Radiation-induced Neurotoxicity Research Articles

Proton therapy induces a local microglial neuroimmune response

Background and purposeAlthough proton therapy is increasingly being used in the treatment of paediatric and adult brain tumours, there are still uncertainties surrounding the biological effect of protons on the normal brain. Microglia, the brain-resident macrophages, have been shown to play a role in the development of radiation-induced neurotoxicity. However, their molecular and hence functional response to proton irradiation remains unknown. This study investigates the effect of protons on microglia by comparing the effect of photons and protons as well as the influence of age and different irradiated volumes. Materials and methodsRats were irradiated with 14 Gy to the whole brain with photons (X-rays), plateau protons, spread-out Bragg peak (SOBP) protons or to 50 % anterior, or 50 % posterior brain sub-volumes with plateau protons. RNA sequencing, validation of microglial priming gene expression using qPCR and high-content imaging analysis of microglial morphology were performed in the cortex at 12 weeks post irradiation. ResultsPhotons and plateau protons induced a shared transcriptomic response associated with neuroinflammation. This response was associated with a similar microglial priming gene expression signature and distribution of microglial morphologies. Expression of the priming gene signature was less pronounced in juvenile rats compared to adults and slightly increased in rats irradiated with SOBP protons. High-precision partial brain irradiation with protons induced a local microglial priming response and morphological changes. ConclusionOverall, our data indicate that the brain responds in a similar manner to photons and plateau protons with a shared local upregulation of microglial priming-associated genes, potentially enhancing the immune response to subsequent inflammatory challenges.

Breast Cancer and the Brain: A Comprehensive Review of Neurological Complications.

Breast cancer, one of the most prevalent malignancies globally, poses a substantial health burden with its diverse neurological complications. This comprehensive review examines the intricate landscape of breast cancer's neurological effects, encompassing brain metastases, non-metastatic complications, and their profound influence on the quality of life, prognosis, and survival of affected individuals. The mechanisms, clinical manifestations, and treatment modalities of brain metastasis and the critical role of interdisciplinary collaboration in their management are explored. Additionally, we address non-metastatic neurological complications, including paraneoplastic syndromes, treatment-related side effects, leptomeningeal carcinomatosis, and radiation-induced neurotoxicity, shedding light on the challenges they present and the importance of cognitive and emotional well-being. Prognostic factors and survival rates are discussed, emphasizing the complexity of variables impacting patient outcomes. Lastly, we underscore the vital role of collaborative care in addressing these multifaceted challenges, highlighting future research directions and the ongoing quest to enhance the quality of life for breast cancer patients.

Oligodendroglioma, IDH Mutation and 1p/19q Codeletion

Oligodendrogliomas were clearly defined as tumors with IDH mutations and 1p/19q codeletion by the World Health Organization(WHO)in 2016. Their prognosis is better than that of morphologic oligodendrogliomas, which might include some other gliomas according to WHO in 2016 and 2021. The term "low-grade gliomas" does not exist in the WHO classification and has changed in meaning over time; prior to WHO 2016, it meant grade I and II gliomas; subsequently, it changed to "lower-grade gliomas," including grade II and III gliomas, with the same molecular features. In the current classification, IDH wild-type grade II and III gliomas have been eliminated, and "lower-grade gliomas" now only include gliomas with IDH mutations. Maximal safe resection is necessary for a proper molecular diagnosis and survival, and awake craniotomy should be aggressively considered to prevent permanent postoperative neurologic deficits for tumors in the eloquent region. Supramarginal resection is an attractive approach for neurosurgeons to improve survival outcomes, but the evidence is still lacking. Chemoradiotherapy with procarbazine, CCNU, and vincristine is recommended for both grade 2 and 3 oligodendrogliomas. However, the risk of radiation-induced neurotoxicity is a concern in long-term survivors, and several clinical trials have tested the efficacy of chemotherapy alone in terms of cognitive function. Since CCNU is not approved in Japan, ACNU-containing regimen as PAV, or temozolomide are commonly used for the tumor.

Research on the Damage of the Central Nervous System Lymphoma to the Nervous System.

Management of central nervous system (CNS) lymphoma requires multidisciplinary care. The disease can manifest in the context of immunocompromised states or in the context of chronic infections. Nervous system damage from this lymphoma has highly variable presentation that is dependent on the location of the tumor lesions. Damage from disease progression can lead to lasting neurologic deficits and even death. However, some lesions are a consequence of radiation-induced neurotoxicity. This review discusses the sources of and consequences of brain damage due to tumor damage and the associated effect of clinical therapies. We discuss workup, management, and treatments. These include chemotherapy and radiation techniques. We discuss potential complications and avoidance strategies. The review will serve as a user-friendly resource for clinicians.

ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

Neurologic Complications of Cancer Therapies.

To review the neurologic complications of systemic anti-cancer therapies and radiation therapy. Although many of the newer systemic therapies have more favorable side effect profiles than traditional cytotoxic chemotherapy, neurotoxicity has been seen with some of newer targeted therapies, immunotherapy, and T cell engaging therapies, including CAR-T therapy. The most recent advances in radiation-induced neurotoxicity have focused on the prevention and the management of cognitive dysfunction, a known long-term complication of brain irradiation. Cancer therapies can damage both the central and the peripheral nervous systems, and the damage may not always be reversible. Neurologists and oncologists must be aware of the neurotoxicities associated with newer treatments, particularly CAR-T therapy and immunotherapy. Early recognition and appropriate management can help minimize neurologic injury.

NCMP-01. NOVEL BIOMARKERS FOR RADIATION-INDUCED NEUROTOXICITY

Abstract BACKGROUND Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation. METHODS We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment. RESULTS Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN. CONCLUSION Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.

Primary central nervous system lymphoma: clinicopathological and genomic insights for therapeutic development.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive, extra-nodal non-Hodgkin lymphoma that is confined to the central nervous system (CNS) and the eyes. Most PCNSLs arise in immunocompetent older patients and less frequently in immunocompromised patients with Epstein-Barr virus infection. Although a patient's initial response to chemotherapy and radiation therapy is favorable, the clinical outcome of PCNSL remains poor compared to that of systemic lymphoma. Radiation-induced neurotoxicity is also a critical problem for patients with PCNSL. Therefore, a novel therapeutic strategy is required to overcome these challenges. Recent studies have largely uncovered the genomic landscape and associated histopathological features of PCNSL. Based on this background, novel therapeutic agents, such as Bruton's tyrosine kinase inhibitors and immune checkpoint inhibitors, have been introduced for patients with PCNSL. Here, we provide an overview of the updated histopathological and genomic characterization of PCNSL and summarize the current therapeutic strategies. We also review current preclinical PCNSL models for translational research.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40Gy with a median fraction of 2Gy. The median number of administered doses of rituximab (375mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Cardiovascular complications after radiotherapy.

Over the past decades, effective cancer therapies have resulted in a significant improvement in the survival rates for a number of cancers and an increase in the number of cancer survivors. Radiation therapy is widely used in the treatment of cancer, and it can induce various cardiotoxicities that differ considerably from chemotherapy-induced cardiotoxicity. They occur primarily as late radiation-induced complications, several years from the end of anticancer treatment and present as coronary artery disease, heart failure, pericardial disease, valvular heart disease and arrhythmias. Patients who recovered from cancer disease suffer from cardiac complications of anticancer treatment, it affects the quality of their lives and life expectancy, especially if the diagnosis is delayed. These patients may present distinct symptoms of cardiac injury, resulting from radiation-induced neurotoxicity and altered pain perception, which makes diagnosis difficult. This review highlights the need for a screening programme for patients who have undergone radiation therapy and which will subsequently have a potentially profound impact on morbidity and mortality.

Increased Radiosurgery Toxicity Associated With Treatment of Vestibular Schwannoma in Multiple Sclerosis

Explore the risk of radiation-induced neurotoxicity in patients with multiple sclerosis (MS) treated with stereotactic radiosurgery (SRS) and better understand the pathophysiology of radiation-induced injury in the central nervous system (CNS). We present the clinical course and magnetic resonance imaging (MRI) findings of a 52-year-old woman with a history of relapsing remitting MS, who developed radiation-induced neurotoxicity following CyberKnife SRS (25 Gy in five fractions) for a left-sided vestibular schwannoma (VS). Risk of radiation-induced damage following SRS to the CNS, including radiation type and dose, toxicity, and time to symptom onset, in patients with MS. Our patient developed increased imbalance (grade 2 toxicity) 3 months following CyberKnife SRS. Brain MRI showed new fluid-attenuated inversion recovery (FLAIR) hyperintensity in the pons and cerebellum. Neurotoxicity from SRS is rare. However, our literature review showed that 19 patients with MS who underwent intracranial radiation therapy sustained radiation-induced toxicity. The potential mechanisms for increased toxicity in MS could be due to a combination of demyelination, inflammatory, and/or vascular changes. Efficacy of treatments including steroids, bevacizumab, and hyperbaric oxygen therapy is currently unknown. Treatment options of SRS and surgery for VS should be carefully considered as patients with known MS may be at increased risk for radiation-induced damage following SRS to the CNS. Thoughtful radiosurgical planning and dosing accounting for this inherent risk is essential for managing patients with MS and VS.

Pulsed Radiofrequency Ablation: An Alternative Treatment Modality for Radiation-Induced Brachial Plexopathy.

Radiation therapy is used as a form of treatment for various neoplastic diseases. There are many potential adverse effects of this therapy, including radiation-induced neurotoxicity. Radiation-induced brachial plexopathy (RIBP) may occur due to the fibrosis of neural and perineural soft tissues, leading to ischemic damage of the axons and Schwann cells. The dose of radiation exceeds 55Gy in many patients who develop symptoms [1]. Current incidence in the United States is 1-2%, and RIBP is most commonly seen in patients who have undergone treatment for breast cancer, lung cancer, or lymphoma [1-3]. Common symptoms include numbness, paresthesia, dysesthesia, and occasional numbness of the arm. Pain is present in the shoulder and proximal arm and is typically mild to moderate in severity. Diagnosis is often made based on clinical presentation and evaluation of imaging to rule out concurrent malignant etiologies of the brachial plexus. Current recommended treatment includes physical therapy and medical management with anticonvulsants, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors.

Solving the Issue of Ionizing Radiation Induced Neurotoxicity by Using Novel Cell Models and State of the Art Accelerator Facilities

Cognitive dysfunction induced by ionizing radiation remains a major concern in radiation therapy as well as in space mission projects. Both fields require sophisticated approaches to improve protection of the brain and its neuronal circuits. Radiation therapy related research focusses on advanced techniques imposing maximal effect on the tumor while minimizing toxicity to the surrounding tissue. Research for example has led to the revival of spatially fractionated radiation therapy (SFRT) and the advent of FLASH radiotherapy. To investigate the influence of the space radiation environment on brain cells, low dose, high LET radiation in addition to simulated microgravity have to be studied. Both research areas, however, call for cutting-edge cellular systems that faithfully resemble the architecture of the human brain, its development and its regeneration to understand the mechanisms of radiation-induced neurotoxicity and their prevention. In this review, we discuss the proposed mechanisms of neurotoxicity such as the loss of complexity within the neuronal networks, vascular changes, or neuroinflammation. We compare the current in vivo and in vitro studies of neurotoxicity including animal models, animal and human neural stem cells and neurosphere models. Particularly, we will address the new and promising technique of generating human brain organoids and their potential use in radiation biology.

Uncertainty Assessment of Quantitative Measurements in Medical Imaging: Applications in Cross-Sectional and Longitudinal Diffusion MRI

The article's abstract is no available.

DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis

Background and purposeHigh-precision radiotherapy is an effective treatment modality for tumors. Intensity-modulated radiotherapy techniques permit close shaping of high doses to tumors, however healthy organs outside the target volume are repeatedly exposed to low-dose radiation (LDR). The inherent vulnerability of hippocampal neurogenesis is likely the determining factor in radiation-induced neurocognitive dysfunctions. Using preclinical in-vivo models with daily LDR we attempted to precisely define the pathophysiology of radiation-induced neurotoxicity. Material and methodsGenetically defined mouse strains with varying DNA repair capacities were exposed to fractionated LDR (5×/10×/15×/20×0.1 Gy) and dentate gyri from juvenile and adult mice were analyzed 72 h after last exposure and 1, 3, 6 months after 20 × 0.1 Gy. To examine the impact of LDR on neurogenesis, persistent DNA damage was assessed by quantifying 53BP1-foci within hippocampal neurons. Moreover, subpopulations of neuronal stem/progenitor cells were quantified and dendritic arborization of developing neurons were assessed. To unravel molecular mechanisms involved in radiation-induced neurotoxicity, hippocampi were analyzed using mass spectrometry-based proteomics and affected signaling networks were validated by immunoblotting. ResultsRadiation-induced DNA damage accumulation leads to progressive decline of hippocampal neurogenesis with decreased numbers of stem/progenitor cells and reduced complexities of dendritic architectures, clearly more pronounced in repair-deficient mice. Proteome analysis revealed substantial changes in neurotrophic signaling, with strong suppression directly after LDR and compensatory upregulation later on to promote functional recovery. ConclusionHippocampal neurogenesis is highly sensitive to repetitive LDR. Even low doses affect signaling networks within the neurogenic niche and interrupt the dynamic process of generation and maturation of neuronal stem/progenitor cells.

Response of neural stem cells to ionizing radiation

Adult neurons are believed to be in a state of growth arrest. The generation of neurons is complete at the time of birth in most of the brain regions. However neurogenesis is present through life in the dentate gyrus of hippocampus and the lateral ventricles due to the presence of neural stem cells (NSC). This postnatal neurogenesis in hippocampus plays a critical role in cognitive development mainly in learning and memory functions. NSC are self-renewing, multipotent cells that generate the neurons and glia of the nervous system. Due to their high proliferation, NSC are highly sensitive to ionizing radiation. This review describes the current knowledge on impact of ionizing radiation on neural stem cells biology. Widening the knowledge of mechanisms involved in radiation-induced neurotoxicity at the level of NSC may help to overcome in the future the side effects occurring after anti-cancer therapies of the brain and help to protect and maintain neurogenesis.

Long-Term Clinical Safety of High-Dose Proton Radiation Therapy Delivered With Pencil Beam Scanning Technique for Extracranial Chordomas and Chondrosarcomas in Adult Patients: Clinical Evidence of Spinal Cord Tolerance

To assess the radiation dose tolerance of the spinal cord by reviewing our institutional experience regarding the incidence of radiation-induced spinal cord toxicity after high-dose pencil beam scanning proton therapy (PBSPT). Seventy-six patients (median age 53years; range, 23-79years) treated for spinal chordoma (n=55) or chondrosarcoma (n=21) met the following criteria and were retrospectively analyzed: PBSPT only, no reirradiation or concomitant chemotherapy, maximum dose (Dmax) to the spinal cord of ≥45Gy(relative biological effectiveness [RBE]), ≥18years of age, and follow-up of ≥12months. The delivered dose was 59.4 to 75.2Gy(RBE) [median 73.9Gy(RBE)] delivered with conventional fractionation between 2000 and 2014. The Dmax, D2%, and V40-V60 of the surface (sSC) and center (cSC) of the spinal cord were recorded. Toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Median follow-up was 65.5months (range, 13-173months). Patients received a mean Dmax and D2% to the sSC of 59.0 (median 58.7; range, 48.3-75.9) and 55.3 (median 52.7; range, 43.1-73.8) Gy(RBE), respectively. The corresponding values for the cSC were 52.3 (median 52.7; range, 32.3-73.3) and 51.1 (median 52.0; range, 25.3-73.1) Gy(RBE), respectively. Four patients (5%) developed acute radiation-induced neurotoxicity (grade [G] 1, n=1; G2, n=3). Twelve patients (16%) experienced late neurologic toxicities (G1, n=7; G2, n=4; G4, n=1). One patient with a history of pre-PBSPT symptomatic spinal cord compression redeveloped tetraplegia (G4) after receiving a Dmax of 57.8Gy(RBE) to the sSC and 54.1Gy(RBE) to the cSC. No significant correlation was found between sSC Dmax and D2%, cSC Dmax and D2%, or the length of CTV and toxicity. High-dose conformal PBSPT may be delivered safely in close proximity to the spinal cord with minimal neurotoxicity. Dose constraints of 64Gy(RBE) as D2% for the sSC and 54Gy(RBE) for the cSC seem appropriate for clinical use.

Combined Modality Therapy in the Upfront Treatment of Patients with Primary Central Nervous System Lymphoma: A Systematic Review

Background: The role of combined modality therapy (CMT) in previously untreated patients with primary central nervous system lymphoma (PCNSL) remains unclear. We performed a systematic review of the available evidence regarding the efficacy and long-term neurotoxicity of consolidative radiation therapy in addition to systemic chemotherapy in the upfront management of fit immunocompetent adult patients with PCNSL.Methods: Peer reviewed literature searches were conducted using the MEDLINE, EMBASE and PubMed databases from 1950 to March 26, 2015. We included all prospective clinical trials (randomized and non-randomized) published on or after January 1, 1998 with at least 20 subjects receiving frontline CMT with CNS-penetrating chemotherapy in addition to radiation therapy. We excluded trials of high-dose chemotherapy followed by autologous stem cell rescue and those involving patients with isolated intra-ocular lymphoma. The primary outcome was overall survival (OS). Secondary outcomes included progression free survival (PFS), overall response rate (ORR), complete remission (CR) rate, partial remission (PR) rate, and incidence of late radiation-induced neurotoxicity. Two reviewers independently performed title and abstract screening, full-text review and data extraction. The Cochrane Risk of Bias Tool was used to assess the quality of randomized trials included in this systematic review.Results: The literature search yielded 10,646 potentially relevant records for primary screening after de-duplication, of which 299 full-text articles were evaluated. Of the 299 full-text articles reviewed, there were 21 publications eligible for inclusion. These 21 publications represented 15 unique clinical trials (4 trials were reported in 2 publications each, and 1 trial was reported in 3 publications; Figure 1). The included studies involved a total of 1123 enrolled subjects. Of the 15 trials included, there was 1 phase III randomized controlled trial, 1 phase II randomized trial, and 2 non-randomized multi-arm trials. The remaining studies were single arm non-comparator trials. Chemotherapy backbones varied, and planned whole brain radiation therapy (WBRT) doses ranged from 23.4 to 50.4 Gy. Due to variation in follow-up time, it was difficult to compare survival endpoints between studies. In the large multicenter phase III randomized controlled trial comparing 202 patients receiving WBRT to 208 patients without WBRT, there was no difference in OS (32.4 months vs. 36.1 months, p=0.98) however WBRT improved PFS from 9.9 months to 15.4 months (p=0.034) (Korfel et al., Neurology. 2015 Mar 24;84(12):1242-8). Response rates were not consistently reported after completion of both chemotherapy and radiation therapy. Amongst those trials reporting response rates after completion of CMT, the CR rate ranged from 28-87% and the ORR ranged from 56-100%. Although there was variability in the definitions and reporting of delayed-onset neurotoxicity, this complication was common, ranging from 0-45.8%. The Cochrane Risk of Bias Tool was only applicable to the 2 randomized trials in this review. On the basis of clinical heterogeneity, we chose not to statistically pool the results of the included trials together in this systematic review.Conclusions: We identified a large body of literature assessing the use of CMT in the upfront management of PCNSL. However, only one randomized study addressed the specific role of consolidative radiation therapy with respect to survival, in which there was no benefit to OS. Consolidative WBRT may improve local disease control and PFS, though late neurotoxicity remains a concern. Our review underscores the need for ongoing collaborative efforts between treatment centers to design and conduct large randomized controlled trials. [Display omitted] DisclosuresBuckstein:Celgene: Honoraria, Research Funding.

Reduced neurotoxicity with combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) and deferred radiotherapy for primary central nervous system lymphoma

ObjectiveAlthough high-dose methotrexate and whole-brain radiation therapy (WBRT) is the current standard for primary central nervous system lymphoma (PCNSL), it has a limited response rate and produces radiation-induced neurotoxicity. We report the effect of a combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) for immunocompetent patients with PCNSL. MethodsWe analyzed 24 patients who had received M-CHOP administered in 28-day cycles with or without WBRT. The response rate to M-CHOP, overall survival (OS), and recurrence-free survival (RFS) were analyzed. ResultsNine patients were treated with M-CHOP plus WBRT and 15 patients were treated with M-CHOP alone. Twenty-one patients achieved a complete response and three patients achieved a partial response to M-CHOP, for a 100% response rate. With a median follow-up of 70 months, the median OS and RFS were 33 and 13 months, respectively. The median OS for patients treated with M-CHOP plus WBRT and M-CHOP alone was 33 and 32 months, respectively. Of the 13 patients whose age was above 65 years, the median OS for the M-CHOP plus WBRT group (two patients) and the M-CHOP alone group (11 patients) was 14 and 32 months, respectively. Toxicities related to M-CHOP were mostly hematologic and generally mild to moderate. Two patients whose age was above 65 years in the M-CHOP plus WBRT group developed neurotoxicity. ConclusionCombined treatment with M-CHOP was well tolerated and produced a high response rate. Deferring WBRT was associated with reduced neurotoxicity without worsening the prognosis, especially in elderly patients.