2-8 hrs: Cisplatin 3.5 mg/kg + mannitol 0.4 g/kg in D5 NS (1000 ml/m2) over 6 hrs at approximately 167ml/m2/hr. 8-12 hrs: D5 NS (665 ml/m2) + KCl (2 mEq/100 ml) +MgSO4 (0.5 mEq/100 ml) at approximately 167ml/m2/hr.

12-24 hrs: D5 NS + KCl (2 mEq/100 ml) + MgSO4 (0.5mEq/100 ml) at approximately 65 ml/m2/hr.

Days 2,3: 0 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg of IVF over 15 min 15 min: Cyclophosphamide 30 mg/kg IV over 30 min 45 min: Post-chemotherapy hydration - D5 1/2 NS + KCl(1 mEq/100 ml) at approximately 130 ml/m2/hr for at least 24 hours.

3 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 6 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 9 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 12 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min Day 4 G-CSF 5 µg/kg subcutaneously, daily until ANC ≥ 2000 on two consecutive days, post ANC nadir.

Day 8: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Day 15: Vincristine 0.05 mg/kg IV push (max dose = 2 mg)

Drugs and doses are same as in Cycle A1. Cycle A2 begins following recovery from Cycle A1, but no sooner than day 21. Patients with delays in recovery beyond day 28 should have dose modifications

Days 43 - 63) Etoposide, 1.7 mg/kg p.o. qd x 21 days. The dose will be diluted immediately prior to administration in juice flavored syrup to a final concentration of 0.4 Each dose should be aken 1 hour before or 2 hours after a meal.

Cycle B begins following recovery from Cycle A2; however, it begin no sooner than 21 days after the start of Cycle A2.

Monitor weekly CBC/diff/plt. If ANC < 500/mm3 or platelets (unsupported) < 50,000/mm3 then discontinue etoposide. A 25% reduction should be made for the next cycle of oral etoposide.

Interim Response Evaluation (Days 64 - 70) Interim Response Evaluation should be performed the week following the completion of Course 1.

6.3.3 Regimen 1, Course 2 Repeat systemic therapy as per Course 1 (Cycle A1, Cycle A2, and Cycle B) in patients with SD or better at the interim response evaluation (see Figure 2 for IT mafosfamide guidelines). Course 2 should not begin any sooner than 7 days after the completion of Course 1.

Regimen 1, Course 1 Mafosfamide, 14 mg, is given two times/week during Cycle A1 and Cycle A2 of Course 1, for 12 total doses during days 1-41. The first dose of Cycles A1 and A2 should be given, if possible, on the same day as the first I.V. cyclophosphamide dose and the second dose 3 to 4 days later. The assigned dose is given one time/week during Cycle B, Course 1 for 3 total doses during days 43 - 63.

Regimen 1, Course 2 The assigned dose is administered once with IV cyclophosphamide during each of Cycle A1 and Cycle A2, and day 1 of Cycle B for a total of 3 doses during Course 2.

Patients with an initially abnormal flow study, who show no evidence of obstructive hydrocephalus or compartmentalization on the repeat study, may begin intrathecal mafosfamide administration with the initiation of Regimen 1, Course 2. The frequency of intrathecal mafosfamide administration, for such patients, will be as outlined in Regimen 1, Course

1.

Cycle C1 (Days 1 - 21) Day 1: Prehydrate with D5W 1/2 NS + KCl 2 mEq/100 ml) at 2 times the hourly maintenance rate until the urine specific gravity is < 1.012.

0 hrs: Mesna 6 mg/kg IV over 15 min. Dilute in 0.65 ml/kg IVF. 15 min: Vincristine 0.05 mg/kg IV push (Day 1 only)(max dose = 2 mg) 20 min: Cyclophosphamide 30 mg/kg IV over 30 min. 50 min: Post-chemotherapy hydration - D5 1/2 NS + KCl

(1 mEq/100 ml) at twice the hourly maintenance rate for at least 24 hours. 3 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 6 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 9 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 12 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min Day 2: Repeat day 1, but omit vincristine. Day 3: G-CSF 5 µg/kg/day subcutaneously, daily, until ANC is > 2000 on two consecutive days, post ANC nadir.

Cycle C1, Weeks 2 and 3 Day 8: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Day 15: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Cycle C2 (Days 22-42) Drugs and doses are same as in Cycle C1. Cycle C2 begins following recovery from Cycle C1, but no sooner than day 21. Patients with delays in recovery beyond day 28 should have dose modificationsCycle D (Days 43 - 63) Etoposide 1.7 mg/kg, po qd x 21 days The dose will be diluted immediately prior to administration in juice or flavored syrup as per section 3.4.3. Each dose should be taken 1 hour before or 2 hours after a meal.

Cycle D should begin following recovery from Cycle C2; however, it should begin no sooner than 21 days after the start of Cycle C2.

Repeat Course 1 (Cycle C1, Cycle C2, and Cycle D) in patients with SD or better at the interim response evaluation. Chemotherapy should begin as soon as the patient has recovered from the toxicities of oral etoposide in cycle D, course 1. However, it should not begin any sooner than 7 days after the completion of Course 1.

Conformal Irradiation Patients who are initially M0 with a CR, PR, or SD to Regimen 1 induction chemotherapy (with or without second surgery) will receive local irradiation using conformal techniques. Treatment will commence within 2 weeks of completing Regimen 1 or second surgery. Treatment planning and technique may involve 3D conformal,IMRT, or proton planning and delivery, provided the guidelines regarding volume, dose,and normal tissue restrictions are honored.

8.3.1 Fraction Size 180 cGy fractions will be used for all target volumes. 8.3.2 Fractionation Conventional fractionation will be used. Treatments will be given once daily, 5 days/week except for necessary interruptions secondary to medical or administrative reasons.