Chemotherapy has not been considered effective for malignant gliomas but there have been recent improvements over the traditional drug (BCNU or Carmustine) particularly using Temodar (temozolomide) or thalidomide or new combinations including placement of Gliadel (BCNU) wafers (see NCCN flow chart, the increasingly longer list of effective chemo drugs, and text and recent trial combining Gliadel and Temodar (here.)

A recent trial showed good results for recurrent glioma with Avastin plus Camptosar (go here) and RTOG is comparing Avastin combined with Temodar or Camptosar (RTOG 0625).

A recent trial combined radiation with CCNU and Temodar with good results (go here). The current state of chemotherapy is discussed below and some of the new experimental approaches are discussed here.


DESPITE OPTIMAL treatment for malignant gliomas, recurrence is common within the first 2 years. This poor outcome was underscored by a recent analysis of eight consecutive phase II trials of 375 patients with recurrent glioma treated with various chemotherapeutic regimens. This analysis revealed a 6-month progression-free survival rate (PFS 6) of only 15% for patients with glioblastoma multiforme (GM) and 31% for patients with anaplastic glioma (AG). After recurrence, response to treatment was observed in only 9% of patients, and overall median survival was only 30 weeks. In meta-analysis studies, there seems to be modest evidence of a survival benefit when chemotherapy is added to standard surgical and radiation therapy, particularly in selected subsets of newly diagnosed glioma patients. However, there is little evidence of benefit of chemotherapy after tumor recurrence or progression, and newer agents and regimens need evaluation.

A survival benefit from chemotherapy was initially demonstrated using the nitrosourea carmustine (BCNU) and the nitrosoureas, either alone or in combination regimens, became the standard of care. Subsequent clinical trials have demonstrated the efficacy and safety of temozolomide (Temodar)  the current standard agent for adjuvant chemotherapy. The benefit of adjuvant temozolomide was demonstrated in a phase III trial in which 573 newly diagnosed patients with GBM were randomly assigned to postoperative involved-field RT (60 Gy in daily 30 fractions) versus the same RT plus concomitant temozolomide (75 mg/m2 daily up to 49 days) followed by up to six cycles of adjuvant temozolomide (150 to 200 mg/m2 daily for five days, every 28 days). At a median follow-up of over five years, the key results of this trial included the following. The combination of temozolomide plus RT was associated with a statistically significant prolongation of overall survival (27 versus 11 percent and 10 versus 2 percent at one and five years, respectively, hazard ratio [HR] for death 0.63). The outcome was particularly good in some subsets, such as those less than 50 years old, in whom the five-year survival was 17 percent with combination therapy.

Methylation of the promoter for methyl guanine methyl transferase (MGMT) was a major prognostic factor for improved survival and was predictive of benefit from chemotherapy. For those with MGMT methylation, the two-year survival rates were 49 and 24 percent with combination therapy and with RT alone, respectively, while for those without MGMT methylation, the two-year survival rates were 15 and 2 percent, respectively.

Anaplastic astrocytoma — Temozolomide appears to be active in patients with AAs as well as GBMs. In a retrospective analysis of 109 patients with pathologically confirmed AA derived from two consecutive trials, adjuvant temozolomide was as effective and less toxic than PCV . . All patients had surgical resection followed by involved field RT (60 Gy in 30 fractions). Among the 60 patients treated with temozolomide, there were no significant differences in the two-year progression-free survival (59 versus 58 percent in patients treated with PCV) or the median progression-free survival (36 versus 34 months).

Oligodendroglial tumors — Patients with grade III oligodendroglial tumors have a better prognosis than those with AAs. Treatment options in patients with anaplastic oligodendroglioma and anaplastic oligoastrocytoma have included RT alone followed by chemotherapy upon progression, concurrent chemotherapy and radiation, or postoperative chemotherapy with radiation reserved until there is evidence of progression. Whether such strategies may also prove useful in patients with AAs is uncertain.

Systemic nitrosoureas — The Brain Tumor Study Group conducted multiple randomized trials evaluating the addition of adjuvant carmustine (alone or in combination with other agents) to postoperative RT. Although results varied between trials, there appeared to be a significant survival benefit from adding carmustine-based chemotherapy to adjuvant RT. The magnitude of the survival benefit was assessed in a meta-analysis that included individual patient data from 3004 patients enrolled in 12 randomized controlled trials comparing RT alone or with chemotherapy. Chemotherapy was associated with a 15 percent decrease in the risk of death (hazard ratio [HR] 0.85), which translated to a 6 percent absolute increase in one-year survival (from 40 to 46 percent) and a two-month improvement in median survival.

Multiple clinical trials compared single agent carmustine with various nitrosourea-based combinations. A meta-analysis of nine randomized trials involving over 2100 patients failed to demonstrate any benefit from combination chemotherapy regimens. Despite these negative results, the PCV regimen (procarbazine, lomustine, and vincristine, was widely used prior to the development of temozolomide.

Carmustine polymer wafers (Gliadel), which consist of carmustine embedded in a biodegradable matrix, function as a slow-release carrier system for local drug delivery. These wafers were originally approved as an adjunct to surgery for patients with recurrent GBM. The use of carmustine wafers was subsequently extended to include its use as an adjunct to surgery and RT for patients with newly-diagnosed malignant glioma. In a phase III trial 240 newly-diagnosed adults undergoing resection of a malignant glioma were randomly assigned to placement of up to eight carmustine wafers or a placebo, followed by standard RT. Patients receiving carmustine polymer had a statistically significant increase in median survival (13.9 versus 11.6 months). When the analysis was restricted to patients with GBM, the difference in survival was not statistically significant. Toxicities were similar in both arms, with the exception of CSF leak and intracranial hypertension, which were more common with carmustine polymer (5 versus 0.8 percent with placebo, and 9.1 versus 1.7 percent, respectively).

Bevacizumab — Bevacizumab (Avastin) is a monoclonal antibody that binds vascular endothelial growth factor (VEGF), which plays a critical role in the development of the abnormal vasculature observed in malignant gliomas and other tumors. In phase II studies, bevacizumab has reduced requirements for steroid therapy and has been associated with imaging evidence of tumor response. In a multicenter phase II study presented at the American Society of Clinical Oncology (ASCO) meeting in 2009, 70 patients with newly diagnosed GBM were treated with bevacizumab (10 mg/kg every two weeks) in combination with a standard regimen of temozolomide plus RT. Compared with a matched control group, there was a significant increase in progression-free survival (13 versus 8 months). There was a nonsignificant increase in overall survival (25 versus 21 months). The side effect profile was consistent with that seen with bevacizumab in other clinical settings.

 

See the sections on Temodar , Thalidomide and the Harvard Chemo Guide

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Examples of radiographic responses to carmustine and thalidomide. (A) A 38-year-old male with a biopsy-confirmed recurrent glioblastoma following two cycles of irinotecan. He subsequently began treatment with carmustine and thalidomide. (B) His magnetic resonance imaging scan after two cycles of treatment.

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
 

Roger Stupp, M.D.,

Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle).

Results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63. The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

Glioblastoma is the most frequent primary malignant brain tumor in adults. Median survival is generally less than one year from the time of diagnosis, and even in the most favorable situations, most patients die within two years. Standard therapy consists of surgical resection to the extent that is safely feasible, followed by radiotherapy; in the United States, adjuvant carmustine, a nitrosourea drug, is commonly prescribed. Cooperative-group trials have investigated the addition of various chemotherapeutic regimens to radiotherapy, but no randomized phase 3 trial of nitrosourea-based adjuvant chemotherapy has demonstrated a significant survival benefit as compared with radiotherapy alone, although there were more long-term survivors in the chemotherapy groups in some studies. A meta-analysis based on 12 randomized trials suggested a small survival benefit of chemotherapy, as compared with radiotherapy alone (a 5 percent increase in survival at two years, from 15 percent to 20 percent). The meta-analysis included 37 percent of patients with prognostically more favorable, lower-grade gliomas.

Temozolomide, an oral alkylating agent, has demonstrated antitumor activity as a single agent in the treatment of recurrent glioma. The approved conventional schedule is a daily dose of 150 to 200 mg per square meter of body-surface area for 5 days of every 28-day cycle. Daily therapy at a dose of 75 mg per square meter for up to seven weeks is safe; this level of exposure to temozolomide  depletes the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT).16 This effect may be important because low levels of MGMT in tumor tissue are associated with longer survival among patients with glioblastoma who are receiving nitrosourea-based adjuvant chemotherapy.

A pilot phase 2 trial demonstrated the feasibility of the concomitant administration of temozolomide with fractionated radiotherapy, followed by up to six cycles of adjuvant temozolomide, and suggested that this treatment had promising clinical activity (two-year survival rate, 31 percent). The European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada (NCIC) Clinical Trials Group therefore initiated a randomized, multicenter, phase 3 trial to compare this regimen with radiotherapy alone in patients with newly diagnosed glioblastoma.

Conclusions The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
 
Survival analysis following the addition of temozolomide to surgery and radiotherapy in patients with glioblastoma multiforme
Gil-Salu JL,  Neurocirugia (Astur). 2004 Apr;15(2):144-50.

OBJECTIVES: To analyze the effect of different therapies -surgery, radiotherapy, and chemotherapy (temozolomide)- on the survival of various groups of patients with glioblastoma multiforme (GBM). METHOD: The overall survival of a total of 85 patients with histopathological diagnosis of GBM was analyzed (descriptive statistics, Kaplan-Meier). Patients were divided into 4 treatment groups: group 1 (n=12), untreated patients (" no treatment" option was chosen by the family); group 2 (n=22), patients undergoing surgery only (retrospective series from the 1980s); group 3 (n=24), patients undergoing surgery + standard radiotherapy (control group, partially effective treatment); group 4 (n=27), patients undergoing surgery + radiotherapy + chemotherapy (temozolomide [TMZ]) (current study group). RESULTS: Mean age (one-way ANOVA) showed no significant difference between the groups. Mean/median survival (weeks) was as follows: group 1, 18/16; group 2, 23/14; group 3, 48/42; group 4, 70/64. The Kaplan-Meier analysis yielded the following 50% survival cutoffs (weeks): group 1, 16.00; group 2, 14.29; group 3, 42.00; group 4, 64.43. This demonstrated a significant difference when radiotherapy (group 3) was added to surgery (group 2) or no treatment (group 1), and a significant difference (p < 0.001) in survival when TMZ (group 4) was added to the so far considered as being the standard treatment (group 3: surgery + radiotherapy). CONCLUSIONS: Surgery alone does not result in a higher survival rate for GBM patients. However, surgery allows to establish a histopathological diagnosis, to improve signs and symptoms which are attributable to intracranial hypertension or tumour topography, and to reduce the number of target cells for adjunctive therapies. Radiotherapy improves survival and TMZ chemotherapy that is given after radiotherapy adds further survival benefit for patients.
Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme.

Baumann F,   J Neurooncol. 2004 Mar-Apr;67(1-2):191-200.

OBJECTIVES: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. PATIENTS AND METHODS: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. RESULTS: Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks) for T-patients (p < 0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20-52 weeks) and 17 weeks (95% CI, 13-21 weeks) for the T-group (p < 0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.