 150 to 200 mg/m2. Patients were treated with rituximab 375 mg/m2 3 days before cycle 1; methotrexate 3.5 g/m2 with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m2 daily for 5 days every 28 days on weeks 14 to 50.ResultsThirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m2. Dose-limiting toxicities w...

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Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followed By Whole-Brain Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227

Primary CNS lymphoma, an uncommon form of extranodal non-Hodgkin’s lymphoma, has increased in incidence and occurs in both immunocompromised and immunocompetent hosts. Primary CNS lymphoma in immunocompetent patients is associated with unique diagnostic, prognostic and therapeutic issues and the management of this malignancy is different from other forms of extranodal non-Hodgkin’s lymphoma. Characteristic imaging features should lead to suspicion of the diagnosis, avoidance of corticosteroids (if possible) and early neurosurgical consultation for stereotactic biopsy. Since primary CNS lymphoma may involve the brain, cerebrospinal fluid and eyes, diagnostic evaluation should include assessment of all of these regions as well as screening for the possibility of occult systemic disease. Resection provides no therapeutic benefit and should be reserved for the rare patient with neurological deterioration due to brain herniation. Whole-brain radiation therapy alone is insufficient for durable tumor control and...

Primary CNS lymphoma.

Background A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. Patients and methods From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. Conclusions In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.

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Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study

Objective

To evaluate long-term progression-free survival and overall survival, quality of life, and cognitive function in primary central nervous system lymphoma after systemic and intraventricular chemotherapy without radiotherapy.



Methods

A long-term follow-up was conducted on surviving primary central nervous system lymphoma patients having been enrolled in a pilot/phase II trial between September 1995 and December 2001. Initially, 65 patients (median age, 62 years) had been treated with systemic and intraventricular chemotherapy without radiotherapy. All living patients were contacted, and a neurological examination, comprehensive neuropsychological testing, quality-of-life assessment, and imaging were performed.



Results

Twenty-one of all 65 patients (32 %) and 17 of 30 patients 60 years or younger (57%), respectively, were still alive at median follow-up of 100 months (range, 77–149 months). Nineteen of 21 patients completed all investigations; 1 was lost to follow-up. In three patients, an exclusively extraneural relapse of a high-grade non-Hodgkin's lymphoma was diagnosed after 9, 31, and 40 months, respectively. All of them experienced complete remission to high dose. Neither late neurotoxicity nor compromise of quality of life was found in any of the patients examined.



Interpretation

Primary polychemotherapy based on high-dose methotrexate (MTX) and cytarabine (Ara-C) is highly efficient in treatment of primary central nervous system lymphoma. About half of patients 60 years or younger can obviously be cured with this regimen without long-term neurotoxic sequelae or quality-of-life compromise. ANN NEUROL 2010;67:182–189

Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma.

Purpose: To determine whether a lower dose of hyperfractionated whole brain radiation reduces central nervous system morbidity without compromising survival for primary CNS lymphoma (PCNSL) patients receiving combined modality treatment. Materials and Methods: One hundred and two patients received a course of pre-radiation chemotherapy, followed by whole brain radiation, followed by cytosine-arabinoside. Initial radiation dose was 45 Gy/25 fractions (RT) then the study was amended to reduce this dose for complete responders to induction chemotherapy to 36 Gy/30 fractions/3 weeks (HFX). Eighty-two patients received radiotherapy and were evaluable for toxicity analysis (66 RT patients and 16 HFX patients). MMSE scores and survival for the 40 patients who received radiotherapy after complete response to chemotherapy (27 RT and 13 HFX) were compared. There were no notable differences in pre-treatment patient characteristics between the RT and HFX groups. Results: Neurotoxicity: By 4 years, there were 8/82 (10%) grade 5 neurotoxicities which included 2/16 (13%) grade 5 encephalopathies and 0/27 in the RT group of complete responders to chemotherapy. Survival: There was no statistically significant difference in overall or progression-free survival (PFS) between the chemotherapy-complete responders who received RT and HFX. Cognitive function testing: MMSE scores improved at 8 months across both treatment groups. Analysis of the area under the MMSE curve at 8 months showed no statistically significant difference between RT and HFX groups (P=0.81). Leukoencephalopathy occurred later in the HFX group than in the RT patients. Conclusion: Although the HFX schedule represented a 25% reduction in biologically effective tumor dose in comparison, PFS and overall survival were not significantly affected. The HFX regimen delayed but did not eliminate severe neurotoxicity from chemoradiation in PCNSL patients.

Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma

297 Secondary Analysis of RTOG 9310: An Intergroup Phase II Combined Modality Treatment of Primary Central Nervous System Lymphoma with Chemotherapy and Hyperfractionated Radiotherapy B.J. Fisher, W. Sieferheld, C. Schultz, L. DeAngelis, D. Nelson, S.C. Schold, W. Curran Radiation Oncology, London Regional Cancer Centre, University of Western Ontario, London, ON, Canada, Statistical Unit, RTOG Headquarters, Philadephia, PA, Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, Neurology, Memorial-Sloan Kettering, New York, NY, Radiation Oncology, Mayo Clinic, Rochester, MN, Neurology, Duke University Medical Center, Durham, NC, Radiation Oncology, Thomas Jefferson University, Philadelphia, PA

Secondary analysis of RTOG 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma with chemotherapy and hyperfractionated radiotherapy

S.C. Schold

Papers

Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma

Secondary analysis of RTOG 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma with chemotherapy and hyperfractionated radiotherapy