To Örebro University

Purpose: MGMT promoter methylation is a key predictive biomarker for response to alkylating agents in glioblastoma. However, there is no consensus regarding optimal analytical method or cut-off. This study aimed to define a clinically relevant survival-based cut-off value for MGMT using a standardized pyrosequencing assay. Methods: Patients from five Swedish university hospitals with MGMT promoter methylation status analyzed using the Therascreen MGMT Pyro Kit, investigating CpGs 76–79, were identified. Glioblastoma patients treated with radiotherapy and concomitant temozolomide were selected from the Swedish CNS Tumor Registry. Quantitative MGMT status, both mean value and percentage of methylation for each individual CpG, was analyzed using an unsupervised bimodal normal mixture model and a survival-informed approach adjusted for established prognostic factors. Results: A total of 451 patients were included. The unsupervised model identified a cut-off at ≥ 11% for methylated MGMT, whereas the supervised, survival-informed analysis defined a cut-off for unmethylated tumors at ≤ 8%. A small intermediate gray zone (> 8% to < 11%) was observed. No individual CpG provided superior predictive performance compared to the mean of all CpGs. Conclusion: A clinically relevant, survival informed three-tier classification of MGMT promoter methylation is proposed for the pyrosequencing kit analyzing CpGs 76–79 in glioblastoma. A threshold of ≤ 8% identifies a subgroup with truly unmethylated tumors, while ≥ 11% defines a clearly methylated group. The intermediate range represents a gray zone. These cut-offs support individualized therapy by improving clinically relevant stratification and facilitate future clinical trials focusing on patients with truly unmethylated MGMT. 

The randomized phase II SAKK 35/14 trial, conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG), compared efficacy and safety of rituximab (375 mg/m2 intravenously for 4 weeks followed by maintenance every 2 months for 24 months) plus placebo (arm A) versus the same schedule of rituximab plus ibrutinib (560 mg daily for 24 months, arm B) in patients with advanced follicular lymphoma in need of systemic therapy. The primary end-point, complete remission (CR) rate at 24 months, was 36% in arm A and 40% in arm B, with no statistically significant difference. Three-year progression-free survival (PFS) was 36% in arm A and 45% in arm B, with a hazard ratio of 0.64 (p = 0.057). Three-year overall survival was about 96% in both arms. A higher percentage of patients in arm B experienced grade ≥3 adverse events, but they were manageable. No toxic deaths were observed. Although the primary end-point (CR rate at 24 months) was not met, a trend towards improved PFS with ibrutinib plus rituximab observed at the prespecified significance level of 0.1 may indicate a potential clinical benefit.

BACKGROUND: Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a predictive factor for glioblastoma (GBM) treated with alkylating agents, such as Temozolomide (TMZ). It correlates with increased survival in GBM patients with MGMT promoter methylated tumours. For methylation specific PCR, used in several trials, the clinically relevant cut-off has previously been defined. However, to date there is no consensus regarding the optimal analytical method for the clinic or relevant cut-off value for the chosen method.

MATERIAL AND METHODS: Glioma patients from five university hospitals in Sweden with MGMT test results using the same pyrosequencing kit analysing four CpGs (Qiagen) were identified. From this cohort patients diagnosed with GBM and reported to have received concomitant chemo-radiotherapy with TMZ (CCRT) were selected from the Swedish quality registry for primary brain tumours (SQR) together with prognostic factors. Quantitative MGMT methylation status in percent was obtained from the departments of pathology, as the mean of the four CpGs clinically used, and the results from each separate CpG will be provided. Both the mean and separate CpGs will be linked to survival and prognostic factors. The clinically relevant cut-off will be calculated at a 50% probability to be unmethylated. ROC analysis will be performed for an optimal cut-off supervised by overall survival (OS).

RESULTS: MGMT results from 2133 patients were identified. Among these, 510 patients were reported to have received CCRT with TMZ. They had available data regarding obtained treatment including received dose of radiotherapy (RT) and had been diagnosed as GBM, all but 22 molecularly confirmed. Of these, 121 patients had received 40Gy hypofractionated RT, 379 patients ≥50Gy, of which 368 patients had received 60Gy. Ten patients who received <40Gy are excluded from further analysis. Hence, a total of 500 patients are included in the final analysis. An optimal cut-off for unmethylated MGMT using multiple discriminant analysis will be proposed after receiving data regarding prognostic factors: age, performance status, type of surgery and MGMT promoter methylation status of the individual CpGs. A grey zone will also be defined. An updated analysis will be presented.

CONCLUSION: In this study we will define the clinically relevant cut-off, and grey zone, when using the pyrosequencing kit analysing four CpGs to determine the MGMT methylation status. Hence, enabling a better treatment prediction for alkylating agents, mainly TMZ, in GBM patients, enhancing individualized treatment. It also enables inclusion of patients in future first line clinical trials omitting TMZ for patients with truly unmethylated MGMT.

Background: Meningioma is typically benign and is occasionally detected during examinations due to other reasons (e.g. suspected stroke, trauma). Reported incidence figures usually come from various registers, and most reported prevalence figures are estimations derived from incidence figures and survival data. The Region Örebro County meningioma project aims to gain a better understanding of the incidence and prevalence of meningioma in the population. With these preliminary data, we seek to ascertain the practical feasibility of our proposed search method.

Material and methods: In the Swedish county of Örebro with 302,252 inhabitants (2019), all radiology departments are within the public healthcare system. The electronic radiology archive (ERA) includes all patients who have undergone any type of radiological examination in the region since its introduction in 1996. To determine the number of individuals with meningioma in the region and when they were diagnosed, we conducted free-text searches for the word “meningioma” with various spelling variations in ERA and included all patients where the word appears in ERA referrals or responses. Subsequently, using data from the region’s electronic medical records (EMR), we excluded all patients not residing within the region. We then manually reviewed these patients’ referrals, written reports and radiology examinations, to determine whether they have meningioma, the date of diagnosis, whether it was an incidental finding, and presence of multiple meningioma.

Results: We identified 3,428 patients, of which 3,064 have been included in this study (being residents of the region). In a preliminary review, we have been able to identify 1,663 (55 %) patients with likely meningioma. Of the 1,663 patients, 5 % had a diagnosis date before the introduction of ERA. The median age was 73 (IQR 61-82) years. There were 24 % males and 76 % females. Multiple meningioma were found in 9 % of the patients. In the preliminary review 64 % were incidental findings, while 21 % and 15 % were classified as non-incidental and indeterminate, respectively.

Conclusion: Performing free-text ERA/EMR searches is a potential avenue to achieve better coverage when investigating incidence and prevalence of a disease such as meningioma in a public healthcare setting. In our initial review, it is evident that the method identifies and can retrieve meningioma patients from the ERA. Gender distribution, median age and multiple meningioma numbers are comparable to other reported meningioma populations. Based on our experience with this dataset, it is not advisable to rely solely on simple automated searches. Projects akin to this would likely be well suited for future automated image analysis (volumetric measurement, meningioma identification, etc.).

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.

The standard treatment of glioblastoma, an aggressive brain tumour, includes radiotherapy combined with temozolomide. Based on a randomised trial, showing five months increased survival, TTF has been introduced in the management of patients with good performance status. Data from the Swedish national quality registry for CNS tumours have been analysed for TTF usage. The results demonstrate that 65 percent of the patients accepted treatment with TTF. More than half of the treated patients interrupted treatment due to low compliance or their own wish. Median treatment time was 164 days, with a range from 0 to 774 days. There was a large variation between different regions in how many patients were offered TTF treatment. A non-significant trend to better survival was seen for the group of TTF-treated patients compared to individually matched controls. In summary, TTF is a new treatment for glioblastoma, with potential to prolong survival also in real world patients. Today, the treatment is not offered equally to all patients, despite national guidelines.

TTF (tumour treating fields) är en ny, nationellt godkänd utrustning, som inducerar alternerande elektriska fält och används vid behandling av hjärntumören glioblastom.

Behandlingen kan vara inskränkande i vardagen, och data från det nationella registret för CNS-tumörer visar att mer än hälften av patienterna avbryter TTF på grund av dålig användningsgrad eller egen önskan.

Genomsnittlig behandlingstid enligt registret är 164 dagar.

Jämfört med matchade kontroller visar data från registret en trend med längre överlevnad för patienter som behandlas med TTF; dock är skillnaden inte statistiskt signifikant.

Det finns en stor regional variation i andelen patienter som erbjudits behandlingen.

BACKGROUND: Meningioma is the most common primary CNS tumour. Most meningiomas are benign, and most patients are 65 years or older. Surgery is usually the primary treatment option. Most prior studies on early surgical outcomes in older patients with meningioma are small, and there is a lack of larger population-based studies to guide clinical decision-making. We aimed to explore the risks for perioperative mortality and morbidity in older patients with meningioma and to investigate changes in surgical incidence over time.

METHODS: In this retrospective population-based study on patients in Sweden, 65 years or older with surgery 1999-2017 for meningioma, we used data from the Swedish Brain Tumour Registry. We analysed factors contributing to perioperative mortality and morbidity and used official demographic data to calculate yearly incidence of surgical procedures for meningioma.

RESULTS: The final study cohort included 1676 patients with a 3.1% perioperative mortality and a 37.6% perioperative morbidity. In multivariate analysis, higher age showed a statistically significant association with higher perioperative mortality, whereas larger tumour size and having preoperative symptoms were associated with higher perioperative morbidity. A numerical increased rate of surgical interventions after 2012 was observed, without evidence of worsening short-term surgical outcomes.

CONCLUSIONS: Higher mortality with increased age and higher morbidity risk in larger and/or symptomatic tumours imply a possible benefit from considering surgery in selected older patients with a growing meningioma before the development of tumour-related symptoms. This study further underlines the need for a standardized method of reporting and classifying complications from neurosurgery.

BACKGROUND: Although high grade gliomas largely affect older patients, current evidence on neurosurgical complications is mostly based on studies including younger study populations. We aimed to investigate the risk for postoperative complications after neurosurgery in a population-based cohort of older patients with high grade gliomas, and explore changes over time.

METHODS: In this retrospective study we have used data from the Swedish Brain Tumour Registry and included patients in Sweden age 65 years or older, with surgery 1999-2017 for high grade gliomas. We analysed number of surgical procedures per year and which factors contribute to postoperative morbidity and mortality.

RESULTS: The study included 1998 surgical interventions from an area representing 60% of the Swedish population. Over time, there was an increase in surgical interventions in relation to the age specific population (p < 0.001). Postoperative morbidity for 2006-2017 was 24%. Resection and not having a multifocal tumour were associated with higher risk for postoperative morbidity. Postoperative mortality for the same period was 5%. Increased age, biopsy, and poor performance status was associated with higher risk for postoperative mortality.

CONCLUSIONS: This study shows an increase in surgical interventions over time, probably representing a more active treatment approach. The relatively low postoperative morbidity- and mortality-rates suggests that surgery in older patients with suspected high grade gliomas can be a feasible option. However, caution is advised in patients with poor performance status where the possible surgical intervention would be a biopsy only. Further, this study underlines the need for more standardised methods of reporting neurosurgical complications.

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.

Background: There is a trend in brain tumor treatments over time to treat patients at a higher age and to perform more advanced and radical surgery. Despite this little is known about the perioperative morbidity and mortality after intracranial tumor surgery, especially regarding the elderly. The Swedish brain tumor registry has collected data since 1999 with good coverage and is considered population based. Among the parameters registered are perioperative complications such as postoperative hematoma and thromboembolism as well as newly diagnosed epilepsy, new focal neurologic deficit and date of death.

Methods: Data from the registry has been collected and analyzed in this retrospective population based study. This study includes patients in the registry at age 65 or older, with high grade glioma (GBM, astrocytoma grIII), low grade glioma (astrocytoma grI-II, oligodendroglioma grII-III and gangliogliomas) registered from 1999 to 2015. Formation of diagnose groups are in conjunction with suggestions from the Swedish National Brain Tumor Trialist Group. From this data we have excluded patients that have not undergone surgery, where surgery (or not) cannot be determined and where data on complications is unavailable. Only the national regions with a high enough coverage are included.

Results: The material contains 1467 evaluable patients. High grade gliomas were 1277 (male 59%, female 41%), median age at surgery 71 (range 65 to 86), women not older (72 VS 71; NS). 17,5% (male 16,4%, female 20,0%; NS) had WHO/ECOG-PS >2. Perioperative mortality was 7,8% (male 9,2%, female 5,9%; p=0,03), associated with WHO/ECOG-PS >2 (p<0,0001). 15,7% (male 17,3%, female 13,5%; NS) had perioperative complications. The most common complication was worsening of neurologic function (7,6%, male 8,4%, female 6,5%; NS) and most patients (10,8%, male 12,8%, female 8,0%; NS) had one recorded complication. The mortality and morbidity remains consistent regardless of year of surgery. Low grade gliomas were 190 (male 55% VS female 45%), median age 70 (65 to 83), men not significantly older (71 VS 69; NS). 16,8% (male 15,7%, female 19,5%; NS) had WHO/ECOG-PS >2. Perioperative mortality was 5,3% (male 6,7%, female 3,5%; NS). 20,0% (male 21%, female 18,8%; NS) had perioperative complications. As with high grade gliomas the most common complication was worsening of neurologic function (13,7%, male 15,2%, female 11,8%; NS) and the mortality and morbidity remains without significant changes regardless of year of surgery.

Conclusion: In this material we can conclude that the perioperative mortality as well as morbidity is higher than in published younger patient materials for gliomas. We cannot see an increase in perioperative mortality or morbidity with higher age within the material but this could be from lack of power and we hope to be able to get a clearer view in a later comparison with the younger patients in the registry.