GLIOBLASTOMA

Natural History and Treatment Options

Background

Glioblastoma (GBM) is an aggressive form of brain cancer that grows and spread rapidly, often creating pressure inside the brain. Around 1,900 people are diagnosed with brain cancer in Australia annually, and approximately 1,500 die from the disease each year. This equates to around 6 or 7 people being affected for every 100,000 persons living in Australia each year.

It is not known why some people develop GBM, but it is important to know that GBM is not inherited and cannot be passed onto your children. There is no evidence to suggest that GBM could have been caused by any dietary factors, activities, potential exposure, or anything you have done.

There are essentially two types of GBM.

  • Primary (or de novo) GBM, which develop spontaneously within the brain (i.e., for no good reason) and are the more common of the two types (account for 90% of cases seen in clinical practice). They have the genetic label of being IDH wild-type tumours. There is a slight male preponderance (1.3 times more common in men), and affected individuals are generally older by the time of diagnosis (mean age around 60 years).

  • Secondary GBM develop from slower growing tumours that evolve to become aggressive over time.  They have the genetic label as IDH mutant. These types of tumours are less common and tend to affect younger aged patients (mean age: 30-50 years), with no clear sex predilection.

Research has shown that GBM can be genetically diverse (i.e., have different types of genetic information and expression). This means the cells within the tumour are not all the same type and may have different expressions and behaviour. Therefore, some tumours may respond well to standard treatment while others continue to grow despite intensive surgery and therapy.



Natural History

Predicting survival (prognosis) is at best an estimate and can be highly variable as this depends on your age, the genetic profile of the tumour, where it’s located, and how well you might respond to treatment. It is important to remember that statistics and averages cannot tell you what will happen to you specifically. This is why prognosis is often an ongoing process, revised at different stages in your journey.

The average survival time following diagnosis of GBM is 12 to 18 months. Only 1 in 4 patients survive more than one year, and only 1 in 20 patients survive more than 5 years.

Factors that may affect your overall survival include:

  1. Age – younger patients have better chance of survival

  2. Genetic profile of the tumour – certain tumour subtypes respond better to chemotherapy and radiation treatment than others.

  3. Your functional performance status – in general, if you remain fit and well during the course of your treatment, you are likely to do better and survive longer.

  4. Extent of disease – tumour that are confined to one part of the brain behave better than those that are diffuse or are located in multiple locations in the brain.  


Tumour recurrence is unavoidable. In 90% of cases, recurrence is within 2cm of the original tumour margin. Time to recurrence can range from 4 to 14 months of diagnosis, either during or after first line treatment. If recurrent GBM is untreated, death occurs within 2 to 7 months.



Treatment Options

Since 2005, the gold standard (ideal) treatment for patients diagnosed with GBM is surgery to remove as much of the tumour as possible, followed by concurrent chemotherapy and radiation therapy as soon as the surgical wound is healed.


Surgery

Surgery is generally required at the time of diagnosis for one or more of the following reasons:

  1. To obtain tissue for formal laboratory diagnosis of the tumour

  2. To relieve pressure inside the brain

  3. To improve symptoms by removing the mass and reducing swelling inside the brain

  4. To reduce tumour burden so that adjuvant radiotherapy and chemotherapy can be more effective

  5. To provide additional tissue for research and clinical trial inclusion

Complete resection is difficult because of the inherent infiltrative nature of the disease, and the ability to completely resect the tumour largely depends on where the tumour is located in the brain. If a tumour is located in a deep part of the brain or near an “important” (eloquent) part of the brain, then complete resection is less likely due to the increased risk of causing a stroke from the surgery.

A meta-analysis of 41,117 GBM patients demonstrated that the more tumour that can be removed during the first operation, the better the overall survival and the lesser chance of tumour returning too soon. In general, removing at least 70% of the tumour is considered satisfactory.


Concurrent chemoradiation therapy

Chemotherapy and radiation therapy are used to slow the growth of any tumour cells that cannot be removed by surgery. The main chemotherapy drug used is Temozolomide (TMZ), which works by stopping tumour cells from making new DNA. Therefore, if tumour cells cannot make DNA, they cannot divide into new tumour cells, so the tumour cannot grow. TMZ is also thought to make the tumour cells sensitive to the radiation and is usually taken for a further 6 months after radiotherapy has finished.

The role of radiotherapy in prolonging survival in GBM is well established. A meta-analysis of 6 randomized controlled trials have demonstrated that radiotherapy reduces the risk of death within 12 months by 19%.




Some useful references

  1. Michaelsen SR, Christensen IJ, Grunnet K, et al. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution. BMC Cancer. 2013;13(1):402.

  2. van Linde ME, Brahm CG, de Witt Hamer PC, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. Journal of Neuro-Oncology. 2017;135(1):183-192.

  3. Bette S, Barz M, Huber T, et al. Retrospective analysis of radiological recurrence patterns in glioblastoma, their prognostic value and association to postoperative infarct volume. Scientific Reports. 2018;8(1):4561.

  4. Park C-K, Kim JH, Nam D-H, et al. A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma. Neuro-oncology. 2013;15(8):1096-1101.

  5. Tully PA, Gogos AJ, Love C, Liew D, Drummond KJ, Morokoff AP. Reoperation for recurrent glioblastoma and its association with survival benefit. Neurosurgery. 2016;79(5):678-689.

  6. Lu VM, Jue TR, McDonald KL, Rovin RA. The survival effect of repeat surgery at glioblastoma recurrence and its trend: A systematic review and meta-analysis. World Neurosurgery. 2018; 115:453-459.