ATLAS/NOA-29 trial

Anterior Temporal Lobectomy (ATL) versus gross-total resection (GTR) in temporal glioblastoma surgery

Objectives and endpoints

The primary objective is to prove superiority of anterior temporal lobectomy (ATL) compared to gross total resection (GTR) in patients with newly-diagnosed glioblastoma of the temporal lobe. Superiority will be defined as significant differences in the primary endpoint overall survival (OS) and non-inferiority regarding the co-primary endpoint quality of life (QoL; domaine „global health“ of the EORTC QLQ C30 questionnaire). Secondary endpoints include progression-free survival (PFS), functional outcome (as measured by modified Rankin Scale (mRS) and Karnofsky Performance Score (KPS)), seizure outcome, neurocognitive outcome (short test battery focused on temporal lobe functions) and evaluation of all QoL domains of EORTC QLQ C30 and BN20 questionnaires over time.

Trial design

The ATLAS-trial is a randomized, controlled phase III trial with 21 German trials sites and Wien as Austrian trial site.

Inclusion criteria

Newly-diagnosed glioblastoma in frozen section procedure
Tumor localization (in gadolinium-enhanced magnetic resonance imaging (MRI)): solely temporal, non-dominant side: within 6.5 cm from the temporal pole; dominant side: within 4.5 cm from the temporal pole
No temporomesial malignant infiltration (in gadolinium-enhanced MRI); the temporomesial structures include the hippocampus, the amygdala, the parahippocampal gyrus and/or the entorhinal cortex)
Decision of the treating neurosurgeon: macroscopic complete re-section (no remaining contrast-enhancing tumoral lesion on early postoperative MRI) is achievable
In case further T1-contrast-enhancing and/or T2 and/or FLAIR lesions are detected beyond the temporal lobe, these lesions are not attributable to glioblastoma, but to other conditions according to the local treating neurosurgeon
> 18 years of age
KPS ≥ 60%
Estimated life expectancy of at least 6 months
Written informed consent
Cognitive state to understand the rationale and necessity of study therapy and procedures
Patient compliance and geographic proximity that allow adequate follow-up examinations
Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test (beta-HCG) must be obtained at baseline visit
Adequate organ function that does not preclude alkylating chemotherapy and neurosurgical procedures, as described below:
- Adequate bone marrow reserve
  - White blood cell (WBC) count ≥ 3000/µl
  - Granulocyte count > 1500/µl
  - Platelets ≥ 100000/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: PTT not exceeding the upper limit of normal range; INR <1.5; in case of intake of anticoagulant medication or platelet function inhibitors:
- Direct acting oral anticoagulants: aXa-activity within the normal range (Rivaroxaban, Apixaban, Edoxaban) or verification of prophylactic plasma levels, aIIa-activity (Dabigatran) not detectable or verification of prophylactic plasma levels
- Vitamin K antagonists: INR < 1.5
- Antiplatelet agents: (Aspirin, Clopidogrel, Prasugrel, Ticagrelor): Aspirin: PFA (platelet function analyzer)-test not exceeding the upper limit of normal range; Clopidogrel/Prasugrel, Ticagrelor: whole blood aggregometry not below lower limits of normal range
- Parenteral anticoagulants:
  - Unfractionated heparin: aPTT not exceeding the upper limit of normal range
  - Low molecular weight heparins including fondaparinux: aXa-activity < 0.2 IE/ml
  - Danaparoid-Sodium: aXa-activity < 0.2 IE/ml
  - Argatroban: aPTT not exceeding the upper limit of normal range

Study protocol

The trial will randomize 170 patients over 3 years with a follow-up of 3 years after inclusion of the last patient. Assuming a prolongation of median survival time from 17 months to 27.5 months for the ATL approach and constant recruitment, this sample size provides a power of above 80% for the intended two-sided stratified log-rank test (level of 5%) to detect differences in OS between the arms.
The trial will be monitored by a Data Safety Monitoring Board. An interim safety analysis 6 months after recruitment of 1/3 of the patients will be performed to make sure that the postoperative clinical status is not significantly worse in the experimental (ATL) arm compared to the standard (GTR) arm. Safety will be objectified by the rate of patients with a postoperative modified ranking scale (mRS) score of 4-6. Particular attention will also be paid to periprocedural adverse events as measured by patient safety indicators and specific cranial surgery-related complications.

Accompanying scientific program

The resected anterior temporal lobe tissue provides the unique opportunity for cross-sectional analyses of tumor infiltration and microenvironment ranging from the central bulky tumor part to various degrees of the infiltration zone including areas without overt signs of infiltration on conventional MRI. We aim at creating a map of cellular components, functional states and network interactions covering vast parts of the infiltration zones of the tumor.