Guidelines For The Management Of Medulloblastoma (children .
Guidelines for the management ofMedulloblastoma (children 3years of age)1
OncologyDr Naureen Mushtaq (PI)Dr Afia ArifDr Syed Ahmer HamidDr Eric BouffetNeurosurgeryDr Syed Ather EnamDr Gohar JavedRadiologyDr Fatima MubarakRadiation OncologyDr Bilal Mazhar QureshiNeuro PathalogyDr Khurram MinhasEndocrinology Disorder in children with brain tumorDr Salman KirmaniPaediatric Palliative care PhysicianDr Shahzadi Resham2
Acknowledgement:These guidelines are supported by generous support of sponsor Sanofi Espoir Fondation forCapacity building of Pediatric Neuro-oncology in Pakistan. We are also thankful to all ourcoordinators of Pakistan s Pediatric Neuro Oncology group from different institutions for theircontributions.AEMC: Dr Hina Hashmi, Dr Raheela Mehmood, Dr Muhammad Ali Memon and Dr AyeshaSiddique, Children Hospital Lahore: Dr Shazia Riaz, Dr Alia Ahmed, Dr Samina Zaman, DrAmber Goraya. Children Hospital Multan: Dr Zulfikar Rana. CMH Rawalpindi: Dr TariqGhafoor. Indus Children Cancer Hospital: Dr Nida Zia. INMOL: Dr Ahmed Farooq and Dr AbuBakr Shahid. Jinnah Hospital Lahore: Dr Shahzad Hussain. JPMC Karachi : Dr LalRehman, DrKamran Saeed, Dr Shazia Kadri. Liaquat University of Medical and Health Sciences Jamshoro:Prof Dr Raja Riaz, Dr Madiha Memon. Mayo Hospital: Dr Shahzad Shams, Dr Hassan. MukhtarA Sheikh Hospital: Dr Aneela Darbar. NICH: Dr Uzma Imam, Dr Syed Habib. NIMRA-DrAmeen Abbasi. North West General Hospital Peshawar: Dr Tariq Khan, Dr Atif Munawar.Pakistan Institute of Medical Sciences, Islamabad: Dr Nuzhat Yasmeen. Pakistan Institute ofNeurosciences.Lahore: Prof Dr Khalid Mehmood , Dr Adeeb ul Hassan. Patel Hospital: DrYaseen Rauf Mushtaq. Shaukat Khanum Cancer Memorial Hospital: Dr Najma Shaheen, Dr SaadBin Anees, Dr Irfan Yousuf. Sidra Medical Center: Dr Ata Ur Rehman Maaz. Tawam HospitalJohn Hopkins Medicine International Al-Ain: Dr Mohammad Saghir.3
Contact DetailsOncology:Radiation Oncology:Dr Naureen MushtaqAssociate ProfessorAga Khan University Hospitalnaureen.mushtaq@aku.eduDr Bilal Mazhar QureshiAssistant ProfessorAga Khan UniversityHospitalbilal.qureshi@aku.eduDr Eric BouffetProfessorThe Hospital for Sick nology:Dr Salman KirmaniAssociate ProfessorAga Khan UniversityHospitalsalman.Kirmani@aku.eduDr Afia ArifFellow of Pediatric Neuro OncologyAga Khan University Hospitalafia.arif@aku.eduPediatric Palliative CarePhysician:Dr Ahmer HamidPediatric OncologistThe Indus Hospitalahmer.hamid@tih.org.pkDr Shahzadi ReshamAssistant ProfessorAga Khan ery:Dr Syed Ather EnamProfessor of NeurosurgeryChair of SurgeryAga Khan University Hospitalather.enam@aku.eduDr Gohar JavedAssistant ProfessorAga Khan University Hospitalgohar.javed@aku.eduRadiology:Dr Fatima MubarakAssociate ProfessorAga Khan University Hospitalfatima.mubarak@aku.eduHistopathalogy:Dr Khurram MinhasAssistant ProfessorAga Khan University Hospitalkhurram.minhas@aku.edu4
Table of ContentsIntroduction: .8Eligibility criteria: .8Patient Criteria .8Performance Level .9Prior Therapy .9Patient Criteria for Standard Risk Patients .9Patient Criteria for High risk patients: .10Radiology Guidelines .10Prior to surgery .10Imaging Technique .10Imaging interpretation .102- During Surgery .113-After Surgery and Prior to Radiotherapy .11Weekly During Radiotherapy .12Four Weeks Post Radiotherapy and Prior to Chemotherapy .12Surgical Guidelines .13Medulloblastoma with hydrocephalus.13Surgery for Medulloblastoma .13Post-Operative Care .14Neuropathology Guidelines .15Definition .15Subgroups: .15WNT subgroup: .15SHH subgroup: .15Group 3: .15Group 4: .16Radiation Therapy Guidelines;.171.Timing of Radiation Therapy: .182.Equipment: .18a.Modality .18b.Calibration .18c.Equipment .183.4.3-D Target volume and organ at risk definition.18a.Gross Tumor Volume (GTV) .19b.Clinical and Planning Target Volumes (CTV and PTV) .19c.Organs at Risk (OAR) .21Dosimetry .215
a. Prescription Point .21b. Dose Definition .22c. Prescribed Dose and Fractionation STANDARD RISK PATIENTS .22d. Dose Fractionation .22e. Dose Uniformity .22f. Treatment Interruptions .235.Treatment Technique .23Craniospinal Axis Irradiation.236.Normal tissue sparing .24Spinal Cord.24Optic Apparatus.24Vertebral Body .257.Supportive Care During Irradiation .25Hematologic .25Gastrointestinal .25Pneumocystis .25Varicella .258. Dose calculation and reporting .25Prescribed Dose .25Isodose Distributions .26Dose Volume Histograms .269. Quality Assurance and documentation .26Chemotherapy .28a.Aerage Risk Medulloblastoma concurrent chemotherapy during radiation 28b. Average Risk Medulloblastoma (Maintenance Chemotherapy) .28c.High Risk Medulloblastoma (Maintenance Chemotherapy) .29d.Dose Modification for Toxicities .30Vincristine Toxicity.30Hematopoietic Toxicity.31Nephrotoxicity .31Ototoxicity .31Hypomagnesemia .32Supportive Care Guidelines .32Supprotive Care Guidelines during Chemoradiotherapy. .32Venous Access: .32Antiemetics: .32Filgrastim (G-CSF): .326
Fever and Neutropenia:.32Prophylactic Antibiotics: .32Blood Products: .33Nutritional Support:.33Endocrine Guidelines: .33Required Evaluations Following Completion of Protocol Therapy .35References .367
Guidelines for the management of Medulloblastoma (children 3years of age)Introduction:Medulloblastoma is the most common malignant brain tumour in children and is a major causeof mortality and morbidity, particularly in low- and middle-income countries. Up to nw,medulloblastoma has been risk-stratified on the basis of clinical (age, metastasis and extent ofresection) and histological subtypes (classic, desmoplastic and anaplastic). However, recentlymedulloblastoma has been sub-grouped by using a variety of different genomic approaches, suchas gene expression profiling, micro-ribonucleic acid profiling and methylation array into 4groups, namely Wingless, Sonic hedgehog, Group 3 and Group 4. This new sub-grouping hasimportant therapeutic and prognostic implications. After acute leukaemia, brain tumour is thesecond most common malignancy in the paediatric age group. The improvement in outcome ofacute lymphoblastic leukaemia in low- and middle-income countries reflects the relativesimplicity of diagnostic procedures and management. Unlike leukaemia, the management of braintumours requires a complex multidisciplinary approach, including neuro-radiologists,neurosurgeons with a paediatric expertise, neuropathologists, radiation oncologists and neurooncologists. In addition, the equipment required for the diagnosis (magnetic resonance imagingscan, histological, molecular and genetic techniques) and the management (operating room,radiation facilities) is a limiting factor in countries with limited resources. In Pakistan, there arevery few centres able to treat children with brain tumours. The current literature review wasplanned to provide an update on the management of this tumour.Key Words: Childhood brain tumours, Medulloblastoma, WNT, SHH.Eligibility criteria:Patient CriteriaAge:Patients must be greater than or equal to 3 years and less than 22 years at the time of diagnosis.Diagnosis:The presence of a posterior fossa medulloblastoma as determined by institutional pathologicevaluation.Preoperative and postoperative cranial MRI with and without contrast must be available. Pre(better) or early postoperative MRI scan of the spine as well.Assessment must include a pre-operative (within 5 days prior to surgery) or postoperativeenhanced MRI of the spine within 28 days after surgery.Cytological examination of CSF performed after surgery but before the time of enrollment.(minimum 14 days after tumour resection)False positive cytology can occur within 10 days of surgery. Patients with positive CSF cytologyobtained before 10 days after surgery may have cytology repeated to determine eligibility.8
Performance LevelPatients must have a Karnofsky performance level of 50 for patients 16 years of age or aLansky performance scale of 30 for patients 16 years of age.Prior TherapyPatients must have no previous radiotherapy or chemotherapy other than corticosteroids.OrganFunction Requirements:a- Adequate renal function defined as:- Creatinine clearance or radioisotope GFR 70ml/min/1.73m2 OR- A serum creatinine based on age/gender as follows:Age Maximum Serum Creatinine (mg/dL)b- Adequate liver function defined as:- Total bilirubin 1.5 x upper limit of normal (ULN) for age, and- SGOT (AST) or SGPT (ALT) 3 x upper limit of normal (ULN) for age.c- Adequate Bone Marrow Function Defined as:- Peripheral absolute neutrophil count (ANC) 1500/μL- Platelet Count 100,000/μL (transfusion independent)- Hemoglobin greater than 10 gm/dL, (may receive RBC transfusions)Patient Criteria for Standard Risk Patients Patients with brain stem involvement are eligible. Presence of minimal volume, non-disseminated disease, as defined by the following criteria:1) There must be unequivocal evidence that the maximal cross-sectional area of residualtumor is 1.5 cm2 or less on MRI, performed with contrast imaging (preferably within 48hours, and at most 28 days following surgery) upon elimination of the tumor.2) No evidence of metastatic disease in the head, spine, or CSF.9
Patient Criteria for High risk patients:Newly diagnosed, previously untreated:1) M0 Medulloblastoma with 1.5 cm2 residual;2) M Medulloblastoma;3) M0 or M ).Patients with diffusely anaplastic medulloblastoma are eligible regardless of M-stage or residualtumor.Radiology Guidelines;Prior to surgery (when possible)1- MRI Brain and Spine2- MRI brain and spine (with contrast) should be done in all patients suspected of havingmedulloblastoma, who are referred to your center prior to surgery. In case surgery hadbeen done in an outside hospital, all pre-surgery scans should be obtained and reviewedin your center.Imaging TechniqueAll patients should underwent brain MR imaging atleast at 0.5T.Following sequences should be obtained: axial and coronal T2 FSE (TR/TE, 2700/100 ms),axial or Coronol FLAIR (TR/TE, 9000/120 ms; TI, 2200 ms), precontrast T1 spin-echo andcontrast-enhanced T1 spoiled gradient-recalled echo (TR/TE, 8/3 ms; 1-mm section thickness, 0skip), followed by 2 planes of contrast-enhanced T1 spin-echo (TR/TE, 600–700/20 ms; 5-mmsection thickness, 0.5 skip).All, patients should undergo DWI; b-value of 1000 s/mm2; 3 directions; 4-mm thickness, 0 skip)SWI/GRE/T2* is optional.Imaging interpretation:All reports should comment on:1.tumor location, 2.enhancement pattern,3. cysts/cavities, 4.hemorrhage/ mineralization,5.intracranial or leptomeningeal seeding, 6.tumor margin, 7.necrosis as suggested by ringenhancement“tumor location” should be defined as midline vermian/fourth ventricle, cerebellar hemisphere,or cerebellar peduncle/cerebellopontine angle cistern (CP/CPA).“Tumor margin” should be characterized as ill-defined if 50% of the margin could not bedistinguished from the surrounding cerebellar parenchyma on the basis of all imagingsequences.“Enhancement pattern” should be defined as minimal/none if 10% was estimated to enhance,solid if 90% of the tumor volume was estimated to enhance, and heterogeneous if varyingdegrees of enhancement were seen in 10%–90% of the tumor volume on the basis ofradiologist’s visual assessments.10
Low signal on 2D gradient recalled-echo or bright on T1W should be used to detecthemorrhage/mineralization.Tumour size should be given in three dimensions and try best to give volume. Formula fortumour volume is: Tumor volume length x width2/2, where length represents thelargest tumor diameter and width represents the perpendicular tumor diameter.Measurements should be taken on postcontrast or T2W/FLAIR.Immediate postop scan should be performed in 24-48 hours and should be MRI Brain.Characteristic MR imagingfeatures according tomedulloblastoma molecularsubgroups. A, In the top row,characteristic location ofWNT tumors in the CP/CPAregion Is shown.B,in the second row, SHHtumors are predominantlylocated in the cerebellarhemispheres.C ,In the third row ,group 3tumors are located in themidline/ fourth ventricle andshow enhancement and illdefined features against theadjacent brain parenchyma.D, In the fourth row, group4 tumors are also located inthe midline fourth ventriclebut tend to show minimal orno enhancement.2- During SurgeryAt surgery, every effort should be made to remove the tumor completely. If not possible, thenthe neurosurgeon should describe, in detail, sites where tumor is believed to remain. Tumormaterials from the biopsy, or from materials collected by the surgical vacuum sucker in a steriletrap should be submitted to Pathology for frozen section (if possible) and.histopathology.3-After Surgery and Prior to RadiotherapyMRI brain with contrast (MRI is preferred) and MRI spine with gadolinium if possible theseexaminations should be performed within 72 hours (if not done before) , or between 18-21 dayspost-op. This is believed to minimize the chances of post-op change being confused with residualtumor. Lumbar CSF cytology examination must be obtained pre-operatively or within 31 daysfollowing surgery. The optimal time for obtaining CSF is 2-3 weeks following surgery.Ventricular CSF (either pre and post-op) may be used only if a post-operative spinal tap is11
contraindicated. CSF should be sampled post op and prior to starting radiotherapy, for cell count,cytology, glucose and protein (if not already performed at the time of surgery).1. CBC, differential and platelet count2. Neurological examinationWeekly During Radiotherapyii. Neurological examination including monitoring for signs of vincristine toxicity.iii. CBC, differential and platelet count (where bone marrow depletion occurs, thesemust be carried out more frequently). It is essential that interruptions totreatment are kept as infrequent, and for as short duration as possible.Four Weeks Post Radiotherapy and Prior to Chemotherapyiv. Neurological examinationv. CBC and differential count, SGOT, SGPT, bilirubin, creatinine and BUN, urineanalysis.vi. MRI brain (CT of the brain may be used if this was the initial diagnostic tool;consistency of diagnostic examinations during follow up is important).vii. MRI spine with gadolinium, only if prior evidence of spinal mets, a positive CSFor new symptoms suggestive of spinal mets.viii. CSF should be sampled for cell count, cytology, glucose and protein ifpreviously positive.ix. Audiogram before start of chemotherapy and after every other chemotherapycycle.12
Surgical Guidelines:Presentation of medulloblastoma in pediatric population may be due to local mass effect of thelesion in the posterior fossa, but more commonly it presents with hydrocephalus and raisedintracranial pressure.Medulloblastoma with hydrocephalus:The hydrocephalus is most commonly due to blockage of the CSF pathway in the fourth ventricleor at the cerebral aqueduct or the outflow foramen. The best strategy would be a definitiveprocedure with resection of tumor and concomitant opening of the CSF pathway. CSF pathwaycan be opened up even without gross total resection of the tumor in most of the cases.A shunt such as ventriculoperitoneal shunt (VPS) should be avoided, if possible. If the patientpresents with acute hydrocephalus and logistics do not allow urgent surgery for the tumor, anexternal ventriculostomy drain (EVD), preferably with long subcutaneous tunnel, can beconsidered. Alternatively, Endoscopic Third Ventriculostomy (ETV) can also be considered. Theproblem with VPS is that the child is then committed to a foreign object for the rest of its life. Inrare instances, it may lead to reverse herniation or seeding of the abdominal cavity with the tumor.One unique problem seen in Pakistan (probably seen in other LMICs too) is the regression of theparents into denial about the tumor. This happens because treating hydrocephalus leads toremarkable improvement of symptoms. In these cases, the parents tend to ignore the primarydisease and fail to follow up. When patient does present back to the oncologist or the surgeon,the tumor is grown tremendously or has seeded into CSF spaces. Therefore, putting VPS is nota good strategy. In rare instances when adequate neurosurgical facility is not within reasonablereach, or nutritional status of the child prohibits tumor surgery, VPS can be considered to avoidany sudden herniation of the brain but then the neurosurgeon has the obligation to keep a closeeye on the patient and to ensure that the patient eventually gets definitive surgical treatment.Wherever possible, ETV should be preferred over VPS.Surgery for Medulloblastoma:Pre-op screening of the spine for metastases is highly recommended. Pre-op counselling of thepatient’s parents with pediatric neuro-oncologist is one of the most important steps in preparationof surgery.The surgery should be performed by a neurosurgeon with experience and expertise in posteriorfossa surgery. The misconception that a pediatric neurosurgeon should do the surgery of thistumor needs to be rectified. What is required, is a neurosurgeon with adequate experience inbrain tumor surgery and particularly in posterior fossa tumor surgery.The surgery for tumor should be carried out in institutions that have a suitable team to handle thiscase in the OR and during post-operative care. The team of anesthesiology should be experiencedin pediatric neurosurgical cases to manage volume loss intraoperatively and to use intravenousfluid and blood transfusion prudently. A team of pediatricians should be available to co-managethe patient during post-operative period.For surgical technique, prone position with head and neck flexed (Concorde position) and amidline incision works reasonably well in most of the cases. Sitting position can be consideredbased on the experience and familiarity of the surgeon, the anesthesiologist and the OR team with13
that position. If a surgeon is meticulous in her/his technique, there is no additional significantbenefit of sitting position, but there is definitely a higher risk of air embolism and other risks withthe sitting position. Use of Mayfield pins is advisable, and the torque and depth of the pins haveto be adjusted based on the age of the child. The surgeon can opt to avoid Mayfield pins and usepadded horseshoe, in children 3 years or below.If the CSF diversion was not performed before tumor surgery, a decision to place an EVDtemporarily is reasonable. This can be done preferably through Frazier’s point in the occipitalregion. A sample of 20-30 cc of CSF for cytology can be considered at this juncture.Dissection of the muscle tissue has to be carried out in the midline raphe to avoid excessive bloodloss. Every attempt should be made to leave a cuff of muscles at the level of inion extendinglaterally and avoiding exposing the skull to the point where the aponeurosis ends. This cuff ofmuscle provides a good closure to prevent post-operative CSF leak or formation ofpseudomeningocele. Besides posterior fossa craniotomy, the surgeon should decide about theremoval of C-1 arch, depending on the extent of the disease and need of exposure forvisualization.Every effort should be made to achieve gross total resection (GTR) of the tumor if possible, butin many cases attachment of the tumor to the obex or the floor of the fourth ventricle may preventGTR, in these cases the strategy should be to attempt Maximum Safe Resection (MSR). It is bestto define the extent of the tumor initially, and to temporarily plug the opening of cerebral aqueductto prevent blood entering into rest of the ventricular system. For very large tumors, defining theextent of the tumor may have to be delayed until significant tumor debulking has been achieved.To minimize the chance of cerebellar mutism, it is best to avoid splitting the vermis and removalof tumor from the roof of the fourth ventricle and the cerebellar peduncles is done with a lot ofcaution and deliberation. With appropriate positioning of the cranium, the tumor can be excisedthrough the foramen of Magendie, which is usually enlarged by this time.Closure of the dura is best done with the help of a patch obtained from the aponeurosis obtainedby sub-galeal dissection further cranial to the muscle cuff at the inion. Water-tight closure is theprimary objective at closure.Post-Operative Care:It is best if the patient is extubated in the OR post-operatively and is taken care of in a highdependency unit for 24 to 48 hours. The EVD should be drained at 10-15 cm. It should bepulled out after 48 hours if possible once it is ascertained that there is not much blood in theCSF.The management of the patient during the post-operative period should be done by the team ofneurosurgeon as well as the pediatrician. Pediatric neuro-oncologist, should be involved in thecare too.An MR with contrast should be obtained within first 48 hours. If it is delayed beyond 72 hoursthen it is best delayed for 3 weeks but should not be delayed more than 4 weeks.14
Neuropathology Guidelines:Medulloblastoma is the most common CNS embryonal tumor and the most common malignanttumors of childhood. Medulloblastoma falls under CNS embryonal tumors and is classifiedaccording to molecular characteristics in addition to histopathological features. Histopathologicalclassification has been retained, due to its clinical utility when mocular nalysis is limited or notfeasible.DefinitionThese are embryonal tumors arising in cerebellum or dorsal brain stem, presenting mainly inchildhood and consisting of densely packed small round undifferentiated cells with mild tomoderate nuclear pleomorphism and a high mitotic count.Subgroups:With the advances in genomics, gene expression profiling, and DNA methylation analysis themedulloblastomas have been divided into subgroups. The current integrated classification ofmedulloblastoma takes into account histological subtype a
North West General Hospital Peshawar: Dr Tariq Khan, Dr Atif Munawar. Pakistan Institute of Medical Sciences, Islamabad: Dr Nuzhat Yasmeen. Pakistan Institute of Neurosciences.Lahore: Prof Dr Khalid Mehmood , Dr Adeeb ul Hassan. Patel Hospital: Dr Yaseen Rauf Mushtaq. Shaukat Khanum Cancer Memorial Hospital:
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