The role of whole brain radiation in primary CNS lymphoma.
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ABSTRACT:
SUBMITTER: Kasenda B
PROVIDER: S-EPMC4968379 | biostudies-literature | 2016 Jul
REPOSITORIES: biostudies-literature
Publications
The role of whole brain radiation in primary CNS lymphoma.
Kasenda Benjamin B Loeffler Jay J Illerhaus Gerald G Ferreri Andrés J M AJ Rubenstein James J Batchelor Tracy T TT
Blood 20160513 1
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Project description:Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the "protective" effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.
| S-EPMC6142584 | biostudies-literature
Project description:Primary CNS lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. The prognosis of patients with PCNSL has improved during the last decades with the introduction of high-dose methotrexate. However, despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. To our knowledge, no randomized trial has been conducted for recurrent/refractory disease, leaving many questions unanswered about optimal first-line and salvage treatments. This review will give an overview of the presentation, evaluation, and treatment of immunocompetent patients with PCNSL.
| S-EPMC5516483 | biostudies-literature
Project description:Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system is an aggressive malignancy that exhibits unique biological features and characteristic clinical behaviour, with overall long-term survival rates of around 20-40%. Clinical outcome has improved following the advent of chemoradiation protocols incorporating high-dose methotrexate in the mid-1980s, but disease relapse and adverse neurocognitive sequelae remain major clinical challenges. To address this, investigators have focused on improving drug therapy with novel cytotoxic combinations, monoclonal antibody therapy, and intensive chemotherapy consolidation approaches, in an attempt to improve disease control whilst reducing the requirement for whole-brain radiotherapy. Outcomes for patients that are older, immunocompromised, or have relapsed/refractory disease remain unsatisfactory and there is a paucity of clinical trial data to guide treatment of these groups. This review highlights recent advances in pathobiology, imaging, and clinical management of PCNSL and looks ahead to research priorities for this rare and challenging lymphoid malignancy.
| S-EPMC4180029 | biostudies-literature
Project description:Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.
| S-EPMC5581705 | biostudies-literature
Project description:Primary central nervous system lymphoma (PCNSL) is an aggressive disease with previously poor prognosis. The advent of high-dose methotrexate-based induction regimens as well as use of consolidation therapy has greatly improved this prognosis in recent decades, but durable remission still eludes half of patients. In this review, we summarize the progress made in the treatment of PCNSL as well as the challenges that remain, with a focus on defining optimal induction and consolidation regimens, including the promise of developing biotherapies. Future studies will help delineate the best combination of existing and novel treatment strategies, with the goal of expanding the cohort of patients achieving a cure.
| S-EPMC10481403 | biostudies-literature
Project description:BackgroundThe goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival.MethodsAn open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ± 10 Gy boost (arm A) or WBRT ± boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS).ResultsBetween September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95-4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response.ConclusionsThis study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.
| S-EPMC10076938 | biostudies-literature
Project description:BACKGROUND: This is the final report of the G-PCNSL-SG-1 trial after a median follow-up of 81.2 months. METHODS: G-PCNSL-SG-1 (www.clinicaltrials.gov NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy followed by whole-brain radiotherapy (WBRT) or chemotherapy alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. FINDINGS: Of 551 patients who entered the study 524 fulfilled the eligibility criteria, 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versus without WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p = 0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p = 0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p = 0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p = 0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p = 0.057), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p = 0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p < 0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16, p = 0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p < 0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p = 0.12). INTERPRETATION: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up analysis. The PFS afforded by WBRT has to be balanced against its long-term toxicity.
| S-EPMC4217839 | biostudies-literature
Project description:Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p < 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer.
| S-EPMC7352658 | biostudies-literature
Project description:BackgroundWhile there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease.Patients and methodsWe reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology.ResultsWhile PCNSL tumors usually express a BCL6+, MUM1+ 'activated, germinal center' immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses.ConclusionsThere is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.
| S-EPMC3905778 | biostudies-literature
Project description:BackgroundWe investigated the prognostic significance of B-cell differentiation status and common B-cell differentiation markers in a post hoc analysis of 119 patients with primary CNS lymphoma (PCNSL) homogeneously receiving high-dose methotrexate (HDMTX)-based chemotherapy within the prospective G-PCNSL-SG1 trial.MethodsWe evaluated protein expression of B-cell lymphoma 2 (BCL2), BCL6, CD10, and multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) by immunohistochemistry and analyzed the association with survival.ResultsThe median follow-up of all patients was 67.5 months. Median progression-free survival (PFS) was 10.61 months (95% CI: 4.23-17.00). Median overall survival (OS) was 28.85 months (95% CI: 17.96-39.73). Eighty-nine tumors expressed BCL2 (92.7%), 24 (20.5%) expressed CD10, 60 (54.1%) expressed BCL6, and 87 (79.0%) expressed MUM1/IRF4. On the basis of the Hans algorithm, 80 tumors (73.4%) were classified to the non-germinal center B group, suggesting a post-germinal center origin of PCNSL. Expression of BCL6 (cutoff point 30%), but none of the other markers, was associated with shorter PFS (P = .047) and OS (P = .035). On multivariate analysis, BCL6 expression was associated with shorter PFS (hazard ratio: 1.95, 95% CI: 1.22-3.12, P = .005) but not OS (hazard ratio: 1.85, 95% CI: 0.71-4.80, P = .21). Classification according to Hans algorithm and expression status of the single B-cell markers BCL2, CD10, and MUM1/IRF4 did not correlate with prognosis.ConclusionThe findings are limited by the fact that only 23% of all G-PCNSL-SG1 patients could be included in the analysis. If validated in an independent cohort, BCL6 may assume clinical relevance as an unfavorable prognostic biomarker in PCNSL.
| S-EPMC5654355 | biostudies-literature