Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor in adults. The standard initial therapy, often called the Stupp protocol, involves maximal safe surgical removal, followed by a six-week course of radiation given concurrently with the chemotherapy drug temozolomide (TMZ). This is typically followed by several months of maintenance TMZ chemotherapy. Despite this multimodal approach, the median overall survival for newly diagnosed GBM patients is typically 12 to 15 months, and the tumor is highly likely to recur. The period after completing initial chemoradiation requires aggressive surveillance because microscopic tumor cells almost always remain in the brain tissue.
Monitoring the Brain After Initial Therapy
The phase following concurrent chemoradiation involves ongoing surveillance and maintenance aimed at delaying tumor progression. This typically includes several cycles of maintenance chemotherapy with lower-dose temozolomide, usually taken for five days every 28-day cycle for up to six to twelve cycles. This adjuvant therapy aims to eliminate residual microscopic disease.
A significant addition to the maintenance phase is the use of Tumor Treating Fields (TTFields). TTFields are a non-invasive, device-based therapy that uses low-intensity, alternating electric fields delivered via transducer arrays placed on the scalp. This therapy interferes with the division of rapidly dividing cancer cells and is often used concurrently with maintenance temozolomide. The addition of TTFields to maintenance TMZ improves both progression-free and overall survival for newly diagnosed patients.
Ongoing surveillance involves continuous clinical assessment for changes in symptoms, such as headaches, seizures, or cognitive changes, which can signal tumor activity. Regular follow-up magnetic resonance imaging (MRI) scans are scheduled, typically every two to three months, to monitor the original tumor site and surrounding brain tissue. These periodic scans are the primary tool for detecting a potential return of the tumor, but their interpretation can be challenging due to treatment effects.
Diagnosing Tumor Progression
GBM recurrence is nearly universal. This high recurrence rate is partly due to the tumor’s infiltrative nature, allowing cells to spread beyond treatment margins, and partly because many GBM cells develop resistance to temozolomide. Careful monitoring is necessary to distinguish between treatment-related changes and true tumor progression, which often occurs within the radiation field.
A major difficulty in interpreting post-treatment MRIs is distinguishing between true tumor recurrence and “pseudo-progression” (PsP). PsP is an increase in contrast enhancement and edema on MRI that mimics tumor growth. It is actually a temporary inflammatory reaction caused by the combined effects of radiation and temozolomide. This reaction occurs in approximately 30-40% of patients, typically within the first three months after completing chemoradiation, and usually resolves without a change in therapy.
To address this diagnostic challenge, specialists rely on advanced imaging techniques and established criteria. Advanced imaging, such as perfusion MRI (Dynamic Susceptibility Contrast-MRI), helps differentiate PsP from recurrence. True tumor progression shows increased blood flow and new blood vessel formation, while PsP is primarily inflammation. Diagnosis of recurrence is guided by the Response Assessment in Neuro-Oncology (RANO) criteria, which use both imaging changes and clinical status. Sometimes, a biopsy is necessary to obtain tissue confirmation, particularly if clinical symptoms are worsening but imaging is inconclusive.
Options for Recurrent Glioblastoma
Once tumor recurrence is confirmed, there is no single established standard of care. Treatment decisions are highly individualized based on the patient’s overall health, and the location and size of the returning tumor. The median overall survival following a recurrence is significantly shorter, often around six to eight months with active treatment. Therapeutic strategies generally fall into three categories: local interventions, systemic therapies, and device-based approaches.
Local Interventions
For localized recurrence, a second surgery (re-resection) may be an option if the tumor is safely accessible and the patient’s performance status is good. The goal of re-resection is primarily to relieve symptoms caused by mass effect and to obtain tissue for molecular analysis. Re-irradiation, often using focused techniques like stereotactic radiosurgery, is another local option. This is considered if the initial radiation dose allows for it without causing damage to surrounding healthy brain tissue, and is typically reserved for smaller, well-defined recurrences.
Systemic Therapies
Systemic therapies for recurrent GBM include alternative chemotherapy agents, such as lomustine (CCNU), a nitrosourea that can cross the blood-brain barrier. Lomustine is often used as a single agent. Another frequently used systemic agent is Bevacizumab (Avastin), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF). Bevacizumab reduces swelling and fluid buildup (edema) around the tumor, which can improve neurological symptoms and reduce the need for steroids. However, it has not been shown to extend overall survival significantly.
Device-Based Therapy
TTFields remains a viable option for recurrent disease, used as a monotherapy or in combination with second-line chemotherapy. Combining TTFields with second-line chemotherapy can lead to a longer progression-free survival rate compared to chemotherapy alone. The choice among all options depends on factors such as the time since initial treatment, tumor characteristics, and patient preferences.
Outlook and Advanced Clinical Trials
The prognosis following glioblastoma recurrence is challenging, highlighting the need for continual research into novel treatments. Clinical trials represent a primary path forward, offering access to therapies not yet approved for standard care, which often represent the best opportunity for improved outcomes.
Advanced clinical trials are currently focused on several promising avenues. These include immunotherapies designed to harness the body’s immune system to attack cancer cells, such as immune checkpoint inhibitors and personalized cancer vaccine trials. Targeted molecular therapies are also being investigated, focusing on specific genetic mutations or signaling pathways identified in the recurrent tumor.
Beyond treatment, quality of life management is a primary concern for patients with recurrent GBM. Early integration of palliative care focuses on alleviating symptoms, supporting patients and caregivers, and ensuring comfort alongside disease-directed treatments. This comprehensive approach includes managing symptoms like fatigue, pain, and cognitive changes.