The Central Nervous System is made up of the brain, spinal cord and the meninges. Cancers of the CNS present as either primary tumours originating from the CNS or as secondary, metastatic cancers originating from areas such as the breast. Of these forms of CNS cancers, however, metastatic cancers present more commonly (Manoj, L. et al., 2011). Some primary CNS tumours include gliomas, spinal cord tumours or intracranial germ cell tumours.
Of the different types of gliomas, glioblastoma is the most common and aggressive. It is classified as a WHO grade IV glioma and generally has a poor prognosis, although this has improved with advancements in treatment regimes. With current treatment regimes, median progression-free survival is quoted to be 7 months and overall survival to be 15 months ( Stupp, R. et al., 2005, Stupp, R. et al, 2009) . This is of course determined by a multitude of factors such as patient age and extent of tumour resection (Mirimanoff, R.O. et al., 2006).
GBMs are also found to have extensive microvascular infiltration, high rates of proliferation and of recurrence which all contribute to the poor prognosis of patients with GBM as well as age, histologic features and performance status (Mason, W.P. et al., 2007). Clinically, patients generally present with headaches, focal neurologic deficits and seizures but this is highly dependent on the location of the tumour. Often, diagnosis results as a consequence of these presenting symptoms rather than as an incidental discovery due to the aggressive nature of GBM (Adamson, C. et al., 2009). The etiology of GBM is greatly unknown but correlations between GBM incidence and ionising radiation and the genetic makeup of patients has been made. These genetic links have opened up a pathway for gene-based therapies, none of which have yet become the standard (Brandes, A.A. et al., 2008).
The diagnostic workup of CNS tumours typically involves: Patient history and physical examination Magnetic Resonance Imaging (MRI) T1 weighted imaging with or without gadolinium T2 weighted images Contrast-enhanced CT if patient is unable to undergo MRI Biopsy for pathologic confirmation (Adamson, C. et al., 2009) They are staged according to the WHO classification system as there is no existent TNM staging system for CNS tumours. Previous attempts to use the TNM staging system were unsuccessful in the prediction of outcomes. This is largely because the size of the tumour is less relevant than the location and histology, the CNS does not have lymphatics and patients with primary CNS tumours are less likely to survive and develop metastases (Greene, F.L. et al. 2002).
The WHO classification of CNS tumours segregates tumours by malignancy. It can be used to determine prognosis and response to therapy and consequentially determines survival (Louis, D.N. et al., 2007). Prognosis and treatment regime is also determined by: Tumour type Location Surgical margins Spread of disease (Manoj, L. et al., 2011).
GBMs can either manifest as primary (de novo) or secondary GBMs. They are also highly likely to recur either at the primary site or at another tumour focus due to migration of proliferating cells away from the primary site. Current therapies and imaging modalities are unable to detect these migrating cells which may partially explain the high incidence of recurrence. There is no current standard for the treatment of recurrent GBM (Brandes, A.A. et al., 2008). Both primary and secondary GBMs are histologically identical and as such are treated in the same way. They differ only in their rate of development and age of presentation. The mainstay treatment for these forms of GBM is surgical resection of the tumour followed by concomitant chemoradiotherapy. Resection of more than 98% of the tumour has shown to double survival rates compared to biopsy alone but this can be affected by proximity to adjacent critical structures. GBM is relatively chemoresistant and so the search for the appropriate chemotherapy drug has been relatively disappointing. Currently, the only drug found to be particularly effective is temozolomide which is prescribed concomittantly with radiotherapy and post-radiotherapy for maintenance. Radiotherapy has also been found to double survival time and is generally prescribed at 60Gy in 30 fractions (Brandes, A.A. et al., 2008, Preusser, M. et al., 2011) . A multidisciplinary team approach is required for the treatment of GBM.
Different techniques for the delivery of radiation therapy have been explored, none of which have so far proved any survival advantage over external beam therapy (Brandes, A.A. et al., 2008). Comparisons between 3DCRT, IMRT and Rapidarc have also been explored and recommended applications for each technique are outlined in table 2 (Wagner, D. et al., 2009, Amelio, D. et al., 2010, Hermanto, U. et al., 2007).
For simulation of radiotherapy, the patient lays supine and a thermoplastic immobilisation mask is fashioned. A c ontrast enhanced CT scan is then taken for accurate delineation of the tumour (Preusser, M. et al., 2011).
For planning, a post-operative MRI scan and the CT scan is fused. This still does not, however, provide accurate imaging of GBM as it is not specific for infiltration (Mundt, A.J. & Roeske, J., 2011). A 2-3cm margin is included around the GTV as about 90% of GBMs recur within 2cm of the primary site of the tumour or progress at the same site as the primary. A 0.5cm margin is then added to create the PTV. This is added to compensate for inter- and intra-fractional errors (Fiveash, J.B. & Spencer, S.A., 2005). Partial and whole brain have been found to have similar results but long-term survivors are more likely to benefit from partial brain RT due to the reduction in radiation of normal brain tissue. There is, however, still a place for the use of whole brain radiotherapy (Adamson, C. et al., 2009).
Example: MRI/CT fusion GTV + 2-3cm margin for microscopic disease + 0.5cm margin for inter/intrafractional movement 3DCRT planned
Tolerance table: (Barrett, et al., 2009, Hansen, E.K. & Roach III, M., 2010) The organs at risk to be aware of when treating GBM are dependent on the area of intended treatment and its proximity to the surrounding critical structures. This slide presents some of the possible organs at risk and their associated tolerance doses. Patient positioning and conformal planning of treatment can assist in reducing dose to or sparing these organs, thus providing the potential clinical benefit of reduction in side effects and in risk of developing secondary cancers later on.
It is recommended that treatment begins 2-6 weeks post-surgery so that any wounds from surgery are allowed to completely heal. Patients will be treated in the same position as they were simulated in where the immobilisation mask will increase the accuracy of tumour localisation, as will daily 2D-2D image matching ( Mundt, A.J. & Roeske, J., 2011, Kuo, L. et al., 2008). Appropriate QA procedures must also be carried out prior to and during treatment. These may include: MLC QA IMRT fluence maps tool calibration reproducibility of patient positioning (Al-Mohammed, H.I., 2011).
CNS irradiation complications: (Rinne, M.L., Lee, E.Q. & Wen, P.Y., 2012, Schiff, D. & Wen, P., 2006, Hansen, E.K. & Roach III, M., 2010) Side effects of irradiation of the CNS present themselves as either acute complications, early delayed complications or late delayed complications. Listed are some of the complications a patient undergoing CNS irradiation may experience. The side effects experienced depend highly upon the area of treatment and the dose (Hansen, E.K. & Roach III, M., 2010). Other treatment modalities such as chemotherapy can also exacerbate the side effects produced by radiation therapy. Acute complications have been hypothesised to occur because of blood brain barrier disruption, causing increased intracranial pressure and cerebral edema. Early delayed complications on the other hand, are hypothesised to be caused by demyelination of oligodendrocytes and late delayed complications are said to be caused by necrosis, axonal, oligodendrocytic and vascular injury, gliosis and demyelination (Rinne, M.L., Lee, E.Q. & Wen, P.Y., 2012, ) . Treatment for acute and early delayed side effects of CNS irradiation usually involves surgical debulking or corticosteroids. Other methods of management currently being researched include anticoagulation drugs or hyperbaric oxygen treatment ( Schiff, D. & Wen, P., 2006). Treatments for the other typical effects of irradiation to the body are treated in the same way as they would be for other parts of the body. For example, treatment of nausea and vomiting with antiemetics.
The Role of External Beam Radiation Therapy
Brain, Spinal cord, Meninges Primary or Metastatic Metastatic cancers of the CNS are more common Types of CNS tumours: Gliomas Spinal cord tumours Intracranial germ cell tumours Figure 1. The brain and spinal cord of the CNS http://www.encognitive.com/node/1115
Figure 2. Frequency of all primary CNS gliomas. Adamson, C., et al. (2009) Glioblastoma multiforme: Areview of where we have been and where we are going. Expert Opinion on Investigational Drugs, 18(8): 1061-1083
Diagnostic workup Patient history and physical examination Magnetic Resonance Imaging (MRI) Contrast-enhanced CT Biopsy – pathologic confirmation Staged according to the World Health Organisation (WHO) classification system
Table 1. WHO classification system for CNS tumours
Figure 3. Treatment management approach for glioblastoma
External beam vs. Stereotactic, Brachytherapy, Hyperfractionation, Radioenhancers, BCNT, Accelerated, Dose escalation 3DCRT vs. IMRT vs. RapidarcTable 2. Recommended techniques for malignant glioma planning and their respective advantages and disadvantages.Wagner, D. et al. (2009) Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (Rapidarc), dynamic intensity-modulated technique and 3D conformal technique. Radiotherapy and Oncology, 93:593-596
Supine Thermoplastic immobilization mask CT with intravenous contrast Figure 4. Contrast enhanced CT of brain. Arrow indicates GBM multiforme. Drislane, F. et al. (2006) Chapter 19: Brain Tumors. Blueprints Neurology, Philadelphia: Lippincott Williams & Wilkins
Post-op MRI scan + CT fusion Target volume: 2-3cm margin around contrast- enhanced lesion Whole brain radiotherapy Multifocal gliomas Gliomas crossing midline or involving both hemispheres
Figure 5. (A) Target delineation of a GBM. GTV outlined in blue. CTV with an additional 2cm margin to cover microscopicdisease is represented by the green line. An additional 0.5cm margin is added to create the PTV for daily setup variability. (B)3 field 3DCRT planned treatment for the same patient. Preusser, M. et al. (2011) Current concepts and management of glioblastoma.Annals of Neurology, 70: 9-21
Recommendations for 2-6 weeks post-surgery Treatment position same as in simulation Immobilisation mask accuracy within order of 5mm Appropriate QA procedures and treatment verification carried out 2D-2D matching IGRT can reduce PTV margin to 3mm Dependent on available imaging modalities at each centre
Patients with GBM have a relatively poor prognosis and much research is needed in the way of improved treatment standards, especially to do with recurrent GBM Requires MDT approach for treatment Care must be taken in the planning of GBM Be aware of proximity of OAR, need for partial or whole brain RT and the advantages/disadvantages of different EBRT techniques which may assist in planning If performing IMRT or Rapidarc, additional QA measure must be taken Be aware of associated side effects and flag to appropriate member of MDT if thought necessary
http://www.encognitive.com/node/1115 Adamson, C., et al. (2009) Glioblastoma multiforme: A review of where we have been and where we are going. Expert Opinion on Investigational Drugs, 18(8): 1061- 1083 Al-Mohammed, H.I. (2011) Patient specific quality assurance for glioblastoma multiforme brain tumours treated with intensity modulated radiation therapy. International Journal of Medical Sciences, 8(6): 461-466 Amelio, D. et al. (2010) Intensity-modulated radiation therapy in newly diagnosed glioblastoma: A systematic review on clinical and technical issues. Radiotherapy and Oncology, 97: 361-369 Barrett, A. et al. (2009) Chapter 4: Organs at risk and tolerance of normal tissues. Practical Radiotherapy Planning, London: Hodder Arnold Brandes, A.A. et al. (2008) Glioblastoma in adults. Critical Reviews in Oncology/Hematology, 67: 139-152 Drislane, F. et al. (2006) Chapter 19: Brain Tumors. Blueprints Neurology, Philadelphia: Lippincott Williams & Wilkins Fiveash, J.B. & Spencer, S.A. (2005) Role of radiation therapy and radiosurgery in glioblastoma multiforme. Glioblastoma Multiforme, Massachusetts: Jones and Bartlett Publishers Greene, F.L. et al. (2002) Chapter 47: Brain and spinal cord. AJCC Cancer Staging Handbook, New York: Springer Hansen, E.K. & Roach III, M. (2010) Part II: Central nervous system. Handbook of Evidence-Based Radiation Oncology, London: Springer Hermanto, U. et al. (2007) Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain? International Journal of Radiation Oncology Biology Physics, 67(4): 1135-1144 Kuo, L. et al. (2008) Setup accuracy of a thermoplastic mask system using two-dimensional (2D) on-board imager (OBI) for fractionated stereotactic radiotherapy (FSRT). Medical Physics, 35(6): 2825 Louis, D.N. et al. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica, 114: 97-109 Manoj, L. et al. (2011) Review of brain and brain cancer treatment. International Journal of Pharma and Bio Sciences, 2(1): 468-477 Mason, W.P. et al. (2007) Canadian recommendations for the treatment of glioblastoma multiforme. Current Oncology, 14(3): 110-117 Mirimanoff, R.O. et al. (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomised trial. Journal of Clinical Oncology, 24: 2563-2569 Mundt, A.J. & Roeske, J. (2011) Chapter 15: Central nervous system tumors: Overview. Image-Guided Radiation Therapy: A Clinical Perspective, Connecticut: Peoples Medical Publishing House – USA Preusser, M. et al. (2011) Current concepts and management of glioblastoma. Annals of Neurology, 70: 9-21 Rinne, M.L., Lee, E.Q. & Wen, P.Y. (2012) Central nervous system complications of cancer therapy. The Journal of Supportive Oncology, 10(4): 133-141 Schiff, D. & Wen, P. (2006) Central nervous system toxicity from cancer therapies. Hematology Oncology Clinics of North America, 20: 1377-1398 Stupp, R. et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine, 352: 987-996 Stupp, R. et al. (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology, 10: 459-466 Wagner, D. et al. (2009) Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (Rapidarc), dynamic intensity-modulated technique and 3D conformal technique. Radiotherapy and Oncology, 93:593-596