What are the newer experimental treatments for glioblastoma?

Newer Experimental Treatments for Glioblastoma

For patients with glioblastoma, enrollment in clinical trials evaluating experimental therapies is strongly recommended as the primary option for recurrent disease, as there are currently no proven therapies that significantly extend overall survival in this setting. 1

Current Standard of Care

Before discussing experimental treatments, it's important to understand the current standard of care:

• Newly diagnosed glioblastoma:
  • Maximal safe surgical resection when feasible
  • Adjuvant radiation therapy (60 Gy in 30 fractions) with concurrent and adjuvant temozolomide for patients up to 70 years with good performance status
  • Hypofractionated radiotherapy for elderly patients (≥70 years), with temozolomide particularly beneficial for those with MGMT promoter methylation

Promising Experimental Treatments

1. Tumor Treating Fields (TTFields)

TTFields represent one of the most promising newer approaches for glioblastoma treatment:

• FDA-approved in 2011 for recurrent glioblastoma and later for newly diagnosed disease
• Delivers alternating electric fields to disrupt cancer cell division
• Key findings:
  • The EF-11 pivotal trial demonstrated comparable overall survival between TTFields and physician's choice chemotherapy with better quality of life in the TTFields arm 2
  • Recent research shows TTFields efficacy is frequency and "dose" dependent, with random sequence output mode being more effective than fixed sequence 3
  • Optimal settings appear to be around 200 kHz frequency with field strength of 2.2V/cm 3
  • In vivo studies show TTFields can reduce tumor volume by up to 63.6% and prolong survival time by nearly 70% 3

Enhancing TTFields Efficacy

• Targeted surgical craniectomy combined with TTFields may enhance field strength by 60-70% in superficial tumors 4
• Combination with bevacizumab is being explored, though clinical trial data is limited 2

2. Bevacizumab

• FDA-approved for recurrent glioblastoma
• Humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF)
• Can result in significant radiographic response, improve progression-free survival, and reduce corticosteroid requirements 2
• Dosing: 10 mg/kg every 2 weeks 5
• Important caveat: Failed to prolong overall survival in a recent phase III trial 2

3. Immunotherapy Approaches

While not yet FDA-approved for glioblastoma, several immunotherapy approaches are under investigation:

• Vaccine therapies represent an emerging field but remain experimental and inaccessible outside clinical trials 1
• Checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 pathways
• CAR-T cell therapy targeting glioblastoma-specific antigens
• Oncolytic virus therapy

Clinical Trial Participation

For recurrent glioblastoma, the ASCO-SNO guideline panel strongly recommends:

• Prioritizing enrollment into clinical trials
• Referral to regional brain tumor programs when local trials are unavailable 1

This recommendation stems from the lack of proven therapies in recurrent glioblastoma, with many trials showing improvement in progression-free survival but none meeting overall survival goals 1.

Special Considerations

Molecular Profiling

Molecular characteristics increasingly guide treatment decisions:

• MGMT promoter methylation status is associated with treatment outcomes in elderly patients
• IDH mutation status affects prognosis and potentially treatment response
• Ongoing trials like CODEL and CATNON are evaluating treatments based on molecular profiles rather than traditional histology 1

Treatment Challenges

Several factors complicate glioblastoma treatment:

• Heterogeneous molecular features not well described at recurrence
• Limited tissue availability for molecular analysis
• Difficulty interpreting results from single-arm studies
• Need for better delineation of populations according to known biomarkers and prognostic factors 1

Conclusion

While standard treatments for newly diagnosed glioblastoma have shown modest improvements in outcomes, recurrent disease remains a significant challenge with no proven therapies that significantly extend overall survival. TTFields therapy and bevacizumab offer some benefits but with limitations. For patients with recurrent glioblastoma, enrollment in clinical trials evaluating novel approaches remains the best option to access potentially effective experimental treatments.