ABSTRACT
PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.
Subject(s)
Brain Neoplasms , Radiosurgery , Adult , Humans , Positron Emission Tomography Computed Tomography/methods , Radiosurgery/adverse effects , Pilot Projects , Prospective Studies , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/radiotherapy , Brain Neoplasms/etiology , Necrosis/diagnostic imaging , Necrosis/etiologyABSTRACT
PURPOSE: We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG). MATERIALS/METHODS: We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time. RESULTS: Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination). CONCLUSION: Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.
Subject(s)
Brain Neoplasms , Glioma , Adult , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/genetics , Cognition , Female , Glioma/genetics , Humans , Male , Temozolomide/therapeutic useABSTRACT
PURPOSE: The role of maintenance immunotherapy with anti-CD20 monoclonal antibody rituximab in primary central nervous system lymphoma (PCNSL) is unclear. We retrospectively reviewed the medical records of all immunocompetent adults with newly diagnosed PCNSL treated at our institution between1996 and 2017. METHODS: We identified 66 patients who attained complete response (CR) after completion of first-line regimen; 20 received maintenance therapy (maintenance therapy group) and 46 were observed with serial MRI scans without maintenance therapy (no-maintenance therapy group). RESULTS: Compared to the surveillance group, there was a significant increase in duration of survival (HR 0.27, 95% CI 0.08-0.98, P = 0.046) in the maintenance therapy group while the reduction in the risk of progression was not significant (HR: 0.61, 95% CI 0.26-1.43, P = 0.259). CONCLUSION: We are evaluating the effectiveness of maintenance immunotherapy in PCNSL in a prospective multicenter randomized clinical trial.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Central Nervous System Neoplasms/therapy , Lymphoma, Non-Hodgkin/therapy , Rituximab/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Humans , Immunotherapy/methods , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM). METHODS: This was an open label phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had progressed on prior anti-angiogenic therapy. Nineteen subjects were enrolled in Arm 1 and 14 subjects in Arm 2. The primary endpoint was 6-month progression-free survival (PFS-6) in Arm 1 and time to progression (TTP) in Arm 2. The secondary endpoints were toxicity, objective response rate (ORR) and overall survival. RESULTS: Patients in Arm 2 (compared to Arm 1) tended to have longer intervals from diagnosis to study entry (median 26.9 vs. 8.9 months, p = 0.002), experienced more recurrences (64%, had 3-4 prior recurrences compared to 0, p < 0.0001) and tended to be heavily pretreated (71% vs. 26-32% p = 0.04 or 0.02). 6-month PFS was 12% ± 6% for the Arm 1 and 0% for Arm 2. TTP was similar in both treatment arms (median 1.8 months Arm 1 and 0.7-1.8 months Arm 2, p = 0.36). Five patients (15%) had grade 4 toxicities and 22 patients (67%) had grade 3 toxicities. There were no significant differences between the two arms with respect to the amount of change in the levels of biomarkers from baseline. CONCLUSION: Dovitinib was not efficacious in prolonging the PFS in patients with recurrent GBM irrespective of prior treatment with anti-angiogenic therapy (including bevacizumab).
Subject(s)
Benzimidazoles/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Quinolones/therapeutic use , Adult , Aged , Biomarkers, Tumor/analysis , Brain Neoplasms/pathology , Female , Follow-Up Studies , Glioblastoma/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Prognosis , Prospective Studies , Survival RateABSTRACT
Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.
Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , Clinical Trials as Topic/methods , Endpoint Determination , Patient Selection , Antineoplastic Agents/adverse effects , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Clinical Trials as Topic/standards , Endpoint Determination/standards , Humans , Treatment OutcomeABSTRACT
BACKGROUND: The current study was conducted to investigate survival and the response to radiotherapy among patients with molecular subtypes of breast cancer brain metastases treated with or without targeted therapies. METHODS: Patients diagnosed with breast cancer brain metastases at a single tertiary care institution were included. The primary outcome was overall survival, whereas secondary outcomes included the cumulative incidences of distant intracranial failure, local failure, and radiation necrosis. Competing risks regression was used to model secondary outcomes. RESULTS: Within the study period, 547 patients presented with 3224 brain metastases and met inclusion criteria. Among patients with human epidermal growth factor receptor 2 (HER2)-amplified disease, 80% received HER2 antibodies and 38% received HER2/epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The median survival was significantly shorter in the basal cohort (8.4 months), and progressively increased in the luminal A (12.3 months), HER2-positive (15.4 months), and luminal B (18.8 months) cohorts (P<.001). Among patients with HER2-amplified disease, the median survival was extended with the use of both HER2 antibodies (17.9 months vs 15.1 months; P = .04) and TKIs (21.1 months vs 15.4 months; P = .03). The 12-month cumulative incidences of local failure among molecular subtypes were 6.0% in the luminal A cohort, 10.3% in the luminal B cohort, 15.4% in the HER2-positive cohort, and 9.9% in the basal cohort (P = .01). Concurrent HER2/epidermal growth factor receptor TKIs with stereotactic radiosurgery significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P<.001). CONCLUSIONS: Molecular subtypes appear to be prognostic for survival and predictive of the response to radiotherapy. TKIs were found to improve survival and local control, and may decrease the rate of distant failure. To preserve neurocognition, these results support a paradigm of upfront radiosurgery and HER2-directed therapy in the HER2-amplified population, reserving whole-brain radiotherapy for salvage. Cancer 2017;123:2283-2293. © 2017 American Cancer Society.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Brain Neoplasms/therapy , Breast Neoplasms/therapy , Cranial Irradiation , Metastasectomy , Protein Kinase Inhibitors/therapeutic use , Radiosurgery , Antineoplastic Agents/therapeutic use , Brain Neoplasms/metabolism , Brain Neoplasms/secondary , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , Female , Humans , Lapatinib , Middle Aged , Molecular Targeted Therapy , Multivariate Analysis , Prognosis , Proportional Hazards Models , Quinazolines/therapeutic use , Receptor, ErbB-2/metabolism , Retrospective Studies , Survival Rate , Trastuzumab/therapeutic useABSTRACT
To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively (p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT.
Subject(s)
Brain Neoplasms/drug therapy , Brain/pathology , Cranial Irradiation/adverse effects , Necrosis/etiology , Radiation Injuries/etiology , Radiosurgery/adverse effects , Aged , Brain Neoplasms/mortality , Cohort Studies , Female , Humans , Karnofsky Performance Status , Male , Middle Aged , Proportional Hazards Models , Radiation Injuries/mortality , Risk FactorsABSTRACT
Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived ≥5 years; 23 patients (1.2 %) survived ≥10 years and the median survival for ≥10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the ≥10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease.
Subject(s)
Brain Neoplasms/mortality , Brain Neoplasms/therapy , Radiosurgery/methods , Adult , Age Factors , Aged , Brain Neoplasms/secondary , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Proportional Hazards Models , Survival Rate , Time FactorsABSTRACT
BACKGROUND: Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases. METHODS: Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity. RESULTS: Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively. CONCLUSIONS: This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.
Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/drug therapy , Epothilones/administration & dosage , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Administration, Intravenous , Adult , Aged , Antineoplastic Agents/adverse effects , Brain Neoplasms/mortality , Carcinoma, Non-Small-Cell Lung/mortality , Disease Progression , Drug Administration Schedule , Epothilones/adverse effects , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Prospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/therapy , Dacarbazine/analogs & derivatives , Oligodendroglioma/therapy , Radiotherapy/methods , Adolescent , Adult , Aged , Dacarbazine/therapeutic use , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Temozolomide , Tomography, X-Ray Computed , Treatment Outcome , Young AdultABSTRACT
Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Oligodendroglioma/drug therapy , Patient Outcome Assessment , Quality of Life , Adolescent , Adult , Aged , Aged, 80 and over , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/genetics , Dacarbazine/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Grading , Oligodendroglioma/genetics , Oligodendroglioma/mortality , Oligodendroglioma/pathology , Prognosis , Survival Rate , Temozolomide , Young AdultABSTRACT
Patients with 1-3 brain metastases (BM) often receive sterotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT). SRS without WBRT carries a high rate of relapse in the central nervous system (CNS). This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Eligible patients with 1-3 newly diagnosed BM, RTOG RPA class 1-2, received sunitinib after SRS. Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/days 1-28 every 42 days until CNS progression. Neuropsychological testing and MRIs were obtained every two cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS6) after SRS. Fourteen patients with a median age of 59 years were enrolled. Primary cancers included lung 43 %, breast 21 %, melanoma 14 %. Toxicity included grade 3 or higher fatigue in five patients and neutropenia in two patients. The CNS PFS6 and PFS12 were 43 ± 14 and 34 ± 14 %, respectively. Of the ten patients who completed >1 neurocognitive assessment, none showed cognitive decline. Sunitinib after SRS for 1-3 BM was well tolerated with a PFS6 of 43 %. The prevention of progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient's primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of BM after definitive local therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/therapy , Indoles/therapeutic use , Neoplasm Recurrence, Local/therapy , Pyrroles/therapeutic use , Radiosurgery/methods , Aged , Aged, 80 and over , Brain Neoplasms/secondary , Cognition Disorders/diagnosis , Cognition Disorders/etiology , Combined Modality Therapy , Dose-Response Relationship, Radiation , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Recurrence, Local/secondary , Neuropsychological Tests , Radiosurgery/adverse effects , Salvage Therapy , Sunitinib , Treatment OutcomeABSTRACT
Glioblastoma is the most common adult malignant primary brain tumor. Despite the advances in therapeutic options, survival of patients with glioblastoma remains dismal at 15-18 months. Current standard of care for newly diagnosed glioblastoma is maximal possible safe resection consistent with the preservation of neurologic function followed by concurrent temozolomide with radiation and adjuvant. Treatment options at recurrence include surgical resection with or without the placement of carmustine wafers, re-irradiation and chemotherapeutics such as nitrosoureas (lomustine, carmustine) or bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF).
Subject(s)
Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Carmustine/therapeutic use , Humans , Molecular Targeted Therapy , Neoplasm Recurrence, Local/drug therapyABSTRACT
Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan-Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19-93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT-sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45-2.95; p < 0.0001) and males (1.51; 95% CI, 1.14-2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01-1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.
ABSTRACT
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
Subject(s)
Brain Neoplasms , Glioma , Humans , Male , Middle Aged , Glioma/drug therapy , Glioma/pathology , Adult , Female , Aged , Administration, Oral , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Aged, 80 and over , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasm Grading , Maximum Tolerated DoseABSTRACT
PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Radiosurgery , Humans , Female , Lapatinib , Breast Neoplasms/pathology , Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Radiosurgery/methods , Brain/pathologyABSTRACT
PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
Subject(s)
Brain Neoplasms , Glioblastoma , Neoplasm Recurrence, Local , Temozolomide , Aged , Female , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Excision Repair/drug effects , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/genetics , Glioblastoma/mortality , Hydroxylamines/therapeutic use , Hydroxylamines/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Prognosis , Temozolomide/therapeutic use , Temozolomide/administration & dosageABSTRACT
BACKGROUND: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM. METHODS: We conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS). RESULTS: 6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed. CONCLUSIONS: Single-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.
Glioblastoma is an aggressive and lethal brain tumor, with patients typically expected to survive for 14 to 16 months after diagnosis. Nearly all patients experience tumor recurrence once conventional treatment strategies fail, after which a drug called bevacizumab is used. However, subsequent treatment options are extremely limited. We performed a clinical trial in which we investigated how safe and effective a new drug called TRC105 (carotuximab) is in patients who no longer respond to chemotherapy, radiotherapy or bevacizumab. We tested TRC105 both with and without bevacizumab, since TRC105 might enhance the activity of bevacizumab. We found that patients survived for an average of 5.7 months when given TRC105 and bevacizumab in combination. These findings suggest that further clinical trials are needed to confirm whether or not this combination therapy is a useful approach in patients with glioblastoma recurrence.
ABSTRACT
â¢First report of a secondary somatic glioblastoma arising from MCT-MT in a patient with underlying Li-Fraumeni syndrome.â¢The rarity of glioblastoma arising from MCT-MT warrants investigation for underlying genetic predisposition.â¢Glioblastomas arising from MCT-MT appear to exhibit wild type IDH gene status.â¢Advanced-stage glioblastoma arising from MCT-MT exhibits aggressive behavior and requires adjuvant therapy.â¢Optimal adjuvant therapy regimen for glioblastoma arising from MCT-MT remains unknown.
ABSTRACT
INTRODUCTION: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. METHODS: A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. RESULTS: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). CONCLUSIONS: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.