CCLG INTERIM GUIDANCE area/Treatment guideline… · It is based on post operative conventional craniospinal radiotherapy with ... CCLG Interim Guidance for High Risk Medulloblastoma

CCLG Interim Guidance for High Risk Medulloblastoma 1

Children’s Cancer and Leukaemia Group

Interim Guidance for High Risk Medulloblastoma

January 2015

Based on SJMB 03 Protocol

Reproduced by kind permission of Professor A Gajjar

St Judes Childrens Research Hospital, Memphis

USA

Professor Simon Bailey Dr Juliet Hale

Professor Barry Pizer Dr James Hayden

Dr Heidi Traunecker Dr Jairam Sastry

Dr Gail Horan Dr Joanne Lewis

The CCLG does not sponsor or indemnify the treatment detailed here. This guidance based on one published treatment strategy was developed to aide clinicians in managing this rare patient group and is for use at the sole discretion of treating clinicians who retain professional responsibility for their actions and treatment decisions. Until the development of national or international research studies, guidance that appraises the literature and offers treatment strategies will fill the gap and is published at the CCLG website


Contacts Professor Simon Bailey – simon.bailey @ncl.ac.uk

Sir James Spence Institute of Child Health Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne NE1 4LP Phone. 0191 2824068

Dr Juliet Hale – [email protected]

Paediatric Oncology Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne NE1 4LP Phone. 0191 2824101

Professor Barry Pizer – [email protected] Department of Paediatric Oncology Alder Hey Hospital Eaton Road Liverpool L12 2AP Phone. 0151 293 3679

Dr James Hayden– [email protected] Department of Paediatric Oncology Alder Hey Hospital Eaton Road Liverpool L12 2AP Phone. 0151 293 3679

Dr Heidi Traunecker- [email protected]

Consultant Paediatric Oncologist Department of Paediatric Oncology University Hospital for Wales Heath Park Cardiff CF14 4XW Phone 02920742285


Dr Jairam Sastry - [email protected] Consultant Paediatric Oncologist Royal Hospital for Sick Children Dalnair street, Yorkhill Glasgow G3 8SJ Phone: 0141 2321894 Email: [email protected]

Dr Gail Horan - [email protected]

Consultant Clinical Oncologist, Oncology Centre, Box 193, Addenbrooke's NHS Trust, Hills Road Cambridge CB2 0QQ Phone 01223 217020 Dr Joanne Lewis – [email protected] Consultant Clinical Oncologist Northern Centre for Cancer Treatment Freeman Hospital Newcastle upon Tyne NE7 7DN Phone 0191 2138471 Acknowledgments Paediatric Oncology Pharmacist Group Steering committee for assistance with chemotherapy administration information Contact Caroline Osborne [email protected] Principal Paediatric Oncology Pharmacist Alder Hey Children’s NHS Foundation TrustEaton Road Liverpool L12 2AP


Contents Page

1) Introduction and Definitions 5

2) Inclusion Criteria 5

3) Treatment Outline 6

4) Stem cell collection 7

5) Radiotherapy 8

6) Chemotherapy 12

7) Dose modifications 13

8) Supportive care drugs 15

9) Suggested monitoring 15

10) Toxicity Monitoring 15

11) Appendix A : Chemotherapy Prescribing Guidance 16

12) Appendix B: Carboplatin dosing tables. 19


Guidance for high risk medulloblastoma This guidance based on one published treatment strategy was developed to aid clinicians in managing this rare patient group and is for use at the sole discretion of treating clinicians who retain professional responsibility for their actions and treatment decisions. Until the development of national or international research studies, guidance that appraises the literature and offer treatment strategies will fill the gap and is published at the CCLG website

This interim treatment guidance is based on the St Jude’s MB03 protocol. It has been chosen as one therapy option following the discontinuation of the use of the “Milan” protocol for high risk medulloblastoma, in the United Kingdom.

It is based on post operative conventional craniospinal radiotherapy with boost to the tumour bed and metastatic sites, given at risk stratified doses followed by 4 sequential courses of high dose cyclophosphamide and cisplatin with stem cell support. This interim guidance does not contain the rationale behind the strategy (refer to Chintagumpala et al., 2009, Neuro Oncol, 11, 33-40; and Gajjar et al., 2006, Lancet Oncol, 7, 813-20).

Definition

High risk medulloblastoma is defined as a medulloblastoma with one or more of the features below:

1. M1-M3 disease 2. Large cell or anaplastic morphology 3. Unresectable residual tumour of > 1.5 cm2 4. MYC or NMYC amplified tumours

Inclusion Criteria

1. High risk medulloblastoma as defined above. 2. Age between 3-21 years at the time of diagnosis. 3. No previous radiotherapy or chemotherapy. 4. Patients must begin treatment as outlined in the protocol within 31 days of definitive

surgery. 5. Diagnostic LP at least 10 days post operatively to define circulating malignant cells as

per standard practice 6. Normal renal function as defined by a corrected GFR ≥ 80 mL/min/1.73 m2. 7. Normal liver function as defined by an ALT concentration < 5 x the normal

concentration and a bilirubin concentration <30 μmol/L 8. Normal bone marrow function as defined by an absolute neutrophil count ANC >1 x

109/L and platelets >100 x 109/L. 9. Adequate performance status: 10. Female patients of childbearing age must not be pregnant (confirmed by pregnancy

test) or lactating and, if appropriate, must use effective contraceptive measures during therapy. Male patients who are sexually active must use appropriate barrier methods of contraception, during therapy.

11. Echocardiogram fractional shortening ≥ 29%


Treatment Outline High Risk Medulloblastoma

Craniospinal irradiation +Primary Site Boost +Local mets Boost

Craniospinal axis –36Gy/20# Residual tumour & M1

OR 39.6 Gy/ 22# M2-3

+3D CRT boost to tumour bed to total dose 55.8Gy / 31# for all patients

M2/3 – appropriate cases boost to metastatic sites to 50.4Gy /28#

High risk medulloblastoma • M1 – 3 • Large cell / anaplastic morphology • Residual tumour after surgery > 1.5cm2 • MYC or NMYC amplification

Stem cell harvest

Weekly bloods

6 week break

4 cycles of high dose chemotherapy with PBSC support Day –4 Cisplatin 75 mg/m2 IV over 6hrs and Vincristine 1 mg/m2 (max 2 mg) IV bolus Day -3 Cyclophosphamide 2 g/m2 IV over 1 hr, mesna by continuous infusion Day -2 Cyclophosphamide 2 g/m2 IV over 1 hr, mesna by continuous infusion Day -1 Hydration after completion of chemotherapy Day 0 Infusion of PBSC Day +4 G-CSF 5 microgram/kg/day SC/IV daily until ANC >1 x 109/L for 2 consecutive days Day +6 Vincristine 1 mg/m2 (max 2 mg) Repeat cycles every 4 weeks. Prior to next cycle of chemotherapy ANC >1x 109 L, platelets > 50 x 109 L, and Hb >80 gm/L , acceptable hearing and renal function MRI brain, MRI spine and LP after cycle 2.


Summary flow sheet for chemotherapy

Notes:

1. Chemotherapy starts 6 weeks after radiotherapy 2. Repeat cycles every 4 weeks 3. Prior to each cycle of chemotherapy ANC >1 x 109/L, platelets >50 x 109/L, and Hb

>80 gm/L. 4. Prior to each cycle check blood biochemistry – electrolytes, creatinine, urea, ALT,

AST, Alkaline phosphatase, bilirubin, albumin, magnesium, calcium, phosphate. 5. MRI brain, MRI spine and LP after cycle 2. 6. Prior to first and third cycle of chemotherapy, perform estimation of GFR by

clearance of radioisotope and echocardiogram at end of treatment 7. Audiometry prior to each cycle and at the end of treatment

Stem Cell collection.

1. This should be undertaken as per local guidance for stem cell collection in accordance with JACIE regulations.

2. A steady state harvest prior to radiotherapy is recommended. 3. G-CSF dose of 10 micrograms /kg/day for steady state harvest with collection on

Day 5 or as per local policy. 4. It is recommended that 2 x 106 CD 34+ cells/kg per cycle of chemotherapy are

collected and frozen in at least 4 appropriate aliquots (ie a minimum of 4 bags of 2 x 106 CD 34+ cells/kg in total).


Radiotherapy

Overview

Craniospinal irradiation (CSI) doses will be 36-39.6 Gy. The CSI component of treatment is planned and administered in a relatively conventional manner; however, irradiation of the primary site boost after CSI is best delivered with conformal planning. Total dose to boost PTV will be 55.8Gy. Sites of brain or spinal metastasis (M2 & M3) to boost also to 50.4Gy (if felt appropriate). The guidance is for RT techniques to provide consistency in the targeting, dosimetry and reporting.

Target Volume Definitions

The volumes that will be targeted and treated are defined in this section and follow standard practice in radiotherapy.

Craniospinal Irradiation (CSI): The CSI volume includes the entire subarachnoid volume with special attention given to include the cribriform plate and temporal fossae intracranially and the inferior aspect of the thecal sac (defined on the pre-operative MRI). The full width of the spinal subarachnoid space should be included.

Tumour Bed Boost - Gross Tumour Volume (GTV): The GTV includes all gross residual tumour and/or the tumour bed at the primary site based on the initial pre-operative MRI that defines the tissues initially involved with disease anatomically and the post-operative and pre-irradiation MRI that identify residual disease and/or the tumour bed. The GTV in most cases will be a contracted or collapsed tumour bed. Tissue defects resulting from surgical approaches will not be included as part of the GTV when not previously involved by tumour.

Tumour Bed Boost - Clinical Target Volume (CTV): The CTV includes the GTV with an added margin that is meant to treat subclinical microscopic disease and is anatomically confined (i.e., the CTV is limited to the confines of the bony calvarium, falx and tentorium where applicable or extends up to but not beyond neuroanatomic structures through which tumour extension or invasion is certain not to have occurred); the CTV margin will be 0.5 cm for all patients. When the GTV approaches the boundary of an anatomic compartment, the CTV will extend up to and include the boundary.

Tumour Bed Boost - Planning Target Volume (PTV): A margin is added to the CTV in 3-dimensions to create the PTV. It is geometric and not anatomically defined. The purpose of the PTV is to account for uncertainty in immobilisation, image registration and daily variability in patient positioning. The PTV margin is 0.3-0.5 cm, depending on each centre’s immobilisation accuracy. Given that the CTV is confined to the intracranial space, the PTV may extend into or beyond bone but is unlikely to extend beyond the surface of the patient.

Extra Note: If the GTV is not anterior to the posterior aspect of the brainstem, the anterior border of the CTV may be limited to the center of the brainstem in axial extent. The primary site PTV will receive a cumulative dose of 55.8 Gy; in patients with significant measurable residual tumour (>1.5 cm2 or 1.4 cm in greatest diameter), an additional local boost to 59.4 Gy can be considered at the investigator's option using a CTV of 0.5 cm and PTV of 0.3-0.5 cm.


Metastatic Target Volume (MTV): Overt metastatic disease > 1cm in maximal diameter will define a volume or volumes for potential boost irradiation. The MTV will include the contoured lesion(s) with a margin of 0.5cm. Intracranially, the aggregate MTV+PTV will not exceed 25% of the intracranial volume. Intraspinally, the MTV will not exceed 8 consecutive or 10 total spinal segments. The St Judes team have advised that boost doses are in a range between 45Gy and 50.4Gy depending on volume of metastatic boost / number of lesions.

Dosimetry and Logistics

1) Craniospinal Dosimetry: Dose will be measured at the midplane of the cranial volume and at the posterior border of the vertebral body the spinal field(s) including the dose at the central ray. Effort should be made to minimise inhomogeneity at the craniocervical junction when possible and the gradient of dose across the spinal cord.

2) 3-D Dosimetry - Coverage: The prescription point for each 3-dimensional target volume is at or near the center of the volume and may be a point other than the central axis. The goal is to prescribe to the highest isodose surface that encompasses the PTV with the least inhomogeneity. The entire PTV should be encompassed within the 100% isodose surface, although 95% is acceptable (i.e., 100% of the PTV receives at least 95% of the prescription dose). In situations where the spinal cord, optic chiasm or nerves will exceed the specified tolerance levels, a reduction in the targeted volume (i.e., conedown) will be required that may underdose the PTV, CTV or GTV in the region of the avoided critical structure. It has been observed that the dosimetry of superficial tumors can be problematic. Treatment planning systems demonstrate underdosage of the PTV based on proximity to the skin surface. In such cases, bolus is not required and efforts should be made to verify coverage of the targeted volumes by other means.

3) 3-D Dosimetry - Uniformity: Tissue inhomogeneity corrections are not required. No more than 10% of the PTV should receive greater than 110% of the prescription dose. Treatment dosimetry should spare the spinal cord, brainstem, optic chiasm, and optic nerves from receiving more than the prescribed daily dose.

4) Dose Fractionation: Patients will receive one fraction of 1.8 Gy per day, five days per week. Exceptions will include logistical considerations owing to holidays, weather, equipment failure and the need to complete the course of treatment in the least number of elapsed days.

Radiation Doses by Treatment Volume (cumulative dose in Gy)

Disease Status CSI Primary Site Spinal/Intra- cranial Boost to metastatic sites

High Risk Medulloblastoma M0-1 M2-3

36

39.6

55.8 55.8

50.4


Treatment Interruptions: CSI may be interrupted as necessary for medical status (e.g.VP shunt surgery, neurologic or general medical problems). Treatment may be interrupted for platelet count <20 x 109/L if the count cannot be supported to a level of >40 x 109/L or if neutrophil<0.5 x ; 109/L consider GCSF. Interruption shall be defined as missing >4 consecutive days during the course of irradiation.

Sequencing Contingencies: CSI will generally be given first, followed by boost therapy. Boost therapy may be initiated prior to craniospinal irradiation if required by the medical condition. In all cases when CSI is deferred, it should be initiated as soon as medically feasible, before the completion of boost therapy if feasible. If CSI is interrupted for >4 days for medical reasons, the boost should be started until CSI can be resumed.

Treatment Planning and Delivery Techniques

1) Craniospinal Irradiation: Patients may be simulated and treated in the prone or supine position using customized immobilisation devices that allow for verification of cranial and spinal field junctions. Treatment will be given using standard techniques, encompassing the entire subarachnoid volume (both intracranial and intraspinal). The technique should assure coverage at the cribriform plate and temporal fossae intracranially; the full width of the spinal subarachnoid space (dosimetrically to include the medial aspect of the neural foramina) down to the bottom of the thecal space (as indicated by sagittal spinal MRI).

2) Craniospinal Irradiation-CT Planning: CT studies will be performed whenever possible and the information may be used for craniocaudal intensity modulation (optional). For the cranial component of treatment, the external contours of the skull and neck are viewed in the AP direction and points are chosen to divide the cranial field into 2-4 fields to achieve a field-within-a-field plan and lateral homogeneity over the craniocervical junction. For the spinal component of treatment, the spinal cord and canal are contoured and viewed laterally and points are chosen to divide the spinal field into 4-6 fields to achieve field-within-a-field plan and antero-posterior homogeneity over the spinal cord and thecal sac.

Tumour Bed Boost Irradiation: The treatment planning objectives for the tumour bed component of treatment are to ensure target volume (PTV) coverage, minimize inhomogeneity, respect normal tissue tolerances and minimise dose to the supratentorial brain, cochleae and hypothalamic-pituitary unit. The full spectrum of conformal treatment techniques may be used including forward or inverse planned beam’s eye view conformal radiation therapy and step and shoot or dynamic MLC intensity modulated radiation therapy.

Tumour Bed Boost Irradiation – CT and MR Planning: Patients may be simulated and treated in the supine or prone position. A treatment planning CT is required and should be performed as close to the start of boost treatment as possible. Registration of MRI to CT is encouraged using a 3-dimensionally acquired post-Gd T1-weighted data set formatted in the transverse plane and matching the section thickness of the CT study. Other data sets representing alternative MR sequences may be registered and used as needed. Whenever feasible the MR studies for RT planning should be obtained as close as possible to the start of boost treatment (about the time of simulation) to account for changes in ventricular volumes, the operative site and extra-axial fluid collections.

CT ONLY PLANNING -When MR registration is not available the following structures will be contoured: GTV, CTV, PTV, the outer (skin) surface of the head and neck regions, entire brain, eyes, optic nerves, optic chiasm, pituitary, hypothalamus, temporal lobes,


spinal cord, cochleae.

CT AND MR PLANNING - When MR registration is available the following structures will be contoured on both CT and MR: outer (skin) surface of the head and neck regions, eyes and spinal cord. The outer surface volumes will be available for dose and unspecified tissue calculations, the ocular volumes may be used to verify laterality and the spinal cord volumes can be compared to assure similar flexion and extension, which is critical in planning treatment for infratentorial tumors. For reporting purposes, only the cochleae, spinal cord and outer (skin) structures will be contoured on CT. It is preferred that the remainder of the structures will be contoured on MR including the GTV, CTV, PTV, entire brain, eyes, optic nerves, optic chiasm, pituitary, hypothalamus, and temporal lobes.

Chemotherapy General remarks

Double lumen central line required for chemotherapy administration

Commence the first cycle of HD chemotherapy with stem cell support 6 weeks after completion of radiotherapy.

ANC is ≥1 x 109/L Unsupported platelet count ≥50 x 109/L Hb 8 gm/dL Normal renal function as defined by a corrected GFR ≥ 80 mL/min/1.73 m2. Normal liver function as defined by an ALT concentration < 5 x the normal concentration and a bilirubin concentration <30 μmol/L

Repeat high dose cisplatin/cyclophosphamide/vincristine cycle three times at four weekly intervals but no sooner than :

ANC is ≥1 x 109/L (no G-CSF for 48 hrs) Unsupported platelet count ≥50 x 109/L Normal blood biochemistry – electrolytes, creatinine, urea, ALT, AST, Alkaline phosphatase, bilirubin, albumin, magnesium, calcium, phosphate. Prior to cycle 3 perform estimation of GFR by clearance of radioisotope and echocardiogram with measurement of fractional shortening.

Drugs

Vincristine 1mg/m2 (max dose 2 mg) IV bolus pre Cisplatin on Day -4 and repeated on Day + 6

Cisplatin 75 mg/ m2 IV over 6 hrs Day -4 with hydration

Cyclophosphamide 2 g/m2 IV over one hour on Day – 3 and -2 with hydration and mesna.

Mesna 2400mg/m2/24 hours starting 3 hours prior to the first cyclophosphamide dose and continuing until 24 hours after the start of the last cyclophosphamide dose.

Refer to Appendix A for detailed chemotherapy prescribing guidance. This may be adapted in line with local practice.


Maintenance hydration fluids should be given on Day -1 if required post completion of chemotherapy hydration Re-infuse PBSC on Day 0 following local policy G-CSF 5 microgram/kg/day SC/IV daily, 4 days after the reinfusion of PBSC. Continue for at least 7 days or until the absolute neutrophil count is greater than 1 x 109/L for 2 consecutive days after nadir. G-CSF must be stopped at least 48 hours before the next cycle of high-dose chemotherapy, and may be administered at home after appropriate instruction if patient is well enough

Day +6 - Vincristine 1mg/m2 (max dose 2 mg) IV bolus

Dose Modifications

1) Vincristine Toxicity a. Seizures: Omit one dose, then consider reinstituting at 0.5 mg/m2 (1mg

maximum) while anticonvulsants are continued. If seizures do not recur, return to full dosage at the time of next scheduled dose.

b. Neurotoxicity (grade 3/4, foot drop, severe paresis, disabling paresthesias) or ileus. Omit one dose, resume vincristine at 0.5 mg/m2 (1 mg maximum), and then return to full dosage when symptoms resolve.

c. Jaw Pain: Treat with analgesics (NOT salicylates or NSAIDS). Do not omit or reduce vincristine.

d. Hepatotoxicity: If total bilirubin is >30 µmol/L, omit vincristine dose. If total bilirubin is 25-30 µmol/L, administer vincristine at 0.5 mg/m2.

2) Cisplatin Toxicity a. Ototoxicity. Grading for Audiometry is based on loss in both ears. Thus the grading (including that for modification of chemotherapy) is based on the Highest Grading i.e. the worst ear. The Dose Modification of cisplatin is as follows: Hearing –Dose Modification: < 16 dB at 1000-3000 Hz or None ≤ 40 dB at 4000-8000 Hz 16-30 dB at 1000-3000 Hz or Substitute Carboplatin 40 dB at 4000-8000 Hz AUC 5.3 (see section b.

nephrotoxicity) for Cisplatin >30 dB at 1000-3000 Hz Omit any platinum

b. Nephrotoxicity:

Isotope GFR > 60 and < 80 ml/min per 1.73 m2 Use carboplatin AUC 5.3 instead of cisplatin for next cycle.

Using 51Cr-EDTA clearance for determination of GFR, the dose of carboplatin is


calculated from the 51Cr-EDTA half-life (t½) value and patient’s body weight using the tables in Appendix B. These tables give the daily dose of carboplatin calculated to give an AUC of 5.3 mg/ml.min by the Newell formula. This approximates to a dose of 400mg/m2 .

For centres using other methods of GFR determination, the uncorrected GFR and BSA can be used to calculate the carboplatin dose using a modified version of the Calvert formula –refer to tables in Appendix C

Isotope GFR < 60 ml/min per 1.73m2 omit any platinum for next course.

Perform estimation of GFR by clearance of radioisotope before next cycle

3) Cyclophosphamide a. Haematopoetic toxicity: Delay cyclophosphamide until the ANC is ≥1 x 109/L

and platelet count ≥50 x 109/L. G-CSF may be used until 48 hrs prior to the next cycle of chemotherapy to get adequate ANC.

b. Hemorrhagic cystitis: The patient should be taken off treatment if patient has a Grade 4 toxicity.

Supportive care drugs

It is suggested that patients receive the following as per local policy:

Aciclovir or valaciclovir prophylaxis PCP prophylaxis Antifungal prophylaxis

Suggested Monitoring

1) MRI scans of brain and spine according to the CCLG radiology guidance: a. Pre surgery including spine b. Within 48 hours of surgery c. Post radiotherapy – pre chemotherapy d. After two cycles of chemotherapy e. Post treatment as per your institutional guidance

2) Audiometry a. Prior to chemotherapy b. After each cycle of chemotherapy c. At the end of treatment d. Follow up as per institutional guidance.

3) Renal functioning a. Glomerular filtration testing using Cr EDTA or test as approved by your

institution. This should be done prior to the first cycle of chemotherapy, after 2 cycles and after completion of treatment. Additional measurement can be operformed before cycles 2 and 4 at the treating clinician’s discretion if there have been concerns about renal function.

4) Echocardiogram including measurement of fractional prior to first and after 3 cycle and after completion of treatment

5) Blood biochemistry prior to each cycle


Toxicity monitoring National evaluation of therapy, treatment toxicity and outcomes:

It is imperative that details of the treatment, outcome and toxicity are collected in order to assess that the reported efficacy and toxicity applies to children treated in the United Kingdom. Until this process is formalised, becoming routine practice, it is anticipated and strongly encouraged that unexpected, severe toxicity will be reported to the PNET group for further discussion. Dr James Hayden and Prof Simon Bailey will be the point of contact.


Appendix A

Chemotherapy Prescribing Guidance Day Time Chemotherapy Line

-4 T=0 T=3 T= 3 T=3 T=15

Pre-hydrate with 200ml/m2/hr of 0.9% sodium chloride (total volume 600ml/ m2, no maximum) NB: It is critical to establish and maintain a good urine output prior to cisplatin administration. Therefore monitor urine output hourly and if urine output falls below 3ml/kg/hr for 2 hours give a bolus of mannitol 0.5g/kg over 15 to 30 minutes and additional fluid of 10ml/kg 2.5% dextrose/0.45% sodium chloride. DO NOT use furosemide as this may impair renal cisplatin clearance. Hydration during and until 6 hours post Cisplatin (i.e. infuse over 12 hours) 2.5% dextrose/0.45% sodium chloride Plus 12g mannitol per 1000ml Plus 20mmol potassium chloride per 1000ml Run fluid at 125mls/m2/hr (total volume 1500ml/ m2, maximum volume 2250ml) Hydration should be in a separate bag from the cisplatin and the two can either run through separate lines of a double lumen central line or can be connected by a Y-junction into a single line. Vincristine 1mg/m2 (max dose 2 mg) IV bolus pre Cisplatin Cisplatin 75mg/m2 in 0.9% sodium chloride over 6 hours. Volume of 0.9% sodium chloride in accordance with local practice. Suggestion: <50mg in 100ml 50 to 100mg in 150ml >100mg in 250ml Hydration for subsequent 18 hours (i.e. until 24 hours after the end of cisplatin infusion) 2.5% dextrose/0.45% sodium chloride Plus 20mmol potassium chloride per 1000ml Plus 10mmol Mg sulphate per 1000ml Plus 0.6mmol Ca gluconate or Calcium chloride per 1000ml Run fluid at 125mls/m2/hr (total volume 2250ml/ m2, maximum volume 3375ml) (hydration will finish on Day -3 at T = 9hrs)

A A B A/B A


Careful monitoring of urine output is mandatory Urine output: Once the infusion is started, monitor hourly for the first 12 hrs; if output falls below 3 mL/kg/hr for 2 hours, give a mannitol bolus of 0.5 g/kg and 10 mL/kg of of 2.5 % dextrose/0.45% sodium chloride. The use of furosemide to promote diuresis is discouraged, since furosemide may impair renal cisplatin clearance. However, if a mannitol bolus fails to increase urine output within an hour and there are no other obvious reasons for poor urine output , give bolus of Sodium Chloride 0.9% (20 mL/kg) over 30 min and consider administering furosemide 1 mg/kg as a slow IV bolus.

-3 T=0 T=3 T =9

Mesna 900mg/m2 in sodium chloride 0.9% over 9 hours Volume in accordance with local practice. Suggested volume of 0.9% sodium chloride: 90ml/m2 (Y site to electrolyte hydration ) Cyclophosphamide 2000mg/m2 in 0.9% sodium chloride (or neat) over 1 hour. Volume in accordance with local practice. Suggested volume of 0.9% sodium chloride ≤ 1000mg in 50ml >1000mg – 2000mg in 100ml ≥2000mg – 3000mg in 150ml Mesna 1800mg/m2 in 2.5 % dextrose /sodium chloride 0.45% Plus potassium chloride 20mmol/1000ml Volume 2250ml/m2 (maximum volume 3375ml) Infuse over 18 hours Maintain urine output >3 mL/kg/hr to prevent hemorrhagic cystitis

A B A

-2 T =3 T =3

Mesna 2400mg/m2 in 2.5 % dextrose /sodium chloride 0.45% Plus potassium chloride 20mmol/1000ml Volume 3000ml/m2 (maximum volume 4500ml) Infuse over 24 hours Cyclophosphamide 2000mg/m2 in 0.9% sodium chloride (or neat) over 1 hour : Volume in accordance with local practice. Suggested volume of 0.9% sodium chloride ≤ 1000mg in 50ml >1000mg – 2000mg in 100ml ≥2000mg – 3000mg in 150ml Maintain urine output >3 mL/kg/hr to prevent hemorrhagic cystitis

A B

-1 T=3 Maintenance fluids


0 Re-infuse PBSC in accordance with local practice

including premedication and hydration

+4 G-CSF, 5 microgram/kg/day SC/IV daily, 4 days after the reinfusion of PBSC. Continue for at least 7 days or until the absolute neutrophil count is greater than 1 x 109/L for 2 consecutive days after nadir. G-CSF must be stopped at least 48 hours before the next cycle of high-dose chemotherapy, and may be administered at home after appropriate instruction if patient is well enough

+ 6 Vincristine 1mg/m2 (max dose 2 mg) IV bolus


Half life EDTA (min)Body Wt (kg) 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115

0.5 30 26 23 20 18 17 15 14 13 13 12 11 11 10 10 9 9 91 56 48 42 38 34 31 29 27 25 23 22 21 20 19 18 17 17 16

1.5 80 69 61 54 49 45 41 38 36 34 32 30 29 27 26 25 24 232 103 89 78 70 64 58 54 50 46 44 41 39 37 35 34 32 31 30

2.5 126 109 96 86 78 71 65 61 57 53 50 48 45 43 41 39 38 363 149 128 113 101 91 84 77 72 67 63 59 56 53 51 49 47 45 43

3.5 171 147 130 116 105 96 89 82 77 72 68 65 61 58 56 53 51 494 192 166 146 131 118 108 100 93 87 81 77 73 69 66 63 60 58 56

4.5 214 184 162 145 132 120 111 103 96 91 85 81 77 73 70 67 64 625 235 203 178 160 145 132 122 113 106 100 94 89 85 81 77 74 71 68

5.5 256 221 194 174 158 144 133 124 116 109 102 97 92 88 84 81 77 746 276 238 210 188 170 156 144 134 125 117 111 105 100 95 91 87 84 81

6.5 297 256 226 202 183 168 155 144 134 126 119 113 107 102 98 94 90 877 317 274 241 216 196 179 165 154 144 135 127 121 115 109 105 100 96 93

7.5 337 291 257 230 208 191 176 163 153 144 135 128 122 116 111 107 102 998 358 309 272 243 221 202 186 173 162 152 144 136 129 123 118 113 109 105

8.5 377 326 287 257 233 213 197 183 171 161 152 144 137 130 125 119 115 1109 397 343 302 271 245 225 207 193 180 169 160 151 144 137 131 126 121 116

9.5 417 360 317 284 257 236 218 202 189 178 168 159 151 144 138 132 127 12210 437 377 332 297 270 247 228 212 198 186 176 166 158 151 144 138 133 12811 476 411 362 324 294 269 248 231 216 203 191 181 173 165 157 151 145 14012 514 444 391 350 318 291 269 250 233 219 207 196 187 178 170 163 157 15113 552 477 420 376 341 313 289 268 251 236 223 211 201 191 183 176 169 16214 590 510 449 402 365 334 308 287 268 252 238 226 215 205 196 188 180 17415 628 542 478 428 388 355 328 305 285 268 253 240 228 218 208 200 192 18516 665 575 507 454 411 377 348 323 303 284 269 255 242 231 221 212 204 19617 702 607 535 479 434 398 367 342 320 300 284 269 256 244 233 224 215 20718 739 639 563 504 457 419 387 360 336 316 299 283 269 257 246 236 227 21819 776 670 591 529 480 440 406 378 353 332 314 297 283 270 258 248 238 22920 813 702 619 554 503 461 425 396 370 348 329 311 296 283 270 259 249 24021 849 733 647 579 525 481 444 413 387 364 343 326 310 295 283 271 261 25122 885 765 674 604 548 502 463 431 403 379 358 339 323 308 295 283 272 26223 921 796 702 629 570 522 482 449 420 395 373 353 336 321 307 294 283 27324 957 827 729 653 592 543 501 466 436 410 387 367 349 333 319 306 294 28325 992 857 756 677 615 563 520 484 453 426 402 381 363 346 331 318 305 29426 1028 888 783 702 637 583 539 501 469 441 416 395 376 359 343 329 316 30527 1063 919 810 726 659 603 557 518 485 456 431 409 389 371 355 341 327 31528 1098 949 837 750 680 623 576 536 501 471 445 422 402 383 367 352 338 32629 1134 980 864 774 702 643 594 553 517 487 460 436 415 396 379 363 349 33730 1169 1010 891 798 724 663 613 570 534 502 474 449 428 408 391 375 360 34731 1203 1040 917 822 746 683 631 587 550 517 488 463 441 420 402 386 371 358

Appendix B

These tables give the daily dose of carboplatin calculated to give an AUC of 5.3 mg/ml.min by the Newell formula.


Half life EDTA (min)Body Wt (kg) 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115

32 1238 1070 944 846 767 703 650 604 566 532 502 476 453 433 414 397 382 36833 1273 1100 970 869 789 723 668 621 581 547 517 490 466 445 426 409 393 37934 1307 1130 997 893 810 743 686 638 597 562 531 503 479 457 438 420 404 38935 1342 1160 1023 917 832 762 704 655 613 577 545 517 492 469 449 431 414 39936 1376 1189 1049 940 853 782 722 672 629 592 559 530 504 482 461 442 425 41037 1410 1219 1075 964 874 801 740 689 645 606 573 543 517 494 472 453 436 42038 1444 1248 1101 987 896 821 758 706 660 621 587 557 530 506 484 464 447 43039 1478 1278 1127 1010 917 840 776 722 676 636 601 570 542 518 496 476 457 44140 1512 1307 1153 1034 938 860 794 739 692 651 615 583 555 530 507 487 468 45141 1546 1336 1179 1057 959 879 812 756 707 665 629 596 568 542 519 498 479 46142 1580 1366 1205 1080 980 898 830 772 723 680 643 609 580 554 530 509 489 47143 1614 1395 1231 1103 1001 917 848 789 738 695 656 623 593 566 542 520 500 48244 1647 1424 1256 1126 1022 937 866 805 754 709 670 636 605 578 553 531 510 49245 1681 1453 1282 1149 1043 956 883 822 769 724 684 649 617 590 564 542 521 50246 1714 1482 1308 1172 1064 975 901 838 785 738 698 662 630 601 576 552 531 51247 1748 1511 1333 1195 1084 994 919 855 800 753 711 675 642 613 587 563 542 52248 1781 1540 1359 1218 1105 1013 936 871 816 767 725 688 655 625 598 574 552 53249 1814 1568 1384 1241 1126 1032 954 888 831 782 739 701 667 637 610 585 563 54250 1847 1597 1409 1263 1147 1051 971 904 846 796 752 714 679 649 621 596 573 55251 1880 1626 1435 1286 1167 1070 989 920 861 811 766 727 692 660 632 607 584 56252 1913 1654 1460 1309 1188 1089 1006 937 877 825 780 740 704 672 643 618 594 57253 1946 1683 1485 1331 1208 1108 1024 953 892 839 793 752 716 684 655 628 604 58254 1979 1711 1510 1354 1229 1126 1041 969 907 854 807 765 728 696 666 639 615 59255 2012 1740 1535 1376 1249 1145 1059 985 922 868 820 778 741 707 677 650 625 60256 2045 1768 1560 1399 1270 1164 1076 1001 937 882 834 791 753 719 688 661 635 61257 2078 1796 1585 1421 1290 1183 1093 1017 953 896 847 804 765 730 699 671 646 62258 2110 1825 1610 1444 1310 1201 1110 1034 968 910 860 816 777 742 711 682 656 63259 2143 1853 1635 1466 1331 1220 1128 1050 983 925 874 829 789 754 722 693 666 64260 2175 1881 1660 1488 1351 1239 1145 1066 998 939 887 842 801 765 733 703 677 65261 2208 1909 1685 1511 1371 1257 1162 1082 1013 953 901 855 814 777 744 714 687 66262 2240 1937 1710 1533 1391 1276 1179 1098 1028 967 914 867 826 788 755 725 697 67263 2273 1965 1735 1555 1412 1294 1196 1114 1043 981 927 880 838 800 766 735 707 68264 2305 1993 1759 1577 1432 1313 1214 1130 1058 995 941 893 850 811 777 746 717 69265 2337 2021 1784 1599 1452 1331 1231 1146 1073 1009 954 905 862 823 788 756 728 70166 2369 2049 1809 1622 1472 1350 1248 1161 1087 1023 967 918 874 834 799 767 738 71167 2402 2077 1833 1644 1492 1368 1265 1177 1102 1037 981 930 886 846 810 777 748 72168 2434 2105 1858 1666 1512 1386 1282 1193 1117 1051 994 943 898 857 821 788 758 73169 2466 2132 1882 1688 1532 1405 1299 1209 1132 1065 1007 955 910 869 832 799 768 74170 2498 2160 1907 1710 1552 1423 1316 1225 1147 1079 1020 968 922 880 843 809 778 750

Daily dose of carboplatin calculated to give an AUC of 5.3 mg/ml.min by the Newell formula


Half life EDTA (min)Body Wt (kg) 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200

0.5 8 8 8 7 7 7 7 7 6 6 6 6 6 6 6 5 51 15 15 14 14 13 13 13 12 12 12 11 11 11 11 10 10 10

1.5 22 21 21 20 19 19 18 18 17 17 16 16 16 15 15 15 142 29 28 27 26 25 24 24 23 22 22 21 21 20 20 20 19 19

2.5 35 34 33 32 31 30 29 28 28 27 26 26 25 24 24 23 233 41 40 39 37 36 35 34 33 33 32 31 30 30 29 28 28 27

3.5 48 46 44 43 42 41 39 38 37 36 36 35 34 33 33 32 314 54 52 50 49 47 46 45 43 42 41 40 39 38 38 37 36 35

4.5 60 58 56 54 53 51 50 48 47 46 45 44 43 42 41 40 395 66 64 62 60 58 56 55 53 52 50 49 48 47 46 45 44 43

5.5 72 69 67 65 63 61 60 58 56 55 54 53 51 50 49 48 476 78 75 73 70 68 66 64 63 61 60 58 57 56 54 53 52 51

6.5 84 81 78 76 73 71 69 67 66 64 63 61 60 59 57 56 557 89 86 83 81 78 76 74 72 70 69 67 65 64 63 61 60 59

7.5 95 92 89 86 84 81 79 77 75 73 71 70 68 67 65 64 638 101 97 94 91 89 86 84 82 79 77 76 74 72 71 69 68 67

8.5 107 103 100 97 94 91 88 86 84 82 80 78 76 75 73 72 709 112 108 105 102 99 96 93 91 88 86 84 82 81 79 77 76 74

9.5 118 114 110 107 104 101 98 95 93 91 89 87 85 83 81 79 7810 123 119 115 112 109 105 103 100 97 95 93 91 89 87 85 83 8211 135 130 126 122 118 115 112 109 106 104 101 99 97 95 93 91 8912 146 141 136 132 128 125 121 118 115 112 110 107 105 103 100 98 9713 157 151 147 142 138 134 130 127 124 121 118 115 113 110 108 106 10414 168 162 157 152 147 143 139 136 132 129 126 123 121 118 116 113 11115 178 172 167 162 157 153 148 145 141 138 134 131 128 126 123 121 11916 189 183 177 172 167 162 157 153 150 146 143 139 136 133 131 128 12617 200 193 187 181 176 171 166 162 158 154 151 147 144 141 138 136 13318 211 204 197 191 185 180 175 171 167 163 159 155 152 149 146 143 14019 221 214 207 201 195 189 184 179 175 171 167 163 160 156 153 150 14720 232 224 217 210 204 198 193 188 183 179 175 171 167 164 160 157 15421 242 234 227 220 213 207 202 197 192 187 183 179 175 171 168 164 16122 253 244 237 229 223 216 211 205 200 195 191 186 182 179 175 172 16823 263 254 246 239 232 225 219 214 208 203 199 194 190 186 182 179 17524 274 264 256 248 241 234 228 222 217 211 207 202 198 194 190 186 18225 284 274 266 258 250 243 237 231 225 219 214 210 205 201 197 193 18926 294 284 275 267 259 252 245 239 233 227 222 217 213 208 204 200 19627 304 294 285 276 268 261 254 247 241 235 230 225 220 216 211 207 20328 315 304 295 286 277 270 262 256 249 243 238 233 228 223 218 214 21029 325 314 304 295 286 278 271 264 258 251 246 240 235 230 226 221 21730 335 324 314 304 295 287 280 272 266 259 253 248 242 237 233 228 22431 345 334 323 313 304 296 288 281 274 267 261 255 250 245 240 235 231



Half life EDTA (min)Body Wt (kg) 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200

32 355 344 333 323 313 305 296 289 282 275 269 263 257 252 247 242 23833 365 353 342 332 322 313 305 297 290 283 276 270 265 259 254 249 24434 375 363 352 341 331 322 313 305 298 291 284 278 272 266 261 256 25135 386 373 361 350 340 331 322 314 306 299 292 285 279 274 268 263 25836 396 382 370 359 349 339 330 322 314 306 299 293 287 281 275 270 26537 406 392 380 368 358 348 339 330 322 314 307 300 294 288 282 277 27238 415 402 389 377 366 356 347 338 330 322 315 308 301 295 289 284 27839 425 411 398 386 375 365 355 346 338 330 322 315 308 302 296 290 28540 435 421 408 395 384 373 364 354 346 337 330 322 316 309 303 297 29241 445 431 417 404 393 382 372 362 353 345 337 330 323 316 310 304 29842 455 440 426 413 402 390 380 370 361 353 345 337 330 323 317 311 30543 465 450 435 422 410 399 388 378 369 361 352 345 337 330 324 318 31244 475 459 445 431 419 407 397 387 377 368 360 352 344 337 331 324 31845 485 469 454 440 428 416 405 395 385 376 367 359 352 344 338 331 32546 494 478 463 449 436 424 413 403 393 383 375 367 359 352 345 338 33247 504 488 472 458 445 433 421 411 401 391 382 374 366 359 351 345 33848 514 497 481 467 454 441 429 419 408 399 390 381 373 366 358 351 34549 524 506 491 476 462 449 438 427 416 406 397 388 380 373 365 358 35250 533 516 500 485 471 458 446 434 424 414 405 396 387 379 372 365 35851 543 525 509 494 479 466 454 442 432 421 412 403 394 386 379 372 36552 553 535 518 502 488 475 462 450 439 429 419 410 402 393 386 378 37153 562 544 527 511 497 483 470 458 447 437 427 417 409 400 392 385 37854 572 553 536 520 505 491 478 466 455 444 434 425 416 407 399 392 38455 582 563 545 529 514 500 486 474 463 452 441 432 423 414 406 398 39156 591 572 554 538 522 508 494 482 470 459 449 439 430 421 413 405 39857 601 581 563 546 531 516 503 490 478 467 456 446 437 428 420 412 40458 611 591 572 555 539 524 511 498 486 474 464 453 444 435 426 418 41159 620 600 581 564 548 533 519 506 493 482 471 461 451 442 433 425 41760 630 609 590 572 556 541 527 513 501 489 478 468 458 449 440 432 42461 639 618 599 581 565 549 535 521 509 497 485 475 465 456 447 438 43062 649 628 608 590 573 557 543 529 516 504 493 482 472 462 453 445 43763 658 637 617 599 581 566 551 537 524 512 500 489 479 469 460 451 44364 668 646 626 607 590 574 559 545 531 519 507 496 486 476 467 458 45065 677 655 635 616 598 582 567 552 539 526 515 503 493 483 473 465 45666 687 664 644 624 607 590 575 560 547 534 522 511 500 490 480 471 46267 696 674 653 633 615 598 583 568 554 541 529 518 507 497 487 478 46968 706 683 661 642 623 606 591 576 562 549 536 525 514 503 494 484 47569 715 692 670 650 632 615 598 583 569 556 544 532 521 510 500 491 48270 725 701 679 659 640 623 606 591 577 563 551 539 528 517 507 497 488



Appendix C

These tables give the daily dose of carboplatin calculated to give an AUC of 5.3 mg/ml.min by the modified Calvert formula.

Uncorrected GFR (ml/min)SA (m2) 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110

0.2 122 148 175 201 228 254 281 307 334 360 387 413 440 466 493 519 546 572 5990.25 126 152 179 205 232 258 285 311 338 364 391 417 444 470 497 523 550 576 6030.3 130 156 183 209 236 262 289 315 342 368 395 421 448 474 501 527 554 580 6070.35 134 160 187 213 240 266 293 319 346 372 399 425 452 478 505 531 558 584 6110.4 138 164 191 217 244 270 297 323 350 376 403 429 456 482 509 535 562 588 6150.45 142 168 195 221 248 274 301 327 354 380 407 433 460 486 513 539 566 592 6190.5 146 172 199 225 252 278 305 331 358 384 411 437 464 490 517 543 570 596 6230.55 150 176 203 229 256 282 309 335 362 388 415 441 468 494 521 547 574 600 6270.6 154 180 207 233 260 286 313 339 366 392 419 445 472 498 525 551 578 604 6310.65 158 184 211 237 264 290 317 343 370 396 423 449 476 502 529 555 582 608 6350.7 162 188 215 241 268 294 321 347 374 400 427 453 480 506 533 559 586 612 6390.75 166 192 219 245 272 298 325 351 378 404 431 457 484 510 537 563 590 616 6430.8 170 196 223 249 276 302 329 355 382 408 435 461 488 514 541 567 594 620 6470.85 174 200 227 253 280 306 333 359 386 412 439 465 492 518 545 571 598 624 6510.9 178 204 231 257 284 310 337 363 390 416 443 469 496 522 549 575 602 628 6550.95 182 208 235 261 288 314 341 367 394 420 447 473 500 526 553 579 606 632 659

1 186 212 239 265 292 318 345 371 398 424 451 477 504 530 557 583 610 636 6631.05 189 216 242 269 295 322 348 375 401 428 454 481 507 534 560 587 613 640 6661.1 193 220 246 273 299 326 352 379 405 432 458 485 511 538 564 591 617 644 6701.15 197 224 250 277 303 330 356 383 409 436 462 489 515 542 568 595 621 648 6741.2 201 228 254 281 307 334 360 387 413 440 466 493 519 546 572 599 625 652 6781.25 205 232 258 285 311 338 364 391 417 444 470 497 523 550 576 603 629 656 6821.3 209 236 262 289 315 342 368 395 421 448 474 501 527 554 580 607 633 660 6861.35 213 240 266 293 319 346 372 399 425 452 478 505 531 558 584 611 637 664 6901.4 217 244 270 297 323 350 376 403 429 456 482 509 535 562 588 615 641 668 6941.45 221 248 274 301 327 354 380 407 433 460 486 513 539 566 592 619 645 672 6981.5 225 252 278 305 331 358 384 411 437 464 490 517 543 570 596 623 649 676 7021.55 229 256 282 309 335 362 388 415 441 468 494 521 547 574 600 627 653 680 7061.6 233 260 286 313 339 366 392 419 445 472 498 525 551 578 604 631 657 684 7101.65 237 264 290 317 343 370 396 423 449 476 502 529 555 582 608 635 661 688 7141.7 241 268 294 321 347 374 400 427 453 480 506 533 559 586 612 639 665 692 7181.75 245 272 298 325 351 378 404 431 457 484 510 537 563 590 616 643 669 696 7221.8 249 276 302 329 355 382 408 435 461 488 514 541 567 594 620 647 673 700 7261.85 253 280 306 333 359 386 412 439 465 492 518 545 571 598 624 651 677 704 7301.9 257 284 310 337 363 390 416 443 469 496 522 549 575 602 628 655 681 708 7341.95 261 288 314 341 367 394 420 447 473 500 526 553 579 606 632 659 685 712 738

2 265 292 318 345 371 398 424 451 477 504 530 557 583 610 636 663 689 716 742 Uncorrected GFR (ml/min)

SA (m2) 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 2000.2 625 652 678 705 731 758 784 811 837 864 890 917 943 970 996 1023 1049 10760.25 629 656 682 709 735 762 788 815 841 868 894 921 947 974 1000 1027 1053 10800.3 633 660 686 713 739 766 792 819 845 872 898 925 951 978 1004 1031 1057 10840.35 637 664 690 717 743 770 796 823 849 876 902 929 955 982 1008 1035 1061 10880.4 641 668 694 721 747 774 800 827 853 880 906 933 959 986 1012 1039 1065 10920.45 645 672 698 725 751 778 804 831 857 884 910 937 963 990 1016 1043 1069 10960.5 649 676 702 729 755 782 808 835 861 888 914 941 967 994 1020 1047 1073 11000.55 653 680 706 733 759 786 812 839 865 892 918 945 971 998 1024 1051 1077 11040.6 657 684 710 737 763 790 816 843 869 896 922 949 975 1002 1028 1055 1081 11080.65 661 688 714 741 767 794 820 847 873 900 926 953 979 1006 1032 1059 1085 11120.7 665 692 718 745 771 798 824 851 877 904 930 957 983 1010 1036 1063 1089 11160.75 669 696 722 749 775 802 828 855 881 908 934 961 987 1014 1040 1067 1093 11200.8 673 700 726 753 779 806 832 859 885 912 938 965 991 1018 1044 1071 1097 11240.85 677 704 730 757 783 810 836 863 889 916 942 969 995 1022 1048 1075 1101 11280.9 681 708 734 761 787 814 840 867 893 920 946 973 999 1026 1052 1079 1105 11320.95 685 712 738 765 791 818 844 871 897 924 950 977 1003 1030 1056 1083 1109 1136

1 689 716 742 769 795 822 848 875 901 928 954 981 1007 1034 1060 1087 1113 11401.05 693 719 746 772 799 825 852 878 905 931 958 984 1011 1037 1064 1090 1117 11431.1 697 723 750 776 803 829 856 882 909 935 962 988 1015 1041 1068 1094 1121 11471.15 701 727 754 780 807 833 860 886 913 939 966 992 1019 1045 1072 1098 1125 11511.2 705 731 758 784 811 837 864 890 917 943 970 996 1023 1049 1076 1102 1129 11551.25 709 735 762 788 815 841 868 894 921 947 974 1000 1027 1053 1080 1106 1133 11591.3 713 739 766 792 819 845 872 898 925 951 978 1004 1031 1057 1084 1110 1137 11631.35 717 743 770 796 823 849 876 902 929 955 982 1008 1035 1061 1088 1114 1141 11671.4 721 747 774 800 827 853 880 906 933 959 986 1012 1039 1065 1092 1118 1145 11711.45 725 751 778 804 831 857 884 910 937 963 990 1016 1043 1069 1096 1122 1149 11751.5 729 755 782 808 835 861 888 914 941 967 994 1020 1047 1073 1100 1126 1153 11791.55 733 759 786 812 839 865 892 918 945 971 998 1024 1051 1077 1104 1130 1157 11831.6 737 763 790 816 843 869 896 922 949 975 1002 1028 1055 1081 1108 1134 1161 11871.65 741 767 794 820 847 873 900 926 953 979 1006 1032 1059 1085 1112 1138 1165 11911.7 745 771 798 824 851 877 904 930 957 983 1010 1036 1063 1089 1116 1142 1169 11951.75 749 775 802 828 855 881 908 934 961 987 1014 1040 1067 1093 1120 1146 1173 11991.8 753 779 806 832 859 885 912 938 965 991 1018 1044 1071 1097 1124 1150 1177 12031.85 757 783 810 836 863 889 916 942 969 995 1022 1048 1075 1101 1128 1154 1181 12071.9 761 787 814 840 867 893 920 946 973 999 1026 1052 1079 1105 1132 1158 1185 12111.95 765 791 818 844 871 897 924 950 977 1003 1030 1056 1083 1109 1136 1162 1189 1215

2 769 795 822 848 875 901 928 954 981 1007 1034 1060 1087 1113 1140 1166 1193 1219

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