Brain Trauma Oncology
Table 1: Summary of Therapeutic Options for High-grade Glioma
Setting Histology
Newly Diagnosed Tumour* Glioblastoma
Anaplastic astrocytoma** Recommended Treatment Options
• RT with concomitant and adjuvant TMZ
• Clinical trial enrolment • RT with concomitant and adjuvant TMZ
• RT with adjuvant TMZ • Clinical trial enrolment
Anaplastic • RT alone oligodendroglioma or • RT with concomitant and oligoastrocytoma**
adjuvant TMZ
• RT with adjuvant TMZ or PCV only • TMZ or PCV alone • Clinical trial enrolment
Recurrent Tumour** Any
• Clinical trial enrolment*** • Surgical resection, re-irradiation or SRS for selected candidates
• Carmustine wafers • Chemotherapy (TMZ, carmustine, lomustine, others)
• Bevacizumab with or without chemotherapy (irinotecan, others)
*Treatment should always begin with maximal surgical resection when possible. **No standard of care has been defined. ***Clinical trial enrolment should be offered to recurrent malignant glioma patients whenever possible. PCV = procarbazine, lomustine (CCNU) and vincristine; RT = radiation therapy; SRS = stereotactic radiosurgery; TMZ = temozolomide. Source: Wen and Kesari, 2008.3
The addition of temozolomide to RT increased median survival compared with RT alone (14.6 versus 12.1 months; p
III study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) in newly diagnosed GBM comparing RT alone (60Gy over six weeks) with RT and concomitant daily temozolomide (75mg/m2/day), followed by adjuvant temozolomide therapy (150–200mg/m2/day for five consecutive days every 28-day cycle, for six cycles).16
regardless of MGMT promoter methylation status. A randomised phase III trial sponsored by the Radiation Therapy Oncology Group (RTOG 0525) will definitively evaluate the utility of MGMT promoter methylation in determining temozolomide sensitivity. In the future, patients whose tumours have unmethylated MGMT promoters may be offered alternatives to the standard temozolomide regimen. Investigational approaches to overcome MGMT activity include dose-intense temozolomide regimens27,28 which may deplete the enzyme,30
or continuous dosing,29 and combination therapy with O6-benzylguanine or other MGMT inhibitors.31–33
An alternative to systemic chemotherapy involves the surgical implantation of carmustine-containing biodegradable wafers (Gliadel) into the resection cavity following tumour debulking. A double-blind, randomised, phase III trial demonstrated a modest benefit in patients with newly diagnosed GBM. Those patients who received radiation and placebo had a median survival of only 11.6 months compared with 13.9 months for patients who received radiation and carmustine wafers, with median overall survival of 11.6 and 13.9 months, respectively (p=0.03),34
resulting in approval of this therapy by the US Food and Drug Administration (FDA). The benefits of traditional cytotoxic chemotherapy have been modest in the treatment of recurrent GBM. Phase II trials of temozolomide for recurrent GBM demonstrated radiographic response rates (RR) of only 5% and six-month progression- free survival (PFS6) of about 21%.35,36
However, the recently published
RESCUE study showed that continuous dosing of temozolomide at 50mg/m2 daily rather than the conventional 5/28 schedule had favourable efficacy and was well-tolerated as a second-line agent.29 Other agents, such as carmustine, carboplatin, etoposide, irinotecan and procarbazine, lomustine (CCNU) and vincristine (PCV), produce low response rates and no significant survival benefit.37
In selected patients
with recurrent GBM who can undergo resection, carmustine implants produce a modest survival advantage of approximately eight weeks.38
In
light of the limited data, treatment decisions for patients with recurrent GBM must be made on an individual basis. Factors to consider include tumour histology, prior therapy, time to relapse and performance status. In general, patients with recurrent disease should be enrolled in clinical trials whenever possible.
An established mechanism of temozolomide resistance is based on DNA repair through O-6-methylguanine-DNA methyltransferase (MGMT), an endogenous DNA-repair enzyme that removes alkyl groups from DNA and thus confers resistance to temozolomide and other alkylating agents. MGMT promoter methylation has been shown to predict temozolomide sensitivity in GBM.6,26
In a companion study
to the EORTC/NCIC, tumour specimens were evaluated for methylation status of the MGMT gene promoter.6
As predicted, the
benefit of temozolomide was significantly increased in patients with MGMT promoter methylation. Among GBM patients with MGMT promoter methylation who were treated with temozolomide, median survival was 21.7 months and two-year survival 46%. Temozolomide-treated patients with unmethylated MGMT promoters had a significantly shorter median survival of only 12.7 months and a two-year survival of 13.8%.6
Because this study was conducted
retrospectively in a relatively small sample of patients, temozolomide remains the standard of care for newly diagnosed GBM patients,
50
More recently, clinical trials in recurrent GBM have focused on agents targeting important pathways involved in gliomagenesis and progression. Most notably, angiogenesis inhibitors have changed the treatment of recurrent GBM and will be discussed in greater detail below. Bevacizumab is a monoclonal antibody that selectively binds vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Favourable initial results of bevacizumab in recurrent GBM led to two phase II trials containing bevacizumab monotherapy arms, which demonstrated an RR of 28–35% and PFS6 of 29–42%.39,40 Bevacizumab monotherapy was well-tolerated with a low incidence of intracranial haemorrhage (0–2.4%) and thromboembolism (8.4–12.5%). Based on the results of these trials, bevacizumab was granted accelerated FDA approval in May 2009 for recurrent GBM. Although several phase II studies have demonstrated improved PFS with bevacizumab for recurrent GBM, its impact on overall survival remains unknown.
The previous practice of combining other cytotoxic agents, such as lomustine, carboplatin and etoposide, with bevacizumab for recurrent GBM that progresses despite bevacizumab and irinotecan has recently been challenged by a study that showed that these
EUROPEAN NEUROLOGICAL REVIEW
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116