Provincial Health Services Authority (PHSA) improves the health of British Columbians by seeking province-wide solutions to specialized health care needs in collaboration with BC health authorities and other partners.
2823 Neuro-Oncology cases were diagnosed between 1 January 1987 and 31 December 1996. This sample includes all BC residents diagnosed with either benign disease or malignant tumours during this ten-year period.
Linear regression analysis of the incidence and mortality trends indicates that incidence tends to increase on average by almost 13 cases each year (p-value < 0.001) and mortality increases on average by 4 cases a year (p-value = 0.02). To determine if those trends are only due to the growth and aging of BC population age-standardized incidence and mortality rates were calculated.
These rates are standardized to the age distribution of the 1991 Canadian Population. The plot indicates only a very slight increasing trend of approximately 1 case per 400,000, per year in the incidence (p-value = 0.061) and no increase in mortality.
These rates are standardized to the age distribution of the 1991 Canadian Population. The plot indicates only a very slight increasing trend of approximately 1 case per 400,000 per year in the incidence (p-value = 0.061) and no increase in mortality.
The age of patients diagnosed in BC during these ten years ranges from 0 to 99 years. Three quarters of diagnosed patients were 39 year old and older, median age at diagnosis was 57 years and the mean was 53.1 years. Age distribution is presented on the histogram below:
The plot shows that the majority (72.3%) of diagnosed cases was referred to BCCA. It also suggests that the number of non-referred cases tends to increase over the ten years. Linear regression analysis indicates that this number increases on average by 9 cases per year (p < 0.001). Such increase is not only due to increase in incidence; relative to the total number of diagnosed cases the percent of non-referred cases increases by about 2 each year (p = 0.001).
As indicated in the table of the incidence by diagnosis type astrocytoma has the most frequent diagnosis (57.95% of incidence). Severity of the disease is reflected by its grade.
The plot indicates substantial difference in survival for the four grades of astrocytoma. The estimates for Grade 1 diagnosis are rather unreliable, due to the low number of cases in the sample; the estimated median survival for this grade is longer than 10 years. The median survival for Grade 2 is 4.9 years, 95% confidence interval for this estimate is from 4.1 to 6.7 years. The median survival time for Grade 3 is only 1 year with 95% confidence interval is from 0.9 to 1.3 years. The median survival time for Grade 4 is even shorter: 0.6 year with 95% confidence interval of 0.6 to 0.7 year.
Tumours of the central nervous system are relatively rare and include tumours in the brain, cranial nerves, or cranial meninges.
High-dose ionizing radiation is a well-recognized risk factor for brain tumours; however, the general population is not generally exposed to high doses, and the association with low doses is controversial. Although there have been some studies reporting elevated brain tumour risk with occupational exposure to benzene or work in the petrochemical industry, other studies have not confirmed these results.
Elevated risks for brain tumours among agricultural workers, and workers in the nuclear and rubber industries have been reported; but the specific causative agents have not been established for these associations. N-nitroso compounds, potent nervous system carcinogens in animals, are hypothesized to be causative agents in brain tumours. Human exposure to these compounds is through tobacco smoke (in particular, sidestream smoke), cosmetics, cured meats, and other N-nitroso containing foods. Studies of pediatric and adult tumours so far have provided limited support for the role of these compounds in human CNS tumours.
Three of the four case-control or cohort studies of meningioma show an elevated risk in subjects with prior head trauma. The relative risks are about 2-fold. Nerve sheath tumours appear to be more common in subjects reporting acoustic trauma.
At this time, not enough is understood of the factors influencing risk of brain tumours to make recommendations for prevention.
Preston-Martin S, Mack WJ,. Neoplasms of the nervous system. In Schottenfeld D, Fraumeni JF Jr. (Eds) Cancer Epidemiology and Prevention.2nd Ed., Oxford University Press, Oxford, Pp1231-1281. 1996.
Revised: February 2004
1. Diagnostic Pathology
Definitive management of CNS tumours, with few exceptions, requires histologic confirmation. For intra-cranial lesions this is achieved either by biopsy or concomitant with an open procedure for resection. Spinal cord tumours require open procedures for tissue diagnosis. Tumours of the skeletal spine can often be sampled via percutaneous needle techniques under image guidance.
Biopsy techniques include CT or MRI-guided stereotactic procedures. Occasionally a formal craniotomy is required to safely acquire an adequate volume of tissue.
CSF sampling can be useful for analysis of markers of germ cell tumours and carcinomatous meningitis. (CSF sampling must be done with caution in the face of an intracranial mass.)
Skull radiographs are sometimes useful in demonstrating enlarged pituitary fossa and associated hyperostosis in meningiomas.
b) Computer Tomography (CT) and/or Magnetic Resonance Imaging (MRI) are the primary imaging modalities for patients expected to have brain tumours. Intravenously enhanced CT examinations are usually adequate for supratentorial mid and high grade gliomas and some instances of metastatic disease, lymphoma and meningioma. Low grade glial neoplasms, neuronal and mixed neuronal-glial tumours, ependymal tumours, most embryonal tumours (including medulloblastomas), pituitary/pineal region masses, cranial nerve tumours and some meningiomas should be studied with Gadolinium-DTPA enhanced MRI. MRI has significantly higher sensitivity than CT toward detecting tiny metastases and leptomeningeal carcinomatosis and should be used for these purposes. In general, the trend is toward using MRI for most brain tumours other than those which have known high conspicuity on CT. CT is still the modality of choice for detecting brain tumour calcification and remains useful for defining calvarial and skull base bony involvement.
c) When surgical resection is considered, patients with solitary brain metastasis should be studied by MRI to exclude additional lesions.
a) The initial investigation should be plain radiographs of the spine. Secondary signs of spinal cord tumour may be shown on the plain films. These include erosion of the pedicles, enlargement of the intravertebral foramina and compression and collapse of vertebral bodies.
b) MRI is definitely the modality of choice in showing intramedullary, intradural, dural and epidural tumours. When MRI is not available the alternative is CT myelography.
c) Routine Staging: MRI of the spine is indicated for medulloblastoma, supratentorial PNETs, pineoblastoma, germ cell tumours due to high risk of spinal cord seeding.
Post-op: CT without/with contrast 1-4 days post-op
Pre-irradiation:CT or MRI with Gd-DTPA
c) Tumours of Meninges
d) Tumours of the Pituitary Gland
e) Tumours of Specialized Tissues
1) Pineal region
a) High grade lesions, i.e. pineoblastoma, embryonal cell, endodermal sinus, choriocarcinoma, germinoma
2) Astrocytoma, pineocytoma (astro/neuronal)
f) Spinal Cord Tumours
1) Vertebral Body and Epidural Metastases
2) Intradural Extramedullary (including leptomeningeal disease)
g) Primary CNS Lymphoma (see Lymphoma, Chronic Leukemia, Myeloma)
h) Solitary Cerebral Metastasis for Surgical Resection
1. Investigations for Staging see 4.0 Diagnosis (Radiology/Imaging: Spine (c))
Revised: June 2014
Brain edema may result from tumour, surgery or radiation treatment. Symptoms may include headache, nausea with or without vomiting, worsening of presenting neurologic symptoms or decreasing level of consciousness. Oral (or intravenous) corticosteroids are very effective in reducing brain edema and alleviating the associated symptoms, often within 24 - 36 hours.
Dexamethasone is used most commonly in a range of doses from 2-16 mg per day (in divided doses) depending on symptom severity. In emergent situations, higher doses of dexamethasone may be used and mannitol may also be employed.
Side effects of dexamethasone include increased appetite, altered mood, impaired glucose tolerance, proximal myopathy, Cushingoid changes, tremor, gastric erosions or ulceration with bleeding, pseudo rheumatism and others. Most of these side effects are reversible when the steroid is discontinued. Rarely, frank psychosis or avascular necrosis of the femoral head may result.
There are some possible important dexamethasone-drug interactions that should be noted: brain tumour patients are often on anti-seizure medication and their serum levels may be affected by dexamethasone (phenytoin or carbamazepine levels should be monitored); if the patient is also on chemotherapy, immunity may be further suppressed and the patient may be at increased risk for opportunistic infections (prophylactic Septra is often started if patients are on both chemotherapy and dexamethasone).
During radiation therapy, a tapering dose of dexamethasone, as clinically tolerated (to alleviate symptoms of brain edema), is prescribed, and the lowest effective dose is used. After completion of radiation therapy, the dexamethasone is tapered and discontinued over 2 - 4 weeks usually. However, there may be periods of brain edema in the few weeks following radiation and in a delayed window of time from 8 - 16 weeks following the completion of radiation therapy (early delayed radiation edema) and dexamethasone may need to be re-instituted. Occasionally, adrenal dependence is seen and prolonged tapering or continued use of low dose steroid replacement is needed.
Although alternate medications are being investigated in the hopes of avoiding the undesirable side effects of dexamethasone, to date it remains the mainstay in the control of brain edema.
Epilepsy is a common disorder in patients with primary brain tumours. Thirty percent will present with a seizure and at least 50% will have a seizure at some time (1). The most common seizure disorder in these patients is partial epilepsy with or without secondary generalization. Because of the high likelihood of recurrence, virtually all brain tumour patients who have a seizure should be started on anticonvulsants. Selection of anticonvulsant will depend on side effect profile, drug interactions, and cost. Medications most commonly prescribed for partial epilepsy include phenytoin, carbamazepine, and levetiracetam. Alternative choices include divalproex sodium, lamotrigine, clobazam, lacosamide, topiramate, oxcarbazepine and phenobarbital. Refractory cases requiring more than one agent should be referred to a Neurologist for specialized care.
Phenytoin is the most frequently used anticonvulsant, as it is available both orally and intravenously, is familiar to most physicians, can be taken once a day and has low cost. The average adult dose is 300-400 mg and can be taken at bedtime as a single oral dose. As it can take up to a week for steady-state levels to be achieved, oral or IV loading can be achieved at a dose of 15 mg/kg. The therapeutic range is 40-80 micromoles/litre but dosage should be titrated to seizure control with minimal side effects. Common toxic effects of phenytoin include drowsiness, dizziness, imbalance and confusion. Other relatively common side effects include hypersensitivity reactions (rashes, fevers), gum hyperplasia, and alterations of liver enzymes. Interactions with other medications especially dexamethasone and other anticonvulsants may require monitoring of serum levels during changes in medications.
Carbamazepine is not available intravenously and due to GI intolerance cannot be loaded orally. Treatment is usually started at 100 mg bid of the long-acting formulation and increased over the next 1-2 weeks to a target dose 800-1000 mg/day. Steady state is usually achieved in 4-7 days and the therapeutic serum concentrations range from 25-50 micromoles/litre. Toxic effects are similar to phenytoin and include imbalance, dizziness, diplopia, dysarthria and confusion. Other side effects include rashes, hepatic enzyme induction, neutropenia, hyponatremia and GI upset. The tendency to cause neutropenia make this agent less desirable for brain tumour patients that may require chemotherapy as part of their treatment.
Levetiracetam has a higher cost than phenytoin or carbamazepine but has a more favorable side effect profile and does not have significant drug interactions. It is an oral agent that can be started at therapeutic dose immediately without titration. Typical starting doses of 500 mg twice daily can be increased as high as 1500 mg twice daily as needed for seizure control. Monitoring levels is not necessary with this agent as there is no toxic level. Chief side effects include mild dizziness, drowsiness or stomach upset. On occasion mood changes and irritability have been noted.
Duration of therapy with anticonvulsants is uncertain. Because of the frequent presence of residual tumour, the residual scarring from prior surgery and radiation and the high risk of tumour recurrence, most patients will require lifelong anticonvulsant therapy. A few patients with low grade neoplasms, who had a tumour resection and have been seizure-free for a number of years, may be considered for anticonvulsant withdrawal under the direction of their neurologist or surgeon.
Driving restrictions are necessary for any patient with a seizure disorder. Brain tumour patients need specific consideration as other neurologic deficits may preclude driving i.e. visual field defects, hemiplegia, dementia, etc. British Columbia law requires a patient be seizure-free for 6 months on treatment prior to recommencing driving.
The use of prophylactic anticonvulsants in patients with brain tumours is controversial. Retrospective reviews and a few small prospective studies have failed to show a significant benefit from the early prophylactic use of anticonvulsants (2,3,4). Anticonvulsants have potentially serious side effects and have been associated with severe rashes (Stevens-Johnson syndrome) in a few patients concurrently receiving cranial radiotherapy (5). At this time the routine use of prophylactic anticonvulsants in brain tumour patients who have yet to experience a seizure is not recommended.
Cascino GD. Epilepsy and brain tumours: implications for treatment. Epilepsia 3: s37-s44, 1990.
Mahalay M, Dudka L. The role of anticonvulsant medications in the management of patients with anaplastic glioma. Surg Neurol 16:399-401, 1981.
Moots PL, Maciunes RJ, Eisert DR, et al. The course of seizure disorders in patients with malignant gliomas. Arch Neurol 52:717-724, 1995.
Glantz M, Friedberg M, Cole B, et al. Double-blind, randomized placebo-controlled trial of anticonvulsant prophylaxis in adults with newly diagnosed brain metastases. Neurology 46:985-991, 1996.
Delattre J-Y, Safari B, Posner JB. Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 40:1144-1145, 1990.
The Stereotactic Radiation Therapy (SRT) program is jointly operated by the Division of Neurosurgery at the Vancouver General Hospital and the BC Cancer Agency, under the auspices of the Stereotactic Therapy Operations Working Group. Although all patients are treated at the Vancouver Cancer Centre, the program serves as a resource for patients and their physicians throughout the province of British Columbia.
SRT is a specialized form of radiation treatment that utilizes a precisely focused beam of radiation to treat a small, stereotactically defined, target lesion while minimizing irradiation of adjacent normal structures. Our treatment technique utilizes a modified linear accelerator technology. Depending on the clinical circumstances, either a single large dose of radiation (single fraction SRT AKA radiosurgery) or multiple small doses over a 5 to 6 week period (fractionated SRT) is given. Some clinical examples that may be suitable for this technique include arteriovenous malformations, acoustic neuromas, small meningiomas, small pituitary adenomas and cerebral metastasis.
All patients to be considered for SRT are discussed in the interdisciplinary SRT Disposition Conference involving neurosurgeons, radiation oncologists, neuro-radiologists and medical physicists. It is held on the first and fourth Wednesdays of each month and referrals may be made by contacting Dr. Michael McKenzie, Dr. Roy Ma, or Dr. Brian Toyota or Dr. Andrew Lee. Whenever eligible, patients will be treated in the context of prospective clinical trials through the Radiation Therapy Oncology Group and Children's Cancer Study Group.
The members are: Andrew Lee, Gary Redekop, Roy Ma, Lorraine Geddes, Karen Goddard, Michael McKenzie, Marnie Besser; Brenda Clark, Brian Toyota, Sharon Allman, Christine Alexander, Emily Vollans, Richard Lee & Bob Harrison.
Low grade astrocytomas include pilocytic astrocytomas and fibrillary (or diffuse) astrocytomas. A distinction is crucial as their respective biologic behaviours are markedly divergent. Other low-grade astrocytomas include protoplasmic astrocytomas, granular cell astrocytomas, pleomorphic xanthoastrocytoma, astroblastomas, and dysembryoplastic neuroepithelial tumours (1).
Fibrillary astrocytomas, in the adult population, are by far the most common type of low-grade astrocytoma. Seizures are the most common mode of presentation. An important feature of these lesions is a high propensity for anaplastic degeneration. These lesions carry a characteristic, but by no means universal, imaging appearance. Typically they appear as low-density/low-signal, non-enhancing lesions with modest mass effect. However, anaplastic tumours can often carry a similar appearance and thus caution must be made in trying to make histologic interpretations based purely on imaging studies. Suffice it to say, tissue diagnosis is generally required for optimal management.
Current management recommendations are very much patient specific. Patient age, neurologic condition, tumour location and size must all be heavily considered before any modality of surgery, radiation or chemotherapy is employed. As a general rule, an early attempt at aggressive surgical resection is considered beneficial to outcome, assuming of course minimal associated surgical morbidity (2). For pilocytic lesions, complete surgical resection is usually considered curative. Recent studies indicate in high risk low grade gliomas (age >40, or incomplete resection) a combination of radiotherapy with adjuvant PCV chemotherapy carries an improved prognosis (3).Currently a watchful waiting approach can be recommended for younger patients with gross total resection, but it may be that these patients would also benefit from combined modality therapy.
Tumour recurrence or latent progression requires a thoughtful re-appraisal of the patient, bearing in mind the frequent degeneration of these tumours into malignancy. Re-resection, palliative chemotherapy and occasionally re-irradiation remain possible interventions for these patients.
Protoplasmic astrocytomas, granular cell astrocytomas, pleomorphic xanthoastrocytoma, astroblastomas, and dysembryoplastic neuroepithelial tumours generally have rather indolent biologic behaviours. Aggressive surgical resection can be curative for such lesions.
The general outlook of patients with low grade astrocytoma is more favourable than a malignant astrocytoma with median survival between 5-10 years, depending on the type of tumour.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.). World Health Organization Histological Classification of Tumours of the Central Nervous System. Lyon: International Agency for Research on Cancer, 2007
Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. Journal of the American Medical Association. 2012; 08(18):1881-1888.
Buckner JC, Pugh SL, Shaw EG, et al. Phase III study of radiation therapy with or without procarbazine, CCNU and vincristine (PCV) in low grade glioma: RTOG 9802 with Alliance, ECOG and SWOG. J Clin Oncol 2014. 32:5s, abstr 2000.
The most important prognostic variables for survival of patients with malignant astrocytoma are age (less than or greater than 50 years), performance status (KPS greater or less than 70) and tumour grade (grade III or grade IV)(1). Additionally, molecular markers of good survival include MGMT promoter methylation and IDH1 mutations (2,3).
Younger patients with a good performance status have a median survival of 59 months with grade III tumours and 18 months with grade IV tumours. Older patients with a good performance status have a median survival of 37 months with grade III tumours and 11 months with grade IV tumours(1).
Patients over 50 years with a poor performance status have a median survival of only 18 months with grade III tumours and 5 months with grade IV tumours(1).
All patients with suspected malignant astrocytoma, based on medical imaging, who are fit for biopsy should have tumour tissue obtained to confirm the diagnosis.
Patients who, after treatment with dexamethasone, are unfit for biopsy are unlikely to benefit from any further treatment because of their very short expected survival.
Tumours suitable for surgery should receive maximal surgical debulking(4).
Prospective randomized controlled trials have confirmed the benefit of postoperative radiation treatment for patients with malignant gliomas, which extends the median survival from 14 weeks to 36 weeks compared to surgery alone(5). The usual course of radiation extends over 6 weeks.
Randomized prospective studies in grade IV astrocytoma have shown that older patients, or patients with poor performance status (KPS = 50), achieve equivalent survival benefit with shorter courses of radiation treatment(6).
A multicentre EORTC/NCIC-sponsored randomized clinical trial comparing radiotherapy alone to radiotherapy with concurrent and adjuvant temozolomide improved median survival by 2.5 months and 2 year survival by 16% (7). Further follow-up revealed the 5 year survival to be improved by 10% with the addition of temozolomide chemotherapy (8). Therefore, the current standard of care for glioblastoma in patients under 70 with acceptable performance status, consists of 60 Gy partial brain RT with concurrent temozolomide and 6 cycles of adjuvant temozolomide.
The role of chemotherapy in elderly patients with GBM is less certain. Two European elderly trials looking at single agent temozolomide vs RT alone for patients with glioblastoma over age 65 showed equivalent outcomes (9,10). Interestingly, in both trials, there was a difference in outcome depending on MGMT methylation status of the tumours. MGMT methylated tumours showed a better outcome with Temozolomide whereas unmethylated patients survived longer with RT. The role of combination of RT + TMZ is being explored with clinical trials in the elderly.
Currently the role for concurrent chemoradiotherapy in the treatment of grade 3 astrocytomas is unknown pending ongoing clinical trials. In the absence of data, centres have adopted either single modality radiotherapy or radiotherapy combined with temozolomide as utilized in glioblastoma.
Patients with good performance status and residual tumour after radiotherapy and/or chemotherapy may benefit from a second surgical resection(11).
For management of recurrent tumours see Cerebral Metastasis.
Curran WJ, Scott CB, Horton J et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group Malignant glioma trials. J Nat Cancer Inst 85(9):704-710, 1993.
Hegi ME, Diserens AC, Gorila T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10): 997-1003, 2005.
Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8): 765-73, 2009.
Wood JR, Green SB, Shapiro WR. The prognostic importance of tumour size in malignant gliomas: a computed tomographic scan study by the Brain Tumour Cooperative Group. J Clin Oncol 6(2): 338-43, 1988.
Walker MD, Alexander E, Hunt WE et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 49(3): 333-43, 1978.
Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med 356(15):1527-35, 2007.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987-96, 2005.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459-66, 2009.
Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomized, phase 3 trial. Lancet Oncol 13(9):916-26, 2012.
Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13(7):707-15, 2012.
Young B, Oldfield EH, Markesbery WR et al. Reoperation for glioblastoma. J Neurosurg 55(6): 917-21, 1981.
Initial treatment of oligodendroglioma is surgical. In feasible cases, gross total resection should be the goal. Pathology from surgery (biopsy or resection) should be reviewed. Oligodendrogliomas should be classified based on both histologic grade and molecular diagnostics. Histologically, oligodendrogliomas are classified by the WHO grading system as low grade (Gr. II) or anaplastic (Gr. III) (1). Low grade tumours show increased cellularity but no anaplastic features of elevated mitotic rate, vascular proliferation or necrosis. Any of these features will lead to an anaplastic grading of the tumour. The molecular classification of oligodendroglioma divides these tumours into those showing co-deletion of chromosomes 1p and 19q and those with retention of those chromosome arms. Most tumours with 1p/19q co-deletion also show IDH1 mutation. Low grade tumours and those with 1p/19q co-deletion are good prognostic markers (1). In addition to a favorable prognosis, tumours with 1p/19q deletions show marked chemosensitivity (>90%) and prolonged responses to radiotherapy (2).
Low grade oligodendrogliomas typically have slow growth patterns and a better prognosis than most gliomas. Treatment of asymptomatic biopsy-proven low grade oligodendrogliomas is controversial (similar to low grade astrocytomas). Although adjuvant radiotherapy has been commonly advocated(3,4), there is evidence suggesting these lesions can be observed for clinical or radiographic progression without adversely affecting overall survival (with the potential benefit of delaying radiation related neurotoxicity)(5). In those with symptomatic residual disease after initial surgery, adjuvant radiotherapy is standard care and should be recommended. The role of adjuvant chemotherapy is currently under investigation. Although evidence exists that low grade oligodendrogliomas respond to chemotherapy (6,7), the impact on overall survival as compared to radiotherapy is unknown. Interest currently exists in treating patients with more indolent 1p/19q co-deleted with up-front chemotherapy (primarily in hopes of reducing late radiation neurotoxicity). Recent evidence from the RTOG 9802 trial indicates higher risk low grade gliomas (age >40, incomplete resection) have longer survival with combinations of chemotherapy and radiotherapy (8).Whether this data applies to all low grade gliomas or certain molecular and risk subsets requires further analysis.
Anaplastic oligodendrogliomas and mixed oligoastrocytomas should be treated with adjuvant therapy after resection or biopsy. Results of recent clinical trials have shown that chemotherapy with radiotherapy offers superior long term survival in anaplastic tumours with 1p/19q co-deletion (9). Radiation therapy alone remains the standard of care for non-deleted anaplastic tumours but interest remains in giving these patients GBM protocols of concurrent temozolomide and radiation.
Intergroup Radiation Therapy Oncology Group Trial 9402, Cairncross G, Berkey B, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 2006; 24:2707.
Shaw, E.G., et al., Oligodendrogliomas: the Mayo Clinic experience. Journal of Neurosurgery, 1992. 76(3): p. 428-34.
Allison, R.R., et al., Radiation and chemotherapy improve outcome in oligodendroglioma [see comments]. International Journal of Radiation Oncology, Biology, Physics, 1997. 37(2): p. 399-403.
Karim, A.B.M.F., et al. Immediate postoperative radiotherapy in low grade glioma improves progression free survival, but not overall survival: preliminary results of an EORTC/MRC randomized phase III study. Proceedings of ASCO, 1998. 17:400.
Mason, W.P., G.S. Krol, and L.M. DeAngelis, Low-grade oligodendroglioma responds to chemotherapy. Neurology, 1996. 46(1): p. 203-7.
Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlations with 1p deletions. Journal of Clinical Oncology, 2004, 22:3133-38.
Cairncross, G., et al., Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 1994. 12(10): p. 2013-21.
Classically, tumour grade and extent of surgery have been thought to be the most important prognostic factors (1,2,3,4). More recently, other factors, including tumour site (5), radiation therapy (6)and initial performance status (7) have been found to impact on survival.
For both intracranial and spinal cord primary lesions, as complete a resection as possible is attempted (8). Progression-free survival is improved if radiation therapy is given, with doses of at least 45 Gy being employed (7).
The optimal radiation volume for intracranial primary lesions is controversial. Regardless of disease grade or degree of resection, post surgical therapy should consist of local radiotherapy 50-55 Gy. Disseminated disease is uncommon but should receive craniospinal radiation, with a dose of approximately 35-40 Gy to the craniospinal axis, and a boost of approximately 15-20 Gy to the intracranial primary site and 10 Gy to drop metastases in the spine (12).
For spinal ependymomas, the use of adjuvant post-operative radiation has been advocated after less than total resection of low-grade lesions (9). However, this has recently been questioned, with some suggesting an expectant policy with possible repeat surgery when complete resection is not achieved (10). A randomized trial would be useful in this situation.
There is no indication that chemotherapy is useful in the treatment of primary ependymomas in adults. Recurrent disease is often treated with palliative chemotherapy approaches including platinum based regimens, temozolomide and/or etoposide.
Postoperative radiotherapy of intra-cranial ependymoma in pediatric and adult patients. Shaw EG, Evans RG, Scheithauer BC, Ilstrup DM, Earle JD. Int J Rad Onc Biol Phys 13(10):1457-62, 1987.
Improved survival in cases of intracranial ependymoma after radiation therapy. Late report and recommendations. Salazar OM, Castro-Vita H, VanHoutte P, Rubin P. J Neurosurgery 59(4):652-9, 1983.
Ependymomas: results of radiation treatment. Garrett PG, Simpson WJ. Int J Rad Onc Biol Phys 9(8):1121-4, 1983.
Intracranial ependymoma: long term results of a policy of surgery and radiotherapy. Vanuytsel LJ, Bessell EM, Ashley SE, Bloom HJ, Brada M. Int J Rad Onc Biol Phys 23(2):313-9, 1992.
Ependymoma: results, prognostic factors and treatment recommendations. McLaughlin MP, Marcus RB Jr., Buatti JM, McCollough WM, Mickle JP, Kedar A, Maria BL. Int J Rad Onc Biol Phys 40(4):845-50, 1998.
The clinical and prognostic relevance of grading in intracranial ependymomas. Ernestus RI, Schroder R, Stutzer H, Klug N. Br. J. of Neurosurgery 11(5):421-8, 1997.
Postoperative radiotherapy of spinal and intracranial ependymomas: analysis of prognostic factors. Stuben G. Stuschke M, Kroll M, Havers W, Sack H. Radiotherapy & Oncology 45(1):3-10, 1997.
Brain Tumor. Part 2 of 2. Black PM. NEJM 324(22):1555-1564, 1991.
The role of radiotherapy in the management of spinal cord glioma. Shirato H, Kamada T, Hida K, Koyanagi I, Iwasaki Y, Miyasaka K, Abe H. Int J Rad Onc Biol Phys 33(2):323-8, 1995.
Spinal ependymomas - the value of postoperative radiotherapy for residual disease control. Sgouros S, Malluci CL, Jackowski A. Br. J. of Neurosurgery 10(6):559-66, 1996.
Practice Guidelines for Brain Tumors - Draft. Krawcczyk, J., Unpublished.
Patients with tumours of the pituitary gland require multi-disciplinary assessment and follow up. Evaluation should include consultation with an endocrinologist, neurosurgeon and neuro-ophthalmologist
Pituitary tumours can present through mass effects, hormone dysfunction or as an incidental finding on a CT or MRI scan. The mass effect can result in compression of the optic chiasm with visual field compromise. The tumour may produce an excess of hormones and result in acromegaly, Cushing's syndrome or hyperprolactinemia. The tumour may compromise pituitary function and result in panhypopituitarism and/or diabetes insipidus
Patients with acute headaches, nausea, vomiting, visual field deterioration or extra ocular muscle palsies require urgent surgical referral and assessment for pituitary apoplexy.
Growth Hormone Secreting Tumour: Somatotropinoma
These tumours produce gigantism in children and acromegaly in adults. The diagnosis is confirmed by endocrine tests in a patient with typical clinical features of acromegaly. The endocrine tests include measurement of growth hormone and insulin-like growth factor-1 (IGF-1). This is a protein produced by the liver in response to growth hormone stimulation. Elevated growth hormone concentration results in elevation of the IGF-1 concentration. IGF-1 has a much longer half-life than growth hormone and therefore provides an assessment of growth hormone secretion over time. Growth hormone has a very short half-life. It is measured in minutes. There is no place for random growth measurement in the diagnosis of acromegaly. To confirm the diagnosis of acromegaly a glucose tolerance test is done. IGF-1 is measured in the baseline sample and growth hormone is measured after glucose ingestion. IGF-1 must be elevated and the growth hormone does not suppress after glucose. In normal subjects the growth hormone should decrease to <1 ug/l.
The primary treatment of acromegaly is surgical removal of the tumour. This is usually successful in patients with a microadenoma (tumour <10mm) but the results in macroadenomas are disappointing with at least a 50% failure rate. After surgery it is important to reassess growth hormone and IGF-1 concentration to determine if surgical cure was achieved. If the patient has not been cured it is important to initiate the second line of treatment. Acromegaly increases the risk of colonic tumours, hypertension, diabetes, arthritis and cardiac disease and, as a result there is an increased death rate. Therefore, it is important to reduce growth hormone levels. The second line of treatment is octreotide (sandostatin). This is variant of somatostatin, a naturally occurring inhibitor of growth hormone release. Octreotide can be given by subcutaneous injection three times per day. However, now it is more common to use sandostatin LAR, a long-acting form, given by an intramuscular injection once per month. The goal of therapy is to normalize IGF-1 levels. The IGF-1 levels must be monitored throughout therapy. A new drug called Pegvisomant is also used to treat acromegaly, but is not yet available in Canada
Radiation therapy is the third line of treatment for persisting acromegaly. It is considered when sandostatin is not successful or results in side effects. It takes many years for radiation to lower growth hormone levels. Radiation may result in hypopituitarism; therefore, pituitary function should be monitored in the post-treatment interval at least on a yearly basis.
Prolactin Secreting Tumour: Prolactinoma
This is the most common hormonally active tumour. The presentation in women includes menstrual dysfunction, amenorrhea, galactorrhea, and infertility. In men hyperprolactinemia produces impaired libido, low testosterone and erectile dysfunction. In patients with prolactinomas the prolactin is usually >100 ug/L. A prolactin >300 ug/L almost invariably confirms the tumour is a macroadenoma. Non-functioning tumours of the pituitary may result in slightly elevated prolactin usually less than 100 ug/L. This is caused by impairment of hypothalamic transmission of dopamine to the pituitary. This is referred to as the stalk effect.
The primary treatment of prolactinomas is with a dopamine agonist. This results in a dramatic reduction of prolactin and tumour shrinkage in the majority of patients. If a patient presents with visual field impairment, a dopamine agonist may still be used as the primary therapy, but visual assessment is required on a weekly basis to document improvement. If visual fields do not improve in 2 weeks, surgical decompression should be considered.
Two dopamine agonist drugs are approved and available for the treatment of prolactinomas. The first, Bromocriptine, is given one to three times per day and has been used routinely since the early 1970. It is safe to use when fertility is desired and even through pregnancy when necessary. The newer dopamine agonist, cabergoline is long-acting and can be given once or twice per week. In some cases it is also more effective.
Bromocriptine often causes nausea, vertigo, and nasal stuffiness. If the medication cannot be tolerated orally it can be used as a vaginal suppository to reduce side effects. Another option is to switch ot cabergoline as it causes fewer side effects. The only disadvantage of cabergoline is the expense. Cabergoline appears to be safe in pregnancy, but because there is less data, Bromocriptine is still the drug of choice in pregnancy. A microadenoma can be cured surgically in the majority of patients and therefore this should be considered if bromocriptine and cabergoline cannot be tolerated. Patients must be advised not to stop the bromocriptine or cabergoline because the tumour can increase in size within days of stopping the medication. When pregnancy is contemplated, the patient should be assessed by an endocrinologist.
A repeat CT scan should be done 6-12 months after the start of bromocriptine to ensure that tumour size has decreased. Occasionally there is a discrepancy between prolactin response and tumour growth. A decrease prolactin does not guarantee tumour shrinkage.
ACTH Secreting Tumour: Corticotropinoma
ACTH producing pituitary tumours cause Cushing's syndrome. When this diagnosis is suspected referral to an endocrinologist is essential. Confirmation of the diagnosis requires extensive endocrine testing with suppression and stimulation tests and often petrosal sinus sampling for ACTH measurement.
Confirmation of pituitary dependent Cushing's syndrome is followed by transphenoidal exploration. Corticotropinomas are often small and may not be visualized on MRI imaging. The cure rate is 60-80% with transphenoidal surgery.
If surgery fails the two options left are bilateral adrenalectomy and pituitary radiation. Patients who have had a bilateral adrenalectomy must be followed by an endocrinologist to replace the adrenal hormones and for the possible development of Nelson's syndrome. This is the development of a pituitary tumour after adrenalectomy. It is a serious complication as the tumour can be locally invasive and may result in distant metastases. The ACTH level rises dramatically and patients often pigment. The tumour must be treated aggressively with surgery and radiation.
Clinically Non-Functioning Adenoma
These tumours are hormonally silent. They can result in mild hyperprolactinemia from the stalk phenomena. They may result in panhypopituitarism from tumour compression of the normal pituitary gland. These tumours are often large at the time of diagnosis. The lack of hormone production delays diagnosis. Diagnosis is suspected by development of mass effects or as an incidental finding on a CT or MRI scan. Surgery is the primary form of therapy and often radiotherapy is required post-operatively to prevent recurrence. If there is considerable tumour bulk after surgery or serial CT scanning shows an increase in the size of the residual tumour mass referral for radiotherapy is required. After surgery pituitary function should be reviewed by an endocrinologist to exclude hypopituitarism.
Many of these tumours secrete gonadotropins (LH, FSH, alpha-subunit). There is no specific clinical syndrome associated with gonadotropin producing tumours. Pituitary tumours that produce no hormones have been called null cell adenomas. Gonadotropin secreting adenomas and null cell adenomas are clinically indistinguishable, are treated the same and therefore are grouped together.
TSH Secreting Pituitary Tumours
TSH secreting tumours are very rare but should be suspected when a patient develops hyperthyroidism, but the TSH level is not markedly suppressed. The TSH level may be elevated, but is often in the normal range. This is, however, inappropriate because other forms of hyperthyroidism are characterized by marked TSH suppression. These tumours are often large at presentation and surgery is necessary. Radiation and/or sandostatin may be also required.
Meningiomas are graded using the WHO grading system. Most meningiomas are grade I with a low proliferative rate. Grade II or atypical meningiomas typically feature an elevated mitotic activity (>4 mitoses per 10 high power fields) whereas grade III or malignant meningiomas show very aggressive features with markedly increased mitotic activity (>20 mitoses per 10 HPF) and brain invasion (1).
Not infrequently, a meningioma may be an accidental radiologic finding on CT scan or MRI booked for various reasons. Where the disease is asymptomatic less than two cm in size and not associated with edema and particularly in patients who are more than 60 years old, observation may be a reasonable approach with annual clinical examination and CT scan. A majority of the other patients and patients who demonstrated radiologic and clinical progression of the tumour are treated surgically. Total excision is usually achieved in tumours located in the convexity dura, falx, lateral aspects of sphenoid wings, frontal base and cerebellar convexity. If pathology demonstrates WHO grade I meningioma after total excision, no further treatment is indicated and the patient should be continued on observation with yearly examination and CT scan. Local recurrence rate, however, varies from 8% to 20% over 10 years (2) and patient may require further re-excision with consideration of radiotherapy.
In other locations, gross total excision may not be possible (sagittal sinus, cerebellopontine angle, clivus, cerebral ventricles, tentorial notch, optic nerve sheath). Local recurrence rate for partially excised meningioma varies from 29% to 55% over 10 years (2), and postoperative radiotherapy always should be considered (it is available in the form of conventional/conformal or stereotactic radiotherapy). Local control rate after postoperative radiotherapy for meningioma is 87% over 15 years (3,4,5).
In case pathology demonstrated WHO grade II meningioma, postoperative radiotherapy should always be considered. Local control rate drops down to 54% for atypical meningiomas (3,4,5).
Malignant meningioma (12% of meningiomas) should be treated aggressively with surgery and postoperative radiotherapy. Investigations, apart from assessment of primary site, should include CXR and bone scan to rule out lung and bony metastasis. Prognosis for this group of patients is poor and five year specific survival is only 34%(6).
There is currently no standard systemic therapy for recurrent unresectable meningioma. Trials of chemotherapy, interferon, progesterone inhibitors, somatostatin analogs, and anti-VEGF therapy have not shown evidence of altering disease outcomes but have occasionally shown some alteration of disease progression (7).
Perry, A, Louis, DN, Scheithauer, BW, et al. Meningiomas. In: WHO Classification of Tumours of the Central Nervous System, Louis, DN, Ohgaki, H, Wiestler, OD, Cavenee, WK (Eds), IARC Press, Lyon 2007.
Mirimanoff R.O, et al: Meningioma: Analysis of Recurrence and Progression Following Neurosurgical Resection. J. Neurosurgery 62:18-24. 1985.
Glaholm J, Bloom H.J.G: The Role of Radiotherapy in the Management of Intracranial Meningiomas: The Royal Marsden Hospital Experience with 186 Patients. I.J.R.O.B.P. 18(9):755-761. 1990.
Condra K.S, et al: Benign Meningiomas: Primary Treatment Selection Affects Survival. I.J.R.O.B.P. 39(2):427-436. 1997.
Maire J.P, et al: Fractionated Radiation Therapy in the Treatment of Intracranial Meningiomas: Local Control, Functional Efficacy and Tolerance in 91 Patients. J.J.R.O.B.P. 33(2):315-321. 1995.
Milosevic M.F, et al: Radiotherapy for Atypical or Malignant Intracranial Meningiomas. I.J.R.O.B.P. 34(4):817-822. 1996.
Norden AD, Drappatz J, Wen PY. Advances in Meningioma Therapy. Curr Neurol Neurosci Rep 9:231, 2009.
Medulloblastomas or posterior fossa primitive neuroectodermal tumours are aggressive tumours characterized histologically by small dark cells with scanty cytoplasm. They constitute 20 – 25% of all pediatric brain tumours but are rare in adults. In the BCCA, only 22 cases were identified between 1978 & 1995(1). Because of their rarity, management has been mainly guided by knowledge derived from pediatric medulloblastomas.
Presentation & Investigations
With its posterior fossa location, symptoms of a medulloblastoma are those of increased intracranial pressure and those related to the cerebellar tracts and brainstem long tracts. Medulloblastomas are well known for their propensity for spread through the craniospinal axis. In the series from B.C., 5 out of the 13 patients who were worked up for craniospinal axis disease had positive CSF dissemination (1). Metastasis outside of the CNS is possible but rare at presentation. All patients diagnosed with medulloblastomas should have an MRI of the craniospinal axis +/- CSF cytology to rule out CSF dissemination.
Recent molecular diagnostic studies have elucidated several different prognostic subtypes of medulloblastoma. Most adult medulloblastomas are of an intermediate prognosis subtype showing upregulation of Sonic Hedgehog pathways (2). While testing for these molecular subtypes is not standard at this time, therapies targeting these pathways are being developed and may lead to subtype specific therapies.
Medulloblastomas are treated with surgical resection, followed by craniospinal radiation with or without chemotherapy.
An attempt should be made to excise as much as possible the gross tumour. Although data in adults are rare, pediatric series have consistently shown significantly better survival in patients with minimal postoperative disease compared to those with gross residual disease (3,4).
Because of the propensity of metastasis through the spinal axis, postoperative radiotherapy to the entire craniospinal axis is the standard treatment in patients with medulloblastomas. Hair loss and general fatigue are common during craniospinal radiation. In addition, patients may have hematological toxicity, particularly lymphopenia, during the 5 – 6 weeks of treatment. Their blood picture will be monitored and prophylactic antibiotics started as indicated.
The role of chemotherapy is not well defined for adult medulloblastomas. Whether chemotherapy can improve the cure rate after optimal surgery and craniospinal radiation is not clear because of the rarity of the disease. Nevertheless, chemotherapy is often given for high risk patients based on the results of adjuvant chemotherapy in the pediatric age group. Patients considered high risk for recurrence are those with gross residual disease and evidence of intracranial or spinal axis dissemination. This definition of high risk group is again an extrapolation from the pediatric literature (5). Many combination therapies have been tried with no superiority of one protocol over another. Commonly used agents include nitrosoureas, platinum-based agents, cyclophosphamide, etoposide and vincristine. The toxicity of these regimens in adults is not insignificant. If chemotherapy is given, it is usually started after surgery and radiation is completed.
Outcome of Treatment
Older series of adult medulloblastoma patients from the Royal Marsden Hospital (6) and the Princess Margaret Hospital (7) included about 50 patients each treated over a 30-year period from the 1950's to the 1980's. The 5-year survival is about 50 – 60% and 10-year survival is about 40%. More recently Padovani et al (8) studied 253 adults between 1975 and 2004 showing 5 and 10 year survivals of 72% and 55%, respectively. The 22 patients treated in BCCA from 1978 – 1995 did slightly better, with a 5 year disease specific survival of over 80%. Even among patients with proven spinal dissemination, only 1 out of 5 failed (1). The reason for this better outcome may just reflect the different time periods in which patients are treated.
After relapse, there is no standard of care for salvage therapy and outcomes are generally poor. Patients treated with high dose myeloablative regimens have not had a significant higher cure rate over less intensive protocols (9,10)
Kwan W, Agranovich A, Rheaume D et al: Adult medulloblastomas, the B.C. experience. Unpublished data, presented at the 8th Biennial Canadian Neuro-Oncology Meeting, Niagara-on-the-Lake. May 1998.
Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, group 3 and group 4 medulloblastomas. Acta Neuropathol 123:473, 2012.
Bourne JP, Geyer R, Berger M et al: The prognostic significance of post-operative residual contrast enhancement on CT scan in paediatric patients with medulloblastoma. J Neuro-Oncology 14: 263-270, 1992.
Jenkin D, Goddard K, Armstrong D, et al: Posterior fossa medulloblastoma in childhood: Treatment results and a proposal for a new staging system. Int J Radiation Oncology Biol Phys 19: 265-274, 1990.
Chang CH, Housepain EM, Herbert C. Radiology 93:1351, 1969.
Bloom HJG, Bessell EM: Medulloblastoma in adults: a review of 47 patients treated between 1952 and 1981. Int J Radiation Oncology Biol Phys 18: 763-772, 1990.
Frost PJ, Laperriere NJ, Wong CS et al: Medulloblastoma in adults. Int J Radiation Oncology Biol Phys 32: 951-957, 1995.
Padovani L, Sunyach MP, Perol D, et al. Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 68(2):433-40, 2007.
Massomino M, Gandola L, Spreafico F, et al. No salvage using high dose chemotherapy plus/minus re-irradiation for relapsing previously irradiated medulloblastoma. Int J Radiat Oncol Biol Phys 73:1358-63, 2009.
Gajjar A, Pizer B. Role of high dose chemotherapy for recurrent medulloblastoma and other CNS primitive neuroectodermal tumors. Pediatr Blood Cancer 54:649-51, 2010.
Tumours of the pineal region are rare, comprising about 1% of intracranial lesions. The majority of these are germinomas in young patients. Other tumour types, arising from the parenchyma, include pineocytoma, pineoblastoma and astrocytoma.
The biologic behaviour of pineocytomas is not well known because of small patient numbers and variable behaviour. Those demonstrating neuronal differentiation have a more favorable prognosis(1). Surgery and observation may be feasible with radiation reserved for progression or recurrence. Tumours that do not show neuronal differentiation or are incompletely resected may benefit from adjuvant focal RT but evidence is limited (2).
Pineoblastomas are primitive neuroectodermal tumours (PNET). They tend to disseminate within the craniospinal axis, therefore, a staging MRI of the spine should be performed. Radiotherapy involves craniospinal radiation along with a boost to the primary. There may be a role for chemotherapy in selected patients (3).
Astrocytic tumours of the pineal are treated like astrocytomas at other intracranial sites. (see low grade astrocytoma and malignant astrocytoma.)
1. Jouvet A, Saint-Pierre G, Fauchon F, et al. Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases. Brain Pathol 2000; 10:49.
2. J, Ramiro J, Martínez R, et al. Clinicopathological experience with pineocytomas: report of five surgically treated cases. Neurosurgery 1990; 27:612.
3. Reddy AT, Janss AJ, Phillips PC, et al. Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 2000; 88:2189.
Revised: June 2014
1. Pineal Region Germ Cell Tumours
Tumours of all types of germ cell origin may arise in the pineal region: germinoma, embryonal carcinoma, dermal sinus tumour, choriocarcinoma, teratoma. It may be possible to make a clinical diagnosis of pineal germ cell tumour in the absence of histology from biopsy: pineal mass in a young patient, usually male, with elevation of serum or CSF tumour markers (AFP + / - HCG).
Because of a high propensity for dissemination within the CSF, MRI staging of the whole of the craniospinal axis is important prior to treatment.
Germinomas are exquisitely radiosensitive. Craniospinal radiation is required for disseminated disease. For localized germinoma, whole ventricular radiation (21-24 Gy) with a boost to the tumour site (40-45 Gy) is recommended (1). The addition of chemotherapy in localized germinoma has not reliably led to a reduction in RT does or volume and should be considered as part of randomized trials.
Non-germinomatous germ cell tumours (NGGCT) are less radiosensitive than pure germinoma. Craniospinal irradiation is recommended for disseminated disease and is controversial with localized NGGCT. Because most radiotherapy regimens are associated with a high failure rate, platinum containing chemotherapy regimens are often used prior to radiotherapy. There are current studies designed to look at reducing CSI fields and doses in patients that achieve a complete response to neoadjuvant chemotherapy.
1. Haas-Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys 2003; 56:511.
Craniopharyngiomas are histologically benign tumours arising in the sellar and suprasellar regions from embryonic squamous cell rests of the pharyngeal-hypophyseal duct. Investigations show a cystic, solid or mixed mass lesion associated typically with calcification.
These lesions are slow growing and may be large by the time they present with endocrine dysfunction (80 - 90%), visual problems or signs of raised intracranial pressure.
The optimum management for these tumours is controversial. Initial surgical resection and cyst decompression is almost always attempted. Management strategies may include radical surgery alone for small lesions, subtotal resection followed by planned post-operative radiotherapy or primary radiation therapy alone. There is evidence to show that subtotal resection and planned post-operative radiotherapy may have less associated morbidity than aggressive surgical intervention (1)and an improved chance of local control (2).
Sanford RA. Craniopharyngioma: results of survey of the American Society of Pediatric Neurosurgery. Pediatric Neurosurgery. 21 Suppl 1:39-43, 1994.
Hetelekidis S. Barnes PD. Tao ML. Fischer EG. Schneider L. Scott RM. Tarbell NJ. 20-year experience in childhood craniopharyngioma. International Journal of Radiation Oncology, Biology, Physics. 27(2):189-95, 1993 Sep 30.
Chordomas are slow-growing tumours arising from the notochord that forms the early embryonal axial skeleton. The vast majority arises from the spheno-occipital area (35%) and from the sacrococcygeal region (50%) (1). Local invasion is the predominant mode of tumour extension; metastasis occurs infrequently and usually is associated with the late stages of tumour evolution.
Due to its locally aggressive nature, complete surgical removal is usually not amenable. Nonetheless, the best local control results published consist of partial resections with advanced skull base surgical techniques followed by proton beam irradiation (2). The latter enables a high dose of radiation deposited in the tumour while minimizing irradiation of adjacent normal critical structures. During follow-up, most will not show any significant decrease in the size of the tumour volume. The tumour is considered controlled if there is no progression on clinical and radiologic grounds.
Heffelfinger M, Dahlin D, MacCarty C, et al: Chordomas and cartilaginous tumors at the skull base. Cancer 32:410-420, 1973
Munzenrider J, Liebsch N, Efird J : Chordoma and chondrosarcoma of skull base: treatment with fractionated x-ray and proton radiotherapy. Head and Neck Cancer, Volume 3:649-654, 1993.
In both intracranial and spinal locations these tumours have a propensity for the sensory roots. The most common intracranial schwannoma is the acoustic neuroma followed by trigeminal neuroma. In the spinal region the lumbar followed by thoracic and cervical regions are most frequently involved. The usual goal of treatment for these tumours is complete surgical excision. Malignant degeneration does occur, most frequently arising de novo from a peripheral nerve.
Stereotactic radiation therapy (SRT) may be useful in patients with acoustic neuroma who decline surgery or who are medically inoperable, or in those with bilateral tumours or tumours in the only hearing ear, since surgery may be associated with a relatively high risk of loss of functional hearing. Single fraction SRT has been shown to lead to high rates of control, defined by tumour stabilization or shrinkage, with good prospects for hearing preservation (1-3). There is no evidence that Gamma Knife SRT is in any way superior to linear-accelerator based SRT. Studies have suggested that fractionated SRT may lead to even better hearing preservation in patients who have functional hearing to start with (4,5). One long term single institution series comparing fractionated stereotactic radiotherapy versus single fraction stereotactic radiosurgery showed similar 5 and 10 year survival rates of 96% in both groups (6). Single fraction doses over 13 Gy were associated with higher rates of hearing loss compares to fractionated treatment or lower dose single fractions.
Flickinger JC, Lunsford LD, Linskey ME, Duma CM, Kondziolka D. Gamma knife radiosurgery for acoustic tumors: Multivariate analysis of four year results. Radiother Oncol 1993;27(2):91-98.
Noren G, Greitz D, Hirsch A, Lax I. Gamma knife surgery in acoustic tumours. Acta Neurochir - Supp 1993;58:104-107.
Mendenhall WM, Friedman WA, Buatti JM, Bova FJ. Preliminary results of linear accelerator radiosurgery for acoustic schwannomas. J Neurosurg 1996;85(6):1013-1019.
Varlotto JM, Shrieve DC, Alexander E, et al. Fractionated stereotactic radiotherapy for the treatment of acoustic neuromas: Preliminary results. Int J Radiat Oncol Biol Phys 1996;36(1):141-145.
Andrews DW, Silverman CL, Glass J et al. Preservation of cranial nerve function after treatment of acoustic neurinomas with fractionated stereotactic radiotherapy: Preliminary observations in 26 patients. Stereotactic Function Neurosurg 1995;64(4):165-82.
Combs SE, Welzel T, Shulz-Ertner D, et al. Differences in clinical results after LINAC-based single dose radiosurgery versus fractionated stereotactic radiotherapy for patients with vestibular schwannomas. In J Radiat Biol Phys 2010;76:193
These are neoplasms composed of neoplastic neuronal cells, a gangliocytoma, or a combination of neoplastic neurons and neoplastic glial cells, a ganglioglioma. At times a low-grade glial neoplasm with trapped, but non-neoplastic neurons, is mistaken for a ganglioglioma. These tumours are more common in children and young adults with a predilection for the temporal lobes. As such seizures are a common presentation. Imaging studies reveal these lesions to be cystic and often large and densely enhancing. Due to this latter feature, they can be mistaken for more malignant tumours when seen on CT or MRI scans.
These tumours are very slow-growing. Surgical resection is usually highly successful at complete or near-complete removal and thus succeeds at symptomatic improvement or symptom control. As these lesions are very slow growing, surgery is often the only intervention required. Malignant transformation is rare, and has been only reported from the glial elements of a ganglioglioma.
Central neurocytomas are discrete intraventricular tumours, typically found in the region of the septum pellucidum. Their histologic appearance mimics that of an oligodendroglioma, but the location of the tumour and the presence of neuronal markers confirms the diagnosis. These tumours can usually be aggressively resected which is felt to be curative. Even with subtotal removal, the slow growth of the tumour still portends a very good prognosis.
Choroid plexus papillomas and carcinomas are rare tumours. Given their location they will often cause hydrocephalus. Imaging studies will reveal a densely enhancing mass. Papillomas can often be completely removed surgically which equates with cure and can preclude the need of a shunt. Carcinomas are predictably more invasive and thus less amenable to surgical resection. Nonetheless, gross total resection has been associated with increased survival. They require evaluation of the craniospinal axis for CSF seeding and adjuvant radiation therapy. Adjuvant chemotherapy is often used in young children < age 3 but its use in older individuals is not standardized. One should bear in mind that the choroid plexus can be a site for metastatic deposits, as well as the site of origin for glial tumours and meningiomas.
The most common CNS tumours of vascular origin are hemangioblastomas and hemangiopericytomas. Other, more rare tumours, include hemangioendothelioma and angiosarcoma.
Hemangioblastomas represent the most common primary intra-axial tumour in the posterior fossa in the adult. They can, however, be found virtually anywhere in the CNS as well as elsewhere in the body. Hemangioblastomas can occur sporadically or, in 20% of cases, in association with Von Hippel Lindau syndrome. The latter is an autosomal dominant, multiple organ neoplastic syndrome with high penetrance. In addition to the CNS hemangioblastomas, patients can also harbour retinal angiomas, renal cell carcinoma, cysts of abdominal organs and suffer from polycythemia. Classically the cerebellar lesions are seen as cystic masses with an enhancing nodule. However solid tumour masses are also seen. Predictably the tumour is highly vascular and is histologically benign. As such ideal treatment is surgical resection. The resection may be rendered more facile by pre-operative embolization of the tumour. The tumours can be multiple, asymptomatic and/or reside within eloquent regions of the brain. For any or all of these reasons surgical resection may not be feasible. In this instance radiation therapy can be considered. There are variable reports of success using stereotactic radiosurgery as a means of treatment. At the present time its role is not clear, but remains a potential alternative.
Hemangiopericytomas are mesenchymal tumours arising from the meninges. Originally classified as angioblastic meningiomas, they are now recognized as a meningeal form of solitary fibrous tumour. They are considered highly aggressive, if not malignant neoplasms, which distinguishes them from the mostly benign meningiomas. They present clinically, and are seen on imaging studies, very much like meningiomas. Primary treatment is an attempt at complete surgical resection. Surgery is often hampered by the vascular nature of the tumour and its propensity to bleed. Because of this, pre-operative angiography and embolization is ideal. Tumour recurrence and progression of residual tumour is common. Metastases have also frequently been recorded. Subtotal removal generally mandates a course of post-operative radiation therapy. Stereotactic radiosurgery has been used with success, but its definitive role is yet to be determined.
Spinal tumours are divided into three general categories: (1) extradural, (2) intradural-extramedullary and (3) intradural-intramedullary (a true spinal cord tumour).
1) Extradural spinal tumours
These include metastatic lesions and primary bone tumours such as chordomas, osteomas, osteoblastomas, sarcomas, vertebral hemangiomas, and plasmacytoma/multiple myeloma and lymphomas.
The most common metastatic neoplasms to the spine include lymphoma, lung, breast and prostate cancer. Patients may present with localized spinal pain, which can progress to devastating neurologic deficits as the tumour advances to compress neural elements. Early diagnosis is thus paramount to minimizing often irreversible complications. Acute spinal cord compression is a medical emergency requiring urgent intervention. In general, the more severe the neurologic deficits (e.g. paralysis, loss of sphincter control) and the longer the duration of symptoms, the less likely the chances for recovery. For most patients with known primary cancer with clinical and imaging studies consistent with metastatic spinal disease, urgent radiation therapy is the primary treatment of choice. Surgical intervention is required in many instances, which include (1) spinal instability with or without neural compression, (2) failure to respond to radiation therapy (i.e. progression of neurologic deficits or persistent debilitating pain) or (3) unclear diagnosis requiring tissue sampling. Modern spinal surgical techniques can provide durable stability, local tumour control, resolution of severe pain and stabilization or improvement of neurologic deficits. A randomized clinical trial looking at modern surgical techniques and radiotherapy showed superior outcomes to radiation alone (1). As such, management requires a combined effort from the radiation oncologist and spinal surgeon.
2) Intradural-extramedullary tumours
Meningiomas and nerve sheath tumours constitute the majority of these lesions. These tumours can also extend outside the dural sleeve. Surgical resection remains the primary means of cure for these benign tumours. Radiation therapy is generally reserved for rare malignant cases or incomplete removals. Occasionally, seeding within the spinal subarachnoid space may take place from distal primary cerebral tumours, e.g. medulloblastomas, ependymomas, or lymphomas and metastatic carcinomas. These lesions are typically treated with spinal axis radiation. Intrathecal or systemic chemotherapy may also play a role.
3) Intramedullary tumours
The majority of true spinal cord tumours are astrocytomas or ependymomas. Other neoplastic lesions include hemangioblastomas, metastases, and frankly malignant astrocytomas. Ependymomas are generally amenable to surgical resection, often complete and curative. Astrocytomas tend to be less well marginated from normal spinal cord tissue, making complete removal difficult. Radiation therapy is generally accepted as the primary adjuvant to incomplete surgical removal of a spinal cord tumour.
1. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643.
Revised: June 2014
Cerebral metastasis is the most common malignancy affecting the brain. The 3 most common sites of the primary tumour are the lung, breast and gastrointestinal tract. Seventy percent of the patients with cerebral metastasis have 1 or 2 lesions and 80% are located in the cerebral hemispheres (1).
Patients with good a neurologic function, a long disease free interval between the diagnosis of the primary tumour and development of the metastases, and lack of progressive systemic disease, tend to have the best prognosis. Therefore, the management of patients with cerebral metastases depends on following factors: the performance status of the patient, the status of the systemic disease, and the number of cerebral lesions.
For patients with progressive systemic disease and/or poor performance status, palliative WBRT or supportive management with dexamethasone alone is considered the most appropriate treatment. On the other hand, patients with solitary brain metastasis, who otherwise have no or stable systemic disease and a good performance status, should be considered for palliative surgical resection prior to whole brain radiotherapy (WBRT). Surgery followed by WBRT has shown to significantly improve both the survival time and the quality of life of patients in this category, when compared to treatment with WBRT alone (2).
Stereotactic Radiosurgery (SRS) followed by whole brain therapy has been investigated in randomized trials (3,4). The largest of these, RTOG 9508, showed that in patients with single metastasis, survival and disease control was improved with SRS + WBRT over WBRT alone (3). For patients with 2-3 metastases, local control was improved with SRS but overall survival was not improved. A smaller clinical trial in patients with 1-4 metastases comparing SRS alone vs SRS + WBRT did not show improvement in survival but better local control with combined SRS and WBRT(5). This trial also showed MMSE scores declined more rapidly in the SRS group. A conflicting randomized study suggested that combined WBRT +SRS had inferior neuro-cognitive outcomes compared to SRS alone but it is uncertain if this has significant impact on functional outcomes compared to the high risk of brain recurrence (6). Currently it is reasonable to consider using a radiosurgery boost in addition to WBRT as initial treatment for patients with the following circumstances: 1) inoperable solitary brain metastasis, 2) up to 3 cerebral lesions, provided that the performance status is good and there is no progressive systemic disease. It may also be useful in the palliation of recurrent cerebral metastases following WBRT in carefully selected cases which there are no more than 3 lesions, performance status is good and there is no progressive systemic disease. Whether SRS or even surgery alone are reasonable first options with WBRT deferred to relapse remains controversial.
Delattre JY, Krol G, Thaler HT, et al. Distribution of brain metastases. Arch Neurol 45:741-744,1988
Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494-500,1990.
Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363:1665-1672, 2004.
Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427-434, 1999.
Aoyama H, Shirato H, Tago M, et al. Stereotactic Radiosurgery plus whole brain therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483-91, 2006.
Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomized controlled trial. Lancet Oncol 2009;10:1037-1044
There is currently no standard approach to recurrent primary brain tumours. Treatment approaches will depend upon tumour histology, tumour location, prior therapy, patient's age and performance status, as well as patient and physician preference. Although a wide number of therapeutic options are available, some more commonly used and potentially beneficial treatments will be covered below for the more common adult CNS malignancies.
Primary brain tumours rarely develop systemic metastases. Occasionally, PNET’s can spread to bone or bone marrow and be detected on bone scan or bone marrow aspirate. More commonly, CNS tumours may spread within the neuraxis along the leptomeninges and into distant intra-parenchymal sites. Again this is most common among PNET’s but has been seen infrequently with ependymoma, malignant gliomas and pineal region tumours. Unfortunately, CSF seeding portends a poor prognosis and treatment is often limited to palliative radiotherapy to symptomatic sites. Chemotherapy may be beneficial in some patients with PNET and germ cell tumours but responses are rarely durable.
Average survival after recurrence of a malignant astrocytoma is brief (4-5 months for Grade IV astrocytomas). All therapeutic options remain palliative and must take into account patient’s quality of life. The following treatment modalities should be considered:
Finally, since treatment is less than ideal and responses are brief, these patients should be considered for experimental trials especially of novel anti-neoplastic agents.
Bernstein M, Laperriere N, Glen J, et al. Brachytherapy for recurrent malignant astrocytoma. Int J Radiat Oncol Biol Phys 30:1213-1217, 1994.
Young B, Oldfield EH, Markesberg WR, et al. Re-operation for glioblastoma. J Neurosurg 55:917-921, 1981.
Wilson CB, Gutin PH, Boldrey EB, et al. Single agent chemotherapy of brain tumours: a 5-year review. Arch Neurol 33:739-744, 1976.
Revised: Feb. 2004
Recurrence of low grade astrocytomas often heralds a change in malignant potential in most cases. Care must be taken to differentiate recurrence from treatment related effects on neuroimaging. Re-resection or biopsy may take on a higher priority in these patients. Otherwise the treatment options are largely similar to those of malignant astrocytomas, although responses may be more durable.
Revised: Feb. 2004
Unlike most astrocytomas, these tumours have a higher response rate to chemotherapy. Work by Cairncross et al (1) has suggested upwards of 70% of anaplastic oligodendrogliomas will respond to chemotherapy and the responses are often quite durable. Even low grade oligodendrogliomas seem to respond to chemotherapy. For this reason, studies are underway looking at adjuvant chemotherapy in this population. For recurrent disease, the most beneficial regimen in chemotherapy-naive patients is PCV combination (CCNU, procarbazine, vincristine). For patients who previously have received PCV chemotherapy, it appears combinations of platinum and etoposide have some activity (2). Surgical and radiation options remain unchanged for anaplastic tumours.
Low grade oligodendrogliomas may be treated up front with surgery alone, surgery with radiotherapy or surgery and PCV chemotherapy. Treatment at time of recurrence of these tumours will depend on prior therapy. Again, surgery should be strongly considered for late recurrences as differentiating from prior treatment effects and re-evaluating histology may be important
For all grades of histology of oligodendrogliomas and mixed oligoastrocytomas, there is interest in trials of new or alternative chemotherapy agents. Certainly patients who have failed after PCV chemotherapy should be considered for such trials.
Cairncross G, MacDonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12(10):2013-2021, 1994.
Peterson K, Paleologos N, Forsyth P, et al. Salvage chemotherapy for oligodendroglioma. J Neurosurg 85:597-601, 1996Peterson K, Paleologos N, Forsyth P, et al. Salvage chemotherapy for oligodendroglioma. J Neurosurg 85:597-601, 1996.
Revised Feb. 04
Recurrent meningiomas often can be managed with re-resection. Post-resection treatment usually consists of radiotherapy in those who have not received such treatment previously. Chemotherapy and hormonal therapy of these tumours has met with little success and is not currently recommended outside of experimental trials.
Ependymoma, primitive neuroectodermal tumours (PNET), germ cell tumours and other pineal region tumours are uncommon in the adult. Other uncommon adult tumours include gangliogliomas, pleomorphic xanthoastrocytoma, brainstem gliomas and pilocytic astrocytomas. Given the rarity of these tumours, there is no standard treatment for recurrences and patients must be considered on an individual basis. Certainly, low grade tumours such as gangliogliomas and pilocytic astrocytomas are often best managed with re-resection. Some tumours, especially PNET and germ cell tumours, can respond to chemotherapy. Discussion amongst an interdisciplinary CNS tumour group is recommended for many of these patients.
When progressive incurable disease has developed, the treatment approach is individualized to optimize quality of life, through the participation of a variety of disciplines, ideally in the form of a team. The task of approaching palliative care needs may be especially challenging in the neuro-oncology patient. From the medical standpoint, in appropriate circumstances, symptoms may be palliated by surgical measures, and occasionally, by further radiation therapy or chemotherapy. Systemic steroids may be extremely useful; the dose should be titrated to maximize therapeutic effect and minimize steroid-related toxicity. Other medications, such as analgesics for headache and antiemetics for nausea and vomiting, may also be helpful. As for other disciplines, in the palliative phase, occupational therapy and physiotherapy are often just as useful as they are earlier in the disease continuum, as much as possible to preserve mobility and function. In this phase, pastoral care, counseling and other support services may be particularly important to assist patients and family cope with financial stresses, anticipatory grief, planning, and other issues.
Almost always, palliative care is most effective when given in a well co-ordinated fashion close to the home of the patient. Information on palliative care and hospice programs available throughout British Columbia may be found in the British Columbia Hospice/Palliative Care Association Resource Directory, which is available at the BCCA Library and hospitals throughout the Province, and may be ordered by contacting:
The British Columbia Hospice/Palliative Care Association1060 West 8th AvenueVancouver, BC V6H 1C4
Phone (604) 734-1661
In addition, further advice on symptom control and other palliative measures may be obtained by referral to Pain and Symptom Management Clinics at the Vancouver and Vancouver Island Cancer Centres, and the Cancer Centre of the Southern Interior; a similar Clinic is planned at the Fraser Valley Cancer Centre. Such referral can be initiated with the assistance of the attending BCCA oncologist
There is currently no standard approach to recurrent primary brain tumours. Treatment approaches will depend upon tumour histology, tumour location, prior therapy, patient's age and performance status, as well as patient and physician preference. Although a wide number of therapeutic options are available, some more commonly used and potentially beneficial treatments will be covered below for the more common adult CNS malignancies.
Primary brain tumours rarely develop systemic metastases. Occasionally, PNET's can spread to bone or bone marrow and be detected on bone scan or bone marrow aspirate. More commonly, CNS tumours may spread within the neuraxis along the leptomeninges and into distant intra-parenchymal sites. Again this is most common among PNET's but has been seen infrequently with ependymoma, malignant gliomas and pineal region tumours. Unfortunately, CSF seeding portends a poor prognosis and treatment is often limited to palliative radiotherapy to symptomatic sites. Chemotherapy may be beneficial in some patients with PNET and germ cell tumours but responses are rarely durable.
Patients with primary brain tumours generally should have ongoing care from their oncologist as well as their family physician. The patient’s neuro-surgeon or neurologist may share the follow-up with the oncologist. If the patient appears to have rehabilitation needs post treatment, the oncologist will refer the patient to either the rehabilitation counsellor or to a community resource that can address these needs. An appointment should be arranged for 4 to 6 weeks after the last treatment.
The oncologist will review the patient by clinical evaluation and imaging studies at regular intervals to monitor the response of the tumour to treatments and check for recurrence of the cancer. The Oncologist also will check for side effects of radiation or drugs used treatment. This may involve tests of brain function, quality of life assessment or blood tests.
The family doctor plays an important role in the day-to day care of the patient within their community. The family doctor monitors the patient’s general condition in addition to checking anti-convulsant levels and maintains those prescriptions as well as prescribes other medications that may be required for symptom relief or for other medical problems. The family doctor is often involved with the Home care Nursing team in the community to provide better at home management. The Home care team may help to coordinate the Community resources that may be required to maintain an incapacitated individual within the home setting for as long as possible (e.g. physiotherapy, occupational therapy speech therapy, hospice).
CT (or MRI) at 3-4 months post-treatment as a baseline, then at appropriate intervals, usually when patients become symptomatic or recurrence is suspected.
If initial examination is equivocal repeat CT or MRI in 6 weeks.
CT without and with contrast every 6 months x 2 years; every year thereafter.
MRI with Gd-DTPA every 6 months x 2 years; every year thereafter.
PNET, pineocytoma (pure), pineoblastoma, embryonal cell, endodermal sinus, choriocarcinoma, malignant germ cell; germinoma, astrocytoma, pineocytoma (astro/neuronal)
MRI with Gd-DTPA every 4 months x 2 years; as clinically indicated thereafter.
MRI with contrast of the primary site
Revised: Feb. 2004
1) Vertebral Body and Epidural Metastases
As clinically indicated.
2) Intradural Extramedullary
MRI every year or as clinically indicated.
MRI with Gd-DTPA.
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