Clinical Guidelines For The Management of Neuro-Oncology

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Neuro-oncology Clinical Guidelines
Clinical Guidelines for the Management of Neuro-Oncology
For approvals and version control see Document Management Record on page 37
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Background and Scope.....................................................................................................4 Management of Brain Tumours in Primary and Secondary Care .....................................4 2.1 Imaging.....................................................................................................................4 2.2 Other investigations ..................................................................................................4 2.3 Treatment .................................................................................................................4 2.4 Steroids ....................................................................................................................4 2.5 Proton pump inhibitors..............................................................................................5 2.6 Analgesia..................................................................................................................5 2.7 Anti-epileptics ...........................................................................................................5 3 Surgical Management of High Grade Glioma ...................................................................7 3.1 No surgical intervention ............................................................................................7 3.2 Biopsy.......................................................................................................................7 3.3 De-bulking surgery ...................................................................................................7 3.4 Surgery for recurrence..............................................................................................8 3.5 Surgery for other situations ......................................................................................8 3.6 Post-operative considerations ..................................................................................8 4 Surgical Management of Low Grade Glioma ..................................................................10 4.1 Image Guided Biopsy .............................................................................................10 4.2 Tumour resection....................................................................................................10 5 Surgical Management of Meningioma.............................................................................11 5.1 Surgical Principles ..................................................................................................12 5.2 Pathology................................................................................................................12 5.3 Surgical Follow-up Protocol ....................................................................................12 6 Oncological Management of Brain Tumours...................................................................13 6.1 Radiotherapy Planning ...........................................................................................13 6.2 High Grade Gliomas ...............................................................................................13 6.3 Chemotherapy for High Grade Glioma ...................................................................16 6.4 Low Grade Gliomas ................................................................................................18 6.5 Glioma Re-treatment ..............................................................................................19 6.6 Meningioma ............................................................................................................19 7 Metastases......................................................................................................................22 7.1 Treatment Policy.....................................................................................................22 7.2 Palliative care .........................................................................................................22 7.3 Surgery ...................................................................................................................22 7.4 Stereotactic radiotherapy / radiosurgery.................................................................22 7.5 Whole brain radiotherapy .......................................................................................22 7.6 Chemotherapy (small cell lung cancer) ..................................................................22 8 Rare Tumours .................................................................................................................24 8.1 Neurocytoma ..........................................................................................................24 8.2 Germinoma / Medulloblastoma...............................................................................24 8.3 Ependymoma (Intra-Cranial) ..................................................................................26 8.4 Supratentorial ependymoma: .................................................................................27 8.5 Vestibular Schwannoma / Acoustic Neuroma.........................................................27 8.6 Neurofibromatosis Type 2 ......................................................................................28 8.7 Glomus Tumours ....................................................................................................30 8.8 Skull Base Tumours (Chordoma / Chondrosarcoma).............................................31 8.9 Intrinsic Spinal Cord Tumours ................................................................................32 8.10 Cerebral Lymphoma ...............................................................................................33 8.11 Spinal and Intracranial Sarcomas...........................................................................33 8.12 Leptomeningeal Carcinomatosis ............................................................................34 8.13 Therapy Target Rationale .......................................................................................34 9 Pathology Guidelines ......................................................................................................36 10 Evidence of Agreement ..............................................................................................37 11 Appendices.................................................................................................................38 11.1 References .............................................................................................................38
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11.2 11.3 11.4 11.5 11.6 11.7 11.8
Imaging Recommendations for Referring Clinicians...............................................41 Leptomeningeal Carcinomatosis Diagram..............................................................42 Performance Status & Glasgow Coma Scale (GCS)..............................................43 Assessment of Vestibular Schwannoma Patients ..................................................44 WHO tumour classification: ....................................................................................44 Clinical Trials Portfolio ............................................................................................45 National Guidelines ................................................................................................46
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1 Background and Scope

These protocols represent the treatment policy for neuro-oncology and are intended as guidance to those working within the Anglia Cancer Network. While very effort has been made to ensure that the guidelines are accurate and unambiguous it must be emphasised that constant modifications will be necessary. These protocols should only be used to give an indication of current management. We do not guarantee the accuracy of these protocols and do not accept any liability if they are used outside of the Anglia Cancer Network.
2 Management of Brain Tumours in Primary and Secondary
Care
The following guidelines should help referring teams to decide what investigations and treatments are appropriate in these patients. Please note that once the investigations have been completed these patients can usually go home. 2.1 Imaging All patients with a suspected primary brain tumour must have an MRI scan that as a minimum includes T1, T2 and T1 with gadolinium. DWI imaging should also be undertaken locally to reduce the risk of missing abscesses. Where feasible, referring hospitals to undertake T1-weighted MRI scans with contrast with 1mm slice thickness without gaps (as per above recommendations) to help neurosurgical planning. This will reduce delays in patients pathways and duplicate scans. All patients with metastases where a Neuroscience SMDT opinion is to be sought must have an MRI scan that as a minimum includes T1, T2 and T1 with gadolinium prior to radiotherapy. All patients with a suspicion of metastatic brain tumours must have a CXR or a CT of the chest abdomen and pelvis. All patients with confirmed metastatic brain tumour must have a CT of the chest abdomen and pelvis. Patients with known primary disease should be restaged. Please see the Imaging Recommendations for Referring Hospitals in Appendix D. 2.2 Other investigations All patients must have fbc, u&e, clotting. Patients with suspected metastases must have relevant tumour markers and calcium. 2.3 Treatment Except with suspected Lymphoma all patients should have dexamethasone 8mgs bd, plus a proton pump inhibitor. Stop Asprin and Clopidogrel (no surgery for ten days after even a single dose of either). 2.4 Steroids Dexamethasone rapidly resolves symptoms, improves appetite and is an antiemetic. It reduces raised ICP by minimising surrounding oedema. Dexamethasone has a half- life of two days and therefore takes days to build up to a steady level. It disturbs sleep if given late in the day. The recommended dose is 8mgs bd. Dexamethasone given for more than 2-3 weeks will suppress adrenal function and therefore needs to be weaned carefully in this group of patients. In general the dexamethasone dose should be the minimum required to control symptoms.
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Try to avoid dexamethasone pre-op in patients with suspected lymphoma. For cases where the patient is rapidly deteriorating, low dose dexamethasone may be given, but this should be discussed with a neurosurgeon first. 2.5 Proton pump inhibitors A proton pump inhibitor such as Omeprazole should be given to protect the stomach lining whilst taking steroids. In some instances, oral thrush may become apparent. Nystatin 1ml QDS or a course of Fluconazole may then be indicated as a form of treatment. 2.6 Analgesia Paracetamol is safe and effective either alone or in combination. Codeine has been used in Neurosurgery because it is said to be less sedative than the other opiods. However this is not proven and Tramadol or Morphine are acceptable alternatives. Non steroidal antiinflammatory drugs are effective analgesics and widely used in these patients. Some surgeons are concerned about there effect on blood clotting and wound healing. In combination with steroids there is a significant risk of gastric ulceration. 2.7 Anti-epileptics Many patients with intracerebral tumours develop epilepsy and have either major seizures or, more frequently, focal attacks. A change in seizure character may indicate a transformation of an existing tumour. Routine prophylactic use of anticonvulsants is unproven but it is not unreasonable to start therapy after a single seizure given the patient has a structural abnormality and is likely to have a continuing liability to epilepsy. Carbamazepine as a Retard preparation is probably the best initial drug and the dose should be adjusted until the blood level is within the therapeutic range. The starting dose is 100 mg bd, increasing after two weeks to 200 mg bd after which the blood level should be estimated and the dose adjusted if necessary. If poorly tolerated then Lamotrigine and Sodium Valproate are alternatives though it should be noted that blood Valproate levels are of limited clinical value. If compliance is a problem then Phenytoin is a suitable alternative as it can be taken once daily. The starting dose is 200 mg per day and once again, blood levels should be estimated after seven to ten days. If seizures continue despite taking a first-line anticonvulsant, Levetiracetam 250 mg bd can be added to the regime, increasing according to response and tolerance with a maximum dose of 1.5 g bd.
Type of seizure Location Freqency Focal Infrequent
Recommendation
Levetiracetam 250mg o.d and increase after 1-2 weeks to 250mg b.d* or \\195.104.155.28\data\Cancer Network\Tumour Site\Brain & 5 of 46 days Sodium Valproate Chrono 300mg bd then increase by 200mgPage every 3-4 CNS\Guidelines\Current\AngCN_SSG_BC3_v2_NeuroOncology_Guidlines.doc according to tolerance and response** Approved and Published: Nov 2011 or Lamotrigine 25mg o.d for 14 days then increase to 50mg o.d*
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Epilepsy due to tumours is focal epilepsy. Some anti-epileptic drugs require slow dose titration and are not appropriate in the acute situation. Some tumour patients present acutely with severe seizure clusters or status epilepticus. For these patients, the first consideration is to control their seizures. Special consideration may be needed because of the interaction of anti-epileptic drugs with chemotherapeutic agents which are metabolised through the liver. This is a particular problem with older anti-epileptic drugs and may impact on the effectiveness of chemotherapy. then follow BNF guidelines **Usual maintenance dose 1-2g per day
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3 Surgical Management of High Grade Glioma

3.1 No surgical intervention This is appropriate in the following groups: Poor pre-morbid levels of function. Significant residual cognitive dysfunction following treatment with steroids. Co-morbidities that makes surgery too dangerous. Patient choice. There is no age cut off but older patients have more co-morbidities and less cerebral reserve. Outcome is worse in older age groups as they derive less benefits from treatments. Biopsy
3.2
Biopsy carries a 2-3% risk of symptomatic complication including the risks of stroke, haemorrhage and death. The risk depends on the tumour location. Biopsies are taken from multiple sites but sampling error is not uncommon such that a low grade result may be falsely reassuring. The older literature suggests little difference in outcome between biopsy and debulking but more recent literature and consensus neurosurgical opinion is that debulking probably does improve outcome. It should be noted that the evidence base for this is poor and that the difference between the two options remains controversial. Biopsy may be done under general or local anaesthetic. It may be done as a day case or with an overnight post-operative stay. It may be done through a burr hole or with a craniotomy. Biopsy should be considered for: Surgically inaccessible lesions (deep or eloquent areas) Patients wishing to minimise risk To exclude the possibility of an abscess where the radiology is unclear
The Neurosciences SMDT will decide on the most appropriate course of action depending on imaging findings. 3.3 De-bulking surgery
Debulking surgery aims to remove as much tumour as possible. It provides the best possible diagnosis and tumour clearance but is not curative. To protect eloquent areas of brain image guidance, functional MRI and awake craniotomies may be used. The risks of debulking surgery are 3-4% risk of a complication including the risks of stroke haemorrhage and death. However the proximity to eloquent areas might significantly increase this risk for example surgery on a lesion in the motor strip might carry a risk anywhere between 10% and 70% depending on the nature, size and location of the lesion. Debulking surgery is appropriate in: Surgically accessible lesions Patients willing to take some risk in return for maximum benefit Patients with good pre-operative function
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3.3.1
Debulking Surgery and insertion of Carmustine wafers (Gliadel)
Carmustine is a chemotherapy agent that can be placed in the tumour cavity at the end of a debulking procedure. Consideration of the use of Carmustine should be undertaken at the MDT. Indications are as made by NICE. primary high grade glioma (WHO grade III or IV) recurrent glioblastoma Carmustine roughly doubles the number of survivors at two and three years and extends median survival from 12 to 14 months
There is an increased risk of wound breakdown, brain swelling and pseudoinfection. The procedure should be performed by named neurosurgical consultants only who have undergone the appropriate training and who are registered on the trust chemotherapy register. 3.3.2 Debulking surgery using 5-ALA fluorescence
5-ALA is a drug that can help identify the edge of the tumour. It is drunk two to four hours before the operation. 5-ALA goes into the tumour cells of the brain but not the normal brain. In the tumour it is converted to a substance that glows pink when exposed to blue light. During the operation the surgeon will use a blue light filter on the microscope and identify remaining tumour cells which can then be removed. Consideration of the use of 5-ALA should be undertaken at the MDT and the procedure performed by named neurosurgical consultants only. 3.4 Surgery for recurrence
Carefully selected cases may benefit from second procedures. It should be noted that complication rates are higher and benefits lower with redo operations. These cases must be discussed at MDT. The following are appropriate: Performance status 0-1 >1 year survival from previous surgery if primary malignant tumour. Metastases are to be considered on an individual basis. Surgically accessible lesion Other non surgical options (usually chemotherapy) to support the surgical debulking
3.5 Surgery for other situations Some patients referred to the Neurosciences MDT may have non-malignant diagnosis. If there is a question that a cystic lesion is a brain abscess it should undergo urgent diffusion weighted MRI looking for restricted diffusion. If suspected, brain abscesses should be treated as an emergency and consideration of drainage or resection of the abscess made. Ideally antibiotics should be withheld until pus is obtained for microbiology. 3.6 Post-operative considerations Early discharge wherever possible Dexamethasone should be weaned down to the minimum dose to control symptoms. Surgical clips can be removed at five days except posterior fossa and redo procedures where clips can be removed at ten days. Most neurosurgical sutures are now self absorbing and will therefore not require clip removals - please ensure this is documented on discharge summary. Post-operative MRI scan on all patients who have undergone debulking surgery. Post-operative CT scan on all patients who have had a biopsy.
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Histology results to be given in private location with appropriate family member(s) present and nursing support / named key worker. This is best done in clinic. Usually on the following Thursday afternoons surgical neuro-oncology clinic, give results and arrange follow up care with oncology / palliative care in accordance with that mornings MDT pathology discussions.
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4 Surgical Management of Low Grade Glioma

The first decision is to decide between active surveillance and surgical intervention. The options include: Active Surveillance - this has been shown to be a safe alternative to early intervention (Recht et al 1992) Tumour biopsy Tumour resection
Options for surgical intervention include: 4.1 Image Guided Biopsy
This allows a diagnosis to be made. Histological diagnosis is important since imaging cannot accurately differentiate low grade gliomas from more aggressive tumours or from nonneoplastic conditions (e.g. encephalitis). Contrast enhancement cannot be reliably used as a marker of low grade behaviour since 35% of low grade gliomas enhance (Al Okaili et al 2007) and a third of malignant tumours do not (Scott et al. 2002). The situation is even more difficult for oligodendrogliomas with 50-60% enhancing, and 38% of anaplastic oligodendrogliomas failing to enhance (White et al 2005). The complication rate is probably about the same for high grade tumours (i.e. 2-3% risk of death or neurological deficit). There is probably more of a problem with sampling error in this group - studies comparing histology from biopsies and resection suggest the diagnosis is changed in up to 38% of patients who subsequently undergo tumour resection (Jackson et al 2001). Indications for Biopsy: 4.2 Unresectable tumours (esp. deep lesions) Patient choice (patient very well) Known low grade tumour that demonstrates changes in appearance on imaging that might represent tumour transformation. Tumour resection
Recent studies suggest a survival advantage from gross total resection of low grade gliomas (McGirt et al 2008). This advantage was not seen in near-total resections. As a result, all low grade glioma resections should be done by neurosurgeons with a declared interest in neurooncology. Methods such as awake craniotomy with cortical mapping and functional MRI should be available, especially in tumours close to eloquent cortex.
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5 Surgical Management of Meningioma

Meningiomas are slow growing tumours. Most small tumours including recurrence / residual tumours may be observed and will usually not require surgery or radiotherapy. Selection of patients for radiotherapy is an area without an evidence base of randomised clinical trials. 2-5% of meningiomas are malignant (WHO grade 3 Please see Appendix H). These patients are normally offered post operative radiotherapy irrespective of the degree of resection. It is important to note that these tumours are one of the few primary brain tumours that can metastasise outside of the CNS. Benign and Atypical (grades 1 and 2) meningiomas where there is macroscopic residuum or a high likelihood of microscopic residuum may be considered for post operative radiotherapy where surgical resection of a recurrence is likely to be difficult. However most grade 1&2 tumours especially where further surgery is feasible are managed with neuro-surgical follow up alone. The probability of tumour control depends on the degree of resection (Simpson grade), grade of the tumour and location of the tumour (skull base is higher risk). For WHO grade 1 meningiomas the Simpson grade is used to predict recurrence as follows: Simpson Grade 1 2 3 4 5 Description Complete resection including dura Complete resection, dura coagulated Complete resection but dura left Subtotal resection Decompression alone Risk of recurrence at 5 years 9% 19% 29% 44% N/A
Complete surgical excision achieves 10-year local control rates of around 80% (Goldsmith 1998). The degree of resection is very dependant on the tumour location. Subtotal resection alone delivers much poorer control rates of around 45% at ten years. Radiotherapy given following subtotal excision raises control rates to around 80% at ten years (Glaholm et al 1990, Goldsmith et al 1994), thus matching control rates for complete excision. Control rates for inoperable tumours treated with radiotherapy alone are less clear. One series quotes local control at ten years of around 50% (Glaholm et al 1990), although in another, 100% were controlled at follow up times of 3 to 6 years (Carella et al 1982). Salvage treatment in patients who relapse after surgical excision may include radiotherapy, and in this setting, control rates of about 80% at ten years are reported (Taylor et al 1988). For malignant tumours local control rates are roughly half that of benign tumours, at around 35% - 50% at five years (Glaholm et al 1990, Goldsmith et al 1994). See also results from Heidelburg (Milker-Zabel et al 2005). It is important to consider the long-term side effects associated with radiotherapy which include the risk of pituitary failure, visual loss and induction of malignancy. Meningiomas in the cavernous sinus and around the optic nerve are almost impossible to remove surgically. Diagnosis and treatment is usually based on imaging findings alone and no surgical intervention is undertaken. Surgical treatment is used to decompress the optic nerves and in this situation may yield a histological diagnosis. Following radiotherapy most patients, and in some series all patients, experience improvement in visual acuity (Goldsmith 1998). It is important for patients to receive treatment (surgery usually with radiotherapy) before visual damage has become too severe.
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5.1 Surgical Principles Surgery is performed to obtain a diagnosis and remove as much tumour as possible. Complete macroscopic excision of a meningioma with its dural origin is desirable however if necessary a small bit of meningioma may be left and this is preferable to giving the patient significant neurological deficits. 5.2 Pathology Once tissue samples have been obtained via a neurosurgical procedure, they are analysed by pathology in order to establish a histopathological diagnosis / WHO grade. This takes 7 to 10 working days to establish. Patients are invited to the next neurosurgical clinic in order to discuss their results and any onward care required. The results will have been discussed at the MDT meeting prior to the patients being seen in clinic. Results are forwarded to the GP via MDT faxed outcomes within 24 hours and this is then followed up by a written clinic letter from the consultant detailing any planned onward treatment. 5.3 Surgical Follow-up Protocol MRI scan either immediately (<72 hrs) or at 3 months. Then scans at six months, one year, two years, five years and ten years where appropriate. Grade 2 tumours, those with brain invasion or significant residual may be followed up more closely.
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6 Oncological Management of Brain Tumours

6.1 Radiotherapy Planning
6.1.1 General principles Throughout the guidelines the following definitions for planning volumes will be used. These include: Gross Tumour Volume (GTV) - extent of visible tumour as demonstrated on imaging. Clinical Target volume (CTV) - GTV plus a margin for sub-clinical disease infiltration. Planning Target volume - CTV plus a margin for geometric uncertainties in planning and delivery.
6.1.2 CT Planning All cases should be imaged by CT. IV Contrast: All Radical CNS cases (including 1#SRS) - require IV contrast. Palliative CNS cases IV contrast may be helpful.
For radical CNS cases, the CT slice spacing is 1mm slices throughout the brain. The whole head should be scanned. For palliative cases the slice spacing is 3mm and again the whole head should be included in the scan. 6.1.3 MRI Imaging All radical CNS cases should have MRI co-registration unless there are contra-indications to acquiring an MRI. The MRI should be co-registered with the planning CT. Pre-operative MRI may be appropriate to be used if biopsy only. De-bulked tumours will require post-operative MRI imaging. The MRI form should request 2mm contiguous axial slices for that sequence. Details of co-registration requirements (including sequence) should be clearly annotated for the radiology department. In general for high grade glioma, meningioma, acoustic and pituitary and glomus tumours the T1W&Gd sequence is used for co-registration. For low grade glioma the T2W sequence is normally used for co-registration. 6.1.4 Immobilisation A Perspex shell is required for radical CNS cases. A thermoplastic shell (zentec) may be used for palliative CNS patients. The SRT frame is used for small intracranial lesions but is not suitable for edentulous patients, patients with poor PS or for lesions that extend below the skull base. Shells should be cut out for treatment. 6.2 High Grade Gliomas
6.2.1 Management Principles Recursive partitioning analysis of the RTOG data revealed four factors which influence outcome in patients with HGG. Age. Performance status. Extent of surgical resection.
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Neurological function.
It is therefore extremely important to establish these parameters before making a decision on post-operative treatment. 6.2.2 Treatment Options The first oncology decision is for treatment intent. The choices are: Radical RT +/- concomitant temozolomide Palliative RT Best supportive care
Data shows a four month statistically significant survival advantage for the use of concomitant and adjuvant temozolomide with radical radiotherapy for GBM (Stupp et al. 2005). A recent update has shown a 4 year survival of 11% in the temozolomide group. This is the current standard of care for GBM and has been approved by NICE. MGMT methylation analysis on tumour tissue has shown that methylation can be predictive for response to treatment this is currently being assessed prospectively in clinical trials. In some cases, the biopsy specimen will suggest a grade 3 tumour, where the clinical history and imaging findings indicate a grade 4 tumour. In these patients, it is demonstrated that the prognosis follows that of grade 4 tumours, and they should therefore be treated in the same fashion Use the following criteria to decide treatment for GBM: - Radical RT (60Gy/30#/6wks) Age < 70-75 + Concomitant temozolomide PS 0 - 1 No significant neurological deficit remaining - Palliative RT Age >/= 70 and PS 0 - 2 Age < 70, with a significant neurological deficit Obvious tumour spread across the midline on imaging Severe residual deficit, eg hemiplegia intellectual impairment, confusion
- Best Supportive care
Use the following criteria to decide treatment for Grade III glioma: - Radical RT (54Gy/30#/6wks) Age < 70-75 PS 0 - 1 No significant neurological deficit remaining Age >/= 70 and PS 0 - 2 Age < 70, with a significant neurological deficit Obvious tumour spread across the midline on imaging Severe residual deficit, eg hemiplegia Intellectual impairment Confusion
- Palliative RT
- Best Supportive care
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6.2.3 Radical Radiotherapy Treatment Planning Perspex beam direction shell - normally supine Neuro CT planning scan with IV contrast - 1mm slices throughout the brain MRI - with 2mm contiguous slices for T1W&Gd sequence (for biopsy only it may be possible to use pre-operative imaging) CT:MR co-registration Conformal radiotherapy planning 6.2.3.1 Planning Target Volumes
GTV: This is the outer edge of contrast-enhancing tumour on CT/MR. Correlation with preoperative diagnostic imaging is useful. The GTV is thus the post-operative tumour volume. CTV: The suggested margins are: Phase 1 - GTV - CTV = 2.5 cm Phase 2 - GTV - CTV = 1.5 cm
Some centres may prefer a single phase using 2.5 cm margin throughout PTV: this margin is according to department data - often in the region of 0.5 cm for both phases. Grow this from the CTV for both phases. 6.2.3.2 Organs at Risk: Outline Pituitary, Orbits, Optic nerves, Optic Chiasm and Lenses 6.2.3.3 Dose Prescription Grade 3 Grade 4 54 Gy/ 30# 2 phases (45/25 + 9/5) 60 Gy/ 30# 2 phases (50/25 + 10/5)
6.2.3.4 Treatment Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. 6.2.4 Palliative Radiotherapy Treatment Planning The patient should be immobilised in a thermoplastic mask. 6.2.4.1 Target Volume These are normally planned using a virtual simulation tool. On the planning CT use the axial images to outline the GTV. Then apply a 3cm margin all round to create the treatment field. Using the lateral DRR rotate the collimator in order to avoid irradiating the eyes and edit the field size where necessary to 0.5cm beyond the skull and 0.5cm below the skull base. 6.2.4.2 Dose Prescription 30 Gy/ 6# / 2 weeks (ie 3x per week) 6.2.4.3 Treatment Implementation PI/beam films as per departmental protocol
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6.3
Chemotherapy for High Grade Glioma
6.3.1 Concomitant & Adjuvant Temozolomide Stupp et al 2005 showed a length of survival benefit for selected patients diagnosed with GBM who receive concomitant and adjuvant temozolomide at the time of diagnosis. Patients eligible for treatment: GBM WHO PS 0-1 Craniotomy + surgical debulk where anatomically possible
6.3.2
Concomitant Temozolomide protocol
D1-42 (should not exceed 49 days) daily including weekends Dose = 75mg/m2 Administer 1 hour prior to radiation (am at weekends) FBC once per week*. U&E, LFT once per week * If platelet count falls need to closely monitor 6.3.3 Other prescriptions: Ondansetron (8mg) prior to first dose then domperidone 20mg PRN Septrin Forte 960mg 3x per week (PCP prophylaxis) If vomiting occurs post temozolomide do not re-dose but await next day for planned dose. If radiotherapy is interrupted for technical or medical reasons unrelated to temozolomide then the daily temozolomide should continue. If radiotherapy is permanently interrupted then treatment with daily temozolomide should stop. Dose modifications Value 0.5 and < 1.5 10 and < 100 CTC Grade 2,3 1,2,3 2 <0.5 <10 4 4 3,4 Action Delay until normalisation Delay until normalisation Delay until normalisation STOP STOP STOP
6.3.4
Toxicity Absolute Neutrophil Count Platelet Count CTC non-haematological toxicity (except alopecia, N&V) Absolute Neutrophil Count Platelet Count CTC non-haematological toxicity (except alopecia, N&V
Following completion of radiotherapy organize follow-up to start adjuvant temozolomide for four weeks. 6.3.5 Adjuvant Temozolomide Starting four weeks after completion of radiotherapy six cycles of adjuvant temozolomide. First cycle of temozolomide at 150mg/m2 D1-5 in a 28 day cycle. Subsequent cycles at 200mg/m2. Assessment with MRI at completion
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6.3.6 Chemotherapy for Relapse First line chemotherapy is with PCV. Second line is with temozolomide. The BR12 study has not shown a difference in OS or PFS between PCV and five day temozolomide. Third line chemotherapy is currently unsatisfactory, but needs to be developed. Occasional patients may be considered for treatment with high dose tamoxifen, at a standard dose of 100 mg (or at 100 - 120 mg/m2). Delay chemotherapy if FBC shows any of the following: WBC < 3.0 Platelets < 100 Neutrophils < 1.5
Liver function should be checked before all courses of PCV and temozolomide as both can cause elevation of liver function tests. Response is assessed after every 3 cycles, using CT or MRI, depending whether CT is good enough to assess the tumour. Chemotherapy should be changed to second line if there is evidence of progression. 6.3.7 Day 1 1-10 1 PCV chemotherapy (Procarbazine, CCNU, Vincristine) Drug Dose CCNU 100 mg/m2 (max 200 mg) PO bolus Procarbazine 100 mg/m2 (max 200 mg) PO Vincristine 1.5 mg/m2 (max 2 mg) IV bolus Route
6.3.7.1 Cycle Repeat 6 weekly. 6.3.7.2 Investigations Before first course
FBC U & Es, LFTs (+/- anticonvulsant levels, if appropriate) FBC LFTs (+/- anticonvulsant levels, if appropriate)
Before successive courses
Notes CCNU comes in 40 mg tablets. For doses which are not multiples, round the dose. Procarbazine comes as 50 mg capsules. Round the dose, or give eg 3 tablets one day and 4 the next, ie 150/200 mg on alternate days. Note interaction with alcohol and some foodstuffs, including cheese and Soy sauce. Procarbazine is a weak MAOI - it was developed as a possible anti-depressant. Delays due to marrow suppression are common. Chemotherapy is often deferred for 2 weeks. 6.3.8 Day 1-5 Temozolomide Drug Dose Temozolomide 150 mg/m2 if previously treated 2 150 - 200 mg/m if previously untreated Route PO PO
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Cycle: Repeat 4 weekly. Investigations: Before first course FBC U & Es, LFTs (+/- anticonvulsant levels, if appropriate) FBC
Before successive courses
Notes: Temozolomide is well tolerated but occasional patients suffer severe unexpected idiosyncratic marrow suppression, which can be life-threatening. This is uncommon, but serious. 6.4 Low Grade Gliomas
6.4.1 Radiotherapy for Low Grade Gliomas The decision is to decide between active surveillance and radiotherapy for low grade glioma. The overall survival is the same for the two strategies, though the progression-free survival is better for early radiotherapy (Van Den Bent et al 2005). Broadly, choose treatment (surgery and/or radiotherapy) for patients who have evidence of progression of neurology, more frequent seizures, progression on imaging, large tumours, older age group and tumours close to eloquent areas. Radiotherapy may also be used to try to improve seizures, and has some benefit in about two thirds of cases. 6.4.2 Radical Radiotherapy -Treatment Planning
Perspex beam direction shell - normally supine Neuro CT planning scan with IV contrast - 1mm slices throughout the brain MRI - with 2mm contiguous slices for T1W&Gd sequence (for biopsy only it may be possible to use pre-operative imaging) CT:MR co-registration - normally the T2W sequence is most useful Conformal radiotherapy planning Planning Target Volumes
6.4.3
GTV: this is the area of abnormality as demonstrated on the T2W MRI sequence. Due to the diffuse invasive nature of low grade lesions this can often be a rather large volume. If the patient has undergone a debulking surgical procedure, correlation with the pre-operative MRI may be useful. CTV: The standard margin is GTV - CTV = 1.5 cm PTV: according to department data - often in the region of 0.5 cm. Grow this from the CTV. 6.4.3.1 Organs at Risk: Consider outlining: Pituitary, Orbits, Optic nerves, Optic Chiasm and Lenses 6.4.4 Dose Prescription 54 Gy/ 30#/ 6 weeks in a single phase
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6.4.5 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. 6.5 Glioma Re-treatment
6.5.1 Treatment Policy Occasional patients may be considered for re-irradiation. In this case, patients must have PS 0 or 1, disease-free interval > 1 year, and small volume recurrence. 6.5.2 Treatment Planning Relocatable Stereotactic head frame preferable. Neuro CT planning scan with IV contrast - 1mm slices throughout the brain. MRI - with 2mm contiguous slices for T1W&Gd sequence. CT:MR co-registration - normally the T1W&Gd sequence is most useful. Conformal/IMRT radiotherapy planning. 6.5.3 Target Volume
GTV - the abnormality as demonstrated on MRI CTV - allow a small margin in the region of 0.5 - 1 cm. PTV - 0.3cm for the SRT frame or 0.5cm for a shell Outline critical normal structures, including the pituitary, the eyes and lenses, and often the optic nerves and chiasm. 6.5.4 Dose Prescription
50 Gy/ 30#/ 6 weeks in a single phase 6.5.5 Implementation
Measure eye TLDs for future reference. Take portal films or images as per protocol. 6.6 Meningioma
6.6.1 Treatment Policy All patients with meningioma should be discussed at the neuro-oncology MDM. 6.6.2 Radical RT - Treatment Planning
6.6.2.1 Immobilisation Stereotactic frame typically for skull base or cavernous sinus lesions. Patients should be WHO PS-0, with good dentition. Not suitable for lesions that extend below the skull base. Perspex Beam Direction Shell Normally supine. A mouth bite may be useful for tumours that extend below the skull base 6.6.2.2 Imaging Neuro CT planning scan with IV contrast 1mm slices throughout the brain. If the tumour extends below the skull base the CT must extend low enough to include the lesion. MRI with 2mm contiguous slices for T1w + Gd sequence. CT:MR Co-registration is often valuable and may be essential. Normally the post op T1w + Gd sequence is the most useful. Co-registration to pre-op imaging (T1W + Gd) may also be useful to assess likely route of microscopic spread along the meninges.
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6.6.2.3 Planning Conformal radiotherapy planning IMRT Planning 6.6.2.4 Target Volumes GTV: treat the post-operative volume - this is the area of abnormality as demonstrated on the T1W + Gd post op MRI sequence. Care must be taken to include tumour infiltration of the meninges, include any meningeal tail on the tumour. If the tumour is close to dense bone, review the CT at bone settings window. CTV: Use the pre-op imaging to show the base of the lesion and ensure that this area is included. The CTV margin is based on a combination of histology and growth pattern, as follows: Grade 1 Grade 2 Grade 3 - CTV = GTV - along the meninges CTV = GTV + 1cm - at other surfaces CTV = GTV - along the meninges CTV = GTV + 1.5-2.5cm - at other surfaces CTV = GTV + 0.5cm
Where no histology is available, consider each case individually PTV: SRT frame CTV PTV = 0.3cm Beam direction shell CTV PTV = In region of 0.5cm This margin should be grown isotropically with the planning software. 6.6.2.5 Organs at Risk: these should be outlined including the pituitary, eyes, lenses, optic nerves and chiasm.
6.6.2.6 Dose Prescription 50 - 55 Gy / 30 - 33 # at 1.67Gy/ # Single phase. 6.6.2.7 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. 6.6.2.8 Patient Care Very occasional patients experience nausea, especially when the brain stem is irradiated. This is usually manageable with 5-HT3 antagonists. Patients rarely require steroids during treatment for meningioma. 6.6.2.9 Hydroxyurea To be considered where no further irradiation is feasible and there is recurrent bulk tumour on imaging. Hydroxyurea comes in 500mg tablets.
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Start at 1g per day. Repeat FBC in one week. If blood counts are satisfactory increase the dose to 1.5g per day. Further FBC at two weeks and then four weeks and providing they remain satisfactory continue at 1.5g od. Repeat FBC every four weeks, aim to keep neutrophils > 2.0 and platelets > 100 Typically FBC falls gradually; this may require a dose reduction. At present there is no intention to increase the daily dose above 1.5g, which equates to 20mg/kg/day for a patient of 75kg. Newton et al 2004 Hahn et al 2005 Loven et al 2004 20mg/kg/day 20mg/kg/day 20mg/kg/day 90% response at early follow up 77% response at 2 years 10% response at early follow up
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7 Metastases
7.1 Treatment Policy Refer to relevant team, unless there is no obvious primary site. For palliative treatments, follow department guidelines. There are a number of treatment options with metastases there is little clear benefit of one type of treatment over any other. The options are: 7.2 Palliative care This may be appropriate for patients with multiple metastases and a poor performance status. 7.3 Surgery The risks of surgery for metastases is 2-3% risk of bleeding, infection or death with the risk of stroke dictated by the location of the tumour. Many metastases have good planes of cleavage and it is frequently stated that most of the patients who have resective surgery will not die from the metastasis that has been resected. Surgery should be considered if: Solitary metastasis (on MRI not just CT) without extensive systemic disease Accessible location Large symptomatic metastasis (sometimes even if there are other smaller ones) No known primary for diagnostic purposes Cerebellar metastasis with hydrocephalus 7.4 Stereotactic radiotherapy / radiosurgery Patients may be referred for stereotactic radiosurgery. This is considered provided that patients are fit (PS 0 or 1), have a long disease-free interval (>1 year) and have controlled systemic disease. They must have good teeth in order to be able to bite down on the mouthpiece. The lesion should be nearly spherical. The recommended treatment is SRS followed by whole brain RT, i.e. the SRS treatment should be done before the whole brain RT. Some patients can be considered for SRS treatment alone. 7.5 Whole brain radiotherapy Some patients warrant radical palliative treatment, e.g. those with solitary mets and no known primary. In these, the diagnosis is usually made after resection, so no GTV remains to localise the boost. Radical palliative treatment involves whole brain RT followed by a high dose boost. 7.6 7.6.1 Chemotherapy (small cell lung cancer) Treatment Planning
SRS is CT planned with MR fusion. 7.6.2 Target Volume For SRS, the current protocol is to place the 90% isodose around the edge of the GTV. This is achieved using an applicator 0.5 cm larger than the maximum diameter of the deposit. Dose Prescription 7.6.3 For radical palliative solitary mets
Whole brain 30Gy/15# / 40 Gy / 20 # Boost 14 Gy / 7 #

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7.6.4
Stereotactic radiosurgery
Whole brain 40 Gy / 20 # Boost 16 Gy / 1 # @ 90% isodose 7.6.5 Implementation Take portal films or images as per protocol. For SRS: i) ii) give Dexamethasone. Give 2 doses of 8 mg, 24 and 12 hours before the SRS, and for 1 day after, then wean off over 3 - 4 days. admit the patient for the night after the SRS.
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8 Rare Tumours
8.1 Neurocytoma Neurocytoma has a WHO grade II. It is not as benign as some texts suggest. Overall, one third of patients develop recurrence or progression within ten years. With RT local control at ten years is 75%, and without RT 50%. 8.2 Germinoma / Medulloblastoma
8.2.1 Surgical principles Germinoma is primarily treated (and usually cured) by radiotherapy. Therefore the aim of surgery is diagnostic only there is no need to debulk these tumours. Germinomas sometimes secrete Placental Alkaline Phosphatase (PLAP) but are usually non secreting. On the other hand non-germinomatous germ cell tumours (with the exception of mature teratoma) usually secrete tumour markers. Therefore if a germ cell tumour is suspected serum and CSF BHcG, AFP and PLAP should be obtained pre-operatively. If these are positive no biopsy is required. If a biopsy or during a surgical procedure a smear result confirms a germinoma then the operation should be stopped and no attempt at debulking should be made. Medulloblastoma should be debulked maximally. The degree of tumour resection predicts outcome. It may even be appropriate to reoperate if >3cc of tumour is seen on the postoperative MRI scan. 8.2.2 Treatment Policy Stage the spine. Scrutinise the cranial MRI for other deposits. For both tumour types, treat the whole cranio-spinal axis (CSA), and boost the primary, and mets if there are any. Neither tumour type should have any interruptions (ie are Category 1 patients), unless bone marrow toxicity demands. Germinomas have a high risk of seeding, and have a predilection for the region of the optic chiasm. They may also progress extremely fast and occasional patients with deteriorating neurology need emergency RT. Germinomas also have an extremely high cure rate with RT alone. For medulloblastoma, consider chemotherapy. The most recent data from paediatric studies suggests that adjuvant chemotherapy confers an advantage. Therefore, standard policy is now to consider chemotherapy. 8.2.3 Radiotherapy - Treatment Planning
8.2.3.1 Immobilisation Perspex beam direction shell prone
8.2.3.2 Imaging RTC/CT for CSA planning - ensure whole brain and spinal cord is imaged.
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Neuro CT planning scan with IV contrast for ph2 planning - 1mm slices throughout the brain Cranial MRI - with 2mm contiguous slices for T1W&Gd sequence - needs to be done before starting CSA RT since response can be extremely quick. Spinal MRI - to identify the lower end of the thecal sac also, in female patients, to identify the position of the ovaries. This will help to estimate the ovary dose CT:MR co-registration - for ph 2 boost planning - normally use the T1W+Gd sequence.
8.2.3.3 Planning CSA Use the virtual simulation tool to plan the cranial and spinal fields Compensators are usually required for the cranial and spinal fields
Ph 2 boost Conformal radiotherapy planning
8.2.3.4 Target Volume Whole CSA - Medulloblastoma & Germinoma: CTV: This is the entire meningeal contents for the brain and spinal cord. The cribiform plate forms the inferior aspect of the CTV in the brain. PTV: Brain CTV- PTV = 0.5cm Spine CTV - PTV = 1cm. Phase 2 boost: Germinoma: GTV: This is the pre-RT volume as demonstrated on the T1W+Gd MR sequence. CTV: allow a small GTV - CTV margin of about 1cm PTV: beam direction shell -the standard CTV - PTV margin is 0.5cm Medulloblastoma GTV: this is residual post-op, pre RT volume as demonstrated on T1W+Gd MR. This volume is currently not usually delineated during planning. CTV: current protocol is to include the whole posterior fossa, including meningocoele. PTV: beam direction shell -the standard CTV - PTV margin is 0.5cm Critical normal structures: these should be outlined including the eyes, lenses and the pituitary. 8.2.4 Dose Prescription Dose prescriptions apply to adult doses. Whilst these are strongly influenced by paediatric practice, higher doses may be possible and desirable in adults than are sometimes used in children. Germinoma Total dose 40 Gy / 24 # at 1.67 Gy/#
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Ph1 - CSA Ph2 - Boost
25Gy / 15 # 15Gy / 9 #
For spinal deposits, aim for a total of 40 Gy. Where there is extensive spinal disease, the whole CSA may be taken to 40 Gy, with careful observation of FBC. Medulloblastoma Total dose Ph1 - CSA Ph2 - Boost 55 Gy / 33 # at 1.67 Gy/# 35 Gy / 21 # 20 Gy / 12 #
8.2.5 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. FBC twice weekly. In men, measure scrotal (ie testicular) dose using TLDs. In women, ovary doses are estimated, based on ovary position on the staging MRI (see above). 8.3 Ependymoma (Intra-Cranial)
8.3.1 Surgical policy With diffuse (grade 2) and anaplastic (grade 3) tumours the degree of surgical resection is critically important. Every effort must be made to remove as much tumour as possible. Subependymomas and myxopapillary ependymomas of the cauda equina are treated with surgical excision alone and are unlikely to recur. 8.3.2 Treatment Policy Maximum possible surgical resection should be undertaken. Stage the spine. Provided there are no spinal metastases, treat only the primary site. Where there is evidence of spinal deposits treat the whole CSA, with a boost volume to the primary site and mets (for details of whole CSA planning see Medulloblastoma and Germinoma. 8.3.3 RT - Treatment Planning
8.3.3.1 Immobilisation Perspex beam direction shell - normally supine unless lesion extends inferiorly below the base of skull when a prone shell will be required.
8.3.3.2 Imaging Neuro CT planning scan with IV contrast - 1mm slices throughout the brain - ensure the scan extends far enough inferiorly to cover lesion. MRI - with 2mm contiguous slices for T1W+Gd sequence CT:MR co-registration - to both the pre-op and post op T1W+Gd sequence.
8.3.3.3 Planning Conformal radiotherapy planning
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Compensators may be required for treatment of post fossa lesions
8.3.3.4 Target Volume Post fossa ependymoma: GTV: this is any residual post operative tumour as demonstrated on T1W+Gd MR and if present forms the volume for a phase 2 boost (3#). CTV: Ph1 = the whole posterior fossa. Ph2 = GTV (or post op cavity) + 1cm
PTV: beam direction shell -the standard CTV - PTV margin is in region of 0.5cm Stereotactic radiotherapy may be investigated for the ph2 boost in due course. 8.4 Supratentorial ependymoma:
GTV: this is any residual post operative tumour as demonstrated on T1W+Gd MR CTV: Ph1 = GTV + 1.5-2.5cm margin PTV: beam direction shell -the standard CTV - PTV margin is 0.5cm 8.4.1 8.4.2 Critical normal structures: these should be outlined including the eyes, lenses and the pituitary. Dose Prescription:
55 Gy / 33 # in 1-2 phases Ph1 = 50 Gy / 30 # Ph2 = 5 Gy / 3 # 8.4.3 Implementation: Always measure eye TLDs for future reference. Take portal films or images as per protocol. 8.5 Vestibular Schwannoma / Acoustic Neuroma
For patients diagnosed with Vestibular Schwannoma there are number of management strategies available: 8.5.1 Surveillance Vestibular schwannomas are normally small, slow growing lesions and for small tumours where there is no evidence of tumour progression or compression of the brain stem a watch, wait and re-scan policy is a good management option. 8.5.2 Surgery Surgery is an excellent treatment, provided complete excision is achieved without undue morbidity. Surgery achieves complete excision in 97% of patients. Total hearing loss is usually present pre-op, brain stem (cochlear) implants are possible for some patients. In a few patients with useful hearing pre-op hearing preservation surgery may sometimes be possible. Surgery has a significant risk of causing a facial nerve palsy which is usually temporary and recovers 6 -12 months after surgery. The majority of patients require a significant period of rehabilitation following surgery.
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8.5.3 Radiotherapy This is an alternative to surgery and can be delivered in two ways: 1) Single fraction radiosurgery (Gamma Knife) 2) Fractionated conformal radiotherapy 8.5.3.1 Single fraction radiosurgery For small (3cm) laterally placed lesions, stereotactic radiosurgery is an excellent choice. At present patients seeking an opinion on radiosurgery should be referred to a Gamma Knife Centre (Royal London or Sheffield). 8.5.3.2 Fractionated conformal radiotherapy For larger lesions and those lesions adjacent to or compressing the brain stem fractionated conformal radiotherapy is a worthwhile treatment. Ideally to reduce PTV margins (normal tissue irradiated) patients should be immobilised in the relocatable SRT frame, however a shell can be used if more appropriate. For patients who have useful hearing this option may preserve hearing. However radiotherapy is designed to stabilize the tumour and will not remove the lesion, so patients will require an active follow up plan. Published results for fractionated radiotherapy suggest excellent efficacy and low morbidity (Fuss et al). 8.6 Neurofibromatosis Type 2
Patients with NF2 appear to be at greater risk of hearing loss, for a given dose, for unexplained reasons and tumour control rates are lower. In general radiotherapy should be avoided for as long as possible in these patients though eventually most will require it. Surgery is also more difficult in this group, with higher complication and recurrence rates. The emphasis of treatment is therefore to maintain hearing for as long as possible and not necessarily to try to remove or treat tumours. 8.6.1 RT -Treatment Planning
8.6.1.1 Immobilisation Relocatable SRT head frame patients who are PS 0 with good upper jaw dentition Perspex beam direction shell - supine 8.6.1.2 Imaging Neuro CT planning scan with IV contrast - 1mm slices throughout the brain MRI - with 2mm contiguous slices for T1W+Gd sequence CT: MR co-registration - to T1W+Gd sequence. 8.6.1.3 Planning Conformal radiotherapy planning use of personalised shielding blocks or mMLC 8.6.1.4 Target Volume GTV: the enhancing lesion as demonstrated on T1W + Gd MR sequence CTV: = GTV
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PTV: This margin should be grown isotropically with the planning software. Stereotactic frame CTV - PTV margin is 0.3cm. Beam Direction Shell - the standard CTV - PTV margin is 0.5cm. Critical normal structures: these should be outlined including the eyes, lenses, brain stem and the pituitary. 8.6.1.5 Dose Prescription 50Gy/30# 8.6.1.6 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. Please see Appendix H for the Vestibular Schwannoma Assessment diagram.
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8.7
Glomus Tumours
8.7.1 Treatment Policy The decision between surgery and radiotherapy may be difficult and needs to be considered individually. Surgery has the advantage of removal of tumour, which is hopefully complete, but the disadvantage of neurological deficits, especially lower cranial nerve palsies. Radiotherapy has the advantage of very low toxicity, but the disadvantages that the tumour remains and late occurrence of second tumours can occur. The risk of this is very low. Local control rates are reported to be very high after radiotherapy, with moderate doses, in the range 90 - 93% (Springate et al 1990, 1991). In one report, the majority of patients noted symptomatic relief of tinnitus after radiation, but objective neurological deficits usually remained unchanged or showed only partial improvement (Powell et al 1992). 8.7.2 Treatment Planning Use a beam-direction shell or stereotactic radiotherapy frame, depending on circumstances. For tumours with any significant extension into the neck, the SRT frame is not suitable. Use CT planning, with IV contrast, which shows glomuses quite well. CT slices spacing is normally 0.1 - 0.2. The CT should cover the whole head to allow the possibility of noncoplanar beams (and NTCP calculations), and must extend low enough in the neck to cover the inferior extent. For large, low lesions a mouth bite may be useful. CT: MR image co-registration is often valuable, and may be essential. Some additional localisation information is often available from the angiogram. 8.7.3 Target Volume Plan conformally, usually with CT: MR co-registration. The CTV is essentially the GTV, with or without an allowance for uncertainty in localisation and co-registration. Always review the CT at bone window settings. The standard CTV - PTV margin for patients in a shell is 0.5 cm, while for patients in the stereotactic frame the margin is 0.3 cm. This margin should be grown tropically with the planning software. Outline critical normal structures, including the pituitary, the eyes, the parotid glands, brain stem etc. 8.7.4 Dose Prescription 50 Gy / 30 # at 1.67 Gy/#
1 phase.
In exceptional circumstances consider a slightly higher dose, of 55 Gy / 33 #. 8.7.5 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. Very occasional patients experience nausea, especially when the brain stem is irradiated. This is usually manageable with 5-HT3 antagonists. Patients rarely require steroids.
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8.8
Skull Base Tumours (Chordoma / Chondrosarcoma)
8.8.1 Treatment Policy Aim for maximum surgical resection. Follow with referral for proton therapy via the National Proton Group (leedsth-tr.ProtonNCG@nhs.net). If not suitable for proton therapy for high dose stereotactic radiotherapy or Image Guided Radiotherapy. 8.8.2 Treatment Planning Use the stereotactic radiotherapy frame. Use CT planning, with IV contrast, and slice spacing of 0.1 - 0.3. Always scan the whole head, for improved DRRs and NTCP calculations, though spacing may be larger outside the target region. CT: MR image co-registration is essential. 8.8.3 Target Volume Plan conformally, with CT: MR co-registration. Treat in 2 phases. For Phase 1, the CTV is essentially the pre-op GTV, with or without an allowance for uncertainty in localisation. For Phase 2, the CTV is the post-op GTV. Add the stereotactic frame PTV margin of 0.3 cm. Outline critical normal structures, including the pituitary, the eyes and lenses, and often the optic nerves and chiasm. Grow these into PRVs. For further planning details see below. 8.8.4 Dose Prescription This is very individual. Aim for 65 - 70 Gy, optimising physical planning and fractionation . 8.8.5 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol.
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8.9
Intrinsic Spinal Cord Tumours
8.9.1 Treatment Policy Surgical resection is usually incomplete though occasionally an ependymoma of the cord may be completely resected. Myxopapillary ependymomas of the cauda equina and extraxial tumours are routinely excised completely. The radiotherapy dose is limited by cord tolerance. For spinal cord glioma grade 3 or 4 (GBM) start with chemotherapy, and commence RT urgently. 8.9.2 Treatment Planning Position supine or prone, depending on individual neurological function and build. As a guide, for cervical lesions, treat prone in an immobilisation shell. Thoracic lesions are usually best treated supine, which avoids movement of the target due to breathing; position the arms above the head, which avoids beams entering or exiting through them and allows lateral tattoos to be used. Lumbar lesions can be treated in either position. As a general guide, remember that the supine position is often more stable. Use CT planning, with slice spacing of 0.5 cm. It is possible, and desirable, to plan from CT even if metal work has been implanted. Likewise, MRI is possible and helpful, even with metal present. 8.9.3 Target Volume The CTV is the spinal canal, in the axial directions. Superior and inferior margins are usually 2 - 3 cm. Add a PTV margin of 1.0 cm, except for cervical lesions in patients in a head shell, when 0.5 cm is acceptable. Outline critical normal structures. These may include the kidneys or lungs. 8.9.4 Dose Prescription 50 Gy / 30 # at 1.67 Gy/#
1 phase
8.9.5 Implementation Take portal films or images as per department protocol.
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8.10 Cerebral Lymphoma 8.10.1 Surgical principles Lymphoma is characterised by periventricular lesions with homogenous enhancement. They are more common in the elderly and progress rapidly. Treatment is generally with a diagnostic biopsy followed by chemo / radiotherapy under the haematologists. Where a lymphoma is suspected do not give steroids pre-operatively. This can result in a negative biopsy. Debulking of lymphomas is usually impractical and has not been shown to be beneficial. Rapid investigation and treatment is important in this group as they progress quickly. Primary CNS lymphoma cases should be referred on to the haematologists at Addenbrookes, NNUHFT and Ipswich.
8.11 Spinal and Intracranial Sarcomas All patients with suspected or proven spinal or intracranial sarcomas must be referred to the sarcoma SMDT. Management will be undertaken in conjunction with spinal surgeons at RNOH or NHNN and neurosurgeons at NHNN. Detailed guidance for the management of spinal sarcomas will be developed by the sarcoma SMDTs.
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8.12
Leptomeningeal Carcinomatosis
8.12.1 Background Appropriate assessment and treatment of patients with leptomeningeal disease is required from within the Oncology Directorate and Haematology SDU. Leptomeningeal disease occurs in approximately 5% of patients with cancer. The median survival for untreated patients is 4-6 weeks. Radiotherapy to bulk disease and intrathecal chemotherapy increases the median survival to 3-6 months. Please see Appendix F for the leptomeningeal carcinomatosis diagram and Appendix G for the WHO Performance Status and Glasgow Coma Scale (GCS). 8.12.2 Factors influencing treatment
8.12.2.1 Good Risk Candidate likely to respond to treatment Performance Status 1,2 No neurological deficits No CSF flow abnormalities absent No Systemic disease Indolent natural history of disease
8.12.2.2 Poor Risk Candidate low likelihood of treatment response PS 3,4 Multiple neurological deficits Ventricular outflow obstruction Extensive systemic disease Aggressive disease
8.13 Therapy Target Rationale Radiation therapy to treat symptomatic sites, areas of bulk disease treat central core of mass lesions and nerve root lesions not reached by intrathecal chemotherapy. Intrathecal chemotherapy to treat microscopic tumour on meningeal surface and floating cells and prevent further seeding of meninges. Systemic therapy to treat systemic cancer patients who may suffer from progressive systemic disease. 8.13.1 Assessment, diagnosis and treatment selection Undertake neurological work up: Neurological examination MRI CSF examination
Diagnosis can be made on: Positive CSF cytology or

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Positive signs and symptoms with supportive radiological or CSF evidence or Positive radiology with supportive clinical or CSF evidence
Selection of treatment will be dependant on risk status: Poor risk patients should receive supportive care and/or radiotherapy to symptomatic sites. Good risk patients should receive radiotherapy to bulk disease and intrathecal chemotherapy.
8.13.2 Intrathecal chemotherapy To initiate intrathecal chemotherapy the Oncology team should co-ordinate the following: Request placement of an OMMAYA reservoir by the neurosurgeons by referring to neurosurgeons. (please contact Mr Price or Mr Watts directly and dont go through MDT) Review a CT head scan, performed post placement, to check the position of the OMAYA reservoir to ensure that it is satisfactory prior to referring the patient to the Haematology team. Note: The neurosurgeons will usually do this prior to the patient being discharged but may need reminding. Refer patient to Consultant Haematologist for the prescription and administration of intrathecal chemotherapy. When commenced on treatment the patient should be reviewed by the referring Oncologist on week one, four, seven, eleven and then monthly whilst receiving treatment or as per department protocol.
Note: There is a low risk of neutropenia from re-circulating Methotrexate. 8.13.3 Communication between Oncology and Haematology Teams Intrathecal chemotherapy will not be prescribed or administered by haematologists unless written instructions are documented within the patients medical notes. 8.13.4 Treatment Administration and Review Methotrexate 10mg intrathecally should be administered twice weekly each week for four weeks. A repeat lumbar puncture should then be performed by the Oncologist to reassess CSF (CSF drawn from the OMMAYA reservoir is not a substitute).
Note: An FBC and clotting should be taken and reviewed prior to the LP being performed. Treatment continuation: a) If the CSF is negative for malignant cells continue maintenance chemotherapy until progression or Methotrexate toxicities occur: Methotrexate 10mgs intrathecally twice weekly for two weeks followed by Methotrexate 10mgs twice weekly for one week every month.
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b) If the CSF is positive for malignant cells, continue induction therapy of Methotrexate 10mgs intrathecally twice weekly each week for 4 weeks and then re-assess CSF (LP by Oncologist) then: If CSF negative continue treatment as outlined in a) If CSF positive consider switching or stopping treatment
If the patient develops systemic side effects from Methotrexate at any point during treatment commence oral Folinic Acid rescue with Folinic Acid 15mgs PO qds for 24 hours after each intrathecal treatment.
9 Pathology Guidelines
See AngCN Document: AngCN-SSG-15 Pathology Guidelines for Brain and CNS for current version see AngCN website http://www.angliacancernetwork.nhs.uk/module_dm.php?menu_id=694&parent_id=44&level =3
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10
Evidence of Agreement
These Clinical Guidelines have been agreed by:

The Chair of the Network Board
Name: Paul Watson Organisation: NHS Suffolk Date agreed: 21/11/11

The Chair of the Brain CNS
Name: Sarah Jefferies Organisation: CUHFT Date agreed: 14/11/11

The NSSG Members
This document was discussed at the Brain and CNS meeting in October 2011 and was agreed to by all members. Document management
Document history
Review period: Authors:
2 years Dr Sarah Jefferies
Date placed on electronic library: Document Owner:
Nov 2011 Anglia Cancer Network Tel: 01638 608208

www.angliacancernetwork.nhs.uk
Version number as approved Unique identifier 2 AngCN-SSG-BC3 and published: no.: Monitoring the effectiveness of the Process a) Process for Monitoring compliance and Effectiveness - Review of compliance as determined by audit. Any non compliance to be presented by QA Manager to the AngCN Business Meeting on an annual basis the minutes of this meeting are retained for a minimum of five years. b) Standards/Key Performance Indicators This process forms part of a quality system working to, but not accredited to, International Standard BS EN ISO 9001:2008. The effectiveness of the process will be monitored in accordance with the methods given in the quality manual, AngCN-QM. Equality and Diversity Statement This document complies with the Suffolk PCT Equality and Diversity statement an EIA assessment is available on request to Anglia Cancer Network QA Manager, Gibson Centre, Exning Road, Newmarket, CB8 7JG. Disclaimer It is your responsibility to check against the electronic library that this printed out copy is the most recent issue of this document. Please notify any changes required to the Anglia Cancer Network Quality Assurance Manager
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11
Appendices
11.1 References Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer. 1991 Oct;64(4):769-74. Mihara F, Numaguchi Y, Rothman M, Sato S, Fiandaca MS. MR imaging of adult supratentorial astrocytomas: an attempt of semi-automatic grading. Radiat Med. 1995 JanFeb;13(1):5-9. Shaw EG, Seiferheld W, Scott C, et al: Reexamining the Radiation Therapy Oncology Group recursive partitioning analysis for Glioblastoma multiforme patients. Int J Radiat Oncol Biol Phys 57:S135-136, 2003 (suppl 2) Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10): 987-96 Recht LD, Lew R, and Smith TW. (1992) Suspected low-grade glioma: is deferring treatment safe? Ann Neurol., 31(4): 431-436. Al Okaili RN, Krejza J, Woo JH, Wolf RL, O'Rourke DM, Judy KD, Poptani H, and Melhem ER. (2007) Intraaxial Brain Masses: MR Imaging-based Diagnostic Strategy--Initial Experience. Radiology, 243(2): 539-550. Scott JN, Brasher PMA, Sevick RJ, Rewcastle NB, and Forsyth PA. (2002) How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology, 59(6): 947949. White ML, Zhang Y, Kirby P, and Ryken TC. (2005) Can Tumor Contrast Enhancement Be Used as a Criterion for Differentiating Tumor Grades of Oligodendrogliomas? American Journal of Neuroradiology, 26(4): 784-790. Jackson RJ, Fuller GN, bi-Said D, Lang FF, Gokaslan ZL, Shi WM, Wildrick DM, and Sawaya R. (2001) Limitations of stereotactic biopsy in the initial management of gliomas. NeuroOncology, 3(3): 193-200. Simpson D The recurrence of intracranial meningiomas after surgical treatment Journal of Neurology, Neurosurgery and Psychiatry 20:22-39, 1957 Van den Bent MJ, Afra D, de Witte O et al: EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council (2005) Long Term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005; 366 (9490): 985-90 Papagikos MA, Shaw EG, Steiber VW. Lessons learned from randomised clinical trials in adult low-grade glioma. Lancet Oncol 2005 6: 240-44 Leenstra JL, Rodriguez FJ, Frechette CM, Giannini C, Stafford SL, Pollock BE, Schild SE, Scheithauer BW, Jenkins RB, Buckner JC, Brown PD. Central neurocytoma: Management
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recommendations based on a 35-year experience. Int J Radiat Oncol Biol Phys. 2007;67(4):1145-54. Carella RJ, Ransohoff J, Newall J. Role of radiation therapy in the management of meningioma. Neurosurgery 1982; 10(3): 332-9 Glaholm J, Bloom HJ, Crow JH. The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 1990; 18(4): 755-61 Goldsmith BJ. Meningioma. In: Textbook of Radiation Oncology. Leibel SA and Phillips TL (eds). WB Saunders Co, Philadelphia, 1998. Grossman S. A, Krabak M. J (1999) Leptomeningeal carcinomatosis. Cancer Treatment Reviews, 25:103-119 Hunt DPJ, Freeman A, Morris LS, Burnet NG, Bird K, Davies TW, Laskey RA, Coleman N. Early recurrence of benign meningioma correlates with expression of mini-chromosome maintenance-2 protein. British Journal of Neurosurgery 2002; 16(1): 10-15 Milker-Zabel S, Zabel A, Schultz-Ertner D, Schlegel W, Wannenmacher M, Debus J. Fractionated stereotactic radiotherapy in patients with benign or atypical intracranial meninigioma: Long term experience and prognostic factors. Int J Radiat Oncol Biol Phys 2004; 61(3): 809-816 Taylor BW Jr, Marcus RB Jr, Friedman WA, Ballinger WE Jr, Million RR. The meningioma controversy: postoperative radiation therapy. Int J Radiat Oncol Biol Phys 1988; 15(2): 299304 Hahn BM, Schrell UM, Sauer R, Fahlbusch R, Ganslandt O, Grabenbauer GG. Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol. 2005; 74(2): 157-65. Loven D, Hardoff R, Sever ZB, Steinmetz AP, Gornish M, Rappaport ZH, Fenig E, Ram Z, Sulkes A. Non-resectable slow-growing meningiomas treated by hydroxyurea. J Neurooncol. 2004; 67(1-2): 221-6. Newton HB, Scott SR, Volpi C. Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg. 2004; 18(5): 495-9. Rogers SJ, Mosleh-Shirazi MA, Saran FH 2005. Radiotherapy of localised intracranial Germinoma: time to sever historical ties? Oncology.the lancet.com Vol 6. Combs SE, Volk S, Schultz-Ertner D, Huber PE, Thilmann C, Debus J. Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution. Int J Radiat Oncol Biol Phys 2005 63(1): 75-81 Combs SE, Thilmann C, Debus J, Schulz-Ertner D. Long-term outcome of stereotactic radiosurgery (SRS) in patients with acoustic neuromas. Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1341-7 Fuss M, Debus J, Lohr F, Huber P, Rhein B, Engenhart-Cabillic R, Wannenmacher M. Conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas. Int J Radiat Oncol Biol Phys 2000 Dec 1;48(5):1381-7.
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Horan G, Whitfield GA, Burton KE, Burnet NG, Jefferies SJ. Fractionated Conformal Radiotherapy in Vestibular Schwannoma: Early results from a single centre. Clin Oncol (2007), doi:10.1016/j.clon.2007.02.017 Springate SC, Weichselbaum RR. Radiation or surgery for chemodectoma of the temporal bone: a review of local control and complications. Head Neck 1990; 12(4): 303-7 Springate SC, Haraf D, Weichselbaum RR. Temporal bone chemodectomas--comparing surgery and radiation therapy. Oncology (Huntingt) 1991; 5(4): 131-7; Powell S, Peters N, Harmer C. Chemodectoma of the head and neck: results of treatment in 84 patients. Int J Radiat Oncol Biol Phys 1992; 22(5): 919-24
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11.2 Imaging Recommendations for Referring Clinicians
CT Head +/- contrast or MRI Head +/- gad
Probable metastasis/metastases*
Probable CNS primary
CT thorax, abdomen & pelvis MRI brain incl. gad, especially if solitary lesion LFTs, calcium, tumour markers
MRI brain incl. gad CXR
Image link all appropriate studies Call neurosurgical registrar (01223 245151 bleep 1560358) Refer to Addenbrookes MDT (fax 01223 274457) by Wednesday lunchtime
* A neuroscience MDT opinion may be appropriate to obtain a diagnosis, to remove a single metastasis or to treat a large symptomatic metastasis particularly in the cerebellum. An MRI is essential in these patients. Multiple small metastases in patients with very limited life expectancy do not require neuroscience MDT opinions.
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11.3 Leptomeningeal Carcinomatosis Diagram
Leptomeningeal carcinomatosis
Good risk
Poor risk
IT methotrexate local radiotherapy
Supportive care local RT
IT methotrexate 10 mg twice weekly for 4 weeks
If CSF cytology positive previouslyrepeat CSF cytology If CSF negative , MRI of craniospinal axis
CSF negative or response on imaging at non- irradiated sites IT methotrexate 10 mg twice weekly for 2 weeks followed by IT methotrexate 10 mg twice weekly for 1 week every month till progression or methotrexate toxicity
CSF positive or no response on imaging at non- irradiated sites
IT methotrexate 10 mg twice weekly for 4 weeks
CSF negative or response on imaging at non- irradiated sites
CSF positive or no response on imaging
Options switching to cytosar or triple IT, if patient still in good risk group Stop treatment
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11.4 Performance Status & Glasgow Coma Scale (GCS) The WHO general PS scale is routinely used in the assessment of patients. The Glasgow Coma Scale (GCS) is sometimes used by the neurosurgeons to describe general intellectual performance.
WHO Performance status 0= 1= 2= 3= 4= Able to carry out all normal activity without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out light work. Ambulatory and capable of all self-care but unable to carry out any work; up and about >50% of waking hours. Capable of only limited self-care; confined to bed or chair >50% of waking hours. Completely disabled. Cannot carry out any self-care; totally confined to bed or chair.
Glasgow Coma Scale (GCS) Eyes Open Spontaneously To speech To stimulus None 4 3 2 1 5 4 3 2 1 6 5 4 3 2 1
Best Verbal response Orientated Confused Inappropriate words Incomprehensible None Best motor response Obeys commands Localise stimulus Flexion - withdrawal Flexion - abnormal Extension No response Best score Worst 3 15
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11.5 Assessment of Vestibular Schwannoma Patients Unterberger's stepping test The Unterberger test, also Unterberger's stepping test, is a test used to help assess whether a patient has a vestibular pathology, and if so on which side. It is not useful for detecting central (brain) disorders of balance. Procedure: ask the patient to undertake stationary stepping for one minute with their eyes closed. A positive test is indicated by rotational movement of the patient towards the side of the lesion
House Brackmann clinical grading for facial nerve function House classification system: Grade Degree Description I Normal Normal facial movements; No synkinesis II Slight Mild deformity, mild synkinesis, good forehead function, slight asymmetry III Moderate Obvious facial weakness, forehead motion present, good eye closure, asymmetry, Bell's phenomenon present
IV Moderately Obvious weakness, increasing synkinesis; no forehead motion V Severe Very obvious facial paralysis, some tone present, cannot close eye VI Total Complete facial paralysis, absent tone Bell's phenomenon = upward outward turning of the eyeball as the patient attempts to close the eyelids. It indicates a peripheral lesion. 11.6 WHO tumour classification: The WHO grade has four categories of tumours: Grade I tumours are slow-growing, nonmalignant, and associated with longterm survival. Grade II tumours are relatively slow-growing but sometimes recur as highergrade tumours. They can be nonmalignant or malignant. Grade III tumours are malignant and often recur as higher grade tumours. Grade IV tumours reproduce rapidly and are very aggressive malignant tumours.
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11.7 Clinical Trials Portfolio The Manual for Cancer Services 2004 states that one of the responsibilities of the MDT Lead Clinician is To ensure mechanisms are in place to support entry of eligible patients into clinical trials. The infrastructure to support clinical trials activity is the responsibility of the West Anglia and Anglia East Cancer Research Networks (WACRN & AECRN) which provide facilities enabling patient entry into clinical trials and other well designed studies in all of its units. The Anglia Cancer Network Brain and CNS NSSG is committed to participation in high quality research studies and clinical trials. Whenever possible, patients should be considered for inclusion in local and national research studies and clinical trials. There is an NSSG agreed single list of clinical trials and research studies supported by the Neurosciences SMDT. This is updated at least annually. Further details and protocols are available as follows: AngCN Trust Cambridge University Hospital Foundation Trust Bedford Hospital NHS Trust Hinchingbrooke Health Care NHS Trust Peterborough and Stamford Hospitals NHS Trust Queen Elizabeth Hospital, Kings Lynn, NHS Trust West Suffolk Hospital NHS Trust Norfolk and Norwich University Hospital Foundation Trust James Paget University Hospital Foundation Trust Ipswich Hospital NHS Trust West Anglia Cancer Research Network (WACRN) 01223 256193
Roy.harris@addenbrookes.nhs.uk
Cancer Research Network
Anglia East Cancer Research Network (AECRN) 01603 289860 Natalie.Barber@nnuh.nhs.uk
Where patients have been enrolled into a clinical trial all aspects of a patient's treatment, assessments, and frequency and duration of follow-up must adhere to the protocol requirements for that clinical trial.
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11.8 National Guidelines National Guidelines for Primary CNS Lymphoma, Medulloblastoma, Optic Nerve Glioma and pineal tumours are awaiting publication. Please see the following link for details on further Guidance relating to Brain and CNS cancer: http://www.nice.org.uk/guidance/index.jsp?action=byTopic&o=7167
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