11/11/2025
🧠 Selected and debated clinical studies in neuro-oncology (as of 2025)
Studies that have generated scientific, clinical, or ethical controversy — due to design limitations, non-reproducible results, translational gaps, or high public attention.
1. EF-14 Trial (Tumor Treating Fields – TTFields in Glioblastoma)
Publication: Stupp et al., JAMA 2017
Design: Phase III randomized trial evaluating TTFields + temozolomide vs. temozolomide alone in newly diagnosed glioblastoma.
Controversy: Demonstrated improved median survival (20.9 vs. 16.0 months), but lack of blinding, limited external validity, unclear mechanistic basis, and very high cost (>€20,000/month).
Discussion: In Europe, adoption has been cautious; in the U.S., rapid integration and commercial promotion.
Status 2025: Standard of care for newly diagnosed glioblastoma and CNS WHO grade 4 astrocytoma, though long-term real-world adherence remains variable.
2. CheckMate 498 & 548 (Nivolumab in Glioblastoma)
Publications: Lim et al., Neuro-Oncology 2022; Omuro et al., Neuro-Oncology 2023
Design: Phase III trials of PD-1 blockade (nivolumab) in newly diagnosed glioblastoma (MGMT-methylated vs. unmethylated).
Controversy: No improvement in overall survival.
Discussion: Checkpoint inhibition remains largely ineffective in “cold” tumors like GBM.
Nonetheless, the trials fuel persistent public and patient optimism about immunotherapy.
Note: Pre-operative or neoadjuvant checkpoint blockade remains experimental; off-label requests continue.
3. NOA-16 (IDH1 Peptide Vaccine in Astrocytoma WHO Grade 2/3)
Publication: Platten et al., Nature 2021
Design: Phase I/II study on safety and immunogenicity of an IDH1(R132H)-targeted vaccine.
Controversy: Highly promising immunogenic results but no proven survival benefit. The trial sparked media overenthusiasm, leading to unrealistic patient expectations of a “cancer vaccine.”
Discussion: Valuable scientific proof of principle, but still translationally premature for broad clinical use.
4. CODEL vs. CATNON (Therapy Strategies in IDH-Mutant Grade 3 Gliomas)
Publications: CATNON: van den Bent et al., NEJM 2017; CODEL: ongoing (ASCO abstracts)
Design: Comparative trials evaluating PCV vs. temozolomide in IDH-mutant anaplastic gliomas.
Controversy: CATNON showed temozolomide benefit but did not account for IDH mutation; CODEL challenges the role of temozolomide in favor of PCV.
Discussion: Discordance between guidelines and real-world practice; significant inter-center variation in treatment choice.
5. German Glioma Network (MGMT Promoter Methylation Substudies)
Publications: e.g., Weller et al., JCO 2015
Design: Translational analyses of MGMT promoter methylation as a predictive biomarker for temozolomide efficacy.
Controversy: MGMT is a well-established marker, but test reproducibility varies between labs; cutoff thresholds are inconsistent.
Discussion: Debate continues whether MGMT is predictive only or also prognostic.
Clinical dilemma: “Borderline MGMT” cases—should temozolomide be offered?
6. Real-World Personalized Neoantigen Peptide Vaccine (Nature Communications 2024)
Publication: Latzer et al., Nature Communications 2024
Design: Retrospective real-world analysis of 173 GBM patients receiving personalized neoantigen-derived peptide vaccines (Germany, 2015–2023).
Findings:
Median overall survival: 31.9 months; 54% of patients alive at cutoff.
Strong vaccine-induced T-cell responses in 90% of monitored patients.
Patients with robust immune responses (immunological responders) achieved median OS of 53 months vs. 27 months in non-responders.
Minimal toxicity (mostly Grade 1–2).
Controversy:
Non-randomized design; self-selected and self-funded cohort.
Confounding by socioeconomic bias and selection of long survivors.
No control arm; only propensity-matched comparison with historical datasets.
Discussion: Despite methodological limitations, this large-scale real-world dataset rekindles enthusiasm for personalized vaccine approaches.
However, experts urge caution until prospective randomized trials confirm causality.
7. ACT IV (Rindopepimut – EGFRvIII Vaccine in Glioblastoma)
Publication: Weller et al., Lancet Oncology 2017
Design: Phase III, double-blind, randomized trial of an EGFRvIII-targeted vaccine plus standard therapy in newly diagnosed EGFRvIII-positive GBM.
Controversy: The trial was terminated early due to futility—no difference in survival.
Discussion: Highlighted the heterogeneity and immune escape of glioblastoma; many tumor cells lose EGFRvIII expression during therapy.
Lesson: “Target loss” and intra-tumoral evolution remain major challenges in glioma immunotherapy.
8. BELOB / EORTC 26101 (Bevacizumab in Recurrent Glioblastoma)
Publications: Taal et al., Lancet Oncology 2014; Wick et al., Lancet Oncology 2017
Design: Phase II–III studies of bevacizumab ± lomustine in recurrent glioblastoma.
Controversy: Improved progression-free survival, but no overall survival benefit.
Discussion: Bevacizumab remains widely used for symptom control (reducing edema, steroid-sparing) but lacks disease-modifying effect.
Ethical discussion: Costly therapy with limited benefit — still part of individualized salvage therapy in 2025.
9. GAPVAC-101 (Actively Personalized Vaccine in Newly Diagnosed GBM)
Publication: Hilf et al., Nature 2019
Design: Phase I personalized multi-peptide vaccine (mutated + non-mutated antigens) in 15 patients post-chemoradiation.
Results:
Feasible production within 12 weeks.
Induced broad T-cell responses.
Median PFS: 14.2 months; median OS: 29 months.
Discussion: Landmark early trial for active personalization — technically feasible but complex and costly; remains a prototype concept for individualized immunotherapy.
10. H3K27M Vaccine in Diffuse Midline Glioma
Publication: Grassl et al., Nature Medicine 2023
Design: Compassionate-use study of an H3K27M-targeted peptide vaccine in adult diffuse midline glioma.
Findings: Strong tumor-specific T-cell responses; early signals of clinical benefit.
Controversy: Small uncontrolled cohort (n=8); heterogeneous background therapy.
Discussion: One of the few promising vaccine strategies for midline gliomas; supports ongoing immunotherapy trials in pediatric-type tumors.
Summary and Outlook (2025)
The field of neuro-oncological immunotherapy is undergoing a paradigm shift:
From standard cytotoxic and radiation-based regimens toward individualized molecular and immunologic strategies.
Yet, most trials show biological activity without robust survival benefit.
Major challenges: patient selection, biomarker validation, tumor heterogeneity, and trial design.
Consensus (2025):
Clinical translation of glioma vaccines and immunotherapies requires controlled, biomarker-guided, randomized studies and international collaboration to move from “promising signals” to true standards of care.
