Clinical Guidelines for the Management of Neuro-Oncology

Transcription

1 Clinical Guidelines for the Management of Neuro-Oncology For approvals and version control see Document Management Record on page 37 Version: 3 Ref: AngCN_SSG_BC3_v3_NeuroOncology_Guidlines Page 1 of 47

2 1 Background and Scope Management of Brain Tumours in Primary and Secondary Care Imaging Other investigations Treatment Steroids Proton pump inhibitors Analgesia Anti-epileptics Surgical Management of High Grade Glioma No surgical intervention Biopsy De-bulking surgery Surgery for recurrence Surgery for other situations Post-operative considerations Surgical Management of Low Grade Glioma Image Guided Biopsy Tumour resection Surgical Management of Meningioma Surgical Principles Pathology Surgical Follow-up Protocol Oncological Management of Brain Tumours Radiotherapy Planning High Grade Gliomas Chemotherapy for High Grade Glioma Low Grade Gliomas Glioma Re-treatment Meningioma Metastases Treatment Policy Palliative care Surgery Stereotactic radiotherapy / radiosurgery Whole brain radiotherapy Chemotherapy (small cell lung cancer) Rare Tumours Neurocytoma Germinoma / Medulloblastoma Ependymoma (Intra-Cranial) Supratentorial ependymoma: Vestibular Schwannoma / Acoustic Neuroma Neurofibromatosis Type Glomus Tumours Skull Base Tumours (Chordoma / Chondrosarcoma) Intrinsic Spinal Cord Tumours Cerebral Lymphoma Spinal and Intracranial Sarcomas Leptomeningeal Carcinomatosis Therapy Target Rationale Pathology Guidelines Evidence of Agreement Appendices References...39 Page 2 of 47

3 11.2 Imaging Recommendations for Referring Clinicians Leptomeningeal Carcinomatosis Diagram Performance Status & Glasgow Coma Scale (GCS) Assessment of Vestibular Schwannoma Patients WHO tumour classification: Clinical Trials Portfolio National Guidelines...47 Page 3 of 47

4 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 patient s 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. Page 4 of 47

5 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. Page 5 of 47

6 Type of seizure Location Freqency Recommendation Focal Infrequent Levetiracetam 250mg o.d and increase after 1-2 weeks to 250mg b.d* or Sodium Valproate Chrono 300mg bd then increase by 200mg every 3-4 days according to tolerance and response** or Lamotrigine 25mg o.d for 14 days then increase to 50mg o.d* and clobazam 10-20mg (if needed) Focal Frequent levetiracetam 500mg bd increasing to 1000mg bd within 1 week generalised up to 1x per day or Sodium Valproate Chrono 300mg bd then increase by 200mg every 3-4 days according to tolerance and response** and consider adding clobazam 10-20mg Generalised Severe clusters Treat as per Trust Status Epilepticus Guideline status epilepticus Once stabilized convert to levetiracetum or lamotrigine under neurologist guidance 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 Page 6 of 47

7 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. 3.2 Biopsy 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 Page 7 of 47

8 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 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. Page 8 of 47

9 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 afternoon s surgical neuro-oncology clinic, give results and arrange follow up care with oncology / palliative care in accordance with that morning s MDT pathology discussions. Page 9 of 47

10 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: 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. 4.2 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. Page 10 of 47

11 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 meningioma s the Simpson grade is used to predict recurrence as follows: Simpson Description Risk of recurrence at 5 years Grade 1 Complete resection including dura 9% 2 Complete resection, dura coagulated 19% 3 Complete resection but dura left 29% 4 Subtotal resection 44% 5 Decompression alone 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. Page 11 of 47

12 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 it s 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. Page 12 of 47

13 6 Oncological Management of Brain Tumours 6.1 Radiotherapy Planning 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 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 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 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 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. Page 13 of 47

14 Neurological function. It is therefore extremely important to establish these parameters before making a decision on post-operative treatment 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 < 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 - Best Supportive care Severe residual deficit, eg hemiplegia intellectual impairment, confusion Use the following criteria to decide treatment for Grade III glioma: - Radical RT (54Gy/30#/6wks) Age < 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 - Best Supportive care Severe residual deficit, eg hemiplegia Intellectual impairment Confusion Page 14 of 47

15 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 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 Organs at Risk: Outline Pituitary, Orbits, Optic nerves, Optic Chiasm and Lenses Dose Prescription Grade 3 54 Gy/ 30# 2 phases (45/25 + 9/5) Grade 4 60 Gy/ 30# 2 phases (50/ /5) Treatment Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol Palliative Radiotherapy Treatment Planning The patient should be immobilised in a thermoplastic mask 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 Dose Prescription 30 Gy/ 6# / 2 weeks (ie 3x per week) Treatment Implementation PI/beam films as per departmental protocol Page 15 of 47

16 6.3 Chemotherapy for High Grade Glioma 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 Concomitant Temozolomide protocol Dose = 75mg/m 2 D1-42 (should not exceed 49 days) daily including weekends 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 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 Toxicity Absolute Neutrophil Count Platelet Count Value 0.5 and < and < 100 CTC Grade Action 2,3 Delay until normalisation 1,2,3 Delay until normalisation CTC non-haematological toxicity (except alopecia, N&V) Absolute Neutrophil Count <0.5 4 STOP Platelet Count <10 4 STOP CTC non-haematological toxicity (except alopecia, N&V 2 Delay until normalisation 3,4 STOP Following completion of radiotherapy organize follow-up to start adjuvant temozolomide for four weeks 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 Page 16 of 47

17 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 mg/m 2 ). Delay chemotherapy if FBC shows any of the following: WBC < 3.0 Neutrophils < 1.5 Platelets < 100 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 PCV chemotherapy (Procarbazine, CCNU, Vincristine) Day Drug Dose Route 1 CCNU 100 mg/m 2 (max 200 mg) PO bolus 1-10 Procarbazine 100 mg/m 2 (max 200 mg) PO 1 Vincristine 1.5 mg/m 2 (max 2 mg) IV bolus Cycle Repeat 6 weekly Investigations Before first course FBC U & E s, LFT s (+/- anticonvulsant levels, if appropriate) Before successive courses FBC LFT s (+/- anticonvulsant levels, if appropriate) 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 Temozolomide Day Drug Dose Route 1-5 Temozolomide 150 mg/m 2 if previously treated PO Page 17 of 47

18 Cycle: Repeat 4 weekly. Investigations: Before first course Before successive courses mg/m 2 if previously untreated PO FBC U & E s, LFT s (+/- anticonvulsant levels, if appropriate) FBC 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 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 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 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 Organs at Risk: Consider outlining: Pituitary, Orbits, Optic nerves, Optic Chiasm and Lenses Dose Prescription 54 Gy/ 30#/ 6 weeks in a single phase Page 18 of 47

19 6.4.5 Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol. 6.5 Glioma Re-treatment 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 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 Target Volume GTV - the abnormality as demonstrated on MRI CTV - allow a small margin in the region of 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 Dose Prescription 50 Gy/ 30#/ 6 weeks in a single phase Implementation Measure eye TLDs for future reference. Take portal films or images as per protocol. 6.6 Meningioma Treatment Policy All patients with meningioma should be discussed at the neuro-oncology MDM Radical RT - Treatment Planning 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 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. Page 19 of 47

20 Planning Conformal radiotherapy planning IMRT Planning 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 - CTV = GTV Grade 2 - along the meninges CTV = GTV + 1cm - at other surfaces CTV = GTV Grade 3 - along the meninges CTV = GTV cm - 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 Organs at Risk: these should be outlined including the pituitary, eyes, lenses, optic nerves and chiasm Dose Prescription Gy / # at 1.67Gy/ # Single phase Implementation Always measure eye TLDs for future reference. Take portal films or images as per protocol 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 Hydroxyurea To be considered where no further irradiation is feasible and there is recurrent bulk tumour on imaging. Hydroxyurea comes in 500mg tablets. Page 20 of 47

21 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 mg/kg/day 90% response at early follow up Hahn et al mg/kg/day 77% response at 2 years Loven et al mg/kg/day 10% response at early follow up Page 21 of 47

22 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 Chemotherapy (small cell lung cancer) Treatment Planning SRS is CT planned with MR fusion 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 For radical palliative solitary mets Whole brain 30Gy/15# / 40 Gy / 20 # Boost 14 Gy / 7 # Page 22 of 47

23 7.6.4 Stereotactic radiosurgery Whole brain 40 Gy / 20 # Boost 16 Gy / 1 90% isodose Implementation Take portal films or images as per protocol. For SRS: i) 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. ii) admit the patient for the night after the SRS. Page 23 of 47

24 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 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 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 Radiotherapy - Treatment Planning Immobilisation Perspex beam direction shell prone Imaging RTC/CT for CSA planning - ensure whole brain and spinal cord is imaged. Page 24 of 47

25 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 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 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 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/# Page 25 of 47

26 Ph1 - CSA 25Gy / 15 # Ph2 - Boost 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 55 Gy / 33 # at 1.67 Gy/# Ph1 - CSA 35 Gy / 21 # Ph2 - Boost 20 Gy / 12 # 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) 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 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 RT - Treatment Planning Immobilisation Perspex beam direction shell - normally supine unless lesion extends inferiorly below the base of skull when a prone shell will be required 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 Planning Conformal radiotherapy planning Page 26 of 47

27 Compensators may be required for treatment of post fossa lesions 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 cm margin 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 Dose Prescription: 55 Gy / 33 # in 1-2 phases Ph1 = 50 Gy / 30 # Ph2 = 5 Gy / 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: 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 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 Page 27 of 47

28 temporary and recovers 6-12 months after surgery. The majority of patients require a significant period of rehabilitation following surgery Radiotherapy This is an alternative to surgery and can be delivered in two ways: 1) Single fraction radiosurgery (Gamma Knife) 2) Fractionated conformal radiotherapy 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) 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 RT -Treatment Planning Immobilisation Relocatable SRT head frame patients who are PS 0 with good upper jaw dentition Perspex beam direction shell - supine 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 Planning Conformal radiotherapy planning use of personalised shielding blocks or mmlc Page 28 of 47

29 Target Volume GTV: the enhancing lesion as demonstrated on T1W + Gd MR sequence CTV: = GTV 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 Dose Prescription 50Gy/30# 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. Page 29 of 47