Glioblastoma (GBM), the most common primary brain tumor in adults worldwide, accounts for approximately 50% of all gliomas. Surgery, as yet the most effective therapeutic approach available for patients with these neoplasms, has been followed over the years by other therapeutic approaches (radiotherapy and chemotherapy) that, step by step, have prolonged the median overall survival of GBM patients. Unfortunately however, several biological and anatomical factors unique to this tumor type make patients particularly prone to local recurrence after treatment. Over the past 20 years, efforts have been made to establish whether or not adjuvant chemotherapy provides GBM patients with any clinically meaningful benefit.
Two different therapeutic approaches with alkylating agents have been developed and tested in Phase III trials in newly diagnosed high-grade gliomas: one consists of interstitial chemotherapy with carmustine wafers implants (Gliadel®) before radiotherapy; the other involves the addition of temozolomide during and after standard radiotherapy. The former was based on the concept of treating residual GBM cells in the interval between surgery and subsequent radiotherapy, and the latter on exploiting the synergistic effects of chemotherapy and radiotherapy.
In clinical trials on newly diagnosed high-grade gliomas, only approximately 100 patients with GBM histology have been treated with Gliadel Citation[1–3]. Two randomized, controlled trials have been conducted to compare the efficacy of carmustine implants plus radiotherapy with that of placebo plus radiotherapy. In the larger trial, which was multinational and involved patients with unrestricted high-grade gliomas, and no difference was found between the different approaches for progression-free survival (5.9 months in both groups) Citation[2]. Furthermore, while the survival of high-grade gliomas treated with radiotherapy plus carmustine implants differed significantly from those treated with radiotherapy plus placebo in the overall population, this advantage was lost when the analysis was restricted to GBM patients (p = 0.1). Of note, the US FDA expressed reservations in its evaluation of the trial, voicing its concern, in particular, over an imbalance between the types of tumors in study arms, which could have favored carmustine implants. The results of a Phase III study subgroup analysis can be reported with caution, but any attempt to extend the results of a trial on tumors with multiple histologies and marked differences between their aggressiveness and prognosis is fraught with potential pitfalls. Furthermore, these authors presented an update of the abovementioned study with a longer follow-up Citation[4], which confirmed the lack of a significant advantage in overall survival for patients treated with Gliadel, also showing a slight decrease in their overall survival (from a median of 13.5 months to a median of 13.1 months). The other randomized trial had a smaller sample size (n = 32) Citation[3]. Recruitment to the study was terminated early as the investigators were unable to source additional carmustine implants. In this trial, fewer patients in the carmustine implant group (69%) had a diagnosis of GBM than in the placebo group (100%). Median survival in the carmustine implant group was 13.4 months, compared with 9.2 months in the placebo group. This difference was statistically significant (p = 0.01). Survival at 24 months was 31.3% in the carmustine implant group and 6.3% in the placebo group. No statistically significant difference was found between the treatment groups for progression-free survival.
Despite the results of these trials, carmustine implants are not considered standard treatment in GBM but only a treatment option owing to the methodological pitfalls entailed. Moreover, some national health institutes, including the National Institute for Health and Clinical Excellence (NICE) in the UK, maintain that carmustine implants are not recommended in the treatment of newly diagnosed high-grade gliomas.
However, in 2005, a novel standard of care was defined for patients with newly diagnosed GBM. In a large and well-designed Phase III study by European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC), patients were randomized postoperatively to receive radiotherapy plus temozolomide (n = 287) or radiotherapy alone (n = 286) Citation[5]. The median survival was 15 months in patients treated with temozolomide and radiotherapy and 12 months for those treated initially with radiotherapy alone. Moreover, the 2-year survival rate was 26% for the combined modality group and 10% in the radiotherapy group. These results translate into a hazards ratio for death of 0.63 (95% confidence interval: 0.52–0.75; p < 0.001), a risk reduction of 37%.
However, further considerations emerge on comparing the EORTC/NCIC temozolomide plus radiotherapy Phase III trial with the Gliadel Phase III trial . While all comparers appear to be in favor of combined temozolomide/radiotherapy, an intriguing observation regards the 2-year survival following this approach, the rate being markedly higher in the temozolomide/radiotherapy group of GBM patients (24.6%) than that in the Gliadel group (15.8%), which also included patients with grade 3 gliomas.
Furthermore, in an updated analysis of the Gliadel Phase III study, only two (aged: 29 and 32 years, respectively) out of 101 GBM patients were alive at a longer follow-up of 56 months Citation[4]. Importantly, in the EORTC/NCIC trial, translational research identified that methylguanine methyltransferase (MGMT) gene-promoter methylation was an important prognostic and predictive factor Citation[6]. In this trial, the overall survival rate in patients with MGMT-promoter methylation was greater irrespective of treatment; but it was significantly greater in patients treated with combined temozolomide/radiotherapy, the median survival time being 22 months and the 2-year survival rate 46% in these patients. Analogous data on carmustine implants are not available.
Evidence from studies on temozolomide therapy combined with radiotherapy and after this concurrent treatment strongly supports the use of systemic therapy in patients with GBM histology.
In view of potentially overlapping toxicities, the combined use of Gliadel implants before temozolomide/radiotherapy is not recommended outside well-designed clinical trials.
New frontiers in clinical research on GBM patients will involve the prolongation and intensification of adjuvant temozolomide treatment or the use of combined temozolomide/radiotherapy with new agents, including antiangiogenetic drugs (e.g., vatalanib). Moreover, MGMT-promoter methylation status should be included as an essential stratification factor in all future clinical trials.
Table 1. Comparison between experimental arms in EORTC/NCIC and Gliadel® Phase III trials.
References
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- Westphal M, Hilt DC, Bortey E et al. A Phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-Oncology5(2), 79–88 (2003).
- Valtonen S, Timonen U, Toivanen P et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41(1), 44–48; discussion 48–49 (1997).
- Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir. (Wien)148(3), 269–275; discussion 275 (2006).
- Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med.352(10), 987–996 (2005).
- Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med.352(10), 997–1003 (2005).