Chemotherapy Combined With Radiation Therapy for Newly Diagnosed CNS AT/RT

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00084838
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 25
• Locations: 12
• Arm: 1
• Duration (Months): 120.9
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving more than one chemotherapy drug with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving intrathecal and systemic combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed central nervous system (CNS) atypical teratoid/rhabdoid tumors.

Condition or Disease	Intervention/Treatment	Phase
Central Nervous System Tumor, Pediatric	Biological: filgrastim; Drug: cisplatin; Drug: cyclophosphamide; Drug: cytarabine; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: leucovorin calcium; Drug: methotrexate; Drug: temozolomide; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy; Drug: Dactinomycin	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of intensive systemic and intrathecal chemotherapy and radiotherapy, in terms of medial survival, in children with newly diagnosed central nervous system atypical teratoid/rhabdoid tumors in comparison with historical outcomes from prior trials.

Secondary

• Determine the toxicity profile and tolerability of this regimen in these patients.

• Determine the chemosensitivity of these patients' tumors by Magnetic Resonance Imaging (MRI) after an attempt at maximum surgical resection after 2 courses of this regimen.

• Determine the predictive value of the INI-1 gene mutation in determining prognosis by comparing tumor samples from patients with vs without this mutation treated with this regimen.

STATISTICAL DESIGN: This was a single arm design evaluating median overall survival. The chosen historical control estimate of 7 months was based on 2 large multi-institutional studies in a similar setting and the alternative of 20.5 months based on a DFCI pilot study. There was 90% power to detect this improvement assuming 1-sided 0.10 alpha and 17 eligible patients. Sample size (n=20 patients) was inflated for expected 10-15% ineligible rate.

TREATMENT: Induction chemotherapy was required to be initiated within 50 days of the most definitive surgery.

• Central Nervous System (CNS)/intrathecal therapy: All patients with M0 disease receive triple intrathecal (IT) chemotherapy comprising methotrexate (MTX), cytarabine, and hydrocortisone on day 1 of weeks 1, 2, 4, 7, 13, 19, 27, 33, 39, 45, and 51 followed by oral or intravenous (IV) leucovorin calcium given 24 hours after each MTX dose. Patients with initially positive cerebrospinal fluid (CSF) cytology (M+) receive triple IT chemotherapy weekly until 2 consecutive CSF samples are negative for malignant cells.

• Pre-irradiation induction therapy (weeks 1-6): Patients receive vincristine IV on day 1 of weeks 1-6; cisplatin IV over 8 hours on day 1 and doxorubicin IV continuously over 48 hours beginning on day 2 of weeks 1 and 4; cyclophosphamide IV continuously over 72 hours beginning on day 2 of week 1; etoposide IV over 1 hour on days 1-3 of week 4; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 of week 1 and day 4 of week 4 and continuing until blood counts recover.

• Induction chemoradiotherapy (weeks 7-12): Patients receive vincristine IV on day 1 of weeks 7-12; cisplatin IV over 8 hours on day 1, cyclophosphamide IV over 1 hour on day 2, etoposide IV over 1 hour on days 1-3 of weeks 7 and 10; and granulocyte-colony stimulating factor (G-CSF) subcutaneous (SC) daily beginning on day 4 of weeks 7 and 10 and continuing until blood counts recover. Patients with M0 disease and patients under 3 years of age with M+ disease undergo radiotherapy to the primary tumor daily on weeks 7-12. Patients 3 years of age and over with M+ disease undergo craniospinal irradiation (CSI) daily on weeks 7-12 until negative cerebral spinal fluid (CSF) cytology is achieved.

• Post-radiation induction therapy (weeks 13-18): Patients receive vincristine IV on day 1 of weeks 13 and 16; doxorubicin and cyclophosphamide as in pre-irradiation induction therapy beginning on day 1 of week 13; cyclophosphamide IV over 1 hour on days 1-3 of week 16; dactinomycin IV on days 1-5 of week 16; and G-CSF SC daily beginning on day 6 of weeks 13 and 16 and continuing until blood counts recover.

• Maintenance chemotherapy (weeks 19-42): Patients receive vincristine IV on day 1 of weeks 27, 33, and 39 and days 1 and 5 of weeks 30, 36, and 42; doxorubicin and cyclophosphamide as in pre-irradiation induction beginning on day 1 of weeks 27 and 33; doxorubicin IV over 15 minutes and dexrazoxane (DX) IV over 15 minutes on days 1 and 2 of week 39; cyclophosphamide IV over 1 hour on days 1-3 of weeks 30, 36, 39, and 42; dactinomycin IV on days 1-5 of weeks 30, 36, and 42 and on day 1 of weeks 19 and 23; oral temozolomide on days 1-5 of weeks 19 and 23; and G-CSF SC daily beginning on day 6 of weeks 19, 23, 30, 36, and 42, day 5 of weeks 27 and 33, and day 4 of week 39 and continuing until blood counts recover.

• Doxorubicin continuation therapy (for patients not receiving CSI and mediastinal radiotherapy)(weeks 45-51): Patients receive vincristine IV on day 1 of weeks 45, 48, and 51 and day 5 of week 48; doxorubicin IV over 15 minutes and DX IV over 15 minutes on days 1 and 2 of weeks 45 and 51; cyclophosphamide IV over 1 hour on days 1-3 of weeks 45, 48, and 51; dactinomycin IV on days 1-5 of week 48; and G-CSF SC daily beginning on day 4 of weeks 45 and 51 and day 6 of week 48 and continuing until blood counts recover.

• Non-doxorubicin continuation therapy (for patients receiving CSI or mediastinal radiotherapy)(weeks 45-51): Patients receive cyclophosphamide and G-CSF as in doxorubicin continuation therapy; vincristine IV on days 1 and 5 of weeks 45, 48, and 51; and dactinomycin IV on days 1-5 of weeks 45, 48, and 51.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Intrathecal and Systemic Chemotherapy With Radiation Therapy for Children With Central Nervous System Atypical Teratoid/Rhabdoid Tumor (AT/RT) Tumor
• Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Multi-agent Intrathecal and Systemic CT with RT (mod IRS III) Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.

Biological: filgrastim; Other Names: filgrastim XM02 G-CSF ; Drug: cisplatin; Other Names: CACP cis-DDP cis-diamminedichloro platinum (II) cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cismaplat Platinol ; Drug: cyclophosphamide; Other Names: Ciclofosfamida Ciclofosfamide Claphene CP monohydrate CPM Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphanum Cytophosphane Mitoxan Syklofosfamid Zytoxan Clafen Cytoxan Neosar ; Drug: cytarabine; Other Names: arabinofuranosylcytosine arabinosylcytosine aracytidine beta-cytosine arabinoside cytarabine hydrochloride cytarabinum cytosine arabinoside cytosine arabinosine hydrochloride Cytosar-U Tarabine PFS ; Drug: dexrazoxane hydrochloride; Other Names: Totect Zinecard ; Drug: doxorubicin hydrochloride; Other Names: Adriamycin PFS Adriamycin RDF ; Drug: etoposide; Other Names: VP-16 ; Drug: leucovorin calcium; Other Names: folinate calcium folinic acid ; Drug: methotrexate; Drug: temozolomide; Other Names: Temodar, Methazolastone, Temodal, TMZ, CCRG-81045 ; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Other Names: leurocristine sulfate Vincasar PFS ; Radiation: radiation therapy; Drug: Dactinomycin; Other Names: ACT-D actinomycin C1 actinomycin D actinomycin I1 actinomycin IV actinomycin X 1 actinomycin-[thr-val-pro-sar-meval] AD dactinomycine meractinomycin

Outcome Measures

Primary Outcome Measures

1. 2-yr Overall Survival [Patients are followed for survival up to 5 yrs post-therapy completion or death; As of this analysis, median follow-up among survivors was 31 months with the longest follow-up being 40 months.]

   Overall survival is defined as the time from date of diagnosis to death or date of last follow-up. 2-year overall survival is the probability of patients remaining alive at 2-years from study entry estimated using Kaplan-Meier (KM) methods which censors patients at date of last follow-up. Precision of this conditional probability estimate was measured in terms of standard error. Median OS, the original primary endpoint, was not estimable based on the Kaplan-Meier method because of insufficient follow-up.

Secondary Outcome Measures

1. Pre-Radiation Therapy Chemotherapeutic Response [Assessed at study entry and pre-RT/post-CT at week 7.]

   Response pre-RT/post-CT was defined as follows with overall response defined as achieving PR or CR. Complete Response (CR): Complete resolution of all initially demonstrable tumor on MRI or CT evaluation w/o appearance of any new areas of disease; negative CSF cytology. Partial Response (PR): >/= 50% decrease in the sum of the products of the maximum perpendicular diameters of the tumor (sum LD) relative to baseline w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Stable Disease (SD): <50% decrease in the sum LD w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Progressive Disease (PD): >/= 25% increase in the sum LD relative to baseline, or the appearance of any new areas of disease or appearance of positive cytology after two consecutive negative samples.

Other Outcome Measures

1. Grade 3/4 Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 events based on CTCAEv2 as reported on case report forms.

2. Grade 3-4 Auditory/Hearing Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Auditory/Hearing events based on CTCAEv2 as reported on case report forms.

3. Grade 3-4 Blood/Bone Marrow Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Blood/Bone Marrow events based on CTCAEv2 as reported on case report forms. Arm Name

4. Grade 3-4 Gastrointestinal Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Gastrointestinal events based on CTCAEv2 as reported on case report forms.

5. Grade 3-4 Metabolic/Laboratory Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Metabolic/Laboratory events based on CTCAEv2 as reported on case report forms.

6. Grade 3-4 Infection/Febrile Neutropenia Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Infection/Febrile Neutropenia events based on CTCAEv2 as reported on case report forms.

7. Grade 3-4 Neurology Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Neurology events based on CTCAEv2 as reported on case report forms.

8. Grade 3-4 Pain Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Pain events based on CTCAEv2 as reported on case report forms.

9. Grade 3-4 Constitutional Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

   All Grade 3-4 Constitutional events based on CTCAEv2 as reported on case report forms.

10. Grade 3-4 Muscloskeletal Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Muscloskeletal events based on CTCAEv2 as reported on case report forms.

11. Grade 3-4 Hepatic Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Hepatic events based on CTCAEv2 as reported on case report forms.

12. Grade 3-4 Cardiovascular Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Cardiovascular events based on CTCAEv2 as reported on case report forms.

13. Grade 3-4 Pulmonary Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Pulmonary events based on CTCAEv2 as reported on case report forms.

14. Grade 3-4 Renal/Genitourinary Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Renal/Genitourinary events based on CTCAEv2 as reported on case report forms.

15. Grade 3-4 Dermatology Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Dermatology events based on CTCAEv2 as reported on case report forms.

16. Grade 3-4 Hemorrhage Events [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Hemorrhage events based on CTCAEv2 as reported on case report forms.

17. Grade 3-4 Allergy/Immunology [Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.]

    All Grade 3-4 Allergy/Immunology events based on CTCAEv2 as reported on case report forms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed primary intracranial Central Nervous System (CNS) atypical teratoid/rhabdoid tumor OR

• Tumor tissue that possesses the INI-1 gene mutation

• No metastases that disseminate outside the CNS by abdominal and chest computer tomography (CT) scans, kidney imaging, and bone marrow biopsy

• No obstruction of cerebrospinal fluid (CSF) flow by CSF flow study

• Definitive surgical resection of tumor within the past 35 days

PATIENT CHARACTERISTICS:

Age

• 18 and under

Performance status

• Karnofsky 50-100% OR

• Lansky 50-100%

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 10 g/dL

• Absolute neutrophil count > 1,000/mm^3

• Platelet count > 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL

• SGPT < 10 times normal

Renal

• Creatinine ≤ 1.5 times normal

Other

• Willing to have placement of central venous access line

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Prior steroids allowed

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics

Other

• No other prior or concurrent investigational agents

• Concurrent anticonvulsant agents allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Center	Stanford	California	United States	94305-5826
2	Yale Cancer Center	New Haven	Connecticut	United States	06520-8028
3	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus	Atlanta	Georgia	United States	30342
4	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
5	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
6	Children's Hospital Boston	Boston	Massachusetts	United States	02115
7	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
8	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
9	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
10	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark W. Kieran, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00084838
• Other Study ID Numbers: 02-294 DFCI; P30CA006516
• First Posted: Jun 11, 2004
• Last Update Posted: Dec 24, 2015
• Last Verified: Dec 1, 2015

• Keywords provided by Mark W. Kieran, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute: childhood atypical teratoid/rhabdoid tumor
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms; Rhabdoid Tumor; Calcium, Dietary; Leucovorin; Cytarabine; Dactinomycin; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Temozolomide; Cisplatin; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Dexrazoxane; Razoxane; Lenograstim; Calcium; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	Enrollment Sep 2004 to Sep 2006 at 9 institutions.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Modified IRS
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
Period Title: Overall Study
STARTED	25
Eligible and Treated	20
COMPLETED	12
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine,and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
Overall Participants	20
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	2.2
Sex: Female, Male (Count of Participants)
Female	11 55%
Male	9 45%
Region of Enrollment (participants) [Number]
United States	20 100%
Chang Stage (participants) [Number]
M0	14 70%
M2	1 5%
M3	5 25%

Outcome Measures

1. Primary Outcome

Title	2-yr Overall Survival
Description	Overall survival is defined as the time from date of diagnosis to death or date of last follow-up. 2-year overall survival is the probability of patients remaining alive at 2-years from study entry estimated using Kaplan-Meier (KM) methods which censors patients at date of last follow-up. Precision of this conditional probability estimate was measured in terms of standard error. Median OS, the original primary endpoint, was not estimable based on the Kaplan-Meier method because of insufficient follow-up.
Time Frame	Patients are followed for survival up to 5 yrs post-therapy completion or death; As of this analysis, median follow-up among survivors was 31 months with the longest follow-up being 40 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all eligible and treated patients.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Modified IRS
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
Measure Participants	20
Number [probability]	0.70

2. Secondary Outcome

Title	Pre-Radiation Therapy Chemotherapeutic Response
Description	Response pre-RT/post-CT was defined as follows with overall response defined as achieving PR or CR. Complete Response (CR): Complete resolution of all initially demonstrable tumor on MRI or CT evaluation w/o appearance of any new areas of disease; negative CSF cytology. Partial Response (PR): >/= 50% decrease in the sum of the products of the maximum perpendicular diameters of the tumor (sum LD) relative to baseline w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Stable Disease (SD): <50% decrease in the sum LD w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Progressive Disease (PD): >/= 25% increase in the sum LD relative to baseline, or the appearance of any new areas of disease or appearance of positive cytology after two consecutive negative samples.
Time Frame	Assessed at study entry and pre-RT/post-CT at week 7.

Outcome Measure Data

Analysis Population Description

The pre-RT CT response evaluable population is defined as patients who completed chemotherapy per protocol.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Modified IRS
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
Measure Participants	12
Number (90% Confidence Interval) [proportion of evaluable patients]	0.58

3. Other Pre-specified Outcome

Title	Grade 3/4 Events
Description	All Grade 3-4 events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
Measure Participants	24
Number [adverse events]	1021

4. Other Pre-specified Outcome

Title	Grade 3-4 Auditory/Hearing Events
Description	All Grade 3-4 Auditory/Hearing events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	8

5. Other Pre-specified Outcome

Title	Grade 3-4 Blood/Bone Marrow Events
Description	All Grade 3-4 Blood/Bone Marrow events based on CTCAEv2 as reported on case report forms. Arm Name
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	564

6. Other Pre-specified Outcome

Title	Grade 3-4 Gastrointestinal Events
Description	All Grade 3-4 Gastrointestinal events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	139

7. Other Pre-specified Outcome

Title	Grade 3-4 Metabolic/Laboratory Events
Description	All Grade 3-4 Metabolic/Laboratory events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	128

8. Other Pre-specified Outcome

Title	Grade 3-4 Infection/Febrile Neutropenia Events
Description	All Grade 3-4 Infection/Febrile Neutropenia events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	49

9. Other Pre-specified Outcome

Title	Grade 3-4 Neurology Events
Description	All Grade 3-4 Neurology events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	45

10. Other Pre-specified Outcome

Title	Grade 3-4 Pain Events
Description	All Grade 3-4 Pain events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	31

11. Other Pre-specified Outcome

Title	Grade 3-4 Constitutional Events
Description	All Grade 3-4 Constitutional events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	22

12. Other Pre-specified Outcome

Title	Grade 3-4 Muscloskeletal Events
Description	All Grade 3-4 Muscloskeletal events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	8

13. Other Pre-specified Outcome

Title	Grade 3-4 Hepatic Events
Description	All Grade 3-4 Hepatic events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	8

14. Other Pre-specified Outcome

Title	Grade 3-4 Cardiovascular Events
Description	All Grade 3-4 Cardiovascular events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	6

15. Other Pre-specified Outcome

Title	Grade 3-4 Pulmonary Events
Description	All Grade 3-4 Pulmonary events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	4

16. Other Pre-specified Outcome

Title	Grade 3-4 Renal/Genitourinary Events
Description	All Grade 3-4 Renal/Genitourinary events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	4

17. Other Pre-specified Outcome

Title	Grade 3-4 Dermatology Events
Description	All Grade 3-4 Dermatology events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	3

18. Other Pre-specified Outcome

Title	Grade 3-4 Hemorrhage Events
Description	All Grade 3-4 Hemorrhage events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	1

19. Other Pre-specified Outcome

Title	Grade 3-4 Allergy/Immunology
Description	All Grade 3-4 Allergy/Immunology events based on CTCAEv2 as reported on case report forms.
Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.

Outcome Measure Data

Analysis Population Description

The analysis population excludes 1 patient who withdrew before treatment.

Arm/Group Title	Multi-agent Intrathecal and Systemic CT With RT (Mod IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine, and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively. filgrastim
Measure Participants	24
Number [adverse events]	1

Adverse Events

Time Frame	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
Adverse Event Reporting Description	SAEs were grade 3+ unexpected, treatment-related events deemed notable by the study chair. Accessible adverse event data represents a count of events by toxicity type rather than worst-grade by toxicity type and therefore cannot be reported in the established framework (Affected/At Risk). See secondary outcomes for events by system organ class.
Arm/Group Title	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
Arm/Group Description	Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen [vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine,and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged <3y received focal RT (3D conformal or intensity-modulated delivery). Pts >3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.
All Cause Mortality
	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
	Affected / at Risk (%)	# Events
Total	4/20 (20%)
Infections and infestations
Sepsis	1/20 (5%)	1
Nervous system disorders
Radiation recall	2/20 (10%)	2
Transverse Myeolitis	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

None. Trial was completed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.