Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
To investigate whether adding autologous tumor lysate-loaded ...dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
ClinicalTrials.gov Identifier: NCT00045968.
Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax
-L) to ...standard therapy for newly diagnosed glioblastoma.
After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).
For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.
Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.
Carboplatin-associated Cranial Neuropathy Stevens, Shanlee M; McClelland, Collin M; Trusheim, John E ...
Neuro-ophthalmology (Amsterdam : Aeolus Press. 1980),
09/2018, Letnik:
42, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Carboplatin is a platinum-based chemotherapeutic agent used for the treatment of many solid tumors. Peripheral neuropathy is a common side effect; but, to our knowledge, ocular motor cranial ...neuropathies have not been reported in the literature. We describe a case of persistent third and fourth nerve palsies after systemic administration of intra-arterial carboplatin for glioblastoma multiforme. Neither nerve regained function after carboplatin was stopped.
Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, ...we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.
In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.
Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease SRD, and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 9% vs 23 6%), fatigue (six 2% vs 19 5%), brain oedema (eight 2% vs 11 3%), seizure (nine 2% vs eight 2%), and headache (six 2% vs ten 3%). Serious adverse events included seizure (18 5% vs 22 6%) and brain oedema (seven 2% vs 12 3%). 16 deaths in the study were caused by adverse events (nine 4% in the rindopepimut group and seven 3% in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut.
Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.
Celldex Therapeutics, Inc.
Following publication of the original article 1, the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and ...the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
Abstract
INTRODUCTION
Despite advances in surgical approaches, followed by chemo-radiotherapy protocols, the overall prognosis for patients with glioblastoma remains poor. Clinical trials have ...demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall survival times when combined with standard chemotherapy. However, the response to TTFields varies across patients, and it is currently unclear why some patients show increased time to tumor progression with TTFields treatment while others do not. One possible answer lies in the biological diversity of the tumors themselves. Genetic alterations are known to impact survival times and chemotherapy sensitivity in glioblastoma, suggesting that certain markers may also predict responsiveness to TTFields. Here, we compare the genetic profile of primary glioblastoma tumors with progression times in patients receiving TTFields treatment.
METHODS
Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and a sample from their primary tumor resection was sent for FoundationONE CDx™ testing. Genetic alteration results, including mutation burden and copy number alterations, were then compared with clinical data and tumor progression times.
RESULTS
Mutations and/or copy number changes in genes that regulate cell growth/proliferation, apoptosis, and interactions with DNA were among the most common alterations observed in our cohort. For patients that recurred within 12 months, we found a common pattern of alterations that includes CDKN2A/2B co-deletion, MTAP deletion, and PIK3 mutations. This pattern was not observed in patients that recurred after 12 months.
CONCLUSION
The identification of genetic markers that predict treatment responsiveness may help direct patients toward optimal treatment options. Ongoing work is aimed at expanding our sample size, correlating these genetic markers with overall patient survival, and determining if this pattern of expression is specifically related to TTFields treatment response.
Abstract
INTRODUCTION
Fatigue and sleep disturbances are among the most common side-effects reported by patients with glioblastoma and contribute significantly to the quality-of-life for this ...population. Non-invasive monitoring of long-term sleep patterns and fatigue levels in this population would allow for comparison between iatrogenic sleep disturbances, disease progression, treatment tolerance, and self-reported levels of fatigue. Here, we describe initial results from the implementation of the Readiband™ Sleep Tracker (Fatigue Science), a wearable actigraph device, for monitoring sleep patterns and fatigue in patients with newly diagnosed glioblastoma.
PATIENTS AND METHODS
Patients were prospectively enrolled and asked to wear the Readiband™ Sleep Tracker for a maximum of twelve months or until disease progression. Patients were also asked to report fatigue levels and sleep quality via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Pittsburg Sleep Quality Index (PSQI) questionnaires. Demographic, pathologic, and clinical information was abstracted from electronic medical records.
RESULTS
When data across all participants was combined, FACIT-F and PSQI scores were negatively correlated (r= -0.78, p< 0.001). Significant correlations were also seen between the Readiband™ measures for alertness, sleep quality, and sleep efficiency (p< 0.05 for all). However, we did not observe any correlations between the Redaiband™ measures and subjective survey responses. Interestingly, when patients were sub-divided based on tumor recurrence, we did see significant correlations between both survey scores and sleep quality and sleep efficiency measures (p< 0.05 for all) in patients that recurred during the study period.
CONCLUSION
The Readiband™ Sleep Tracker is a convenient and viable approach for monitoring sleep and fatigue in glioblastoma patients. Our preliminary findings suggest that actigraph measures may be a better indicator of subjective sleep quality and fatigue levels in specific sub-sets of this population. Ongoing research is exploring other clinical factors that might impact the accuracy of Readiband™ measures.
Abstract
INTRODUCTION
Clinical trials have demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall ...survival times in patients with glioblastoma when combined with standard chemotherapy. In addition to survival time, quality of life (QOL) is an important factor in treatment decisions for life-limiting diagnoses. Examinations of the impact of TTFields on QOL have yielded mixed RESULTS: Here, we describe patient-reported symptoms in patients with glioblastoma undergoing treatment with TTFields and compare symptom burden and associated interference with daily life to that of a historic non-TTFields cohort.
METHODS
Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and asked to complete the brain tumor-specific MD Anderson Symptom Inventory (MDASI-BT) approximately every 8 weeks through cessation of active disease treatment. MDASI-BT assessments were examined for symptom frequency, severity, and relationships between symptom severity and interference with daily life. These results were also compared with a matched cohort of patients who did not chose TTFields treatment and completed MDASI-BT assessments as part of a previous study.
RESULTS
The most commonly reported symptoms for Optune™ users were fatigue, sleep disturbance and speaking/word finding. Fatigue and sleep disturbance were also among the symptoms rated as most severe, along with feeling drowsy/sleepy. Interference with general activities and overall enjoyment of life as both were reported as both the most common and most severe impacts on daily life. When compared with historic data from non-Optune™ users at the same point in treatment, we found no difference in either symptom burden (p=0.48) or interference scores (p=0.72).
CONCLUSION
Attention to both survival benefit and symptom experience related to treatment options can inform patient decisions and direct approaches to symptom management as well as improved QOL.
Abstract
INTRODUCTION
Standard care for newly diagnosed glioblastoma consists of maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Prognosis for ...glioblastoma still remains poor, with a reported median survival of 14.6 months. Published data indicate that optimal outcomes in this population require involvement of an experienced team providing multidisciplinary care. We report here the outcomes in a real-world setting for glioblastoma patients treated at a specialized neuro-oncology cancer care program.
PATIENTS AND METHODS
Data from fifty consecutive patients with primary glioblastoma pursuing care at the Givens Brain tumor Center were analyzed. Coordinated medical care was provided by dedicated neuro-oncology and surgical clinicians, supplemented by care from nurse coordinators, social workers, care guides, genetic counselors, and other specialties. Demographic, pathologic, and clinical information was abstracted from electronic medical records.
RESULTS
Median patient age was 58 (range, 23–80) years and 26% were ≥65 years of age. Gross total resection was achieved in 91.5% patients, with 56% of resections performed in the Institution’s iMRI suite. A majority of patients received radiation and chemotherapy. In accordance with cancer program guidelines, 48% of the cases were presented at multidisciplinary tumor conferences. A LifeCourse™ care guide was utilized by 30% of the patients. Bevacizumab was used as second-line therapy with/without carboplatin in 63.2% patients. Optune treatment was administered to 27 patients. Additionally, eligible patients enrolled in clinical trials both at primary and recurrent stages. Median progression-free survival (PFS) and overall survival (OS) was 9.1 (range, 2.2–30.5) months and 19.4 (range, 4.6–31.8) months, respectively. End-of-life hospice care was elected by 48% patients.
CONCLUSION
PFS and OS in this real-world settings were comparable to outcomes noted in controlled clinical trials. These results indicate that efficient, quality care may be achieved with a multidisciplinary treatment approach, producing exceptional survival rates in patients with glioblastoma.
Abstract
INTRODUCTION
Standard care for glioblastoma consists of maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Fatigue and sleep disturbances are ...among the most common side-effect reported by these patients. Monitoring long-term sleep patterns and fatigue levels in this population would allow for comparison between iatrogenic sleep disturbances, disease progression, treatment tolerance, and self-reported levels of fatigue. Wearable actigraph devices provide a potential alternative approach to polysomnography for long-term sleep monitoring. Here, we describe initial results from the implementation of the Readiband™ Sleep Tracker (Fatigue Science) for monitoring sleep patterns and fatigue in newly diagnosed glioblastoma patients.
PATIENTS AND METHODS
Patients with primary glioblastoma were prospectively enrolled and asked to wear the Readiband™ Sleep Tracker for a maximum of twelve months or until disease progression. Data regarding alertness levels and sleep patterns were collected from Fatigue Science. Patients were also asked to report fatigue levels and sleep quality via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Pittsburg Sleep Quality Index (PSQI) questionnaires, respectively. Demographic, pathologic, and clinical information was abstracted from electronic medical records.
RESULTS
The Readiband™ data includes sleep/wake assessments, as well as sleep quality, sleep efficiency, and alertness scores. The overall sleep patterns reported by Readiband™ align with self-reported sleep times and sleep quantity. In addition, the SAFTE™ alertness scores show a positive correlation with FACIT-F (r=0.80) scores, and the sleep quality scores generated by Readiband™ show a negative correlation with PSQI (r=-0.83) scores.
CONCLUSION
The Readiband™ Sleep Tracker is a convenient and viable approach for monitoring sleep and fatigue in glioblastoma patients. Our preliminary findings suggest that actigraph measures can be used to monitor sleep quality and predict fatigue in this population. The study is ongoing to understand implications of sleep patterns on disease progression and treatment tolerance in primary glioblastoma.
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