Clinical Pearls for Practice: Treatment options in the management of glioblastoma multiforme: a focus on Gliadel®

Guest post by Sarah Lutes, Pharmacy Resident, AHS Cancer Control

Currently, the standard practice at Alberta Health Services for newly diagnosed grade 3 and 4 glioma is surgery plus radiation.  Patients with 1p/19q-codeleted tumors are also given six cycles of procarbazine, lomustine and vincristine (PCV).  There is currently no accepted standard practice for recurrent glioblastoma mulitforme (GBM), however the RESCUE protocol (temazolamide 50mg/m2 given daily) or Avastin® (bevacizumab) are used most often.  Other options include lomustine or etoposide. 

Approved in Canada in 2011, Gliadel® wafer is a novel approach to treating recurrent GBM.  Comprised of a biodegradable copolymer matrix polifeprosan 20, Gliadel® is impregnated with carmustine, an alkylating agent used as chemotherapy that inhibits several key processes within the tumor cell.  As with many other chemotherapy agents, carmustine has been found to have poor penetration into the CNS, which has created the need for an alternate approach towards treating these tumors.  This wafer, with its controlled release delivery system, is implanted during surgery after tumor resection has been completed.  Each wafer contains 7.7mg of carmustine, which is released upon exposure to the surgical cavity.  The proposed benefit to this type of system is that the toxic therapy is more localized to the tumor area, theoretically providing better drug penetration to the malignant cells, while minimizing side effects from systemic exposure.

Several reviews by various clinicians have been conducted on the use of this product, including a Cochrane Database systematic review completed in 2011 (1). Studies over the past few years have provided conflicting results.  Since its development, the Stupp protocol consisting of surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ) followed by six cycles of TMZ alone, has been the standard of care for both newly diagnosed and recurrent glioblastoma.  The introduction of the Gliadel® wafer created a need for more studies evaluating its efficacy and safety when used alongside this standard therapy.

What We Know:

Clinical use of the Gliadel® wafer formulation was largely based on the phase III trial by Westphal et al. that included 240 newly diagnosed patients, half of which were randomized to receive Gliadel® along with the standard radiation therapy (2).  The Gliadel® group demonstrated a modest benefit in overall survival (OS) of 2.3 months (13.9 months vs. 11.6 months).  When other prognostic factors such as performance status and age were analyzed using multivariateanalysis, the survival benefit remained significant. However, when the subgroup of patients who had actual histological diagnosis of glioblastoma was analyzed, these results were not statistically significant.  To defend their research, Westphal et al. conducted a combined analysis with the results from another trial by Valtonen at al. in order to increase the power of their glioblastoma data (3).  These results did show a statistically significant survival benefit, with an increase of 1.2 months (13.1 vs. 10.9 months). 

In a 2011 Cochrane review, three studies were evaluated, two of which studied Gliadel® use as primary therapy (including the one by Westphal et al.) and one looking at use in recurrence (1).  Studies again showed modest survival benefit with primary therapy, however Gliadel® did not demonstrate any survival benefit in recurrent disease.  

A couple retrospective studies (4,5) and several reviews (1,6,7) have also looked at the efficacy of Gliadel® in addition to radiotherapy and temozolomide.  Although not an approved indication in Canada, there is some evidence of survival benefit using Gliadel® in addition to the Stupp protocol over the Stupp protocol alone, however more side effects were reported and prognostic factors, such as degree of surgical resection were shown to influence outcome (8).  Conversely, one small retrospective study looking at the combination of Gliadel® and the Stupp protocol concluded no difference in relapse-free survival and overall survival between the two groups (4).  The most recent study prospectively analyzed the efficacy of the Stupp protocol alone compared to the protocol with the addition of Gliadel® in both newly diagnosed and recurrent glioblastoma (8). The results showed a trend towards increased overall survival with Gliadel® use, however the results were not statistically significant (14 months, 95% CI 818 vs. 11 months,95 % CI 814, log-rank test, p=0.77).  The addition of Gliadel® in treating recurrent tumor actually showed a decrease in overall survival (although not statistically significant), and these patients also experienced far more toxicity.  In fact, further examination revealed that the only factor that was significantly associated with longer survival was the extent of surgical tumor removal.

As far as safety of this drug, the Cochrane review concluded that the rate of adverse events was not significantly higher in the patients receiving Gliadel® (1).  The most common side effects included healing abnormalities, cerebral edema, intracranial infections and seizures (9, 10).  A retrospective study by Bock et al. also determined that that there was no significant increase in risk of adverse events when Gliadel® is added to the treatment regimen (9). Westphal et al. also reported similar event rates for both groups, with the only difference being that more patients in the Gliadel® arm experienced intracranial hypertension, which was not felt to be directly linked to the Gliadel® due to the distant temporal relationship.  However, in the study by DeBonis et al., it was shown that both patients with recurrent tumors and patients with a higher number of wafers implanted were at a much higher risk for adverse events (2.8-fold and 5.6-fold, respectively) (10).  

Conclusion:

Unfortunately there is still no straightforward consensus on which regimen is best.  As discussed, the landmark trial by Westphal et al. has come under scrutiny as more and more studies have failed to show statistically significant survival benefit with Gliadel®.These studies, along with several smaller retrospective studies, only highlight the need for larger prospective trials to analyze the efficacy of Gliadel® wafer for these indications.

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Photo credit: AboutCancer.com