The methylating agent temozolomide, given in the form of an orally administered prodrug, has lower toxicity and has been shown in several trials to produce slightly superior results to the aforementioned agents. In a large trial conducted by Stupp and colleagues, the median survival was 14.6 months with radiation and temozolomide, compared to 12.1 months with radiation alone, but 2-year survival was more than doubled from 10 to 27 percent. The drug is administered daily (75 mg/m2) concurrently with radiotherapy and, after a hiatus of 4 weeks, given for 5 days every 28 days for 6 cycles. Its main complications are thrombocytopenia or leukopenia in 5 to 10 percent of patients, and rare cases of Pneumocystis carinii pneumonia. Furthermore, high levels of a methyltransferase protein (MGMT) in some glioblastomas lead to resistance to chemotherapy. Hegi and colleagues found a relationship between the epigenetic silencing of the promoter of this gene (“methylation status”) and the response to temozolomide. In fact, almost all the marginal benefit of the drug in their study could be attributed to improved survival in this group who displayed a methylated gene. However, there is still activity of temozolomide in nonmethylated tumors and it is used in almost all cases. Additionally, there may be an interaction between MGMT methylation and mutations in other genes such as IDH1 (Wick et al).
Tyrosine kinase inhibitors (erlotinib, gefitinib) have been developed in response to the upregulation of EGFR mentioned earlier. In a preliminary but provocative study, Mellinghoff and coworkers found that a deletion mutation of the gene for this protein and expression of the tumor suppression protein PTEN predicted responsiveness of recurrent gliomas to treatment with EGFR kinase inhibitors. This represents one example in a growing field of prediction of treatment response in relation to tumor genetics; however, phase III studies of a tyrosine kinase inhibitor failed to improve outcome (Bode et al).
The treatment of recurrent glioblastoma or anaplastic astrocytoma after surgery and radiation, almost inevitable occurrences, is controversial and must be guided by the location and pattern of tumor growth and the patient’s age and relative state of health. Almost all glioblastomas recur within 2 cm of their original site and 10 percent develop additional lesions at distant locations. Reoperation is sometimes undertaken for local recurrences. The most aggressive approach—a second surgery and chemotherapy—can prove effective and has been generally used in patients younger than age 40 years whose original operation was many months earlier. If the PCV regimen discussed earlier has not already been used, some neurooncologists resort to that combination or the newer and better-tolerated alkylating agent temozolomide (which may be used if the PCV regimen was administered previously). These chemotherapeutic drugs may prolong the symptom-free interval but have little effect on survival. A promising approach for recurrent malignant gliomas is the use of drugs that target the tumor’s vasculature. A recent but preliminary provocative observation from retrospective series has been that patients with glioblastoma receiving valganciclovir, ostensibly for concurrent CMV infections, had better survival than those who did not receive the drug (Söderberg-Nauclér and colleagues).
With aggressive surgical removal and radiotherapy, as described above, median survival for patients with glioblastoma is approximately 12 months, compared to 7 to 9 months without such treatment.