Therapy options for glioblastoma

Glioblastoma is an extremely aggressive brain tumour, despite various therapeutic approaches, with a mostly poor prognosis. Which treatment is recommended?

Standard treatment protocols for glioblastoma

Based on the results of a phase III EORTC study in 2005, patients with newly diagnosed glioblastoma are treated with maximal safe resection (while maintaining neurological function), followed by radiotherapy and concurrent continuous administration of temozolomide (TMZ).3 In addition to first-line TMZ, the chemotherapy regimen includes either bevacizumab or nitrosourea compounds (lomustine), which serve as second-line therapy.1

The extent of resection is an important prognostic factor, with intraoperative MRI (iMRI) and 5‑aminole vulinic acid (5-ALA) supported surgical techniques contribute to comparable improvements in survival (no superiority of iMRI for achieving complete resections), according to a recent prospective study.2,4 The avoidance of new permanent neurological deficits takes precedence over surgical radicalism.5

Neuro-oncological centres evaluate the treatment options in the context of a clinical therapy study at every stage of the disease. These studies are concerned with biomarker-, cell- or antibody-based concepts, therapeutic vaccinations and approaches to optimising current standard therapies. For treatment recommendations outside of clinical studies, the molecular profile of the tumour, the patient's age and clinical condition (KPS/ECOG performance status) are crucial.2

Patient-centred supportive therapy is important at all stages

Due to the often pronounced neurological symptoms and psychological stress, early symptom-oriented therapy, psycho-oncological support and the establishment of outpatient palliative care are important.2

Another treatment option is provided by tumour-treating fields (Optune®), in which transducer arrays attached to the patient's scalp generate alternating electrical fields that are thought to interfere with cell division. The technology is currently only offered by its developer, Novocure.6 Based on the promising results of two phase III studies, the FDA granted approval and relevant professional associations issued recommendations for use.

Nevertheless, the results of the studies were also discussed critically in professional circles. In addition to the unblinded design and the lack of a sham device, it was criticised that the control group received less adjuvant chemotherapy than the treatment group and that one of the two studies was terminated prematurely based on the results of an interim analysis. Further points of criticism expressed by experts were a problematic delay between diagnosis and randomisation, the unclear mechanism of action of the device, the very high costs (approx. US$21,000 per month) and the complicated application.

Unfortunately, as with many proprietary treatments, the literature on TTFields appears to be influenced by financial relationships, with a strong association between positive views on its use and financial conflicts of interest with the device manufacturer, a recent meta-analysis points out.1,6

Interdisciplinary, multiprofessional therapeutic approach needed

Glioblastoma is the most common and deadliest primary malignancy of the central nervous system (accounting for 46 percent of malignant CNS tumours; with an annual incidence rate of ~3.2 per 100,000).1 Despite significant resources devoted to this disease and numerous phase III clinical trials in the last 20 years, little therapeutic progress has been made since the introduction of the EORTC protocol and 5-year overall survival rates remain poor (< 10 per cent).2,6 Median overall survival (OS) from diagnosis ranges from 14.6 to 16.7 months and median PFS ranges from 5.5 to 7.3 months. After recurrence, treatment options are limited, with median survival with active treatment in the range of 7 months.1

There is therefore increasing interest in adjunctive therapies. The restrictive ketogenic diet (RKD) has become an increasingly important topic in the field of neuro-oncology. After the anti-tumour effects of RKD were demonstrated in preclinical studies, clinical studies were able to confirm an increase in survival with no toxicity or major side effects.7,8 ‘Taken together, the results suggest that RKD in combination with standard treatment could provide a promising new therapeutic approach for GBM patients, with more encouraging results than existing treatments,’ the authors of a recent review conclude.7

Most recently, tumour energy metabolism is an enormously promising target that an increasing number of studies are successfully addressing. The aim of ongoing research is to establish specific patient subgroups with tailored genetic profiles and individual treatment protocols.

References
  1. Regev, O., Merkin, V., Blumenthal, D. T., Melamed, I. & Kaisman-Elbaz, T. Tumor-Treating Fields for the treatment of glioblastoma: a systematic review and meta-analysis. Neuro-Oncology Practice 8, 426–440 (2021).
  2. Rieger, D. et al. Glioblastom – aktuelle Therapiekonzepte. Onkologie 30, 145–156 (2024).
  3. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987–996 (2005).
  4. Roder, C. et al. Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial. J Clin Oncol 41, 5512–5523 (2023).
  5. S2k-Guidelines. https://register.awmf.org/de/leitlinien/detail/030-099.
  6. Hayes, M. J. & Prasad, V. Association between conflict of interest and published position on tumor-treating fields for the treatment of glioblastoma. Journal of Cancer Policy 21, 100189 (2019).
  7. Brotis, A. G., Arvaniti, C., Kontou, M., Tsekouras, A. & Fountas, K. N. Ketogenic Diet in the Management of Glioblastomas: A Bibliometric Analysis. Neuroglia 5, 63–79 (2024).
  8. Seyfried, T. N. et al. Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report. Front Nutr 8, 682243 (2021).

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