Repeat radiation therapy (re-irradiation)
Because there are no randomized trials, the role of repeat radiation after disease progression or the development of radiation-induced cancers is also ill defined. The literature is limited to small retrospective case series, which makes interpretation difficult. The decision to use repeat radiation must be made carefully because of the risk of neurocognitive deficits and radiation-induced necrosis. One advantage of radiosurgery is the ability to deliver therapeutic doses to recurrences that may require the re-irradiation of previously irradiated brain tissue beyond tolerable dose limits.
For many years, the nitrosourea carmustine (BCNU) was the standard chemotherapy added to surgery and radiation for malignant gliomas. This was based upon a randomized trial (RTOG-8302) of 467 patients conducted by the Brain Tumor Study Group that compared four regimens after initial resection, including semustine (methyl-CCNU), radiation therapy, radiation therapy plus carmustine, and radiation therapy plus semustine.
The radiation therapy plus carmustine arm had the best survival rate.[Level of evidence: 1iiA] A modest impact on survival using nitrosourea-containing chemotherapy regimens for malignant gliomas was confirmed in a patient-level meta-analysis of 12 randomized trials (combined HR death = 0.85; 95% CI, 0.78-0.91).
However, the oral agent, temozolomide, has since replaced the nitrosoureas as the standard systemic chemotherapy for malignant gliomas based upon a large multicenter trial (NCT00006353) of glioblastoma patients conducted by the EORTC-National Cancer Institute of Canada that showed a survival advantage.[21,22][Level of evidence: 1iiA] (Refer to the Glioblastoma section of the Management of Specific Tumor Types and Locations section of this summary for more information.)
Because malignant glioma-related deaths are nearly always the result of an inability to control intracranial disease (rather than the result of distant metastases), the concept of delivering high doses of chemotherapy while avoiding systemic toxicity is attractive. A biodegradable carmustine wafer has been developed for that purpose. The wafers contain 3.85% carmustine, and up to eight wafers are implanted into the tumor bed lining at the time of open resection, with an intended total dose of about 7.7 mg per wafer (61.6 mg maximum per patient) over a period of 2 to 3 weeks. Two randomized, placebo-controlled trials of this focal drug-delivery method have shown an OS advantage associated with the carmustine wafers versus radiation therapy alone. Both trials had an upper age limit of 65 years. The first was a small trial closed because of a lack of continued availability of the carmustine wafers after 32 patients with high-grade gliomas had been entered. Although OS was better in the carmustine-wafer group (median 58.1 vs. 39.9 weeks; P = .012), there was an imbalance in the study arms (only 11 of the16 patients in the carmustine-wafer group vs. 16 of the 16 patients in the placebo-wafer group had Grade IV glioblastoma tumors).