Abstract Background Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not ...known. Methods EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m 2 every 6 weeks) or lomustine (110 mg/m 2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene ( IDH ) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0–2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union’s Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. Discussion EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. Trial registration ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023
Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a ...combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.
There is growing evidence that antitumor treatment contributes to better seizure control in low-grade glioma patients. We performed a systematic review of the current literature on seizure outcome ...after radiotherapy and chemotherapy and evaluated the association between seizure outcome and radiological response. Twenty-four studies were available, of which 10 described seizure outcome after radiotherapy and 14 after chemotherapy. All studies demonstrated improvements in seizure outcome after antitumor treatment. Eight studies reporting on imaging response in relation to seizure outcome showed a seizure reduction in a substantial part of patients with stable disease on MRI. Seizure reduction may therefore be the only noticeable effect of antitumor treatment. Our findings demonstrate the clinical relevance of monitoring seizure outcome after radiotherapy and chemotherapy, as well as the potential role of seizure reduction as a complementary marker of tumor response in low-grade glioma patients.
We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We ...retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were a ≥50 % seizure reduction and MRI response 6, 12 and 18 months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95 % CI 0.19–0.73; p = 0.004) and OS (HR 0.39; 95 % CI 0.18–0.85; p = 0.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95 % CI 62.0–112.9) than patients without a response (median 34.4mo; 95 % CI 26.1–42.6; p = 0.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.
Treatment with AEDs can be challenging in glioma patients as several aspects need to be considered: potential interactions between AEDs and chemotherapy (6), increased occurrence of adverse effects ...compared with nontumoral epilepsy patients receiving AEDs (7) and pharmacoresistance, in other words, failure to achieve seizure freedom even after AED dual therapy (8), in approximately20% of glioma patients (9). Here, we discuss different aspects regarding measuring AED outcomes in glioma studies: the difference between efficacy and effectiveness of AED treatment;why AED retention rate seems the most appropriate primary outcome in brain tumor related epilepsy studies;how the retention rate should statistically be analyzed and current literature on AED retention rates in glioma patients. The management of AED treatment in glioma patients is mostly done by either the treating neurologist or neurosurgeon and they see the glioma patient in regular follow-up visits every 3- or 6months, depending on the tumor grade. ...a change in AED regimen and the reasons for this change are generally reported adequately in medical electronical records, supporting our belief that the retention rate is the most appropriate outcome in epilepsy studies. In studies estimating time to first seizure, or seizure freedom rates, in glioma patients (18), where a patients dies before the occurrence of a first seizure, KM’s methodology yields to bias as discussed previously. ...to estimate the cumulative incidence of nonretention or first seizure, a competing risks model with death as competing risk must be used.
This study aimed to assess the prevalence of symptoms glioma patients may present with to the general practitioner, and whether these can be distinguished from patients with other CNS disorders or ...any other condition.
Glioma patients were matched to CNS patients and ‘other controls’ using anonymized general practitioner registries. Prevalences were evaluated in the 5 years prior to diagnosis.
CNS patients reported significantly more motor symptoms in the period 60–24 months, (p = 0.039). Moreover, <6 months before diagnosis CNS patients differed significantly in mood disorders/fear compared with ‘other controls’ (p = 0.012) but not glioma patients (p = 0.816).
Glioma patients could not be distinguished from both control groups with respect to the number or type of prediagnostic symptoms.
Background: The aim of this study was to explore the impact of the timing of Health-Related Quality of Life (HRQoL) measurements in clinical care on the obtained HRQoL scores in glioma patients, and ...the association with feelings of anxiety or depression. Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC)’s Quality of Life Questionnaires (QLQ-C30 and QLQ-BN20), and the Hospital Anxiety and Depression Scale (HADS) twice. All patients completed the first measurement on the day of the Magnetic Resonance Imaging (MRI) scan (t = 0), but the second measurement (t = 1) depended on randomization; Group 1 (n = 49) completed the questionnaires before and Group 2 (n = 51) after the consultation with the physician. Results: median HRQoL scale scores on t0/t1 and change scores were comparable between the two groups. Between 8–58% of patients changed to a clinically relevant extent (i.e., ≥10 points) on the evaluated HRQoL scales in about one-week time, in both directions, with only 3% of patients remaining stable in all scales. Patients with a stable role functioning had a lower HADS anxiety change score. The HADS depression score was not associated with a change in HRQoL. Conclusions: Measuring HRQoL before or after the consultation did not impact HRQoL scores on a group level. However, most patients reported a clinically relevant difference in at least one HRQoL scale between the two time points. These findings highlight the importance of standardized moments of HRQoL assessments, or patient-reported outcomes in general, during treatment and follow-up in clinical trials.
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