The prognosis of patients with glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma remains poor despite standard treatment with radiotherapy and temozolomide. Molecular targeted ...therapy holds the promise of providing new, more effective treatment options with minimal toxicity. However, the development of targeted therapy for gliomas has been particularly challenging. The oncogenetic process in such tumors is driven by several signaling pathways that are differentially activated or silenced with both parallel and converging complex interactions. Therefore, it has been difficult to identify prevalent targets that act as key promoters of oncogenesis and that can be successfully addressed by novel agents. Several drugs have been tested, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib), mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and vascular endothelial growth factor receptor (VEGFR), protein kinase C-beta, and other angiogenesis pathways inhibitors (vatalanib, bevacizumab, and enzastaurin). Although preliminary efficacy results of most trials in recurrent disease have fallen short on expectations, substantial advances have been achieved by associated translational research. In this article, we seek to recapitulate the lessons learned in the development of targeted therapy for gliomas, including challenges and pitfalls in the interpretation of preclinical data, specific issues in glioma trial design, insights provided by translational research, changes in paradigms, and future perspectives.
The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and ...tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development.
We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.
A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values.
PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to ...determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval CI, 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.
•The MTD of POM for relapsed/refractory PCNSL is 5 mg orally daily for 21 days every 28 days.•POM and DEX combination has therapeutic activity against relapsed/refractory PCNSL.
Display omitted
Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction. This review focuses on recent ...developments in the field, with an emphasis on clinical management. The growing clinical trials landscape reflects advanced insights into cancer immunology and genomics and the need to address molecular and clinical heterogeneity. Recent phase 3 trials investigating anti–PD‐1 immunotherapies, particularly nivolumab, have failed to demonstrate improved survival in glioblastoma, underscoring the need to better understand the complexity of CNS immunologic surveillance. Conversely, targeted therapies have accounted for several US Food and Drug Administration approvals extended to brain tumors, particularly therapies directed to BRAF V600E mutations and TRAK fusions, underscoring a need to routinely screen patients for these rare molecular abnormalities. In primary CNS lymphoma, attention has turned to long‐term outcomes of consolidation therapies, and recent studies have highlighted the excellent disease control afforded by high‐dose chemotherapy and stem cell transplantation. Meningiomas remain a focus of investigations, with preliminary promising results observed with octreotide combined with mTOR inhibition, and immunotherapy with single‐agent pembrolizumab. Finally, proton radiotherapy has emerged as a novel alternative for leptomeningeal metastases from solid tumors, which can now be treated more safely with craniospinal irradiation and monitored by the enumeration of circulating tumor cells in the cerebrospinal fluid as a biomarker. Taken together, these incremental advances have improved outcomes in select brain tumor patient populations, whereas ongoing clinical trials hold the promise of meaningful advances and breakthroughs for larger proportions of patients with brain tumors.
Progress in the management of brain tumors has been slow relative to systemic cancers; however, notable advances have been achieved in several diseases, such as glioblastoma, primary central nervous system lymphoma, meningioma, and leptomeningeal metastasis, showing that the field of neuro‐oncology is far from stagnant.
Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron ...emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.
Emerging therapies for glioblastoma Thomas, Alissa A; Brennan, Cameron W; DeAngelis, Lisa M ...
JAMA neurology,
11/2014, Letnik:
71, Številka:
11
Journal Article
Recenzirano
Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median ...survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed.
Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors' files. Clinical trials were identified in the Clinicaltrials.gov registry.
Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed.
Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.
Primary CNS lymphoma (PCNSL), a rare CNS malignancy, is usually treated with high-dose methotrexate in the first-line setting, typically followed by consolidation therapy. Due to the broad range of ...currently available treatments for PCNSL, comparability in long-term follow-up studies is limited, and data are scattered across small studies.
In this study, we report the long-term survival of patients with newly diagnosed immunocompetent PCNSL, enrolled in a phase II trial from June 2005 to September 2011. Patients were treated using rituximab, methotrexate, vincristine, and procarbazine (R-MVP) chemotherapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in those with partial or complete response to R-MVP. In a post hoc analysis, clinical and imaging features were evaluated in those still alive.
26 of 32 patients underwent HDC-ASCT consolidation. Of them, 3 patients died of treatment-related toxicity and 2 due to disease progression within 1 year of ASCT. None of the remaining 21 patients had disease progression with a median follow-up of 12.1 years and were included in the analysis. Compared with the post-HDC-ASCT assessment, at the last follow-up, there was no significant difference in the median Karnofsky Performance Status (80 range: 60-100 vs 90 range: 70-100), the median Neurologic Assessment in Neuro-Oncology score (1 range: 0-4 vs 1 range: 0-5), and leukoencephalopathy score (1 range: 0-3 vs 1 range: 1-4).
Long-term follow-up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.
Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with ...recurrent glioblastoma with PI3K pathway activation.
This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.
Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT
immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6
and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 10.8%), fatigue (n = 4 6.2%), hyperglycemia (n = 3 4.6%), and elevated ALT (n = 3 4.6%).
Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has ...emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy.
Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m(2) on days 1, 10, and 20, and temozolomide 100 mg/m(2) on days 1-5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m(2) on day 1, and temozolomide 100 mg/m(2 )days 1-5). Non-responders were treated on an individual basis.
Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction.
Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.
The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality ...regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.
PDF
