Traditionally, chemotherapy was felt to be of marginal value in the treatment of newly diagnosed patients with high-grade gliomas. Walker and colleagues did a randomized study of (1) a nitrosourea alone, versus (2) radiation alone, versus (3) radiation plus a nitrosourea. Although a slight improvement in survival was noted at 18 months in the group of patients who were treated with radiation plus BCNU compared with those who had received radiation alone, the difference in survival curves between the two groups was not statistically significant. More than 20 years later (2001), the Medical Research Council reported results from the largest randomized trial of adjuvant chemotherapy in high-grade gliomas. In this study, 674 patients were randomly assigned to either radiation alone or radiation plus PCV (procarbazine, lomustine [CCNU], and vincristine). No survival benefit was seen with the addition of PCV, even in patients with anaplastic astrocytomas.
In contrast, two meta-analyses reviewed data from randomized trials of high-grade glioma patients, and both found a modest survival benefit when chemotherapy was added to postoperative radiation. Specifically, in the most recently published metaanalysis (GMT Group, 2002) of 12 studies involving approximately 3000 patients with high-grade gliomas who were treated either with postoperative radiation alone or with radiation plus chemotherapy, there was an absolute increase in 1-year survival from 40% to 46% and a 2-month increase in median survival when chemotherapy was added to postoperative radiation. Most of these trials studied nitrosourea-based chemotherapy regimens. Temozolomide, a newer drug that is classified as an atypical alkylating agent, received U.S. Food and Drug Administration (FDA) approval for the treatment of patients newly diagnosed with glioblastoma multiforme in March 2005. Temozolomide received accelerated FDA approval for recurrent anaplastic astrocytomas in 1999; however, the accelerated approval requirements no longer apply. In Europe, temozolomide's approved indication is for the treatment of both recurrent anaplastic astrocytoma and recurrent glioblastoma multiforme. A recent phase III, randomized study assessed temozolomide in 573 patients with glioblastoma multiforme who received either (1) daily temozolomide (75 mg/m ) administered with postoperative RT followed by 6 cycles of adjuvant temozolomide (150-200 mg/m /day times 5 days during each 28-day cycle); or (2) radiotherapy alone. Temozolomide resulted in a statistically better median survival (14.6 versus 12.1 months) and 2-year survival (26.5% versus 10.4%) when compared with RT. However, the design of this study does not shed light on what is responsible for the improvements in survival: the temozolomide administered with radiation, following radiation, or both. Subsequent analyses suggest that MGMT (O(6)- methylguanine DNA methyltransferase) status may determine which patients obtain benefit from adjuvant temozolomide therapy. MGMT (a DNA repair enzyme) may cause resistance to DNAalkylating drugs commonly used in the treatment of anaplastic oligodendrogliomas and other malignant gliomas. Note that side effects for temozolomide include nausea, vomiting, headaches, fatigue, and anorexia. Preventive treatment for pneumonia (PCP) is required when temozolomide is administered with radiotherapy (FDA Talk Paper, March 16, 2005). In elderly patients with glioblastoma multiforme, temozolomide alone may be useful to avoid side effects with RT (eg, excessive fatigue and frequent worsening of neurologic deficits). However, in elderly patients with good performance status, adjuvant chemotherapy and RT may be useful. In terms of adjuvant treatment for anaplastic astrocytomas, the PCV regimen has commonly been used, in large part, based on the results of a phase III trial that compared BCNU to PCV following RT in patients with high-grade gliomas. This study found a survival benefit for patients with anaplastic astrocytomas who received PCV. However, a subsequent retrospective analysis determined that there is little difference between PCV and BCNU. Additionally, the Medical Research Council study (2001) previously discussed found no improvement in survival when patients with anaplastic astrocytomas were treated with PCV. There are no published data directly comparing the benefit of postoperative chemotherapy with temozolomide to a nitrosourea in patients with newly diagnosed anaplastic astrocytomas. This study is currently underway through the RTOG; however, no results have been reported yet. Given the better side-effect profile of temozolomide and the recent positive results of the phase III trial reported by Stupp and colleagues, temozolomide is recommended (category 1) for postoperative chemotherapy in patients with glioblastoma multiforme.Unfortunately, currently available chemotherapy does not provide cures in any of these patients. In addition to temozolomide and the nitrosoureas, agents that also have some activity against gliomas and are commonly used as second-line chemotherapy include procarbazine, irinotecan, cisplatin, and carboplatin. Many other agents are currently being studied. For chemotherapy-naïve patients with glioblastoma multiforme who experience recurrence or progression, temozolomide and cisplatin may be useful. Other routes of drug delivery have been evaluated.
Local administration of BCNU using a biodegradable polymer (Gliadel wafer) placed intraoperatively in the surgical cavity has demonstrated a statistically significant, improvement in survival for patients with recurrent high-grade gliomas. As a result, the FDA approved the Gliadel wafer for this indication. A study in 32 patients with malignant glioma showed a statistically significant prolongation of survival when BCNU polymer was used as initial therapy in combination with RT. A phase III trial of the Gliadel wafer compared to placebo in newly diagnosed patients (240) with malignant glioma also found a statistically significant improvement in median survival from 11.6 months in the placebo group to 13.9 months in the BCNU-wafer treated group. This benefit was maintained 2 and 3 years after implantation. On the basis of these studies, the FDA extended the approval of BCNU polymer wafers for use in malignant gliomas as initial therapy (February 2003). The European regulatory agencies similarly extended their approval to its initial use in October 2004.Patients with primary brain tumors or brain metastases frequently take medications to control seizures. Some of the more commonly used anticonvulsants, such as phenytoin and carbamazepine, are known to induce the hepatic cytochrome P450 isoenzyme system. Induction of these hepatic enzymes can enhance clearance of concurrently administered drugs that are eliminated by hepatic oxidative metabolism, resulting in lower blood levels of a drug and decreased efficacy. Hepatic enzyme-inducing anticonvulsants (HEIAs) have been shown to dramatically affect the pharmacology of some chemotherapy agents, such as irinotecan and paclitaxel. As a result, a patient who is taking an HEIA will require a higher than standard dose of these particular chemotherapy agents in order to obtain therapeutic plasma levels. One way to avoid this problem is to switch the patient to a non-HEIA, such as gabapentin, lamotrigine, or levetiracetam.