Glioblastoma
Often referred to as "glioblastoma multiforme"; the latest WHO Blue Book has removed the multiforme part.
The diagnosis of glioblastoma is devastating for a patient and their family. Without adjuvant treatment, survival is typically measured in months. Even with adjuvant radiotherapy and temozolamide, the median survival is only 18 months.
The standard of care is currently high-dose radiotherapy given with concurrent temozolamide, followed by adjuvant temozolamide alone for up to twelve months. There is an increased length of survival with this treatment but cure remains elusive.
Critical Studies in Glioblastoma Management
BTSG 69-01, published in 1978, was the first randomised study to demonstrate a benefit for adjuvant radiotherapy (50-60 Gy). Median overall survival was about 14 weeks in the surgery-alone arm versus 35 weeks with surgery + radiotherapy. There was no additional benefit from addition of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy.
EORTC 22981/26981 was a multicentre trial that spanned Europe and North America. Patients were given radiotherapy alone (Arm A) or radiotherapy with concurrent temozolamide, followed by 6 months of adjuvant temozolomide (Arm B). The latest update was in 2009, demonstrating a significantly improved survival in the chemotherapy arm. This trial demonstrated significantly improved outcomes, including a 2 year survival of 27% at 2 years versus 11% between the CRT and RT alone arms.
RTOG 97/10 was a phase II study that attempted to evaluate the use of recombinant human interferon in the management of glioblastoma. Although this has not gone on to become standard practice, the contouring guidelines from this study are in common use (see below).
Radiotherapy
- Target volumes for treatment are usually based on pre-operative imaging, using the enhancing area as well as the oedema as the volume to be treated. An additional margin may also be added to account for microscopic spread; this margin is variable.
- The usual dose is 60 Gy in 30 fractions (used for both the RTOG and EORTC studies)
- Voluming guidelines differ:
- EORTC guidelines specify MRI/CT fusion, with the enhancing area as GTV and a 2-3 cm margin as CTV.
- RTOG guidelines specify a two phase technique. Phase I involves treatment of the enhancing tumour, surrounding oedema and an additional 2 cm margin as PTV1. PTV1 is treated to 46 Gy. Phase II involved a 2.5 cm expansion from the contrast enhancing lesion on the pre-operative MRI as PTV, and received an additional 14 Gy.
- Patients aged 60-70 have a benefit from combined chemoradiotherapy at high dose, if they have a good performance status. Data for patients over 70 is limited.
- Dose escalation beyond 60 Gy has not shown greater benefit in overall or median survival
- There is minimal evidence for benefits of radiosurgery, fractionated stereotactic radiotherapy, radiosensitisers or brachytherapy
General Guidelines for Chemotherapy
Temozolomide is an orally administered alkylating agent that penetrates brain tissue. It has a good toxicity profile (main concern is low platelets). In the EORTC 22981/26981 trial it improved survival significant when added as both a concurrent and adjuvant agent. There is limited evidence for its use alone.
* The effectiveness of temozolamide is thought to be related to the activity of MGMT, a DNA repair protein critical for repair of alkylation by temozolamide. About 40% of glioblastoma tumours have hypermethylation of the MGMT gene, with corresponding low levels of this enzyme.
Management of Recurrence
Nearly all glioblastomas will recur and they will usually cause the death of the patient. In some cases the tumour will progress during conventional treatment. Canadian guidelines state:
- Patients should be reviewed by a multidisciplinary team
- Assessment should be based on contrast enhanced MRI
- Progressive disease should not be diagnosed on MRI until at least 12 weeks after diagnosis due to pseudoprogression
- Pseudoprogression is diagnosed when the post-RT MRI appears worse than a subsequent MRI despite no additional treatment. Radiotherapy is thought to increase capillary permeability and therefore increase enhancement from gadolinium
- Repeat surgery is indicated if the patient has a good performance status (ECOG 0-2 or KPS > 70) and the tumour is accessible
- Repeat radiotherapy is rarely indicated
- Systemic therapy is experimental; temozolomide is frequently used. Bevacizumab has been used with good effect on progression free survival but no effect on overall survival. Clinical trials are recommended
Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, and Anaplastic Oligoastrocytoma
These high grade tumours lack necrosis or microvascular proliferation. They are often included in trials of glioblastoma.
The main difference in treatment is that temozolomide is authorised for use concurrently with radiotherapy for GBM, but sequentially for use in anaplastic astrocytoma
There are five important studies for management of anaplastic glial tumours.
EORTC 26951 and RTOG 9402
Anaplastic Oligodendroglioma or oligoastrocytoma treated with radiotherapy with or without PCV. The most important factor identified was the presence of 1p/19q codeletion (median survival 2 years without, median survival > 8 years with). Chemotherapy made minimal difference in overall survival. However, chemotherapy was associated with improved progression free survival as opposed to radiotherapy alone for patients with 1p/19q. The lack of overall survival advantage may be due to use of chemotherapy for relapsed disease.
Long term follow up of RTOG 9402 and EORTC 26951 demonstrated that an overall survival benefit did exist. A trend towards better overall survival for patients with 1p/19q codeletion was observed. This effect only becomes apparent at 6 years but median survival was 14.7 years with combined therapy compared with 7 years for radiotherapy alone.
NOA 04
Published in 2009, this study randomised patients to radiotherapy or chemotherapy with PCV or temozolomide followed by the alternative treatment as salvage. The study is important as it compares radiotherapy vs chemotherapy as well as comparing different chemotherapy regimens. It also included patients with anaplastic astrocytoma. This study demonstrated:
- Poorer survival in patients with anaplastic astrocytoma regardless of treatment (median survival ~ 3 years).
- Similar survival in patients with anaplastic oligoastrocytoma or oligodendroglioma.
- Similar progression free survival with chemotherapy or radiotherapy first (exception: anaplastic astrocytoma showed higher rates of early recurrence with radiotherapy; this is likely due to pseudoprogression)
- Perhaps most importantly, the study showed that temozolomide was equivalent to PCV in terms of effectiveness. This has led to a reduction in the use of PCV for this group of tumours.
EORTC CATNON
This trial is exploring treatment options in non-codeleted patients. It is a 2x2 randomisation:
- Radiotherapy vs Radiotherapy + temozolomide
and
- Adjuvant temozolomide vs no temozolomide
This should help to explore the role of the Stupp like protocol for GBM in anaplastic tumours without good prognostic features.
Other Biomarkers
IDH1 mutation was identified as an important positive prognostic factor (+ve - median survival 5 years; -ive median survival 14 months). It is often expressed in grade II and III astrocytomas and secondary glioblastoma. It is rare in pilocytic astrocytoma and glioblastoma. It has a similar prognostic effect as 1p/19q but the interaction between IDH1 and 1p/19q is not known.
The so called 'triple negative astrocytoma' group has no codeletion of 1p19q, no TP53 mutation, and no IDH1/2 mutation. These tumours tend to behave similarly to glioblastoma.
SUMMARY FOR GRADE III GLIOMA
Patients should be assessed for 1p19q codeletion, IDH1/2 mutation, and TP53
Patients with codeletion should receive radiotherapy (60 Gy in 30#) followed by 6 cycles of temozolomide (not funded in Australia)
If codeletion -ve, but IDH +ve, then consider for clinical trial (CATNON) or consider patients for adjuvant chemotherapy (not funded in Australia)
If triple negative then consider treating as per GBM (not funded in Australia)
Gliosarcoma
This is a much rarer form of high grade glioma with about 2% the incidence of glioblastoma. Due to its rarity there is little evidence regarding treatment; it appears to have a similar survival to glioblastoma following surgical resection and radiotherapy also appears to improve life expectancy. There is not significant evidence for the use of temozolomide.
