Anterior Temporal Lobectomy in Temporal Glioblastoma

Phase 3RecruitingNCT07021339

University Hospital, Bonn178 enrolled

Overview

The ATLAS/NOA-29 trial is a prospective, multicenter, phase III randomized controlled study evaluating whether anterior temporal lobectomy (ATL), a standardized resection technique adapted from epilepsy surgery, improves clinical outcomes in patients with newly diagnosed glioblastoma of the anterior temporal lobe compared to conventional gross-total resection (GTR). The rationale is based on the concept of glioblastoma as a diffusely connected tumor network, with infiltrative spread extending beyond MRI-detectable tumor margins. ATL offers a reproducible supramarginal resection approach within anatomical boundaries that are routinely respected in epilepsy surgery. Patients are randomized intraoperatively in a 1:1 ratio following histopathological confirmation via intraoperative frozen section procedure. The trial's primary objective is to demonstrate superiority of ATL in overall survival (OS), while confirming non-inferiority in health-related quality of life (QoL), measured by the global health status scale of the European Organisation for Research and Treatment of Cancer (EORTC) - Quality of Life Questionnaire Core 30 (QLQ-C30). Secondary outcomes include progression-free survival (PFS), seizure control, neurocognitive functioning, and longitudinal assessments of selected EORTC QLQ-C30 and BN20 domains. A total of 178 patients will be enrolled over three years, with a minimum follow-up of three years. An interim safety analysis after inclusion of 57 patients will assess functional outcome differences using the modified Rankin Scale (mRS) at 6 months postoperatively. The study is powered (\>80%) to detect a survival benefit assuming a median OS increase from 17 to 27.5 months. If proven superior to GTR, ATL could emerge as the preferred surgical strategy for isolated temporal lobe glioblastoma, offering robust evidence in favor of extending supramarginal resection principles to the broader context of glioblastoma care.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Interventions

Anterior temporal lobectomy (ATL)PROCEDURE

Patients assigned to the experimental group will undergo an anterior temporal lobectomy (ATL) according to established protocols adapted from epilepsy surgery. ATL is a reproducible and anatomically well-defined procedure routinely performed in patients with pharmacoresistant temporal lobe epilepsy. On the non-dominant hemisphere, the neocortical resection typically extends 6.5 cm posteriorly from the temporal pole, while on the dominant side, the resection length is limited to 4.0 cm, both measured along the superior temporal gyrus and guided by the Sylvian fissure. Language dominance is determined based on handedness, as specified in the inclusion criteria. In most cases, the lateral neocortical segment can be removed en bloc. The mesial component of ATL encompasses resection of the uncus, amygdala, and the anterior hippocampus, typically including both the head and body. Resection is carried out to the level of the tectal plate or, at minimum, to the lateral mesencephalic sulcus.

Gross Total Resection (GTR)PROCEDURE

Patients will be surgically treated with GTR in terms of removing 100% of the tumor tissue in gadolinium-enhanced MRI.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 74 Years

Medical Language ↔ Plain English

* Suspected glioblastoma with contrast-enhancement in preoperative MRI * Diffuse high-grade glioma in frozen section procedure, newly-diagnosed * Tumor localization (in gadolinium-enhanced MRI): solely temporal, non-dominant side (right hemisphere in right-handed patients, or left-handed patients after testing for dominance): within 6.5 cm from the temporal pole; dominant side (left hemisphere in right-handed patients, all left-handed patients unless additional testing for dominance performed): within 4.0 cm from the temporal pole, as determined dorsally along the Sylvian fissure. * Macroscopic complete resection (no remaining contrast-enhancing tumoral lesion on early postoperative MRI) is achievable (decision of the treating neurosurgeon) * In case further T1-contrast-enhancing and/or T2/FLAIR lesions are detected beyond the resection margins (6.5 cm on the non-dominant side and 4.0 cm on the dominant side), these lesions are not attributed to the tumor (except perifocal edema) but to other conditions according to the local treating neurosurgeon * ≥ 18 and \< 75 years of age * KPS ≥ 70% * Estimated life expectancy of at least 6 months * Written informed consent * Cognitive state to understand the rationale and necessity of the study therapy and procedures * Patient compliance and geographic proximity that allow adequate follow-up * For patients with childbearing potential: negative serum pregnancy test (beta-HCG) at baseline visit, patient's commitment to use an approved contraceptive method during the trial and for 3 months after (Pearl index \< 1%) * Adequate organ function at baseline visit that does not preclude alkylating chemotherapy and neurosurgical procedures (all criteria required): * Adequate bone marrow reserve: white blood cell (WBC) count ≥ 3.000/µl; granulocyte count \> 1.500/µl; platelets ≥ 100.000/µl; haemoglobin ≥ 10 g/dl * Adequate liver function: bilirubin \< 1.5 times above upper limit of normal range (ULN); alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/ALAT) \< 3 times ULN * Adequate renal function: creatinine \< 1.5 times ULN * Adequate blood clotting: Partial Thromboplastin Time (PTT) not exceeding the upper limit of normal range and International Normalized Ratio (INR) \<1.5; in case of intake of anticoagulant medication or platelet function inhibitors, the coagulation analysis must show no detectable effect in specific blood tests (as described below) at the time of surgery, and discontinuation of the anticoagulant medication must be justifiable for at least 1 week postoperatively * Direct acting oral anticoagulants (e.g., rivaroxaban, apixaban, edoxaban, dabigatran): anti-Factor Xa (aFXa)-activity within the normal range (rivaroxaban, apixaban, edoxaban), TT/TCT (thrombin clotting time) or ecarin clotting time (ECT) not exceeding the upper limit of normal range (Dabigatran) or verification of subtherapeutic drug levels (apixaban, edoxaban, rivaroxaban, dabigatran) * Vitamin K antagonists (coumarins): INR \< 1.5 * Unfractionated heparin (UFH) and argatroban: activated Partial Thromboplastin Time (aPTT) not exceeding the upper limit of normal range * Fractionated heparin/low-molecular-weight heparin (e.g., dalteparin, enoxaparin), heparinoid (e.g., fondaparinux, danaparoid): aFXa-activity within the normal range * Antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor): platelet function analyzer (PFA) test not exceeding the upper limit of normal range (aspirin), whole blood aggregometry not below lower limits of normal range (clopidogrel, prasugrel, ticagrelor) For details see study protocol.

Outcomes

Primary Outcomes

Overall survival

OS in the modified intention to treat (mITT) population of patients with glioblastoma, Central Nervous System (CNS) World Health Organization (WHO) grade 4, Isocitrate Dehydrogenase wild-type (IDHwt)

Time frame: From randomization until death or 36 months after recruitment of the last patient

Patient-reported Quality of Life

In case of significant OS differences, the patient-reported QoL domain "global health status" (EORTC QLQ-C30 questionnaire) in the modified intention to treat (mITT) population is the co-primary endpoint. Over-all superiority of ATL requires significantly prolonged OS and non-inferiority regarding the development of the global health status over time in the mITT population.

Time frame: From randomization until death or 36 months after recruitment of the last patient

Secondary Outcomes

Progression-free survival

Progression is defined as the first documented evidence of progression of disease according to the Response Assessment in Neuro-Oncology 2.0 (RANO 2.0) criteria. Progression will be evaluated using the RANO (Response Assessment in Neuro-Oncology) 2.0. criteria.

Time frame: PFS is measured from randomization at the day of surgery until progression or death. PFS will be assessed at the 12-week follow-up visit and at all subsequent visits scheduled at 12-week intervals up to three years.

Neurocognitive Outcome

All patients will undergo testing with the Brain Lesion Tracking Test (BLTT). The test covers all relevant domains of neurocognition-including episodic and semantic memory as well as executive functions-without excluding patients due to neurological impairments such as visual deficits or hemiparesis. The BLTT includes interlocking word list learning with delayed free recall and recognition, semantic word generation and fluency, phonemic fluency, reverse digit span, and incidental memory, providing a rapid screening of neurocognitive function. Results are categorized into three performance domains: executive functions, episodic memory, and semantic memory. In addition, figural memory is assessed through a visual recognition task involving drawn objects presented on a series of cards.

Time frame: Cognitive performance across all domains will be quantitatively assessed at baseline (preoperatively), and at follow-up visits on day 90 (visit 8) and one year after surgery (visit 11).

Karnofsky Performance Scale

Karnofsky Performance Scale (KPS) is an attempt to quantify cancer patients' general well-being and activities of daily life. The KPS ranking runs from 100 to 0, where 100 is "perfect" health and 0 is death.

Time frame: KPS will be assessed at baseline, on postoperative day 1, and at follow-up visits on days 3, 14, 30, and 90, and subsequently at 12-week intervals.

Seizure outcome

Analysis of postoperative seizure outcome will be assessed referring to the ILAE classification system in the course of epilepsy surgical procedures: seizure freedom (ILAE class 1) will be de-fined as a favorable seizure outcome; ILAE classes 2-6 (i.e. pure auras, rare to no improvement and worsening of seizure frequency) will be referred to as unfavorable seizure outcome.

Time frame: Seizure outcome will be assessed at the 12 weeks, the 6 months and all 12 week follow-up examination.

Modified Rankin Scale assessment (mRS)

The mRS will be used for measuring the degree of disability or dependence in the daily activities of patients. The mRS ranking runs from 0 to 6, where 0 is "perfect" health and 6 is death. Furthermore, 6 months after randomization of the 57th patient there will be carried out an interim safety analysis, which will evaluate differences in clinical performance (mRS) between the experimental and conventional intervention groups.

Time frame: The mRS will be assessed at baseline, on postoperative day 1, and at follow-up visits on days 3, 14, 30, and 90, and subsequently at 12-week intervals.

Quality-of-life (QoL)

The EORTC quality of life (QoL) questionnaire modules QLQ-C30 and BN20 will be used to assess patients' QoL. These internationally recognized and well-validated instruments cover 26 QoL domains. Based on previous studies, particular emphasis will be placed on domains especially relevant to brain tumor patients, including global health status, physical functioning, social functioning, cognitive functioning, communication deficits, and motor dysfunction. The questionnaires are designed for completion within approximately 10 minutes, both in the pretreatment phase and during ongoing treatment. Their validity has been demonstrated across various cancer populations and disease stages, including different treatment contexts. Test-retest reliability assessed over a four-day interval has shown good to excellent consistency across all functional domains, with Pearson's r values ranging from 0.72 to 0.91.

Time frame: QoL will be assessed at baseline, at follow-up visits on days 14, 30, and 90, and subsequently at 24-week intervals.