ABSTRACT
Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.
Subject(s)
Lymphoma, Mantle-Cell , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Adult , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Lymphoma, Mantle-Cell/drug therapy , Receptors, Chimeric Antigen/therapeutic use , Receptors, Antigen, T-Cell/therapeutic use , T-Lymphocytes , Treatment Outcome , Antigens, CD19 , Central Nervous System , Neurotoxicity Syndromes/drug therapy , Cell- and Tissue-Based TherapyABSTRACT
PURPOSEOF REVIEW: Health disparities are preventable differences in the diagnosis, treatment, and outcomes of many diseases, including central nervous system (CNS) tumors. This review will summarize and compile the existing literature on health disparities in neuro-oncology and provide directions for future research and interventions. RECENT FINDINGS: Patients from historically marginalized groups are more likely to receive inadequate treatment, develop complications, and experience a shorter life expectancy. Financial toxicity can be particularly severe for patients with CNS tumors due to the high costs of treatment. Additionally, CNS clinical trials and research lack diverse representation.
Subject(s)
Central Nervous System Neoplasms , Humans , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/therapy , Medical Oncology , ForecastingABSTRACT
PURPOSE OF REVIEW: The management of brain and leptomeningeal metastases has changed significantly over the past decade. RECENT FINDINGS: Historically, radiation therapy had been the mainstay of treatment. Several strategies to limit toxicities with radiation have been developed in the recent years. Increasingly systemic therapy options are being considered an important therapeutic option for CNS metastases. Numerous novel small molecule inhibitors and immunotherapy agents have intracranial activity to varying degrees, in addition to good extracranial disease control. Overall, the prognosis of select patients with CNS metastases has improved over the past several years with advent of new therapeutic strategies. Systemic therapy options with CNS benefit should be considered in select patients with small and asymptomatic CNS metastases. Further areas of research focus on molecular alterations predisposing to CNS metastases, identification of small molecule inhibitors with CNS activity, and the combination of radiation therapy and immunotherapy.
Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Brain , Brain Neoplasms/therapy , Humans , Immunotherapy , PrognosisABSTRACT
OPINION STATEMENT: Brain metastases represent a common and devastating complication of cancer with survival on the order of a few months in most patients. Melanoma, breast cancer, and lung cancer remain the primary disease histologies with the highest rates of metastatic spread to the brain. The incidence of brain metastases has continued to rise, likely explained by multiple factors. Improvement in progression-free survival in systemic cancer is likely attributable to advances in medical therapy, earlier supportive and symptomatic care, and improved precision around diagnosis and detection. In this context, longer survival and improved extracranial control disease has likely contributed to the increased development of metastatic spread intracranially. The foundation of management remains systemic therapy, as well as a combination of surgery and radiation therapy. In the era of targeted therapies, specific agents have demonstrated improved CNS penetration, however with varying degrees of durable responses. Most patients develop resistance to targeted agents, limiting their duration of use for patients. In this era of personalized medicine, the role of genomic characterization in cancer has been critical in the field of brain metastases, as alterations unique to both the brain metastases and its systemic predecessor have been identified, potentially offering new avenues for therapy.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/secondary , Brain Neoplasms/therapy , Precision Medicine , Biomarkers, Tumor , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Disease Management , Genomics/methods , Humans , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/standards , Precision Medicine/methods , Precision Medicine/standardsABSTRACT
BACKGROUND: Leptomeningeal metastases occur across multiple solid and lymphoid cancers, and patients typically undergo cytopathologic assessment of cerebrospinal fluid (CSF) in this setting. For patients diagnosed with metastatic cancer, the detection of actionable somatic mutations in CSF can provide clinically valuable information for treatment without the need for additional tissue collection. METHODS: The authors validated a targeted next-generation sequencing assay for the detection of somatic variants in cancer (OncoPanel) on cell-free DNA (cfDNA) isolated from archival CSF specimens in a cohort of 25 patients who had undergone molecular testing of a prior tumor specimen. RESULTS: CSF storage time and volume had no impact on cfDNA concentration or mean target coverage of the assay. Previously identified somatic variants in CSF cfDNA were detected in 88%, 50%, and 27% of specimens diagnosed cytologically as positive, suspicious/atypical, and negative for malignancy, respectively. Somatic variants were identified in 81% of CSF specimens from patients who had leptomeningeal enhancement on magnetic resonance imaging compared with 31% from patients without such enhancement. CONCLUSIONS: These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next-generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases.
Subject(s)
Cell-Free Nucleic Acids , Neoplasms , Humans , Cell-Free Nucleic Acids/genetics , Mutation , Neoplasms/diagnostic imaging , Neoplasms/genetics , High-Throughput Nucleotide Sequencing/methodsABSTRACT
Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.
Subject(s)
Brain Neoplasms , Humans , Brain Neoplasms/therapy , Medical Oncology , EthnicityABSTRACT
Leptomeningeal metastases are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options and clinical research protocols for patients with leptomeningeal metastases from solid tumors have similarly evolved to improve survival within specific populations. Recent expansion in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multi-modality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of leptomeningeal metastases, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of leptomeningeal metastases and serve as a platform for further discussion and patient advocacy.
ABSTRACT
Background: Glioblastoma (GBM) patients are treated with radiation therapy, chemotherapy, and corticosteroids, which can cause myelosuppression. To understand the relative prognostic utility of blood-based biomarkers in GBM and its implications for clinical trial design, we examined the incidence, predictors, and prognostic value of lymphopenia, neutrophil-to-lymphocyte ratio (NLR), and platelet count during chemoradiation (CRT) and recurrence. Methods: This cohort study included 764 newly diagnosed glioblastoma patients treated from 2005 to 2019 with blood counts prior to surgery, within 6 weeks of CRT, and at first recurrence available for automatic extraction from the medical record. Logistic regression was used to evaluate exposures and Kaplan-Meier was used to evaluate outcomes. Results: Among the cohort, median age was 60.3 years; 87% had Karnofsky performance statusâ ≥â 70, 37.5% had gross total resection, and 90% received temozolomide (TMZ). During CRT, 37.8% (248/656) of patients developed grade 3 or higher lymphopenia. On multivariable analysis (MVA), high NLR during CRT remained an independent predictor for inferior survival (Adjusted Hazard Ratio [AHR]â =â 1.57, 95% CIâ =â 1.14-2.15) and shorter progression-free survival (AHRâ =â 1.42, 95% CIâ =â 1.05-1.90). Steroid use was associated with lymphopenia (ORâ =â 2.66,1.20-6.00) and high NLR (ORâ =â 3.54,2.08-6.11). Female sex was associated with lymphopenia (ORâ =â 2.33,1.03-5.33). At first recurrence, 28% of patients exhibited grade 3 or higher lymphopenia. High NLR at recurrence was associated with worse subsequent survival on MVA (AHRâ =â 1.69, 95% CIâ =â 1.25-2.27). Conclusions: High NLR is associated with worse outcomes in newly diagnosed and recurrent glioblastoma. Appropriate eligibility criteria and accounting and reporting of blood-based biomarkers are important in the design and interpretation of newly diagnosed and recurrent glioblastoma trials.
ABSTRACT
PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/pathology , Random Allocation , Bayes Theorem , Brain Neoplasms/therapy , ErbB Receptors/genetics , BiomarkersABSTRACT
Since the 2002 Institute of Medicine report, which many cite as a landmark in first defining and calling attention to the concept of health disparities in medicine, much work has been dedicated to characterizing health disparities in medical care with the aim of eliminating them. Importantly, this report, "Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care," laid bare the differences in quality of health care that are based on race, ethnicity, and socioeconomic status. Here, the authors elaborate on these issues and discuss the role of the neuro-oncologic workforce in potentially mitigating these disparities.
Subject(s)
Central Nervous System Neoplasms , Ethnicity , Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/therapy , Delivery of Health Care , Humans , Socioeconomic Factors , United StatesABSTRACT
Importance: Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians' ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care. Observations: In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas. Conclusions and Relevance: The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.
Subject(s)
Astrocytoma , Brain Neoplasms , Central Nervous System Neoplasms , Glioblastoma , Glioma , Oligodendroglioma , Humans , Adult , Child , Isocitrate Dehydrogenase/genetics , Glioma/genetics , Glioma/therapy , Oligodendroglioma/genetics , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Astrocytoma/genetics , Central Nervous System Neoplasms/therapy , World Health Organization , MutationABSTRACT
BACKGROUND: The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks. METHODS: Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χâ2 tests were used for data analysis. RESULTS: Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship. CONCLUSIONS: Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.
Subject(s)
Clinical Trials as Topic , Neoplasms , Patient Selection , Female , Humans , Male , Minority Groups , National Institutes of Health (U.S.) , Neoplasms/therapy , Research Design , United StatesABSTRACT
It is widely recognized that subspecialized multidisciplinary care improves neuro-oncology outcomes. Optimizing patient outcomes relies on the expertise of the treating physicians, neuroradiology and neuropathology, and supportive services familiar with common neurologic syndromes that occur after brain tumor diagnosis and treatment. Despite an increasing number of providers, patient access to specialized multidisciplinary care and clinical trials remains limited. Barriers to equitable health care exist across the United States, with marginalized communities being impacted disproportionately. Such disparity causes increased morbidity and mortality for patients from backgrounds with various elements of diversity. Limited attention to this inequity has resulted in an incomplete understanding of the spectrum of experiences that patients with neuro-oncologic diseases encounter. Clinical trials represent the highest standard and quality of care in medicine, but inclusion of under-represented and underserved groups consistently lags behind counterpart participants from majority racial and ethnic groups. Through provider education as it pertains to issues from bias and health literacy to increasing clinical trial enrollment and offering opportunities through telemedicine, opportunities for improving access to high-quality neuro-oncologic care are explored.
Subject(s)
Brain Neoplasms , Medically Underserved Area , Brain Neoplasms/diagnosis , Brain Neoplasms/epidemiology , Brain Neoplasms/therapy , Ethnicity , Humans , Racial Groups , United States/epidemiology , Vulnerable PopulationsABSTRACT
BACKGROUND: Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers, and clinicians led us to conduct a survey to identify opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals. METHODS: In summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates including the European Association of Neuro-Oncology (EANO), Asian Society for Neuro-Oncology (ASNO), Society for Neuro-Oncology Latin America (SNOLA) and Society for Neuro-Oncology Sub-Saharan Africa (SNOSSA). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career service metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic, and sexual identity. Standard descriptive statistics characterized the study population. RESULTS: The 386 respondents were predominantly female (58%) with a median age range of 40-49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology field. CONCLUSIONS: The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field.
Subject(s)
Benchmarking , Medical Oncology , Adult , Ethnicity , Female , Humans , Middle Aged , Societies , Surveys and QuestionnairesABSTRACT
Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy.
Subject(s)
Brain Neoplasms , Cyclin-Dependent Kinase 6 , Brain Neoplasms/drug therapy , Cyclin-Dependent Kinase 4 , Humans , Piperazines/therapeutic use , PyridinesABSTRACT
Meningiomas are the most frequently occurring primary brain tumors in adults, representing almost one-third of all primary central nervous system tumors. Several factors have been suggested as an underlying cause in the development of meningiomas, such as ionizing radiation (therapeutic or other incidental exposure), hormonal factors, and genetic predisposition syndromes. Other established factors associated with meningiomas include age, female gender, and those from non-Hispanic Black backgrounds. Though the 2016 World Health Organization Classification of Brain Tumors largely preserves the existing grading scheme for organization of meningioma, there is increasing understanding of the molecular factors underlying the development of meningioma, some of which now form the basis for active clinical investigation. The mainstay of treatment has been the combination of radiation therapy and surgery, with a limited role for systemic therapy due to low efficacy, short duration of treatment response, and lack of uniform response criteria. Similar to other primary and metastatic brain tumors, immune-based therapies hold promise and are still under investigation.
Subject(s)
Antineoplastic Agents/therapeutic use , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Humans , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningioma/genetics , Meningioma/pathologyABSTRACT
INTRODUCTION: Dissemination of tumor to the leptomeninges, subarachnoid space, and cerebrospinal fluid (CSF) is termed leptomeningeal metastasis (LM) and occurs in approximately 5% of patients with solid tumors. LM is associated with dismal clinical prognosis, and routine cytologic and radiologic methods for diagnosing LM have limited sensitivity. The CellSearch immunomagnetic rare cell capture assay is FDA-approved to detect circulating tumor cells (CTCs) in peripheral blood, but whether it may have a role in identifying CSF CTCs is still unclear. MATERIAL AND METHODS: CSF specimens from 20 patients with clinically suspected solid tumor LM collected from 2 institutions between October 2016 and January 2019 were evaluated with routine CSF cytology and underwent concurrent CTC testing with the CellSearch assay (Menarini-Silicon Biosystems, Huntingdon Valley, PA). The results of CTC testing were compared to routine CSF cytology and radiologic studies for detecting LM. RESULTS: The CellSearch assay achieved a sensitivity of 88.9% and specificity of 100% for detecting LM (using a threshold of 1 CTC/mL of CSF as the definition of a positive CTC result). One patient with negative CSF cytology but positive CTCs developed positive cytology 37 days later. CONCLUSIONS: In this proof-of-principle pilot study, we demonstrate that the CellSearch assay can be successfully integrated with the routine CSF cytologic workflow to aid in the diagnosis of solid tumor LM. Importantly, CTCs detected by this rare cell capture assay are found in a subset of patients with non-positive routine CSF cytology, which may have significant implications for patient management.
Subject(s)
Adenocarcinoma of Lung/cerebrospinal fluid , Carcinoma, Adenosquamous/cerebrospinal fluid , Carcinoma, Ductal, Breast/cerebrospinal fluid , Cytodiagnosis/methods , Lung Neoplasms/cerebrospinal fluid , Meningeal Carcinomatosis/secondary , Small Cell Lung Carcinoma/cerebrospinal fluid , Triple Negative Breast Neoplasms/cerebrospinal fluid , Adenocarcinoma of Lung/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/cerebrospinal fluid , Carcinoma, Adenosquamous/pathology , Carcinoma, Ductal, Breast/pathology , Cohort Studies , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplastic Cells, Circulating , Pilot Projects , Sensitivity and Specificity , Small Cell Lung Carcinoma/pathology , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: Although surgery plays a crucial diagnostic role in World Health Organization (WHO) grade II 1p/19q-codeleted oligodendrogliomas, the role of maximal tumor surgical resection remains unclear, with early retrospective series limited by lack of molecular classification or appropriate control groups. METHODS: The characteristics, management, and overall survival (OS) of patients ≥20 years old presenting with histology-proven WHO grade II 1p/19q-codeleted oligodendrogliomas during 2010-2016 were evaluated using the National Cancer Database and validated using multi-institutional data. Patients were stratified by watchful waiting (biopsy only) versus surgical resection. OS was analyzed using Kaplan-Meier methods and risk-adjusted proportional hazards. RESULTS: Five hundred ninety adults met inclusion criteria, of whom 79.0% (n = 466) underwent surgical resection. Of patient and tumor characteristics, younger patients were more likely to be resected. Achieving gross total resection (GTR; n = 320) was significantly associated with smaller tumors, management at integrated network cancer programs (vs community cancer programs), and Medicare insurance (as compared with no, private, or Medicaid/other government insurance) and independent of other patient or tumor characteristics. In risk-adjusted analyses, GTR, but not subtotal resection (STR), demonstrated improved OS (vs biopsy only: hazard ratio 0.28, 95% CI: 0.09-0.85, P = 0.02). CONCLUSIONS: WHO grade II 1p/19q-codeleted oligodendrogliomas amenable to resection demonstrated improved OS with GTR, but not STR, compared with biopsy-only watchful waiting. The OS benefits of GTR were independent of age, tumor size, or tumor location. Medicare-insured and integrated network cancer program patients were significantly more likely to have GTR than other patients, suggesting that insurance status and care setting may play important roles in access to timely diagnosis or innovations that improve maximal resection.
Subject(s)
Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 1/genetics , Oligodendroglioma/surgery , Adult , Chromosome Deletion , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Grading , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Retrospective Studies , Treatment Outcome , World Health OrganizationABSTRACT
Primary central nervous system lymphoma (PCNSL) is an uncommon subtype of extranodal non-Hodgkin lymphoma (NHL) with less than 1500 cases annually. Incidence of PCNSL has remained stable in the post-highly active antiretroviral therapy era, owing to increasing incidence in elderly, immunocompetent patients. Most PCNSL is diffuse large B cell in origin, with less frequent involvement of T-cell and Burkitt lymphoma. Secondary central nervous system lymphoma is more likely to occur in the relapsed setting of a systemic NHL. Methotrexate forms the backbone of management for prophylaxis and treatment of disease. Treatments are currently under investigation for both disease entities.
Subject(s)
Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/therapy , Immunocompromised Host , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/epidemiology , Combined Modality Therapy , Humans , Immunotherapy , Incidence , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, T-Cell/epidemiology , RadiotherapyABSTRACT
BACKGROUND: Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance. METHODS: We performed a phase II trial of ponatinib in patients with bevacizumab-refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab-containing regimen was allowed. Primary endpoint was 3-month progression-free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment. RESULTS: The study closed after the first stage. Fifteen patients enrolled: median age 61 [27-74]; median KPS 80 [70-90]; median number of prior relapses 2 [2-4]. Three-month progression-free survival rate was 0, median overall survival was 98 days [95% CI 56, 257], and median PFS was 28 days [95% CI 27, 30]. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-8, and IL-10 and decreased sVEGFR2. CONCLUSIONS: Ponatinib was associated with minimal activity in bevacizumab-refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.