Current Standard Treatment Options for Malignant Glioma

Fig. 8.1

a Magnetic resonance imaging of brain—glioblastoma magnetic resonance imaging reveals the aggressive nature of glioblastoma with the typical ring enhancement, central necrosis, and significant mass effect. b Magnetic resonance imaging of brain—anaplastic astrocytoma. Magnetic resonance imaging demonstrates the radiographic features of a WHO grade III anaplastic astrocytoma with bulky FLAIR signal suggestive of mass and absence of contrast enhancement

Anaplastic gliomas (Fig. 8.1b) can be defined based upon morphologic features of increased hypercellularity, nuclear atypia with alteration of the nuclear–cytoplasmic ratio, and increased mitotic activity. Although early studies often did not distinguish among the various subtypes (or even WHO grade 3 from grade 4 tumors), we now know that the oligodendroglioma feature is often associated with 1p/19q co-deletion and a favorable prognosis. The current median life expectancy after diagnosis of a WHO grade 3 tumor is 2–3 years [2] for the general patient population; however, this can be further broken down when taking into account IDH1 mutation status and 1p/19 co-deletion [3].

Chemotherapy

Nitrosoureas

Nitrosoureas such as carmustine (BCNU) and lomustine (CCNU) are highly lipophilic compounds that exhibit excellent blood–brain barrier penetration with lomustine reaching brain concentrations nearly equal to serum levels. Nitrosoureas are spontaneously broken down into two active metabolites; chloroethyldiazohydroxide and an isocyanate group. The chloroethyldiazohydroxide moiety mediates DNA–DNA and DNA–protein cross-linking and the isocyanate group carbamoylates amino acids which leads to disruption of RNA synthesis and DNA repair. The use of these agents is dose-limited by cumulative myelosuppression and potential pulmonary toxicity.

Nitrosoureas—Newly Diagnosed Anaplastic Gliomas

Historically, nitrosoureas have been the most common chemotherapy class used in the management of malignant gliomas with widespread use since the 1970s. The approval of temozolomide in March 2005, with its improved adverse effect profile and efficacy, largely relegated these agents to the treatment of recurrent disease with several notable exceptions. In the RTOG 9402 clinical trial, lomustine combined with vincristine and procarbazine as part of the “PCV protocol” was evaluated for newly diagnosed malignant gliomas [4]. In this study, 291 patients with either anaplastic oligodendroglioma or anaplastic oligoastrocytoma were randomized to receive radiation therapy alone or up to 4 cycles of PCV chemotherapy followed by radiation therapy. In the end, there was no difference in median survival between the PCV-radiation group versus the radiation therapy-alone group (4.6 vs. 4.7 years; hazard ratio [HR] = 0.79; 95% CI, 0.60–1.04); however, subgroup analysis demonstrated that patients with 1p/19q co-deletions had a significant survival advantage when treated with PCV radiation compared to patients treated with radiation therapy alone (14.7 vs. 7.3 years; HR = 0.59; 95% CI, 0.37–0.95; p = 0.03). These findings suggested that 1p/19q co-deletion was predictive for chemotherapy response.

A role for the use of PCV chemotherapy for patients with 1p/19 co-deleted tumors was further defined by the findings of EORTC 26951 clinical trial which randomized 368 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma to receive either radiation therapy or radiation followed by up to six cycles of PCV [5]. Unlike the RTOG trial, survival in the radiation group combined with chemotherapy was prolonged versus the radiation therapy-alone group (42.3 vs. 30.6 months, hazard ratio [HR], 0.75; 95% CI, 0.60–0.95); however, in the 80 patients identified with 1p/19q co-deletion survival was further augmented by addition of PCV following radiation (OS not reached in the RT/PCV group versus 112 months; HR, 0.56; 95% CI, 0.31–1.03). These findings support the use of chemotherapy for malignant tumors with 1p/19q co-deletion, i.e., oligodendrogliomas and mixed gliomas.

Several questions arose out of these findings including whether temozolomide could be substituted for the PCV regimen and whether it is important to start with radiation followed by chemotherapy or chemotherapy followed by radiation. An attempt to address both these questions was undertaken with the NOA-04 clinical trial [6]. In this phase III clinical trial, patients with newly diagnosed anaplastic glioma were randomly assigned to receive either 60 Gy fractionated radiation, 4 cycles of PCV, or 8 cycles of temozolomide. At the time of disease progression or with the development of unacceptable toxicity, patients were then allowed to cross-over to receive either radiation (PCV and temozolomide arms) or PCV or temozolomide (radiation arm, randomized 1:1). Initial analysis revealed there were no differences between progression-free survival between the radiation versus chemotherapy group (30.6 months vs. 31.9 months, HR 1.0; p = 0.87) or median overall survival (72 months vs. 82 months, HR 1.2). This was further confirmed with long-term analysis after following patients for 11.8 years which showed there were no differences among the treatment groups [7]. Several conclusions arose out of this study. It appeared that PCV and temozolomide had equivalent efficacy at least for all gliomas and that there was no difference in survival whether patients were treated with radiation or chemotherapy upfront or at recurrence; however, the mature data from this trial have yet to be published in a peer-reviewed journal. Molecular analysis also revealed that isocitrate dehydrogenase 1 mutations were stronger positive prognostic factors than either MGMT methylation status or 1p/19 co-deletion.

There are ongoing studies including the Alliance trial—CODEL clinical trial which is currently recruiting patients with 1p/19q co-deleted anaplastic gliomas (astrocytoma, oligoastrocytoma, and oligodendroglioma) and WHO grade II low-grade gliomas. This study is evaluating temozolomide and PCV chemotherapy head to head following fractionated radiation therapy. Another trial, the EORTC 26053/RTOG 0834 CATNON phase III clinical trial is an ongoing study evaluating the timing of temozolomide and whether adding temozolomide to fractionated radiation is beneficial compared to radiation treatment alone for patients with 1p/19q intact anaplastic gliomas. Given the nature of clinical trials and the involvement of both low-grade and anaplastic tumors, it will likely be many years before we have definitive data regarding this important question; however, a general trend at least in the USA is to treat patients with oligodendrogliomas with PCV and other tumors with temozolomide.

Nitrosoureas—Recurrent Glioblastoma

The phase II “BELOB” clinical trial investigated the role of lomustine alone and combined with bevacizumab versus monotherapy bevacizumab for recurrent glioblastoma. This study enrolled 153 patients with recurrent glioblastoma who were randomized to receive either lomustine 110 mg/m² every 6 weeks, lomustine at either 90 or 110 mg/m² along with bevacizumab 10 mg/kg given every 2 weeks, or bevacizumab alone. The investigators found that the nine-month overall survival was 43% in the lomustine arm, 38% in the bevacizumab arm, and 63% in the bevacizumab and lomustine (combined 90 and 110 mg/m²) arm and progression-free survival at 6 months was 13% for lomustine, 16% for bevacizumab, and 42% for combined bevacizumab and lomustine. Although these results appear to be an improvement over the results of bevacizumab and irinotecan studied in the BRAIN trial [8], a more definitive answer awaits the conclusions of the EORTC 26101 phase III clinical trial which has recently completed enrollment of patients with progressive glioblastoma to either lomustine 90 mg/m² every six weeks along with bevacizumab 10 mg/kg every two weeks versus monotherapy lomustine 110 mg/m² every six weeks.

The first clinical trial to prospectively evaluate nitrosoureas and temozolomide head to head for recurrent glioblastoma (and a small subset of anaplastic gliomas—26% of enrollees) was undertaken by Brada et al. [9]. In this study, 447 chemotherapy-naïve patients at first relapse following radiotherapy were randomized to receive either 6 cycles of PCV every six weeks or temozolomide at 150–200 mg/m²/day on a 5 of 28-day schedule or 100 mg/m²/day on a 21 of 28-day schedule. After a median follow-up time of 10.4 months for the PCV and 14 months for the temozolomide arm, there was no survival benefit seen when comparing PCV to the combined arms of temozolomide (6.7 months for PCV and 7.2 months for combined temozolomide, HR 0.91; 95% CI 0.74–1.11, p = 0.36); however, the 5 of 28-day schedule of temozolomide did modestly improve survival compared to PCV (5 months for temozolomide and 3.6 months for PCV; HR 0.8; 95% CI, 0.63–1.03, p = 0.038). The conclusion of this trial was that PCV and temozolomide on a 5 of 28-day schedule were similar in efficacy but given an observed improvement in quality of life and ease of administration, temozolomide should be favored over PCV.

Temozolomide

Temozolomide is an oral alkylating chemotherapy agent whose drug development arose out of the clinical trial failure of dacarbazine and mitozolomide for patients with melanoma. At physiologic pH, temozolomide undergoes base catalyzation to monomethyl-triazeno-imidazole-carboxamide (MTIC) which spontaneously converts to the bio-reactive methyldiazonium cation. Methyldiazonium goes on to alkylate the N⁷ and O⁶ positions of guanine and N³ position of O⁶ alkylation of guanine is thought to mediate the predominant anti-tumor effect. Although early studies demonstrated a variety of adverse effects including fatigue, nausea/vomiting, and myelosuppression, these have proven to be relatively mild in clinical practice and predictable compared to previously used cytotoxic agents.

The first clinical trial evaluating temozolomide solely for malignant glioma was conducted by O’Reilly et al. [10] who enrolled 28 patients with 18 of the patients having a high-grade glioma. Of the 10 evaluable patients who received adjuvant temozolomide, 5 patients (4 had WHO grade IV tumors) experienced significant clinical and radiographic improvement. These findings led Roger Stupp and colleagues to design a phase II study and ultimately the seminal EORTC-NCIC phase III study which established temozolomide along with fractionated radiation followed by adjuvant temozolomide administered at 150–200 mg/m²/day on a 5 of 28-day schedule as the standard of care for patients with newly diagnosed glioblastoma. This combination led to median survival ranges of 15–23 months or a 3- to 11-month median survival improvement beyond surgery followed by radiation therapy alone [11, 12].

An additional important finding that arose from the EORTC-NCIC trial was that patients with methyl-guanine-methyltransferase (MGMT) methylation were more responsive to temozolomide and had prolonged survival compared to patients with hypomethylated MGMT [13]. This led to the hypothesis that temozolomide given over a prolonged period could possibly lead to MGMT depletion and improved chemoresponsiveness. This theory was tested in a randomized phase II study which enrolled 85 patients with newly diagnosed glioblastoma treated with six weeks of concurrent radiation and temozolomide to receive adjuvant treatment with either dose-dense temozolomide (150 mg/m²/day—7 days on, 7 days off) or metronomic (daily) temozolomide (50 mg/m²/day) [14]. One-year survival for patients treated with the dose-dense regimen was 80% which was superior to metronomic dosing (69% survival at one year) and also an improvement from the 61% one-year survival observed with the EORTC-NCIC clinical trial [11]. This was further studied in the randomized phase III RTOG 0525 clinical trial which compared adjuvant temozolomide given on a 5 of 28-day schedule at 150–200 mg/m²/day versus temozolomide at 75 mg/m²/day on a 21 of 28-day schedule [15]. Both dosing schedules were given up to 12 cycles. No survival benefit was seen for dose-dense temozolomide (median overall survival 14.9 months, 95%, CI 13.7–16.5 months) versus standard dosing (16.6 months, 95% CI, 14.9–31.5 months, HR, 1.03, p = 0.63). On the basis of these studies and others [9], there is currently no role for dose-dense temozolomide for newly diagnosed glioblastoma.

Gliadel Wafers

Gliadel wafers are biodegradable wafers consisting of a poly (carboxyphenoxy-propane sebacic acid) matrix embedded with the nitrosourea, carmustine (BCNU). The wafers were developed by Henry Brem and colleagues in an attempt to avoid the hematologic and pulmonary toxicity associated with the systemic administration of BCNU [16].

In 1993, Tamargo et al. were the first to demonstrate that the interstitial release of BCNU through BCNU-embedded polymer wafers was superior to systemic administration in a gliosarcoma animal model [17]. This ultimately led to a series of clinical trials for patients with malignant gliomas. Gliadel was approved by the Federal Drug Administration (FDA) in 1996 for the treatment of recurrent glioma on the basis of the findings of a phase III clinical trial. In this randomized, placebo-controlled trial, 222 patients with recurrent malignant glioma were randomized to receive either surgically implanted wafers embedded with 3.85% BCNU or placebo. The median overall survival for patients on the experimental arm was 31 weeks versus 23 weeks for patients receiving placebo wafers (HR = 0.67, p = 0.06). Subanalysis of glioblastoma patients demonstrated a survival advantage of 50% at six months (44% vs. 64%, p = 0.02), and there were no significant adverse events observed [18].

A large, international, randomized phase III clinical trial [19] for patients with newly diagnosed malignant glioma was initiated after the encouraging results of a small randomized, placebo-controlled trial [20]. In this trial, 240 patients with newly diagnosed glioma were randomized to receive either BCNU wafer or placebo at the time of the initial surgical resection followed by fractionated radiation therapy. At the time of early follow-up (12–30 months), a survival benefit was observed for patients treated with BCNU wafers (13.9 vs. 11.6 months, p = 0.03). These findings were confirmed in a long-term (59 months) follow-up report [21]. A meta-analysis of these two trials by Meldorf et al. [22] further demonstrated a reduction in the risk of death of 29% with the implantation of BCNU wafers. On the basis of these findings, FDA approved Gliadel for patients with newly diagnosed glioma in 2003.

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