Lessons Learned: Clinical Trials and Other Interventions for Glioblastoma

Intraoperative MRI

Intraoperative MRI (iMRI) has been studied extensively in the past decade. Although several groups have reported increased extent of resection with iMRI, few data exist regarding the clinical benefit of iMRI as measured by overall and progression-free survival as well as performance status. Thus far only 1 randomized controlled study confirmed that the use of iMRI led to higher rates of complete tumor resection compared with conventional surgery. This study also showed that postoperative complications and new neurologic deficits were comparable in both groups and therefore that the use of iMRI was safe. However, no improvement of progression-free survival was observed. The use of iMRI has implications in terms of cost and operative time. iMRI prolongs the surgical procedure and overall time spent in the operating room. In an era of medical care cost escalation, clinicians must decide whether the benefits outweigh the costs of acquisition and maintenance associated with MRI equipment located in the operating room. The authors have learned that difficult decisions such as these will become part of the success or failure of medical innovation in the future.

5-Aminolevulinic Acid as a Tumor Marker

In 2006, the ALA-Glioma Study Group conducted the only prospective randomized study that assessed the efficacy and safety of using 5-aminolevulinic acid (5-ALA) for the resection of malignant gliomas. 5-ALA is a hemoglobin precursor that leads to accumulation of fluorescent porphyrins in malignant glioma cells but not in healthy brain tissue. The use of 5-ALA and fluorescence-guided surgery was compared with traditional microsurgery using white light. Although the use of 5-ALA led to increased rates of complete resection and to longer progression-free survival, which were the 2 primary end points of the study, no benefit was found in overall survival, postoperative neurologic status, or Karnofsky Performance Score.

Barone and colleagues performed a systematic review of the role of imaging guidance in brain tumor surgery, including iMRI, fluorescence-guided surgery using 5-ALA, neuronavigation, and ultrasonography. Three large databases and an extensive literature review, including 4 randomized controlled trials, were performed up to 2013. Their goal was to answer 2 essential questions: (1) is image-guided surgery more effective at removing brain tumors than surgery without image guidance? (2) Is one image guidance technology or tool better than another? Based on their review, there is low to very low evidence (according to GRADE [Grading of Recommendations Assessment, Development and Evaluation] criteria) that image-guided surgery using iMRI, 5-ALA, or diffusion-tensor imaging neuronavigation increases the proportion of patients with high-grade glioma who have a complete tumour resection on postoperative MRI. Similarly, there was poor evidence that image-guided surgery increases overall or progression-free survival or quality of life. Thus, although the 5-ALA randomized trial did meet its primary end points, it did not extend survival or quality of life, showing that a well-executed trial that does not show improvement in these metrics may fail to attain regulatory approval (at least in the United States) and acceptance as a standard of care.

Carmustine Wafers

Biodegradable polymers (wafers) containing carmustine have proved safe when implanted in the glioma tumor cavity after resection. The US Food and Drug Administration (FDA) approved this agent for the treatment of recurrent GBM based on the results of a multicenter, randomized controlled study. Carmustine wafers were inserted into the tumor bed following gross total resection of recurrent high-grade gliomas. A clear survival benefit was found in patients with GBM treated with carmustine wafers compared with placebo wafers.

The benefit of carmustine wafers in patients with newly diagnosed GBM is less clear. The first prospective, randomized, double-blinded study using carmustine wafers in newly diagnosed high-grade gliomas was performed in Finland. The subgroup analysis of patients diagnosed with GBM showed a significant survival benefit in the carmustine wafer group compared with the placebo group. Four years later, a phase III trial in 240 patients with newly diagnosed high-grade gliomas was performed. Although patients treated with carmustine wafers had a long-term overall survival benefit compared with the placebo group, no significant survival benefit was found in the GBM subgroup. None of the aforementioned studies used treatment with temozolomide in the postoperative phase because the studies were performed before temozolomide was established as standard of care for GBM.

Several retrospective studies assessed the safety and efficacy of combining carmustine wafers with radiation therapy and temozolomide (Stupp regimen ) in patients with GBM and concluded that the triple regimen was safe. Few prospective data are available comparing treatment with carmustine wafers and Stupp regimen with Stupp regimen alone in patients with newly diagnosed GBM. Only 1 prospective, but nonrandomized, study in 787 patients in France compared the survival rates and postoperative complications in both treatment groups. The carmustine plus Stupp regimen arm showed significantly longer progression-free survival, but no statistically significant benefit was observed for overall survival. In contrast with previous studies, patients receiving carmustine wafers and Stupp regimen had significantly more postoperative complications such as postoperative infections and increased intracranial pressure caused by edema compared with patients treated with the Stupp regimen only.

The advantages of carmustine wafers seem obvious: they provide localized treatment without significant systemic side effects and they are complementary to systemic therapy. However, the complications mentioned earlier associated with the wafers can also be significant. Note that most data on carmustine wafers do not differentiate between GBM and non-GBM gliomas and caution should be used when extrapolating the results to the subgroup of patients with GBM. In addition, carmustine wafers can interfere with the interpretation of MRIs because of local increase in enhancement caused by the wafers. For this reason, many GBM clinical trials exclude patients who have received carmustine wafers. Overall, despite being FDA approved, the enthusiasm for general use of the wafers seems modest based on modest efficacy and the clinical trial exclusion described earlier.

However, a phase 1 trial that increased the percentage of carmustine in wafers reached a maximum tolerated dose of 20% carmustine by weight, representing a 5-fold increase compared with the standard 3.8% wafer. However, a phase II trial at this dose was never conducted, representing a missed opportunity in drug development. Such a trial may have improved the efficacy of the wafer, showing that the phase II trials are critical to the further development of promising therapies. Further development of this technology should be explored using other agents.