Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma: A Randomized Clinical Trial.

Importance: Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma. Objective: To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma. Design, Setting, and Participants: This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022. Interventions: Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily). Main Outcomes and Measures: The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life. Results: Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects. Conclusions and Relevance: This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma. Trial Registration: ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.

Changes in clinical management of diffuse IDH-mutated lower-grade gliomas: patterns of care in a 15-year period.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutated diffuse lower-grade gliomas (dLGG) are infiltrating brain tumors and increasing evidence is in favor of early multimodal treatment. In a Scandinavian population-based setting, we wanted to study treatment patterns over the last 15 years, focusing on the short-term postoperative course to better understand the potential negative consequences of treatment. METHODS: Patients ≥ 18 years with primary IDH-mutated dLGG grade 2 and 3, operated between January 2007-June 2021 were identified. Patients were divided into subgroups (2007-2011, 2012-2016, and 2017-2021) and comparisons regarding tumor- and disease characteristics, treatment, and postoperative outcome were performed. RESULTS: We identified 202 patients (n = 61, 2007-2011; n = 72, 2012-2016; n = 69, 2017-2021), where of 193 underwent resection without change in proportion of resections over time. More patients underwent complete resections in recent times (6.1%; 15.7%; 26.1%, respectively; p = 0.016). Forty-two patients had any neurological deficit postoperatively (14.8%; 23.6%; 23.2%; p = 0.379), mostly minor and transient. Differences in oncological therapy were seen between the investigated subgroups. Early radiotherapy alone (32.8%; 7%; 2.9%; p < 0.001), concomitant chemoradiotherapy (23%; 37.5%; 17.4%; p = 0.022), sequential chemoradiotherapy (0%; 18%; 49.3%; p < 0.001), and no adjuvant treatment (42.6%; 23.6%; 18.8%; p = 0.009) shifted during the studied period. Increasingly more patients received proton radiotherapy compared to photon radiotherapy during the later time periods (p < 0.001). CONCLUSION: Complete resections were performed more often in later time periods without an apparent increase in surgical morbidity. Early adjuvant oncological treatment shifted towards providing chemotherapy and combined chemoradiotherapy more often in later time periods. Protons replaced photons as the radiation modality of choice.

A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma.

BACKGROUND: There is an urgent need for effective treatments against glioblastoma (GBM). In this trial, we investigated the efficacy and safety of an adoptive cell-based immunotherapy. METHODS: Patients with newly diagnosed GBM were recruited at 4 study sites in Sweden. The patients were randomized 1:2 to receive either radiotherapy (RT), 60 Gy/30 fractions, with concomitant and adjuvant temozolomide (TMZ) only, or RT and TMZ with the addition of Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT) in an open-label phase II trial. The primary endpoint was investigator-assessed progression-free survival (PFS). The secondary endpoints were survival and safety of ALECSAT. RESULTS: Sixty-two patients were randomized to either standard of care (SOC) with RT and TMZ alone (n = 22) or SOC with ALECSAT (n = 40). Median age was 57 years (range 38-69), 95% of the patients were in good performance status (WHO 0-1). There was no significant difference between the study arms (SOC vs ALECSAT + SOC) in PFS (7.9 vs 7.8 months; hazard ratio [HR] 1.28; 95% confidence interval [CI] 0.70-2.36; P = .42) or in median overall survival (OS) (18.3 vs 19.2 months; HR 1.16, 95% CI 0.58-2.31; P = .67). The treatment groups were balanced in terms of serious adverse events (52.4% vs 52.5%), but adverse events ≥grade 3 were more common in the experimental arm (81.0% vs 92.5%). CONCLUSION: Addition of ALECSAT immunotherapy to standard treatment with radiochemotherapy was well tolerated but did not improve PFS or OS for patients with newly diagnosed GBM.

Patterns of care and clinical outcome in assumed glioblastoma without tissue diagnosis: A population-based study of 131 consecutive patients.

BACKGROUND: Elderly patients with glioblastoma and an accumulation of negative prognostic factors have an extremely short survival. There is no consensus on the clinical management of these patients and many may escape histologically verified diagnosis. The primary aim of this study was to characterize this particular subgroup of patients with radiological glioblastoma diagnosis without histological verification. The secondary aim was to evaluate if oncological therapy was of benefit. METHODS: Between November 2012 and June 2016, all consecutive patients presenting with a suspected glioblastoma in the western region of Sweden were registered in a population-based study. Of the 378 patients, 131 (35%) met the inclusion criteria of the present study by typical radiological features of glioblastoma without histological verification. RESULTS: The clinical characteristics of the 131 patients (72 men, 59 women) were: age ≥ 75 (n = 99, 76%), performance status according to Eastern Cooperative Oncology Group ≥ 2 (n = 93, 71%), significant comorbidity (n = 65, 50%) and multilobular tumors (n = 90, 69%). The overall median survival rate was 3.6 months. A subgroup of 44 patients (34%) received upfront treatment with temozolomide, with an overall radiological response rate of 34% and a median survival of 6.8 months, compared to 2.7 months for those receiving best supportive care only. Good performance status and temozolomide treatment were statistically significant favorable prognostic factors, while younger age was not. CONCLUSION: Thirty-five percent of patients with a radiological diagnosis of glioblastoma in our region lacked histological diagnosis. Apart from high age and poor performance status, they had more severe comorbidities and extensive tumor spread. Even for this poor prognostic group upfront treatment with temozolomide was shown of benefit in a subgroup of patients. Our data illustrate the need of non-invasive diagnostic methods to guide optimal individualized therapy for patients considered too fragile for neurosurgical biopsy.

Proton therapy for low-grade gliomas in adults: A systematic review.

For adult patients with diffuse low-grade glioma (LGG) proton therapy is an emerging radiotherapy modality. The number of proton facilities is rapidly increasing. However, there is a shortage of published data concerning the clinical effectiveness compared to photon radiotherapy and potential proton-specific toxicity. This study aimed to systematically review and summarize the relevant literature on proton therapy for adult LGG patients, including dosimetric comparisons, the type and frequency of acute and long-term toxicity and the clinical effectiveness. A systematic search was performed in several medical databases and 601 articles were screened for relevance. Nine articles were deemed eligible for in-depth analysis using a standardized data collection form by two independent researchers. Proton treatment plans compared favorably to photon-plans regarding dose to uninvolved neural tissue. Fatigue (27-100%), alopecia (37-85%), local erythema (78-85%) and headache (27-75%) were among the most common acute toxicities. One study reported no significant long-term cognitive impairments. Limited data was available on long-term survival. One study reported a 5-year overall survival of 84% and 5-year progression-free survival of 40%. We conclude that published data from clinical studies using proton therapy for adults with LGG are scarce. As the technique becomes more available, controlled clinical studies are urgently warranted to determine if the potential benefits based on comparative treatment planning translate into clinical benefits.

Determinants for Effective ALECSAT Immunotherapy Treatment on Autologous Patient-Derived Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of less than 15 months, emphasizing the need for better treatments. Immunotherapy as a treatment for improving or aiding the patient's own immune defense to target the tumor has been suggested for GBM. A randomized clinical trial of adoptive cell transfer using ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumor Cells) is currently ongoing in Sweden. Here we performed a paired pre-clinical study to investigate the composition and in vitro effect of ALECSAT and identify determinants for the effect using autologous GBM-derived cancer stem cells (CSC), immunocytochemistry and flow cytometry. We show a clear dose-response relationship of ALECSAT on CSC, suggesting that the number of infused cells is of importance. In addition, the in vitro effect of ALECSAT on CSC correlated significantly to the blood count of T helper (Th) cells in the patient indicating a potential benefit of collecting cells for ALECSAT preparation at an even earlier stage when patients generally have a better blood count. The factors identified in this study will be important to consider in the design of future immunotherapy trials to achieve prolonged survival.

Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial.

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.